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predictive of prolonged length of stay due to postoperative hypertension. Thus, we make an effort to have hypertension under control before proceeding with CAS [111]. (See "Anesthesia for carotid endarterectomy and carotid stenting", section on 'Hemodynamic monitoring'.) Prophyactic antibiotics Although not routinely recommended for all percutaneous interventional procedures, antibiotic prophylaxis prior to CAS is standard practice, regardless of approach. Appropriate antibiotic choices are given in the table ( table 1). Dual antiplatelet therapy Prior to CAS, we recommend pretreatment with dual antiplatelet therapy (DAPT) using aspirin and clopidogrel ( algorithm 1); however, data are limited regarding the effectiveness of DAPT; the optimal timing, dose and duration of treatment for CAS is unknown [112]. Our specific pretreatment and post-treatment dosing regimens for percutaneous CAS and TCAR are provided separately. (See "Percutaneous carotid artery stenting", section on 'Antiplatelet/statin therapy' and "Transcarotid artery revascularization", section on 'Dual antiplatelet therapy and statins'.) A systematic review identified only two small trials comparing single with dual antiplatelet therapy in patients undergoing CAS. In a meta-analysis of these two trials [113-115], the risk for transient ischemic attack (TIA) was reduced for dual compared with single antiplatelet therapy (1.3 versus 14.6 percent; risk difference -0.13; 95% CI -0.22 to -0.05). However, there were no differences in stroke, major bleeding, or hematoma formation, or incidence of MI or death. In a separate meta-analysis of these same trials, the risk for restenosis was similar [116]. In the absence of any other robust data, we initiate DAPT using aspirin and clopidogrel prior to the procedure (at least 48 hours for percutaneous CAS; the TCAR trial favored 72 hours pretreatment) and continue dual antiplatelet therapy post-procedure for at least four weeks. Thereafter, aspirin should be continued indefinitely to reduce the risk for future cardiovascular events. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk", section on 'Antiplatelet therapy'.) In an observational study from the Vascular Quality Initiative looking at 31,036 total CAS procedures (approximately 50/50 TCAR and TF-CAS), perioperative P2Y12 inhibitors (clopidogrel, prasugrel, or ticagrelor taken within 36 hours of the procedure) markedly reduced the perioperative neurologic event rate [117]. Among patients on P2Y12 inhibitors, 92.7 percent were also taking aspirin. P2Y12 inhibitors were significantly more likely to be used in TCAR cases compared with TF-CAS cases (87.3 versus 76.8 percent). Of the patients on P2Y12 inhibitors, 77.3 https://www.uptodate.com/contents/overview-of-carotid-artery-stenting/print 12/41 7/5/23, 11:42 AM Overview of carotid artery stenting - UpToDate percent were on clopidogrel. This study demonstrated there is considerable room for improving compliance with recommended perioperative DAPT. For patients with a history of neck irradiation, we suggest long-term DAPT with aspirin and clopidogrel following CAS, provided the risk of bleeding remains low. While there are no studies available that have specifically evaluated such a protocol in this subset of patients, radiated patients are at high risk for recurrent carotid stenosis following CAS, as high as 30 percent in some series. In CAS trials, the following protocols were used: In the CREST trial, patients were treated with aspirin (325 mg twice daily) and clopidogrel (75 mg twice daily) starting at least 48 hours before the CAS procedure [4]. Those scheduled for CAS within 48 hours received aspirin 650 mg and clopidogrel 450 mg at least four hours before the CAS procedure. Following CAS, treatment included aspirin 325 mg once or twice daily and clopidogrel 75 mg daily (or ticlopidine 250 mg twice daily) for at least 30 days, with a recommendation to continue aspirin indefinitely (at least one year). In a survey of participants of the Asymptomatic Carotid Surgery Trial 2 (ACST2 trial), 82 percent of sites used dual antiplatelet therapy (DAPT) preoperatively and 86 percent postoperatively with a mean postprocedural duration of three months (range 1 to 12), while 9 percent continued DAPT lifelong [118]. For those prescribing postprocedural mono antiplatelet therapy (76 percent), aspirin was more commonly prescribed than clopidogrel (59 versus 6 percent), and 11 percent did not show a preference for either aspirin or clopidogrel. Eleven centers (16 percent) tested for antiplatelet therapy resistance. In the ROADSTER 2 study, early postoperative outcomes in the intention-to-treat population (692 patients) included stroke in 13 patients (1.9 percent), death in 3 patients (0.4 percent), and MI in 6 patients (0.9 percent) [88]. Sixty patients had major protocol deviations, and among these, 48 patients were not on dual antiplatelet and statin therapy while undergoing carotid intervention or during the periprocedural follow-up period. Among the 60 patients with protocol violations, perioperative (30-day) stroke occurred in 9 (26 percent); death in 2 (3.3 percent); MI in none. Guidelines have suggested a range of periprocedural aspirin therapy ranging from 75 mg to 325 mg daily [82,83,119,120]. Various loading doses of clopidogrel have also been used. Other doses of clopidogrel have also been investigated. In the Clopidogrel and Atorvastatin Treatment During Carotid Artery Stenting (ARMYDA-9 CAROTID) trial, 156 patients were randomly assigned to receive a loading dose of clopidogrel (600 mg or 300 mg) before stenting https://www.uptodate.com/contents/overview-of-carotid-artery-stenting/print 13/41 7/5/23, 11:42 AM Overview of carotid artery stenting - UpToDate with or without a statin reload (2 x 2 trial design) [121]. The perioperative (30-day) incidence of TIA/stroke or new ischemic lesions on magnetic resonance imaging was lowest in the 600 mg clopidogrel plus statin reload group. By contrast, in a smaller trial, no differences were seen between groups for asymptomatic patients (n = 35) undergoing CAS assigned to 300 mg or 600 mg of clopidogrel with respect to the sum of all microembolic signals on transcranial Doppler, or platelet aggregation measurements [122]. Cilostazol is a phosphodiesterase inhibitor that is commonly used in the treatment of claudication. A systematic literature review identified seven studies evaluating outcomes using cilostazol in association with CAS [123]. Major outcomes included in-stent restenosis within the observation period, revascularization rate, major/minor bleeding, and MI/stroke/death rate at 30 days and within the observation period. A significantly lower rate of in-stent stenosis was seen with cilostazol treatment after a mean follow-up of 20 months (odds ratio [OR] 0.158, 95% CI 0.072-0.349). No significant differences were found between the groups among five studies (649 patients) for periprocedural MI/stroke/death or in three studies (1076 patients) for MI/stroke/death for the entire follow-up period. Statin therapy Statin therapy is recommended for patients following TIA or ischemic stroke or in those with coronary artery disease risk equivalents. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease" and "Overview of secondary prevention of ischemic stroke", section on 'LDL-C lowering therapy'.) Whether statin therapy can reduce the risk of cerebral embolization during or after CAS is debated [121,124-129]. A small study compared debris collected from embolic protection devices in 62 patients who were or were not taking statins [129]. Statin use (HMG-CoA-reductase inhibitor) was associated with significantly fewer embolic particles (16.4 versus 42.4 particles). Coronary artery disease, prior coronary artery bypass grafting, and hyperlipidemia were more prevalent in those receiving statins. The authors speculated that statin use stabilizes atherosclerotic plaque, resulting in a more fibrous plaque that is less vulnerable. Our specific pretreatment and post-treatment dosing regimens for percutaneous CAS and TCAR are provided separately. (See "Percutaneous carotid artery stenting", section on 'Antiplatelet/statin therapy' and "Transcarotid artery revascularization", section on 'Dual antiplatelet therapy and statins'.) Patients requiring long-term anticoagulation A decision to stop versus bridge long-term oral anticoagulation (OAC) prior to carotid stenting is individualized and made together with the patient's cardiologist or medical physician [130]. Regardless of whether OAC is continued or temporarily discontinued (with or without bridging anticoagulation), antiplatelet therapy (ie, https://www.uptodate.com/contents/overview-of-carotid-artery-stenting/print 14/41 7/5/23, 11:42 AM Overview of carotid artery stenting - UpToDate aspirin and clopidogrel) is initiated prior to the carotid procedure in the manner discussed above. (See 'Dual antiplatelet therapy' above and "Perioperative management of patients receiving anticoagulants".) Following carotid stenting, if OAC was temporarily discontinued, it is resumed and aspirin and clopidogrel initiated preoperatively are continued for at least four weeks, at which point aspirin is discontinued while clopidogrel is continued along with the anticoagulation. Any new ischemic or bleeding episodes (or change in bleeding risk) should lead to a re-evaluation of antithrombotic therapy. This approach is based on outcomes from coronary stenting. There are no data to suggest that a different approach is warranted when performing a carotid stent. (See "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy", section on 'Our approach'.) Outcomes from studies of percutaneous coronary procedures with or without stenting also do not demonstrate any increase in adverse outcomes for uninterrupted compared with interrupted OAC, suggesting that continuing OACs is safe [131,132]. In one retrospective review of patients undergoing CAS, among 502 patients, there were 20 patients who did not discontinue OACs. There were no complications in this group [133]. In another review that included 511 CAS procedures, among 30 patients taking OACs, outcomes were similar to those not taking OACs [30]. Postprocedure care and duplex surveillance Postprocedure care following CAS is similar to that following carotid endarterectomy [111]. (See "Carotid endarterectomy", section on 'Postoperative care'.) Patients are transferred to a monitored setting for frequent blood pressure and neurologic assessment. CAS is associated with a slightly higher rate of postprocedural hypotension compared with CEA, likely related to the continued outward force of the implanted stent on the carotid body [109,110]. As such, measures should be taken to closely monitor for this occurrence and aggressively treat postoperative hypotension. Repeat duplex ultrasonography should be obtained within three months following CAS to establish a new baseline for future comparison. Duplex surveillance is performed every six months for two years and then annually thereafter until stable (ie, no restenosis observed in two consecutive annual scans) [134]. More frequent intervals may be warranted if a contralateral stenosis is being observed. COMPLICATIONS https://www.uptodate.com/contents/overview-of-carotid-artery-stenting/print 15/41 7/5/23, 11:42 AM Overview of carotid artery stenting - UpToDate Complications associated with carotid revascularization can be grouped into systemic complications that, in general, are related to the revascularization (stroke), patient comorbidities (eg, myocardial infarction [MI], chronic kidney disease), related to the stent (in-stent restenosis, stent fracture), and related to the revascularization approach. Complications specific to the approach include complications related to arterial access or related to the embolic protection system. Approach-specific complications are reviewed separately. (See "Percutaneous carotid artery stenting", section on 'Complications' and "Transcarotid artery revascularization", section on 'Complications'.) In a study that evaluated the timing of complications following CAS, 53 percent of postoperative events/complications occurred within 6 hours of CAS, 5.3 percent between 6 and 12 hours, 8 percent between 12 and 24 hours, and 34.2 percent >24 hours postprocedure [105]. Late events >24 hours were access site-related, and neurologic events included transient ischemia, minor stroke, and major stroke. Stroke The most serious acute complication associated with CAS is stroke. Periprocedural stroke related to CAS may be due to several mechanisms, alone or in combination, including the following [135]: Thromboembolism Hypoperfusion due to bradycardia and/or baroreceptor stimulation Cerebral hyperperfusion Intracerebral hemorrhage Stent thrombosis Noncompliance with antiplatelet therapy Combined 30-day stroke and death rates for transfemoral CAS (TF-CAS) in randomized trials range from 6 to 9 percent for symptomatic patients and 2 to 4 percent for asymptomatic patients [1,66,136]. Stroke rates have improved since the first introduction of CAS. The 30-day death and stroke rate was 3.6 percent in an analysis of two multicenter postmarket surveillance registries of CAS (EXACT, CAPTURE-2) that included 6320 high-risk patients [77]. A similar rate was found in later large reviews [10,79-81]. (See 'Transfemoral carotid revascularization' above.) Transcarotid artery revascularization (TCAR) appears to be associated with a lower risk for stroke compared with TF-CAS. In a study in which 3286 propensity matched pairs were studied, stroke rates were 1.3 and 2.4 percent in the TCAR and TF-CAS groups, respectively [90]. The theoretical explanation for these observations is that TCAR eliminates the need to traverse the aortic arch during the intervention where there is often considerable concomitant atherosclerotic https://www.uptodate.com/contents/overview-of-carotid-artery-stenting/print 16/41 7/5/23, 11:42 AM Overview of carotid artery stenting - UpToDate thromboembolic debris. The effectiveness of flow reversal in preventing distal embolization may also play a role. (See 'Transcarotid revascularization' above.) The main strategies used to reduce the risk of thromboembolic complications during and following CAS are appropriate patient selection, perioperative treatment with optimal medical therapy (including dual antiplatelet therapy [aspirin and clopidogrel] and statin), optimal intraoperative anticoagulation, strict postprocedural blood pressure control, and possibly choice of approach (TCAR versus TF-CAS) and choice of embolic protection. (See 'Dual antiplatelet therapy' above and 'Transcarotid revascularization' above and "Percutaneous carotid artery stenting", section on 'Embolic protection devices' and "Transcarotid artery revascularization", section on 'Establishing flow reversal and carotid stenting'.) Hyperperfusion syndrome Cerebral hyperperfusion syndrome is an uncommon sequela of CAS, and its occurrence after carotid stenting follows a similar path to that following carotid endarterectomy (CEA) [137]. The syndrome is often heralded by headache ipsilateral to the revascularized internal carotid artery. Focal motor seizures and intracerebral hemorrhage may follow. As with CEA, hypertension is a frequent predecessor of the syndrome, underscoring the importance of adequate control of perioperative blood pressure. (See 'Preoperative control of blood pressure' above and "Complications of carotid endarterectomy", section on 'Hyperperfusion syndrome'.) Scant data exist concerning the incidence of the hyperperfusion syndrome after carotid stenting. In a retrospective review of 450 patients treated with CAS, the following observations were made [138]: Hyperperfusion developed in five patients (1.1 percent), all of whom had correction of a severe internal carotid stenosis (mean 96 percent). All five patients with hyperperfusion syndrome had contralateral carotid stenosis >80 percent or occlusion, and baseline hypertension. Intracerebral hemorrhage developed in three of the five patients, two of whom developed significant periprocedural hypertension preceding the intracerebral hemorrhage. Two of the patients with intracerebral hemorrhage died. Myocardial infarction In major randomized trials, the periprocedural incidence of MI with CAS has ranged from <1 to 4 percent [4,66]. In a study comparing 3286 propensity-matched pairs of patients undergoing TCAR and TF-CAS, there was no statistically significant difference in the risk of perioperative MI (0.2 versus 0.3 percent). In the author's experience, acute coronary syndromes can be precipitated by profound bradycardia and transient hypotension associated https://www.uptodate.com/contents/overview-of-carotid-artery-stenting/print 17/41 7/5/23, 11:42 AM Overview of carotid artery stenting - UpToDate with ballooning the stent. Even with routine prophylactic strategies to avoid bradycardia, cardiac ischemia still sometimes occurs. Other risk factors for cardiac complications in noncardiac surgery and management of perioperative MI are discussed in detail elsewhere. (See "Evaluation of cardiac risk prior to noncardiac surgery" and "Perioperative myocardial infarction or injury after noncardiac surgery".) Data from the National Inpatient Sample on 1,083,688 patients who underwent CEA or CAS found that 11,341 (approximately 1 percent) developed non-ST elevation MI (NSTEMI) during hospitalization. NSTEMI was associated with a significantly higher rate of in-hospital mortality (6.2 versus 0.4 percent), neurologic complications (6 versus 1.4 percent), and longer hospital stay (12.2 versus 2.8 days) [139]. (See "Acute coronary syndrome: Terminology and classification" and "Overview of the acute management of non-ST-elevation acute coronary syndromes".) Renal dysfunction Renal dysfunction following CAS can be related to contrast-induced nephropathy, renal atheroemboli (during TF-CAS), or renal hypoperfusion due to hemodynamic instability. The risk of contrast nephropathy following CAS is greatest in patients with moderate- to-severe renal insufficiency and diabetes. (See "Contrast-associated and contrast-induced acute kidney injury: Clinical features, diagnosis, and management" and "Prevention of contrast- associated acute kidney injury related to angiography".) Instrumentation of the aorta during TF-CAS can lead to atheroembolic events, which in turn can result in renal dysfunction. (See "Clinical presentation, evaluation, and treatment of renal atheroemboli" and "Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism)".) Carotid thrombosis and restenosis Acute and subacute in-stent thrombosis has been reported in 0.5 to 5 percent of patients with CAS [140,141]. Some cases of carotid restenosis following CAS may be related to inadequate or discontinued antiplatelet therapy [142-144]. Beyond 30 days, early restenosis after CAS is mainly due to neointimal hyperplasia, which is related to vascular injury related to the stent regardless of the technique used to place the stent (ie, TF-CAS, TCAR) [145-147]. Neointimal hyperplasia related to CAS may be due to stent overdilation or imperfect positioning of the carotid stent in the vessel leading to ongoing vascular injury, and it may occur more often in women and in patients with poorly controlled diabetes or hyperlipidemia [148]. Prior radiation is also a risk factor. Data regarding restenosis come primarily from trials and observational studies evaluating TF-CAS. Reported rates of early restenosis after CAS vary widely [64,148-154]. In a systematic review that analyzed 34 carotid stenting studies involving 3814 arteries, angiographic restenosis, defined as 50 to 70 percent stenosis (a lower threshold), occurred in approximately 6 percent of arteries https://www.uptodate.com/contents/overview-of-carotid-artery-stenting/print 18/41 7/5/23, 11:42 AM Overview of carotid artery stenting - UpToDate after one year [149]. This compares favorably with reported rates of restenosis in the first 12 to 18 months after CEA, which range from 5.2 to 11.4 percent [150-152]. In a review of 1060 patients, independent risk factors for restenosis 70 percent identified on logistic regression included hypertension (hazard ratio [HR] 6.2, 95% CI 1.9-19.9), impaired vasoreactivity (HR 1.7, 95% CI 1.09-2.8), and angioplasty without stent (HR 2.9, 95% CI 1.2-6.8) [154]. In the SAPPHIRE trial, target vessel revascularization (TVR) was performed for a stenosis of 50 percent with ischemic neurologic symptoms or a stenosis of 80 percent without neurologic symptoms [64,155]. At one year after the procedure, the rate of TVR was significantly lower for the stenting group compared with the endarterectomy group (0.6 versus 4.3 percent) [64]. At three years postprocedure, the rate of TVR remained lower for TF-CAS compared with endarterectomy (2.4 versus 5.4 percent), but the difference was not significant [155]. In the Asymptomatic Carotid Trial I (ACT-1), the one-year rate of TVR was also lower for the stenting group (0.6 versus 2.6 percent) [62]. In a secondary analysis of the CREST trial, 2191 patients with appropriate postoperative ultrasonography were available for study (CAS 1086, CEA 1105) [148]. The rates for restenosis at two years were similar for CAS compared with CEA. Female sex, diabetes, and dyslipidemia were independent predictors of restenosis or occlusion after the two procedures. Smoking predicted an increased rate of restenosis after CEA but not after CAS. At 10-year follow-up, there was no statistically significant difference in the development of restenosis or need for revascularization between transfemoral CAS and CEA (12.2 versus 9.7 percent) [69]. A single-center case series with long-term follow-up of 221 carotid stenting procedures on 193 patients showed a restenosis rate (>50 percent on duplex scan) at 10 years was 6.8 percent [156]. [149] Stent fracture Stent fracture may be a common complication of CAS, but its clinical significance is unknown. Data regarding stent fracture come from studies evaluating TF-CAS. In a retrospective report of 48 carotid stents in 43 patients, stent fracture was detected at a mean radiologic follow-up of 18 months in 29 percent [157]. The risk of stent fracture was associated with the presence of arterial calcification in the region of the deployed stent (odds ratio 7.7, 95% CI 1.9-32.0). Restenosis >50 percent was present in 3 of the 14 fractured stents and 3 of 34 stents without fracture. In a review of the outcomes of the ACT-1 trial, in which CAS was used in 1021 standard surgical risk patients with asymptomatic carotid stenosis, stent fracture was detected in 5.4 percent of 939 patients who had at least one radiograph during follow-up [158]. There was no association between stent fracture and the occurrence of carotid restenosis or for a primary composite endpoint of stroke, death, or MI. https://www.uptodate.com/contents/overview-of-carotid-artery-stenting/print 19/41 7/5/23, 11:42 AM Overview of carotid artery stenting - UpToDate SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Occlusive carotid, aortic, renal, mesenteric, and peripheral atherosclerotic disease".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Carotid artery disease (The Basics)") SUMMARY AND RECOMMENDATIONS Carotid artery stenting (CAS) can be performed percutaneously (eg, transfemoral CAS [TF- CAS]) or through a small incision in the neck (ie, transcarotid artery revascularization [TCAR]). A comparison of these methods is provided above. During CAS, several methods of embolic protection are used and are intended to prevent stroke; however, the superiority of one method over another, and furthermore, an overall benefit has not been definitively established. (See 'Approach to carotid artery stenting' above and "Percutaneous carotid artery stenting", section on 'Embolic protection devices' and "Transcarotid artery revascularization", section on 'Transcarotid stenting system'.) For patients with severe bilateral carotid stenosis, we prefer a staged approach rather than simultaneous CAS. Simultaneous CAS theoretically increases the risk for cerebral https://www.uptodate.com/contents/overview-of-carotid-artery-stenting/print 20/41 7/5/23, 11:42 AM Overview of carotid artery stenting - UpToDate hyperperfusion syndrome, as well as severe bradycardia or hypotension related to bilateral baroreceptor irritation. (See 'Timing and other considerations' above.) For patients in whom CAS is scheduled or anticipated, we recommend pretreatment with dual antiplatelet therapy (DAPT) using aspirin and clopidogrel, rather than monotherapy or no antiplatelet therapy (Grade 1B). DAPT is continued for at least four weeks after the procedure. Aspirin alone is subsequently continued indefinitely to reduce the risk of future cardiovascular events. (See 'Dual antiplatelet therapy' above and "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".) For patients with a history of neck irradiation, we suggested continuing DAPT using aspirin and clopidogrel indefinitely (Grade 2C). Radiated patients are at high risk for recurrent carotid stenosis following CAS (See 'Dual antiplatelet therapy' above.) Specific pre- and post-treatment DAPT dosing regimens for TF-CAS and TCAR are provided separately. Statin therapy is also recommended. (See "Percutaneous carotid artery stenting", section on 'Antiplatelet/statin therapy' and "Transcarotid artery revascularization", section on 'Dual antiplatelet therapy and statins'.) The most serious acute complication associated with carotid artery stenting (CAS) is stroke, which can occur due to thromboembolism, hypoperfusion, hyperperfusion syndrome, or hemorrhage. Potential factors that have an impact on the risk of stroke with CAS include older age, carotid plaque morphology, prior neck irradiation, and contralateral carotid occlusive disease. The main strategies used to reduce the risk of thromboembolic complications during and following CAS are appropriate patient selection, perioperative treatment with aspirin and clopidogrel (dual antiplatelet therapy), and optimal intraoperative anticoagulation. (See 'Complications' above and 'Risk assessment' above.) Other complications associated with CAS include access-related issues (eg, hematoma, bleeding, pseudoaneurysm formation, and distal atheroembolization), myocardial infarction, contrast-related renal failure, restenosis of the target lesion, and carotid stent fracture. (See 'Complications' above and "Percutaneous carotid artery stenting", section on 'Complications' and "Transcarotid artery revascularization", section on 'Complications'.) ACKNOWLEDGMENTS The UpToDate editorial staff acknowledges Emile R Mohler, III, MD (deceased), who contributed to an earlier version of this topic review. https://www.uptodate.com/contents/overview-of-carotid-artery-stenting/print 21/41 7/5/23, 11:42 AM Overview of carotid artery stenting - UpToDate The editorial staff at UpToDate also acknowledges Ronald M Fairman, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. 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Editor's Choice - European Society for Vascular Surgery (ESVS) 2023 Clinical Practice Guidelines on the Management of Atherosclerotic Carotid and Vertebral Artery Disease. Eur J Vasc Endovasc Surg 2023; 65:7. 120. Brott TG, Halperin JL, Abbara S, et al. 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease: executive summary. Stroke 2011; 42:e420. 121. Patti G, Tomai F, Melfi R, et al. Strategies of clopidogrel load and atorvastatin reload to prevent ischemic cerebral events in patients undergoing protected carotid stenting. Results of the randomized ARMYDA-9 CAROTID (Clopidogrel and Atorvastatin Treatment During Carotid Artery Stenting) study. J Am Coll Cardiol 2013; 61:1379. 122. Van Der Heyden J, Van Werkum J, Hackeng CM, et al. High versus standard clopidogrel loading in patients undergoing carotid artery stenting prior to cardiac surgery to assess the number of microemboli detected with transcranial Doppler: results of the randomized IMPACT trial. J Cardiovasc Surg (Torino) 2013; 54:337. 123. Galyfos G, Geropapas G, Sigala F, et al. Meta-Analysis of Studies Evaluating the Effect of Cilostazol on Major Outcomes After Carotid Stenting. J Endovasc Ther 2016; 23:186. 124. Reiff T, Amiri H, Rohde S, et al. Statins reduce peri-procedural complications in carotid stenting. Eur J Vasc Endovasc Surg 2014; 48:626. 125. Rizwan M, Faateh M, Dakour-Aridi H, et al. Statins reduce mortality and failure to rescue after carotid artery stenting. J Vasc Surg 2019; 69:112. 126. Krafcik BM, Farber A, Eberhardt RT, et al. Preoperative Antiplatelet and Statin Use Does Not Affect Outcomes after Carotid Endarterectomy. Ann Vasc Surg 2018; 46:43. 127. Texakalidis P, Giannopoulos S, Jonnalagadda AK, et al. Preoperative Use of Statins in Carotid Artery Stenting: A Systematic Review and Meta-analysis. J Endovasc Ther 2018; 25:624. 128. Hong JH, Sohn SI, Kwak J, et al. Dose-Dependent Effect of Statin Pretreatment on Preventing the Periprocedural Complications of Carotid Artery Stenting. Stroke 2017; 48:1890. 129. Tadros RO, Vouyouka AG, Chung C, et al. The effect of statin use on embolic potential during carotid angioplasty and stenting. Ann Vasc Surg 2013; 27:96. 130. Brand AR, de Borst GJ. Evidence for periprocedural antiplatelet therapy, heparinization and bridging of coumarin therapy in carotid revascularization. J Cardiovasc Surg (Torino) 2017; https://www.uptodate.com/contents/overview-of-carotid-artery-stenting/print 31/41 7/5/23, 11:42 AM Overview of carotid artery stenting - UpToDate 58:143. 131. Kowalewski M, Suwalski P, Raffa GM, et al. Meta-analysis of uninterrupted as compared to interrupted oral anticoagulation with or without bridging in patients undergoing coronary angiography with or without percutaneous coronary intervention. Int J Cardiol 2016; 223:186. 132. Shahi V, Brinjikji W, Murad MH, et al. Safety of Uninterrupted Warfarin Therapy in Patients Undergoing Cardiovascular Endovascular Procedures: A Systematic Review and Meta- Analysis. Radiology 2016; 278:383. 133. Pini R, Faggioli G, Mauro R, et al. Chronic oral anticoagulant therapy in carotid artery stenting: the un-necessity of perioperative bridging heparin therapy. Thromb Res 2012; 130:12. 134. Zierler RE, Jordan WD, Lal BK, et al. The Society for Vascular Surgery practice guidelines on follow-up after vascular surgery arterial procedures. J Vasc Surg 2018; 68:256. 135. Moulakakis KG, Mylonas SN, Lazaris A, et al. Acute Carotid Stent Thrombosis: A Comprehensive Review. Vasc Endovascular Surg 2016; 50:511. 136. Mas JL, Chatellier G, Beyssen B, et al. Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis. N Engl J Med 2006; 355:1660. 137. Timaran CH, Veith FJ, Rosero EB, et al. Intracranial hemorrhage after carotid endarterectomy and carotid stenting in the United States in 2005. J Vasc Surg 2009; 49:623. 138. Abou-Chebl A, Yadav JS, Reginelli JP, et al. Intracranial hemorrhage and hyperperfusion syndrome following carotid artery stenting: risk factors, prevention, and treatment. J Am Coll Cardiol 2004; 43:1596. 139. Khan A, Adil MM, Qureshi AI. Non-ST-elevation myocardial infarction in patients undergoing carotid endarterectomy or carotid artery stent placement. Stroke 2014; 45:595. 140. Roubin GS, Yadav S, Iyer SS, Vitek J. Carotid stent-supported angioplasty: a neurovascular intervention to prevent stroke. Am J Cardiol 1996; 78:8. 141. Diethrich EB, Ndiaye M, Reid DB. Stenting in the carotid artery: initial experience in 110 patients. J Endovasc Surg 1996; 3:42. 142. Tong FC, Cloft HJ, Joseph GJ, et al. Abciximab rescue in acute carotid stent thrombosis. AJNR Am J Neuroradiol 2000; 21:1750. 143. Chaturvedi S, Sohrab S, Tselis A. Carotid stent thrombosis: report of 2 fatal cases. Stroke 2001; 32:2700. 144. Buhk JH, Wellmer A, Knauth M. Late in-stent thrombosis following carotid angioplasty and stenting. Neurology 2006; 66:1594. https://www.uptodate.com/contents/overview-of-carotid-artery-stenting/print 32/41 7/5/23, 11:42 AM Overview of carotid artery stenting - UpToDate 145. Bonati LH, Gregson J, Dobson J, et al. Restenosis and risk of stroke after stenting or endarterectomy for symptomatic carotid stenosis in the International Carotid Stenting Study (ICSS): secondary analysis of a randomised trial. Lancet Neurol 2018; 17:587. 146. Lattimer CR, Burnand KG. Recurrent carotid stenosis after carotid endarterectomy. Br J Surg 1997; 84:1206. 147. Willfort-Ehringer A, Ahmadi R, Gschwandtner ME, et al. Healing of carotid stents: a prospective duplex ultrasound study. J Endovasc Ther 2003; 10:636. 148. Lal BK, Beach KW, Roubin GS, et al. Restenosis after carotid artery stenting and endarterectomy: a secondary analysis of CREST, a randomised controlled trial. Lancet Neurol 2012; 11:755. 149. Gr schel K, Riecker A, Schulz JB, et al. Systematic review of early recurrent stenosis after carotid angioplasty and stenting. Stroke 2005; 36:367. 150. Frericks H, Kievit J, van Baalen JM, van Bockel JH. Carotid recurrent stenosis and risk of ipsilateral stroke: a systematic review of the literature. Stroke 1998; 29:244. 151. Moore WS, Kempczinski RF, Nelson JJ, Toole JF. Recurrent carotid stenosis : results of the asymptomatic carotid atherosclerosis study. Stroke 1998; 29:2018. 152. McCabe DJ, Pereira AC, Clifton A, et al. Restenosis after carotid angioplasty, stenting, or endarterectomy in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS). Stroke 2005; 36:281. 153. Dorigo W, Pulli R, Fargion A, et al. Comparison of open and endovascular treatments of post-carotid endarterectomy restenosis. Eur J Vasc Endovasc Surg 2013; 45:437. 154. Zapata-Arriaza E, Moniche F, Gonz lez A, et al. Predictors of Restenosis Following Carotid Angioplasty and Stenting. Stroke 2016; 47:2144. 155. Gurm HS, Yadav JS, Fayad P, et al. Long-term results of carotid stenting versus endarterectomy in high-risk patients. N Engl J Med 2008; 358:1572. 156. Bergeron P, Roux M, Khanoyan P, et al. Long-term results of carotid stenting are competitive with surgery. J Vasc Surg 2005; 41:213. 157. Ling AJ, Mwipatayi P, Gandhi T, Sieunarine K. Stenting for carotid artery stenosis: fractures, proposed etiology and the need for surveillance. J Vasc Surg 2008; 47:1220. 158. Weinberg I, Beckman JA, Matsumura JS, et al. Carotid Stent Fractures Are Not Associated With Adverse Events: Results From the ACT-1 Multicenter Randomized Trial (Carotid Angioplasty and Stenting Versus Endarterectomy in Asymptomatic Subjects Who Are at Standard Risk for Carotid Endarterectomy With Significant Extracranial Carotid Stenotic Disease). Circulation 2018; 137:49. https://www.uptodate.com/contents/overview-of-carotid-artery-stenting/print 33/41 7/5/23, 11:42 AM Overview of carotid artery stenting - UpToDate Topic 1104 Version 36.0 https://www.uptodate.com/contents/overview-of-carotid-artery-stenting/print 34/41 7/5/23, 11:42 AM Overview of carotid artery stenting - UpToDate GRAPHICS Angiographic criteria for internal carotid near-occlusion The figures illustrate the four criteria for internal carotid near-occlusion on conventional angiography. In all figures, the intravenous contrast (gray color) is shown emanating from a catheter positioned in the CCA. (A) Delayed filling (B) Evidence of intracranial collaterals when the contralateral side is examined (C) Ipsilateral distal ICA diameter less than the contralateral distal ICA diameter (D) Ipsilateral distal ICA diameter equal to or less than the ipsilateral ECA diameter CCA: common carotid artery; ICA: internal carotid artery; ECA: external carotid artery. Modi ed with permission of the American Society of Neuroradiology, from: Johansson E, Fox AJ. Carotid Near- Occlusion: A Comprehensive Review, Part 1 De nition, Terminology, and Diagnosis. AJNR Am J Neuroradiol 2016; https://www.uptodate.com/contents/overview-of-carotid-artery-stenting/print 35/41 7/5/23, 11:42 AM Overview of carotid artery stenting - UpToDate 37:2; permission conveyed through Copyright Clearance Center, Inc. Copyright 2016. Graphic 129242 Version 1.0 https://www.uptodate.com/contents/overview-of-carotid-artery-stenting/print 36/41 7/5/23, 11:42 AM Overview of carotid artery stenting - UpToDate Antimicrobial prophylaxis for percutaneous procedures in adults Potential Routine First- Common Procedure organisms prophylaxis choice Comment antibiotic choices encountered recommended antibiotic Angiography, Staphylococcus No None Cefazolin (2 g IV if Procedure angioplasty, aureus, S. <120 kg, 3 g IV if 120 kg IV) (if high- risk stent infection). If penicillin-allergic, can classificatio thrombolysis, arterial closure epidermidis clean device use vancomycin (15 placement, stent mg/kg IV; max 2 g) or clindamycin (900 mg placement IV). Endograft placement S. aureus, S. epidermidis Yes Cefazolin (2 g IV if <120 kg, 3 g IV if 120 kg IV) If penicillin-allergic, can use vancomycin or clindamycin Procedure classificatio clean Superficial venous S. aureus, S. epidermidis No None None Procedure classificatio insufficiency treatment clean IVC filter placement S. aureus, S. epidermidis No None None Procedure classificatio clean Tunneled central venous S. aureus, S. epidermidis No consensus None Cefazolin (2 g IV if <120 kg, 3 g IV if 120 kg IV) (eg, immunocompromised patients before chemotherapy; Procedure classificatio clean access (nontunnele catheter: no prophylaxis history of catheter infection). If penicillin- allergic, can use vancomycin (15 mg/kg IV; max 2 g) or clindamycin (900 mg IV). IV: intravenous; IVC: inferior vena cava. https://www.uptodate.com/contents/overview-of-carotid-artery-stenting/print 37/41 7/5/23, 11:42 AM Overview of carotid artery stenting - UpToDate Reproduced from: Venkatesan AM, Kundu S, Sacks D, et al. Practice guideline for adult antibiotic prophylaxis during vascular and interventional radiology procedures. J Vasc Interv Radiol 2010; 21:1611. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 63103 Version 9.0 https://www.uptodate.com/contents/overview-of-carotid-artery-stenting/print 38/41 7/5/23, 11:42 AM Overview of carotid artery stenting - UpToDate Periprocedural DAPT for transfemoral carotid artery stenting* Refer to UpToDate topics on carotid artery stenting for additional details of our approach to treatment and the overall efficacy of these treatments. DAPT: dual antiplatelet therapy; ASA: aspirin; TF-CAS: transfemoral carotid artery stenting. We use a regimen based on the Carotid Revascularization Endarterectomy versus Stent (CREST) Trial. We also provide statin therapy. For those not already on statins, we initiate atorvastatin 40 mg orally once daily for seven days before the procedure or we give a loading dose of 80 mg orally once 12 hours before the procedure. The timing of the DAPT loading and subsequent dosing depends on procedure scheduling. Typically, we provide loading doses once the procedure is scheduled and provide daily dosing starting 12 hours after the loading doses up until the time of the procedure. For urgent cases, loading doses are provided no less than four hours before the procedure. For TF-CAS, although we favor higher doses, guidelines support a range of 75 to 325 mg ASA. https://www.uptodate.com/contents/overview-of-carotid-artery-stenting/print 39/41 7/5/23, 11:42 AM Overview of carotid artery stenting - UpToDate For patients with a history of neck irradiation, we continue DAPT indefinitely. Graphic 131243 Version 2.0 https://www.uptodate.com/contents/overview-of-carotid-artery-stenting/print 40/41 7/5/23, 11:42 AM Overview of carotid artery stenting - UpToDate Contributor Disclosures Jeffrey Jim, MD, MPHS, FACS Consultant/Advisory Boards: Endospan [Aortic interventions]; Medtronic [Aortic interventions]; Silk Road Medical [Carotid stent]. All of the relevant financial relationships listed have been mitigated. John F Eidt, MD Grant/Research/Clinical Trial Support: Syntactx [Clinical events, data/safety monitoring for medical device trials]. All of the relevant financial relationships listed have been mitigated. Joseph L Mills, Sr, MD No relevant financial relationship(s) with ineligible companies to disclose. Kathryn A Collins, MD, PhD, FACS No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/overview-of-carotid-artery-stenting/print 41/41

7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Overview of secondary prevention of ischemic stroke : Natalia S Rost, MD, MPH, Alexis Simpkins, MD, PhD, MSCR, FAHA : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jan 27, 2023. INTRODUCTION The management of treatable risk factors and common mechanisms of brain ischemia is important for reducing the risk of ischemic stroke. This topic will review the risk factors for stroke, with a focus on secondary prevention in patients who have a history of transient ischemic attack or ischemic stroke, or who have an elevated risk of ischemic stroke due to the presence of coronary heart disease or diabetes. Risk factors for hemorrhagic stroke are reviewed elsewhere. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Risk factors' and "Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis", section on 'Risk factors'.) The role of primary prevention for cardiovascular disease, including stroke, is discussed separately. (See "Overview of primary prevention of cardiovascular disease".) MAJOR RISK FACTORS Control of atherosclerotic risk factors is important for the primary and secondary prevention of stroke. Control of risk factors also reduces the risk of coronary events, a common comorbidity in patients with cerebrovascular disease. (See "Overview of primary prevention of cardiovascular disease" and "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".) https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 1/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate Modifiable risk factors The major modifiable risk factors for stroke are the following [1- 4]: Hypertension (see 'Hypertension' below) Dyslipidemia (see 'Dyslipidemia' below) Diabetes mellitus (see 'Diabetes mellitus' below) Smoking (see 'Smoking cessation' below) Physical inactivity (see 'Physical activity and exercise' below) Unmodifiable risk factors Important but unmodifiable risk factors for stroke include the following [3,5-8]: Older age, particularly age >80 years [3] Race and ethnicity, with risk higher for Black than for White patients [8] Sex, with risk higher at most ages for men compared with women, except for ages 35 to 44 years and >85 years, where women have a similar or higher risk than men [9,10] Family history and genetic disorders, with a higher risk for monozygotic twins and those with genetic disorders (see "Pathophysiology of ischemic stroke", section on 'Monogenic disorders') such as sickle cell disease or cerebral autosomal dominant arteriopathy with subcortical infarctions and leukoencephalopathy [5-7] Stroke risk assessment The risk of stroke is particularly increased in patients with two or more risk factors, as suggested by calculators for female (calculator 1) and male (calculator 2) patients, derived from the Framingham Study [11]. These risk factor assessment tools incorporate atrial fibrillation, a common cause of ischemic stroke, and the presence of coronary heart disease and other types of cardiovascular disease ( table 1), which are markers of increased risk for subsequent cardiovascular and cerebrovascular events. When all of these risk factors and stroke mechanisms are considered together, they account for 60 to 80 percent of the population-attributable risk of ischemic stroke [2]. Treatment Most patients with an ischemic stroke or transient ischemic attack should be treated with all available risk reduction strategies, including blood pressure reduction, low- density lipoprotein cholesterol lowering therapy, antithrombotic therapy, and lifestyle modification [12]; select patients with symptomatic carotid disease may benefit from revascularization. By some estimates, treatment of all major stroke risk factors, compared with no treatment, would reduce the risk of recurrent stroke by 80 percent [13]. https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 2/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate Guidelines from the American Heart Association and American Stroke Association advocate a multidisciplinary, team-based approach to effectively manage these risk factors, with treatment tailored to the individual patient [12]. To promote health equity and reduce healthcare disparities, the approach should evaluate and address social determinants of health, including literacy level, language proficiency, medication affordability, food insecurity, housing needs, and transportation obstacles. ANTITHROMBOTIC THERAPY Antithrombotic therapy with antiplatelet or anticoagulant agents is an important part of secondary stroke prevention for patients with ischemic stroke or transient ischemic attack (TIA) ( algorithm 1) [12]. Noncardioembolic ischemic stroke or TIA Antiplatelet agents are effective for the prevention of recurrent ischemic stroke in patients with a history of noncardioembolic ischemic stroke or TIA of atherothrombotic, lacunar (small vessel occlusive), or cryptogenic type. Aspirin (50 to 100 mg daily), clopidogrel (75 mg daily), and the combination of aspirin- extended-release dipyridamole (25 mg/200 mg twice a day) are all acceptable long-term options for preventing recurrent noncardioembolic ischemic stroke. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) Role of DAPT Early, short-term dual antiplatelet therapy (DAPT), typically with aspirin plus clopidogrel, is beneficial for select patients with high-risk TIA or minor ischemic stroke and may be beneficial for patients with recently symptomatic intracranial large artery atherosclerosis, as outlined in the algorithms ( algorithm 2 and algorithm 3). (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Efficacy of DAPT'.) Dissection For patients with ischemic neurologic symptoms caused by cervical artery dissection, antithrombotic therapy is indicated, but the choice between antiplatelet and anticoagulant therapy remains somewhat controversial. (See "Cerebral and cervical artery dissection: Treatment and prognosis", section on 'Choosing between antiplatelet and anticoagulation therapy'.) Cardiogenic embolism Long-term anticoagulation with warfarin or a direct oral anticoagulant (dabigatran, apixaban, rivaroxaban, or edoxaban) is recommended as prevention for patients with chronic nonvalvular atrial fibrillation who have had an ischemic stroke or TIA. While the use of anticoagulant therapy is also associated with an increased risk of major bleeding, the benefit outweighs the risk in most patients. These https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 3/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate issues are discussed elsewhere. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation" and "Atrial fibrillation in adults: Use of oral anticoagulants".) In addition to atrial fibrillation, other potential cardiac sources of embolism for which anticoagulation therapy may be indicated for select patients include the following (see "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack", section on 'Cardiogenic embolism'): Mechanical heart valves and a subpopulation of high-risk patients with bioprosthetic valves (see "Antithrombotic therapy for mechanical heart valves") Left ventricular thrombus (see "Antithrombotic therapy in patients with heart failure", section on 'Left ventricular thrombus' and "Left ventricular thrombus after acute myocardial infarction", section on 'Prevention of embolic events') Dilated cardiomyopathy (see "Antithrombotic therapy in patients with heart failure") Rheumatic valve disease (see "Management and prevention of rheumatic heart disease", section on 'Management of carditis in acute rheumatic fever') Recent myocardial infarction in high-risk patients (see "Anticoagulant therapy in non-ST elevation acute coronary syndromes" and "Acute ST-elevation myocardial infarction: Management of anticoagulation" and "Acute coronary syndrome: Oral anticoagulation in medically treated patients") HYPERTENSION Hypertension and stroke risk Hypertension, which promotes the formation of atherosclerotic lesions, is the single most important treatable risk factor for stroke [4]. Epidemiologic studies of treated and untreated patients reveal that there is a gradually increasing incidence of cardiovascular mortality as the blood pressure rises above 110/75 mmHg ( figure 1A-B) [14,15]. Hypertension is associated with an increased likelihood of subclinical or silent stroke, which in turn has been linked with an elevated risk of vascular dementia and recurrent stroke [16-18]. In addition to hypertension defined by systolic and diastolic blood pressure, stroke risk may be associated with other blood pressure variables including mean blood pressure, pulse pressure, blood pressure variability, blood pressure instability, and nocturnal nondipping [19,20]. However, these observations alone do not prove a causal relationship, since increasing blood pressure could be a marker for other risk factors such as increasing body weight, dyslipidemia, https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 4/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate glucose intolerance, and the metabolic syndrome. The best evidence supporting a causal role of increasing blood pressure in cardiovascular complications comes from studies that show outcome reduction in the risk of recurrent stroke with antihypertensive therapy. This evidence is reviewed elsewhere. (See "Antihypertensive therapy for secondary stroke prevention".) Antihypertensive therapy Treatment of hypertension is important for both prevention of recurrent stroke and prevention of other vascular events. We recommend antihypertensive therapy for patients with any type of ischemic stroke or transient ischemic attack (TIA) who have an established blood pressure that is above goal, as outlined in the table ( table 2) for higher- risk populations, which includes all patients with ischemic stroke or TIA. Similarly, the 2021 American Heart Association/American Stroke Association (AHA/ASA) guidelines recommend an office measurement blood pressure goal of <130/80 mmHg for most patients to reduce the risk of recurrent stroke and vascular events [12]. Lifestyle modifications that have been associated with blood pressure reductions should be included as part of the antihypertensive regimen [12]. Important modifications include weight loss; salt restriction; a diet rich in fruits, vegetables, and low-fat dairy products; regular aerobic physical activity; and limited alcohol consumption. (See 'Lifestyle modification' below.) The role of antihypertensive therapy in secondary stroke prevention is discussed in detail separately. (See "Antihypertensive therapy for secondary stroke prevention".) The appropriate time to initiate or reinstate antihypertensive drug therapy in hypertensive patients who have had a stroke or TIA can vary according to several factors, including stroke mechanism (eg, whether the stroke was ischemic or hemorrhagic), neurologic stability, and comorbid medical problems. This issue is discussed in detail separately. (See "Antihypertensive therapy for secondary stroke prevention", section on 'When to initiate (or reinstate) antihypertensive therapy'.) In patients with acute ischemic stroke (ie, the first hours and days after onset), it is important not to lower the blood pressure too quickly. The management of blood pressure in the setting of acute stroke is reviewed elsewhere. (See "Initial assessment and management of acute stroke", section on 'Blood pressure management'.) DYSLIPIDEMIA Lipids and stroke risk Hyperlipidemia is a major risk factor for atherosclerotic cardiovascular disease (see "Overview of established risk factors for cardiovascular disease"). However, the relationship between the serum cholesterol concentration and stroke incidence appears to be https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 5/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate more complex, in that cholesterol is an established risk factor for atherosclerosis, but the degree of risk varies for stroke subtypes [21]. Studies that have examined ischemic and hemorrhagic stroke types have generally found a weak but positive association of elevated cholesterol with ischemic stroke, particularly for large artery atherosclerotic and lacunar stroke subtypes, and an inverse association of cholesterol levels with hemorrhagic stroke [22]. Most [23-26] but not all [27,28] large observational studies have found that elevated cholesterol and low-density lipoprotein levels are associated with an increased risk of ischemic stroke [21]. The strong association between cholesterol and carotid atherosclerosis also supports the role of cholesterol in the pathogenesis of large artery ischemic stroke [29]. The relationship of cholesterol levels and statin therapy with intracerebral hemorrhage is discussed in greater detail separately. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Other risk factors'.) LDL-C lowering therapy Statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to reduce the risk of major adverse cardiovascular events. Among these three, statins are the best studied and have proven efficacy for reducing the risk of recurrent ischemic stroke. The available evidence suggests that lipid lowering by other means (eg, fibrates, bile acid sequestrants, niacin, diet) has no significant impact on the secondary prevention of stroke or prevention of other cardiovascular events. (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors" and "Lipid management with diet or dietary supplements" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".) Therefore, it seems plausible that the protective effects of statins are not mediated by cholesterol lowering alone [30], but by pleiotropic (eg, anti-atherothrombotic, anti-inflammatory) properties [31,32]. (See "Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease".) Even patients with "average" serum cholesterol concentrations appear to benefit from statin therapy in terms of stroke reduction. This was demonstrated in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial [33], in which the mean baseline low- density lipoprotein cholesterol (LDL-C) level was 133 mg/dL (3.4 mmol/L), and in the Heart Protection Study trial [34], in which the mean baseline LDL-C level was 131 mg/dL (3.4 mmol/L). Approach to LDL-C lowering https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 6/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate High-risk patients For high-risk patients (eg, those with atherosclerotic cardiovascular disease, including with transient ischemic attack [TIA] or ischemic stroke) who are able to tolerate statins, we begin LDL-C lowering with high-intensity statin therapy, independent of the baseline LDL-C, to reduce the risk of stroke and cardiovascular events [12,35]. We generally treat with atorvastatin 80 mg/day, since this was the agent and dose used in the SPARCL trial that showed a benefit for secondary ischemic stroke prevention. (See "Statins: Actions, side effects, and administration".) While the entirety of the evidence does not clearly identify a threshold below which further LDL-C lowering leads to little benefit, we believe that efforts to lower the LDL-C to <70 mg/dL (1.8 mmol/L) should be made in most patients with cardiovascular disease. A similar approach is recommended for patients with other types of cardiovascular disease at high risk for a recurrent or initial cardiovascular event ( table 1). (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".) Statin intolerance For patients who are intolerant of high-intensity statin therapy, the maximally tolerated dose of a statin can be used; alternatives are moderate-intensity statin therapy (eg, atorvastatin 10 to 20 mg daily, rosuvastatin 5 to 10 mg daily, simvastatin 20 to 40 mg daily, pravastatin 40 to 80 mg daily, lovastatin 40 mg daily, or fluvastatin 40 mg daily in two divided doses) or low-intensity statin therapy (eg, pravastatin 10 to 20 mg daily or lovastatin 20 mg daily). For patients whose LDL-C level remains 70 mg/dL ( 1.8 mmol/L) despite maximally tolerated statin therapy, adding ezetimibe or a PCSK9 inhibitor is reasonable [35]. For patients who are unable to tolerate any statin regimen, we treat with ezetimibe and consider adding a PCSK9 inhibitor if LDL-C remains 70 mg/dL ( 1.8 mmol/L) [35]. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease" and "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors".) Monitoring Fasting lipid levels should be measured 4 to 12 weeks after starting LDL-C lowering therapy and then every 3 to 12 months thereafter. Benefit of LDL-C lowering Data from randomized controlled trials has established that LDL-C lowering, primarily with statins, reduces the risk of major cardiovascular events, including both initial and recurrent stroke, regardless of age, gender, or pretreatment blood lipid concentration. A systematic review of the literature up to July 2017 identified nine randomized controlled trials assessing statins in over 10,000 patients with ischemic https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 7/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate stroke or TIA [36]. A network meta-analysis of these data showed that the risk of ischemic stroke was reduced with statin treatment versus no statin (7.6 versus 9.3 percent, OR 0.81, 95% CI 0.70-0.93; absolute risk reduction [ARR] 1.6 percent, 95% CI 0.6-2.6), as was the risk of cardiovascular events (22.8 versus 28 percent, OR 0.75, 95% CI 0.69-0.83; ARR 5.4 percent, 95% CI 3.6-6.8). The greatest benefit was observed with high-dose statin treatment (eg, atorvastatin 80 mg daily or simvastatin 40 mg daily). The 2006 SPARCL trial was the first to show that statin treatment decreased the risk of recurrent ischemic stroke among patients with a history of stroke or TIA [33]. The trial enrolled 4731 ambulatory patients with no known coronary heart disease (CHD) who had a stroke or TIA within one to six months; patients were randomly assigned to treatment with either atorvastatin 80 mg/day or placebo. Patients were required to have a baseline LDL-C of 100 to 190 mg/dL (2.6 to 4.9 mmol/L). The mean baseline LDL-C level was 133 mg/dL (3.4 mmol/L). Patients with hemorrhagic stroke were included if they were deemed to be at risk for ischemic stroke or CHD. Patients were excluded if they had atrial fibrillation, other cardiac sources of embolism, or subarachnoid hemorrhage. At a median follow-up of 4.9 years, atorvastatin led to a mean reduction in LDL-C of 56 mg/dL (1.4 mmol/L) and reduced fatal or nonfatal stroke (11.2 versus 13.1 percent, adjusted hazard ratio [HR] 0.84, 95% CI 0.71-0.99, ARR at five years 2.2 percent, 95% CI 0.2- 4.2 percent) [33]. Atorvastatin also led to a reduction in all coronary events (5.2 versus 8.6 percent, HR 0.58, 95% CI 0.46-0.73) and all cardiovascular events (22.4 versus 29 percent, HR 0.74, 95% CI 0.66-0.83). There was no difference between the atorvastatin and placebo groups in overall mortality. The lower the LDL-C, the greater the benefit In the Treat Stroke to Target (TST) trial, patients with a recent ischemic stroke or TIA were randomly assigned to a lower target LDL-C level of <70 mg/dL (1.8 mmol/L) or to a higher target LDL-C level of 90 to 110 mg/dL (2.3 to 2.8 mmol/L) [37]. The mean LDL-C level at baseline was 135 mg/dL (3.5 mmol/L). The LDL-C level was lowered by adjustment of the statin dose in most cases, with addition of ezetimibe in approximately 34 percent of patients in the lower-target group. The trial was stopped early due to lack of funding, with data for 2860 patients who were followed for a median 3.5 years. The mean achieved LDL-C level in the lower-target group was 65 mg/dL (1.7 mmol/L) and in the higher-target group was 96 mg/dL (2.5 mmol/L). The composite primary end point of major cardiovascular events (ie, ischemic stroke, myocardial infarction, new symptoms leading to urgent coronary or carotid revascularization, or cardiovascular death) was reduced in the lower-target LDL-C group compared with the higher-target group (8.5 versus 10.9 percent, adjusted HR 0.78, 95% CI 0.61-0.98, ARR 2.4 percent). https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 8/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate A 2022 meta-analysis identified 11 randomized trials (including the TST trial) that enrolled over 20,000 patients with stroke and compared more intensive versus less intensive LDL-C lowering statin-based therapies [38]. More intensive LDL-C lowering led to a reduced risk of recurrent stroke compared with less intensive LDL-C lowering (8.1 versus 9.3 percent; RR 0.88, 95% CI 0.80-0.96; number needed to treat, 90) and to a lower risk of major cardiovascular events (13.9 versus 16.7 percent; RR 0.83, 95% CI 0.78-0.89). The benefit of LDL-C lowering was similar among different LDL-C lowering strategies (statins versus no statins, more statins or ezetimibe versus less statins or ezetimibe, and PCSK9 inhibitors plus statins versus placebo plus statins). The benefit of more intensive LDL-C lowering may apply only to patients with atherosclerosis In the 2022 meta-analysis, more intensive LDL-C versus less intensive LDL-C-lowering led to a reduced risk of recurrent stroke in trials with all patients having evidence of atherosclerosis (RR 0.79, 95% CI 0.69-0.91) but not in trials with most patients not having evidence of atherosclerosis (RR 0.95, 95% CI 0.85-1.07) [38]. LDL-C lowering and hemorrhagic stroke The 2022 meta-analysis found that more intensive versus less intensive LDL-C lowering led to a small increased risk of hemorrhagic stroke when patients with all types of stroke at entry were included (1.3 versus 0.9 percent; RR 1.46, 95% CI 1.11-1.91; number needed to harm 242) [38]. However, sensitivity tests restricting analysis to only patients with ischemic stroke as an entry event found that more intensive versus less intensive LDL-C lowering led to a nonsignificant increased risk of hemorrhagic stroke while maintaining a significant reduction in the risk of recurrent ischemic stroke. The relationship between statin therapy and hemorrhagic stroke is reviewed in greater detail separately. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Other risk factors' and "Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis", section on 'Management of statins'.) Lipoprotein(a) Lipoprotein(a), also referred to as Lp(a), is a modest independent risk factor for atherosclerotic cardiovascular disease and cerebrovascular events. Note that LDL-C measurements include the cholesterol component of Lp(a). In an occasional patient, a substantial fraction of LDL-C may be carried in Lp(a) particles rather than in normal LDL. In these cases, treatment with a statin may lead to a lesser reduction in LDL-C than expected, as statins do not effectively reduce Lp(a) levels. However, there is only limited evidence that Lp(a) lowering reduces atherosclerotic cardiovascular disease risk, as discussed separately. (See "Lipoprotein(a)".) https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 9/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate Hypertriglyceridemia Some [39-41], but not all [27,42,43] observational studies suggested that hypertriglyceridemia is a risk factor for ischemic stroke. Management involves lifestyle modification (eg, weight loss, smoking cessation, aerobic exercise, healthy diet, limited alcohol consumption), treatment of hypertension, glycemic control for patients with diabetes, and LDL-C lowering therapy (most LDL-C lowering medications also reduce triglyceride levels). (See "Hypertriglyceridemia in adults: Management", section on 'General measures'.) For patients with high atherosclerotic cardiovascular disease risk (including those with atherosclerotic ischemic stroke or TIA) whose triglyceride levels remain >150 mg/dL after lifestyle interventions and optimal LDL-C lowering therapy, it is reasonable to treat with high- dose marine omega-3 fatty acid using icosapent ethyl, 2 g twice daily. This in general agreement with the AHA/ASA guideline recommendation for the treatment of hypertriglyceridemia [12]. The evidence regarding the efficacy and safety of omega-3 fatty acid therapy for cardiovascular outcomes is reviewed separately. (See "Hypertriglyceridemia in adults: Management", section on 'Marine omega-3 fatty acid effects'.) DIABETES MELLITUS Diabetes and stroke risk Patients with diabetes mellitus have approximately twice the risk of ischemic stroke compared with those without diabetes [44-48]. In addition, the risk of stroke associated with diabetes is higher in women than in men [48]. Dyslipidemia, endothelial dysfunction, and platelet and coagulation abnormalities are among the risk factors that may promote the development of carotid atherosclerosis in diabetics. (See "Prevalence of and risk factors for coronary heart disease in patients with diabetes mellitus".) However, there is no proven benefit of intensive glucose-lowering therapy for reducing macrovascular outcomes (eg, stroke and death) in patients with type 2 diabetes [12]. Impaired glucose tolerance may be a risk factor for ischemic stroke in patients with a history of transient ischemic attack (TIA) or minor ischemic stroke [49]. It may also be a risk factor for carotid atherosclerosis, as illustrated by studies in nondiabetics showing that elevated serum hemoglobin A1C is associated with an increased risk of carotid plaque development [50,51]. Glycemic control For most patients with diabetes, a reasonable goal of therapy is a glycated hemoglobin (A1C) value of 7 percent [12]. Diet, exercise, oral hypoglycemic drugs, and insulin are proven methods to achieve glycemic control. https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 10/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate This recommendation is based on evidence that tight glucose control reduces microvascular complications. The available evidence has not demonstrated a consistent beneficial effect of intensive glucose-lowering therapy for macrovascular outcomes (eg, stroke and death) in patients with type 2 diabetes. Nevertheless, for patients with ischemic stroke or TIA, the 2021 American Heart Association/American Stroke Association (AHA/ASA) guidelines recommend screening for diabetes mellitus using A1C [12]. These issues are discussed in detail elsewhere: (See "Glycemic control and vascular complications in type 1 diabetes mellitus".) (See "Glycemic control and vascular complications in type 2 diabetes mellitus".) (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus".) Metabolic syndrome The metabolic syndrome, defined as the presence of three or more components that include high fasting glucose, hypertension, low serum high-density lipoprotein, elevated serum triglycerides, and abdominal obesity, is considered a prediabetic condition linked to increased risk of cardiovascular disease. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)".) However, it is unclear if the metabolic syndrome is an independent risk factor for ischemic stroke beyond the sum of its individual components, and the available evidence is inconsistent. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)", section on 'A critical look at the metabolic syndrome'.) Furthermore, the utility of the metabolic syndrome to predict stroke risk does not appear to improve upon more conventional assessments such as the Framingham Risk Score [52]. (See "Cardiovascular disease risk assessment for primary prevention: Risk calculators".) Although the metabolic syndrome is not clearly established as an independent stroke risk factor, it is important to treat the underlying causes such as obesity and physical inactivity. Management should include counseling for lifestyle modification (diet, exercise, and weight loss) and appropriate treatment for individual components of the metabolic syndrome, particularly hypertension and dyslipidemia, which are also stroke risk factors. (See 'Hypertension' above and 'Dyslipidemia' above and "Metabolic syndrome (insulin resistance syndrome or syndrome X)", section on 'Therapy'.) Treatment of insulin resistance Pioglitazone treatment appears to reduce the risk of recurrent stroke and myocardial infarction in nondiabetic patients who have insulin resistance, though this benefit is partially offset by an increased risk of adverse effects such as bone https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 11/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate fracture. These points are illustrated by the findings of the multicenter Insulin Resistance Intervention After Stroke (IRIS) trial, which randomly assigned over 3800 subjects with recent ischemic stroke or TIA and insulin resistance to treatment with pioglitazone (target dose 45 mg daily) or placebo [53]. The trial defined insulin resistance as a value of >3 on the homeostasis model assessment of insulin resistance (HOMA-IR) index, calculated as the level of fasting glucose (measured in mmol/L) times the level of fasting insulin (measured in microU/mL) divided by 22.5. Patients with diabetes, heart failure, or active liver disease were excluded. After 4.8 years, the composite outcome of stroke or myocardial infarction in IRIS was significantly reduced in the pioglitazone group compared with the placebo group (9 versus 11.8 percent, hazard ratio [HR] 0.76, 95% CI 0.62-0.93); the absolute risk reduction with pioglitazone for the composite outcome was 2.8 percent [53]. Several adverse effects were significantly more common with pioglitazone compared with placebo, including bone fracture requiring surgery or hospitalization (5.1 versus 3.2 percent), edema (36 versus 25 percent), and weight gain exceeding 4.5 kg (52 versus 34 percent). There was no difference between groups in the incidence of heart failure (the pioglitazone dose was adjusted for symptoms such as new or worsening edema, shortness of breath, or excessive weight gain during the trial). However, there is good evidence from other studies that thiazolidinediones increase the risk of heart failure. (See "Thiazolidinediones in the treatment of type 2 diabetes mellitus", section on 'Fluid retention/heart failure'.) Based upon the results of the IRIS trial [53], the number needed to treat (NNT) with pioglitazone to prevent one patient from developing stroke or myocardial infarction is 36, while the number needed to harm (NNH) to cause one patient to develop bone fracture requiring hospitalization is 53. Given the benefit of pioglitazone in this setting, it is an option for carefully selected nondiabetic patients with insulin resistance who are willing to accept the risk of adverse events such as bone fracture and heart failure. Since there is no validated test for measuring insulin resistance in clinical practice, clinicians should emulate the IRIS methodology as closely as possible by calculating the HOMA-IR index using laboratories that adapt the IRIS trial assays for plasma insulin level. LIFESTYLE MODIFICATION A number of behavioral and lifestyle modifications may be beneficial for reducing the risk of ischemic stroke and cardiovascular disease [12,54]. These include smoking cessation, regular aerobic physical activity, salt restriction, a Mediterranean diet, limited alcohol consumption, and https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 12/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate weight control. Our recommendations are in general agreement with the national guidelines [12]. Smoking cessation All patients who are recent or current tobacco smokers should be counseled routinely to quit smoking. (See "Overview of smoking cessation management in adults".) Cigarette smoking is associated with an increased risk for all stroke subtypes and has a strong, dose-response relationship for both ischemic stroke and subarachnoid hemorrhage [55-61]. In the Nurses' Health Study, smokers had a relative risk of stroke of 2.58 compared with never smokers [56]. Evaluation of former smokers found that the excess risk disappeared within two to four years after the cessation of smoking. In the Framingham Heart Study, the odds ratio for moderate carotid stenosis was 1.08 for each five pack-years of smoking [58]. Among 10,938 normotensive subjects in a prospective Swedish cohort study, approximately 39 percent of strokes were attributable to smoking [59]. There are no randomized controlled trials of smoking cessation compared with no intervention for stroke prevention. However, observational studies have shown that the elevated risk of stroke due to smoking declines after quitting and is eliminated by five years later [56,60,62]. Therefore, American Heart Association/American Stroke Association (AHA/ASA) guidelines recommend smoking cessation for patients with stroke or transient ischemic attack (TIA) who smoke tobacco, counseling with or without pharmacologic therapy to assist in quitting, and avoidance of environmental tobacco smoke [12]. (See "Overview of smoking cessation management in adults".) Physical activity and exercise Patients with ischemic stroke or TIA who are capable of regular exercise should engage in moderate-intensity physical exercise performed for a minimum of 10 minutes four times a week or vigorous-intensity exercise performed for a minimum of 20 minutes twice a week. Moderate-intensity exercise is defined as activity sufficient to break a sweat or noticeably raise the heart rate (eg, walking briskly, using an exercise bicycle) [12]. (See "The benefits and risks of aerobic exercise", section on 'Benefits of exercise'.) Increasing evidence suggests that low physical activity and prolonged sitting increases the risk of cardiovascular disease, including stroke [4,63,64]. Additional support that physical inactivity is a risk factor for stroke comes from studies showing the benefit of increased physical activity and exercise for reducing the risk of cardiovascular events [65]. Diet Emerging evidence suggests that dietary interventions, and in particular a Mediterranean diet (see "Healthy diet in adults", section on 'Mediterranean diet'), improves https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 13/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate outcomes in patients with established cardiovascular disease [66]. Until further studies evaluate the magnitude of benefit of a Mediterranean diet, it is reasonable to advise all patients to adhere to its components. For patients with a history of stroke or TIA, we encourage patients to follow a Mediterranean-type diet that emphasizes the intake of vegetables, fruits, whole grains, low-fat dairy products, poultry, fish, legumes, nontropical vegetable oils, and nuts. It limits the intake of sweets, sugar-sweetened beverages, and red meats. Calories from saturated fat should be limited to 5 to 6 percent and calories from trans-fat should be reduced. For patients who would benefit from blood pressure lowering, a reduction in sodium intake of at least 1 g/day (or daily sodium intake of <2.5 g per day) is also suggested. (See "Salt intake, salt restriction, and primary (essential) hypertension".) These recommendations are consistent with the 2021 AHA/ASA guideline for stroke prevention in patients with stroke or TIA [12] and the 2013 AHA/American College of Cardiology (ACC) guideline on lifestyle management to reduce cardiovascular risk [67]. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk", section on 'Diet'.) Supplementation with beta-carotene, vitamin E, and vitamin C, either alone or in combination with each other or other antioxidant vitamins does not appear to be effective in the primary or secondary prevention of cardiovascular disease. The data supporting these conclusions are reviewed elsewhere. Alcohol and substance use All patients with ischemic stroke or TIA who are heavy drinkers should eliminate or reduce their alcohol consumption because of the increased risk of stroke and high morbidity associated with alcoholism, despite the lack of clear evidence from clinical trials that reduction of alcohol intake decreases the risk of recurrent stroke [12]. (See "Cardiovascular benefits and risks of moderate alcohol consumption", section on 'Stroke risk' and "Screening for unhealthy use of alcohol and other drugs in primary care" and "Approach to treating alcohol use disorder" and "Brief intervention for unhealthy alcohol and other drug use: Efficacy, adverse effects, and administration" and "Alcohol use disorder: Psychosocial treatment".) Alcohol affects the risk of stroke in different directions depending upon level of consumption, type of stroke, and possibly ethnicity. Light drinking (one to two drinks per day) is associated with a reduced risk of ischemic stroke, while heavy drinking is associated with an increased risk. (See "Cardiovascular benefits and risks of moderate alcohol consumption", section on 'Stroke risk'.) https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 14/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate The risk of stroke is increased with infective endocarditis related to intravenous drug use, and with the use of certain stimulants (eg, cocaine, amphetamine and its derivatives) [68,69]. The

hospitalization (5.1 versus 3.2 percent), edema (36 versus 25 percent), and weight gain exceeding 4.5 kg (52 versus 34 percent). There was no difference between groups in the incidence of heart failure (the pioglitazone dose was adjusted for symptoms such as new or worsening edema, shortness of breath, or excessive weight gain during the trial). However, there is good evidence from other studies that thiazolidinediones increase the risk of heart failure. (See "Thiazolidinediones in the treatment of type 2 diabetes mellitus", section on 'Fluid retention/heart failure'.) Based upon the results of the IRIS trial [53], the number needed to treat (NNT) with pioglitazone to prevent one patient from developing stroke or myocardial infarction is 36, while the number needed to harm (NNH) to cause one patient to develop bone fracture requiring hospitalization is 53. Given the benefit of pioglitazone in this setting, it is an option for carefully selected nondiabetic patients with insulin resistance who are willing to accept the risk of adverse events such as bone fracture and heart failure. Since there is no validated test for measuring insulin resistance in clinical practice, clinicians should emulate the IRIS methodology as closely as possible by calculating the HOMA-IR index using laboratories that adapt the IRIS trial assays for plasma insulin level. LIFESTYLE MODIFICATION A number of behavioral and lifestyle modifications may be beneficial for reducing the risk of ischemic stroke and cardiovascular disease [12,54]. These include smoking cessation, regular aerobic physical activity, salt restriction, a Mediterranean diet, limited alcohol consumption, and https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 12/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate weight control. Our recommendations are in general agreement with the national guidelines [12]. Smoking cessation All patients who are recent or current tobacco smokers should be counseled routinely to quit smoking. (See "Overview of smoking cessation management in adults".) Cigarette smoking is associated with an increased risk for all stroke subtypes and has a strong, dose-response relationship for both ischemic stroke and subarachnoid hemorrhage [55-61]. In the Nurses' Health Study, smokers had a relative risk of stroke of 2.58 compared with never smokers [56]. Evaluation of former smokers found that the excess risk disappeared within two to four years after the cessation of smoking. In the Framingham Heart Study, the odds ratio for moderate carotid stenosis was 1.08 for each five pack-years of smoking [58]. Among 10,938 normotensive subjects in a prospective Swedish cohort study, approximately 39 percent of strokes were attributable to smoking [59]. There are no randomized controlled trials of smoking cessation compared with no intervention for stroke prevention. However, observational studies have shown that the elevated risk of stroke due to smoking declines after quitting and is eliminated by five years later [56,60,62]. Therefore, American Heart Association/American Stroke Association (AHA/ASA) guidelines recommend smoking cessation for patients with stroke or transient ischemic attack (TIA) who smoke tobacco, counseling with or without pharmacologic therapy to assist in quitting, and avoidance of environmental tobacco smoke [12]. (See "Overview of smoking cessation management in adults".) Physical activity and exercise Patients with ischemic stroke or TIA who are capable of regular exercise should engage in moderate-intensity physical exercise performed for a minimum of 10 minutes four times a week or vigorous-intensity exercise performed for a minimum of 20 minutes twice a week. Moderate-intensity exercise is defined as activity sufficient to break a sweat or noticeably raise the heart rate (eg, walking briskly, using an exercise bicycle) [12]. (See "The benefits and risks of aerobic exercise", section on 'Benefits of exercise'.) Increasing evidence suggests that low physical activity and prolonged sitting increases the risk of cardiovascular disease, including stroke [4,63,64]. Additional support that physical inactivity is a risk factor for stroke comes from studies showing the benefit of increased physical activity and exercise for reducing the risk of cardiovascular events [65]. Diet Emerging evidence suggests that dietary interventions, and in particular a Mediterranean diet (see "Healthy diet in adults", section on 'Mediterranean diet'), improves https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 13/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate outcomes in patients with established cardiovascular disease [66]. Until further studies evaluate the magnitude of benefit of a Mediterranean diet, it is reasonable to advise all patients to adhere to its components. For patients with a history of stroke or TIA, we encourage patients to follow a Mediterranean-type diet that emphasizes the intake of vegetables, fruits, whole grains, low-fat dairy products, poultry, fish, legumes, nontropical vegetable oils, and nuts. It limits the intake of sweets, sugar-sweetened beverages, and red meats. Calories from saturated fat should be limited to 5 to 6 percent and calories from trans-fat should be reduced. For patients who would benefit from blood pressure lowering, a reduction in sodium intake of at least 1 g/day (or daily sodium intake of <2.5 g per day) is also suggested. (See "Salt intake, salt restriction, and primary (essential) hypertension".) These recommendations are consistent with the 2021 AHA/ASA guideline for stroke prevention in patients with stroke or TIA [12] and the 2013 AHA/American College of Cardiology (ACC) guideline on lifestyle management to reduce cardiovascular risk [67]. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk", section on 'Diet'.) Supplementation with beta-carotene, vitamin E, and vitamin C, either alone or in combination with each other or other antioxidant vitamins does not appear to be effective in the primary or secondary prevention of cardiovascular disease. The data supporting these conclusions are reviewed elsewhere. Alcohol and substance use All patients with ischemic stroke or TIA who are heavy drinkers should eliminate or reduce their alcohol consumption because of the increased risk of stroke and high morbidity associated with alcoholism, despite the lack of clear evidence from clinical trials that reduction of alcohol intake decreases the risk of recurrent stroke [12]. (See "Cardiovascular benefits and risks of moderate alcohol consumption", section on 'Stroke risk' and "Screening for unhealthy use of alcohol and other drugs in primary care" and "Approach to treating alcohol use disorder" and "Brief intervention for unhealthy alcohol and other drug use: Efficacy, adverse effects, and administration" and "Alcohol use disorder: Psychosocial treatment".) Alcohol affects the risk of stroke in different directions depending upon level of consumption, type of stroke, and possibly ethnicity. Light drinking (one to two drinks per day) is associated with a reduced risk of ischemic stroke, while heavy drinking is associated with an increased risk. (See "Cardiovascular benefits and risks of moderate alcohol consumption", section on 'Stroke risk'.) https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 14/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate The risk of stroke is increased with infective endocarditis related to intravenous drug use, and with the use of certain stimulants (eg, cocaine, amphetamine and its derivatives) [68,69]. The AHA/ASA guideline recommends counseling patients about these risks and offering services to manage substance use disorders [12]. (See "Clinical assessment of substance use disorders".) Obesity and weight reduction Obesity is associated with an increased risk of cardiovascular disease, including ischemic stroke [12,70]. As with glycemic control, the available data do not show that weight reduction reduces the risk of recurrent stroke [12]. However, weight reduction for obese patients is potentially beneficial for improved control of other important parameters, including blood pressure, blood glucose, and serum lipid levels. Thus, the AHA/ASA guidelines for stroke prevention recommend screening all patients with stroke or TIA for obesity with measurement of body mass index, and recommend weight loss for patients who are overweight or obese [12]. Patients identified as candidates for weight loss should receive multidisciplinary team management and appropriate interventions, beginning with a combination of diet, exercise, and intensive behavioral intervention. These issues are reviewed in detail separately. (See "Obesity in adults: Overview of management".) OTHER RISK FACTORS In addition to the traditional stroke risk factors, myriad other risk factors and pathologic mechanisms are associated with ischemic stroke [71]. Sleep-related breathing disorders Patients with obstructive sleep apnea appear to be at increased risk for stroke. It is unknown whether patients with central sleep apnea syndrome, including Cheyne-Stokes breathing, also have an increased risk. (See "Sleep-related breathing disorders and stroke", section on 'Sleep apnea as a risk factor for stroke'.) Limited data suggest that the presence of sleep-related breathing disorders following a stroke may be a marker of a poorer long-term outcome. (See "Sleep-related breathing disorders and stroke", section on 'Complications'.) Clinically significant sleep apnea is highly prevalent in patients with acute stroke. Clinical features that have been associated with an increased risk for sleep-disordered breathing in patients with stroke include obesity, systolic hypertension, nocturnal oxygen desaturations, and increased stroke severity. The diagnosis of a sleep-related breathing disorder in patients with stroke requires a high index of suspicion and formal sleep testing, since clinical features and questionnaires lack high predictive value in patients with stroke. (See "Sleep-related breathing disorders and stroke", section on 'Diagnosis'.) https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 15/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate Positive airway pressure therapy and behavioral modifications are the mainstays of treatment for patients diagnosed with sleep-related breathing disorders. These issues are reviewed elsewhere. (See "Sleep-related breathing disorders and stroke", section on 'Management'.) Hypercoagulability The approach to secondary stroke prevention for hypercoagulable states, including antiphospholipid syndrome, inherited thrombophilias, and cancer-related hypercoagulability, is reviewed separately. (See "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack", section on 'Hypercoagulable states'.) Hyperhomocysteinemia Increased serum homocysteine concentrations are associated with an increased risk of coronary and cerebrovascular disease, as discussed separately (see "Overview of homocysteine"). Elevated homocysteine appears to be associated with an increased risk of the large artery subtype of ischemic stroke, and possibly to the small artery subtype; it does not appear to be associated with cardioembolic or other stroke subtypes [72,73]. However, there is evidence from several clinical trials that treatment with homocysteine-reducing vitamins is not beneficial for secondary prevention of cardiovascular disease or stroke [12]. Thus, we do not routinely screen patients with ischemic stroke or transient ischemic attack for homocysteine levels or vitamin levels associated with homocysteine metabolism. Head and neck radiotherapy Head and neck radiotherapy for cancer treatment may lead to a delayed vasculopathy of large and small vessels mediated by endothelial damage, fibrosis, and accelerated atherosclerosis [74-76]. Radiotherapy-related occlusive disease is often diffuse and occurs in uncommon locations, in contrast to the typical focal lesions that develop at vessel bifurcations from atherosclerosis in the absence of radiation. Depending on the site and dose of radiation, the involved vessels may include the extracranial carotid and vertebral arteries and the intracranial circle of Willis vessels [74,77]. This process may lead to symptomatic carotid disease, moyamoya syndrome, and ischemic stroke. (See "Management of late complications of head and neck cancer and its treatment", section on 'Carotid artery injury' and "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis", section on 'Associated conditions'.) While data are limited, secondary prevention of stroke attributed to radiation-induced stenosis typically involves maximal medical therapy including an antiplatelet agent; revascularization with stenting may be appropriate for select patients with extracranial carotid involvement, whereas intracranial stenting is used as a last resort for intracranial large artery involvement, similar to patients with atherosclerotic intracranial large artery disease. Management should be multidisciplinary and tailored to the patient's anatomy and comorbidities. (See "Management of symptomatic carotid atherosclerotic disease" and "Intracranial large artery atherosclerosis: Treatment and prognosis".) https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 16/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate TREATMENT BY STROKE MECHANISM Several important mechanisms of ischemic stroke are amenable to effective secondary prevention, including anticoagulation for atrial fibrillation, revascularization for internal carotid artery stenosis, and device closure for patent foramen ovale with paradoxical embolism. An overview of the treatment for specific causes of ischemic stroke and transient ischemic attack, including large and small artery disease, cardiogenic embolism, aortic atherosclerosis, and blood disorders, is presented separately. (See "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack".) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Stroke (The Basics)" and "Patient education: Medicines after an ischemic stroke (The Basics)" and "Patient education: Lowering the risk of having a stroke (The Basics)") Beyond the Basics topics (see "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)") https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 17/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate SUMMARY AND RECOMMENDATIONS Major risk factors The major treatable stroke risk factors are hypertension, dyslipidemia, diabetes, smoking, and physical inactivity. Most patients with an ischemic stroke or transient ischemic attack (TIA) should be treated with all available risk reduction strategies, ideally by a multidisciplinary team, including antithrombotic therapy, blood pressure reduction, low-density lipoprotein (LDL)-lowering therapy, and lifestyle modification. (See 'Major risk factors' above.) Antithrombotic therapy Nearly all patients with TIA or ischemic stroke of atherosclerotic origin should be treated with an antiplatelet agent ( algorithm 2 and algorithm 3 and algorithm 1). Early short-term dual antiplatelet therapy (DAPT) is beneficial for select patients with high-risk TIA or minor ischemic stroke and may be beneficial for patients with recently symptomatic intracranial large artery atherosclerosis. The combination of aspirin- extended-release dipyridamole, clopidogrel alone, or aspirin alone are all acceptable options for long-term therapy. Long-term oral anticoagulation should be used as prevention for patients with chronic nonvalvular atrial fibrillation who have had an ischemic stroke or TIA. (See 'Antithrombotic therapy' above.) Antihypertensive therapy After the acute phase of stroke, antihypertensive therapy should be resumed in previously treated, neurologically stable patients with known hypertension for both prevention of recurrent stroke and prevention of other vascular events. In addition, antihypertensive therapy should be initiated in previously untreated, neurologically stable patients with stroke or TIA who have an established blood pressure that is above the goal blood pressure indicated in the table ( table 2) for higher-risk populations, which includes all patients with ischemic stroke or TIA. (See 'Hypertension' above and "Antihypertensive therapy for secondary stroke prevention".) LDL-C lowering therapy Detailed low-density lipoprotein cholesterol (LDL-C) lowering recommendations are provided separately. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".) High-intensity statin therapy For patients with atherosclerotic cardiovascular disease, including TIA or ischemic stroke, we treat with high-intensity statin therapy (eg, atorvastatin 80 mg/day), independent of the baseline LDL-C, to lower the LDL-C to <70 mg/dL (1.8 mmol/L) in order to reduce the risk of stroke and cardiovascular events. https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 18/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate Intolerance of high-intensity statin therapy For patients who are intolerant of high- intensity statin therapy, the maximally tolerated dose of a statin therapy can be used. LDL-C above goal despite statin therapy For patients whose LDL-C level remains 70 mg/dL ( 1.8 mmol/L) despite maximally tolerated statin therapy, adding ezetimibe or a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor is reasonable. Patients unable to tolerate statin therapy For patients who are unable to tolerate any statin regimen, we treat with ezetimibe; we consider adding a PCSK9 inhibitor if LDL-C remains 70 mg/dL ( 1.8 mmol/L). Glycemic control For most patients with diabetes, a reasonable goal of therapy is a glycated hemoglobin (A1C) value of 7 percent. Diet, exercise, oral hypoglycemic drugs, and insulin are proven methods to achieve glycemic control. (See 'Glycemic control' above.) Lifestyle modification A number of behavioral and lifestyle modifications may be beneficial for reducing the risk of ischemic stroke and cardiovascular disease (see 'Lifestyle modification' above): Smoking cessation for tobacco smokers (see 'Smoking cessation' above) Eliminating or reducing alcohol consumption for heavy drinkers (see 'Alcohol and substance use' above) Regular exercise for patients who are capable of physical activity (see 'Physical activity and exercise' above) Healthy diet and salt restriction (see 'Diet' above) Weight reduction for obese patients (see 'Obesity and weight reduction' above) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Karen L Furie, MD, MPH, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Harmsen P, Lappas G, Rosengren A, Wilhelmsen L. Long-term risk factors for stroke: twenty- eight years of follow-up of 7457 middle-aged men in G teborg, Sweden. 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Plasma lipid profile and incident ischemic stroke: the Atherosclerosis Risk in Communities (ARIC) study. Stroke 2003; 34:623. 28. Bots ML, Elwood PC, Nikitin Y, et al. Total and HDL cholesterol and risk of stroke. EUROSTROKE: a collaborative study among research centres in Europe. J Epidemiol Community Health 2002; 56 Suppl 1:i19. 29. Amarenco P. Lipid lowering and recurrent stroke: another stroke paradox? Eur Heart J 2005; 26:1818. 30. Donnan GA, Davis SM. Stroke and cholesterol: weakness of risk versus strength of therapy. Stroke 2004; 35:1526. 31. Oesterle A, Laufs U, Liao JK. Pleiotropic Effects of Statins on the Cardiovascular System. Circ Res 2017; 120:229. https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 21/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate 32. Biasucci LM, Biasillo G, Stefanelli A. Inflammatory markers, cholesterol and statins: pathophysiological role and clinical importance. Clin Chem Lab Med 2010; 48:1685. 33. Amarenco P, Bogousslavsky J, Callahan A 3rd, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006; 355:549. 34. Collins R, Armitage J, Parish S, et al. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004; 363:757. 35. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019; 73:e285. 36. Tramacere I, Boncoraglio GB, Banzi R, et al. Comparison of statins for secondary prevention in patients with ischemic stroke or transient ischemic attack: a systematic review and network meta-analysis. BMC Med 2019; 17:67. 37. Amarenco P, Kim JS, Labreuche J, et al. A Comparison of Two LDL Cholesterol Targets after Ischemic Stroke. N Engl J Med 2020; 382:9. 38. Lee M, Cheng CY, Wu YL, et al. Association Between Intensity of Low-Density Lipoprotein Cholesterol Reduction With Statin-Based Therapies and Secondary Stroke Prevention: A Meta-analysis of Randomized Clinical Trials. JAMA Neurol 2022; 79:349. 39. Lindenstr m E, Boysen G, Nyboe J. Influence of total cholesterol, high density lipoprotein cholesterol, and triglycerides on risk of cerebrovascular disease: the Copenhagen City Heart Study. BMJ 1994; 309:11. 40. Freiberg JJ, Tybjaerg-Hansen A, Jensen JS, Nordestgaard BG. Nonfasting triglycerides and risk of ischemic stroke in the general population. JAMA 2008; 300:2142. 41. Bansal S, Buring JE, Rifai N, et al. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA 2007; 298:309. 42. H heim LL, Holme I, Hjermann I, Leren P. Risk factors of stroke incidence and mortality. A 12-year follow-up of the Oslo Study. Stroke 1993; 24:1484. 43. Bowman TS, Sesso HD, Ma J, et al. Cholesterol and the risk of ischemic stroke. Stroke 2003; 34:2930. 44. Arvanitakis Z, Schneider JA, Wilson RS, et al. Diabetes is related to cerebral infarction but not to AD pathology in older persons. Neurology 2006; 67:1960. https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 22/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate 45. Janghorbani M, Hu FB, Willett WC, et al. Prospective study of type 1 and type 2 diabetes and risk of stroke subtypes: the Nurses' Health Study. Diabetes Care 2007; 30:1730. 46. Emerging Risk Factors Collaboration, Sarwar N, Gao P, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 2010; 375:2215. 47. Luitse MJ, Biessels GJ, Rutten GE, Kappelle LJ. Diabetes, hyperglycaemia, and acute ischaemic stroke. Lancet Neurol 2012; 11:261. 48. Peters SA, Huxley RR, Woodward M. Diabetes as a risk factor for stroke in women compared with men: a systematic review and meta-analysis of 64 cohorts, including 775,385 individuals and 12,539 strokes. Lancet 2014; 383:1973. 49. Vermeer SE, Sandee W, Algra A, et al. Impaired glucose tolerance increases stroke risk in nondiabetic patients with transient ischemic attack or minor ischemic stroke. Stroke 2006; 37:1413. 50. Vitelli LL, Shahar E, Heiss G, et al. Glycosylated hemoglobin level and carotid intimal-medial thickening in nondiabetic individuals. The Atherosclerosis Risk in Communities Study. Diabetes Care 1997; 20:1454. 51. J rgensen L, Jenssen T, Joakimsen O, et al. Glycated hemoglobin level is strongly related to the prevalence of carotid artery plaques with high echogenicity in nondiabetic individuals: the Troms study. Circulation 2004; 110:466. 52. Wannamethee SG, Shaper AG, Lennon L, Morris RW. Metabolic syndrome vs Framingham Risk Score for prediction of coronary heart disease, stroke, and type 2 diabetes mellitus. Arch Intern Med 2005; 165:2644. 53. Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after Ischemic Stroke or Transient Ischemic Attack. N Engl J Med 2016; 374:1321. 54. Zhang Y, Tuomilehto J, Jousilahti P, et al. Lifestyle factors on the risks of ischemic and hemorrhagic stroke. Arch Intern Med 2011; 171:1811. 55. Ockene IS, Miller NH. Cigarette smoking, cardiovascular disease, and stroke: a statement for healthcare professionals from the American Heart Association. American Heart Association Task Force on Risk Reduction. Circulation 1997; 96:3243. 56. Kawachi I, Colditz GA, Stampfer MJ, et al. Smoking cessation and decreased risk of stroke in women. JAMA 1993; 269:232. 57. Kurth T, Kase CS, Berger K, et al. Smoking and risk of hemorrhagic stroke in women. Stroke 2003; 34:2792. https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 23/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate 58. Wilson PW, Hoeg JM, D'Agostino RB, et al. Cumulative effects of high cholesterol levels, high blood pressure, and cigarette smoking on carotid stenosis. N Engl J Med 1997; 337:516. 59. Li C, Engstr m G, Hedblad B, et al. Risk factors for stroke in subjects with normal blood pressure: a prospective cohort study. Stroke 2005; 36:234. 60. Wolf PA, D'Agostino RB, Kannel WB, et al. Cigarette smoking as a risk factor for stroke. The Framingham Study. JAMA 1988; 259:1025. 61. Peters SA, Huxley RR, Woodward M. Smoking as a risk factor for stroke in women compared with men: a systematic review and meta-analysis of 81 cohorts, including 3,980,359 individuals and 42,401 strokes. Stroke 2013; 44:2821. 62. Wannamethee SG, Shaper AG, Whincup PH, Walker M. Smoking cessation and the risk of stroke in middle-aged men. JAMA 1995; 274:155. 63. Chomistek AK, Manson JE, Stefanick ML, et al. Relationship of sedentary behavior and physical activity to incident cardiovascular disease: results from the Women's Health Initiative. J Am Coll Cardiol 2013; 61:2346. 64. Gillum RF, Mussolino ME, Ingram DD. Physical activity and stroke incidence in women and men. The NHANES I Epidemiologic Follow-up Study. Am J Epidemiol 1996; 143:860. 65. Billinger SA, Arena R, Bernhardt J, et al. Physical activity and exercise recommendations for stroke survivors: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014; 45:2532. 66. English C, MacDonald-Wicks L, Patterson A, et al. The role of diet in secondary stroke prevention. Lancet Neurol 2021; 20:150. 67. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 129:S76. 68. Indave BI, Sordo L, Bravo MJ, et al. Risk of stroke in prescription and other amphetamine- type stimulants use: A systematic review. Drug Alcohol Rev 2018; 37:56. 69. Sordo L, Indave BI, Barrio G, et al. Cocaine use and risk of stroke: a systematic review. Drug Alcohol Depend 2014; 142:1. 70. Guo Y, Yue XJ, Li HH, et al. Overweight and Obesity in Young Adulthood and the Risk of Stroke: a Meta-analysis. J Stroke Cerebrovasc Dis 2016; 25:2995. 71. Bang OY, Ovbiagele B, Kim JS. Nontraditional Risk Factors for Ischemic Stroke: An Update. Stroke 2015; 46:3571. 72. Eikelboom JW, Hankey GJ, Anand SS, et al. Association between high homocyst(e)ine and ischemic stroke due to large- and small-artery disease but not other etiologic subtypes of https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 24/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate ischemic stroke. Stroke 2000; 31:1069. 73. Iso H, Moriyama Y, Sato S, et al. Serum total homocysteine concentrations and risk of stroke and its subtypes in Japanese. Circulation 2004; 109:2766. 74. Morris B, Partap S, Yeom K, et al. Cerebrovascular disease in childhood cancer survivors: A Children's Oncology Group Report. Neurology 2009; 73:1906. 75. Lam WW, Leung SF, So NM, et al. Incidence of carotid stenosis in nasopharyngeal carcinoma patients after radiotherapy. Cancer 2001; 92:2357. 76. Plummer C, Henderson RD, O'Sullivan JD, Read SJ. Ischemic stroke and transient ischemic attack after head and neck radiotherapy: a review. Stroke 2011; 42:2410. 77. Kasner SE. Treatment of "other" causes of stroke. In: Stroke: Pathophsyiology, Diagnosis, an d Management, 4th ed, Mohr JP, Choi DW, Grotta JC, et al (Eds), Churchill Livingstone, Philad elphia 2004. p.1059. Topic 1120 Version 65.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 25/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate GRAPHICS Known cardiovascular disease and similar risk Patients with the following are at high risk for a second (or first) cardiovascular disease event: Coronary heart disease Myocardial infarction Angina Coronary revascularization Cerebrovascular disease Stroke Transient ischemic attack Peripheral arterial disease Multiple risk factors that confer a 10-year risk of CVD >20% 2 Chronic kidney disease with estimated GFR <45 mL/min per 1.73 m * CVD: cardiovascular disease; GFR: glomerular filtration rate. Statin doses may require adjustment in patients with chronic kidney disease. Graphic 91576 Version 3.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 26/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate Antithrombotic therapy according to cause of acute ischemic stroke This algorithm is intended to provide basic guidance regarding the immediate use of antithrombotic therapy with an acute ischemic stroke. For further details, including scoring of the NIHSS and suggested dosing regim antithrombotic agents, refer to the relevant UpToDate topic reviews. https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 27/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate HTN: hypertension; SBP: systolic blood pressure; DBP: diastolic blood pressure; ICA: internal carotid artery; C endarterectomy; OA: oral anticoagulation; CAS: carotid artery stenting; DAPT: dual antiplatelet therapy (eg, a clopidogrel, or aspirin and ticagrelor); NIHSS: National Institutes of Health Stroke Scale; CT: computed tomog magnetic resonance imaging. Brain and neurovascular imaging, cardiac evaluation, and (for select patients) other laboratory tests. Indications for long-term oral anticoagulation include atrial fibrillation, ventricular thrombus, mechanical h treatment of venous thromboembolism. "Large" infarcts are defined as those that involve more than one-third of the middle cerebral artery territor one-half of the posterior cerebral artery territory based upon neuroimaging with CT or MRI. Though less relia infarct size can also be defined clinically (eg, NIHSS score >15). Long-term aspirin therapy is alternative (though less effective) if OA contraindicated or refused. Direct oral anticoagulant agents have a more rapid anticoagulant effect than warfarin, a factor that may inf choice of agent and timing of OA initiation. Some experts prefer DAPT, based upon observational evidence. Long-term single-agent antiplatelet therapy for secondary stroke prevention with aspirin, clopidogrel, or as release dipyridamole. Graphic 131701 Version 2.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 28/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate Immediate antithrombotic treatment of transient ischemic attack (TIA) This algorithm is intended to provide basic guidance regarding the use of immediate use of antithrombotic therapy for patients with a TIA. For further details, including suggested dosing regimens of antiplatelet and anticoagulant agents, refer to the relevant UpToDate topic reviews. 2 ABCD : age, blood pressure, clinical features, duration of symptoms, and diabetes; DAPT: dual antiplatelet therapy (eg, aspirin and clopidogrel, or aspirin and ticagrelor); BP: blood pressure; SBP: systolic blood pressure; DBP: diastolic blood pressure. Indications for long-term oral anticoagulation include embolism prevention for patients with atrial fibrillation, ventricular thrombus, mechanical heart valve, and treatment of venous thromboembolism. Graphic 131692 Version 1.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 29/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate Immediate antithrombotic treatment of acute ischemic stroke This algorithm is intended to provide basic guidance regarding the immediated use of antithrombotic therapy for patients with an acute ischemic stroke. For further details, including scoring of the NIHSS and suggested dosing regimens of antithrombotic agents, refer to the relevant UpToDate topic reviews.

pressure: a prospective cohort study. Stroke 2005; 36:234. 60. Wolf PA, D'Agostino RB, Kannel WB, et al. Cigarette smoking as a risk factor for stroke. The Framingham Study. JAMA 1988; 259:1025. 61. Peters SA, Huxley RR, Woodward M. Smoking as a risk factor for stroke in women compared with men: a systematic review and meta-analysis of 81 cohorts, including 3,980,359 individuals and 42,401 strokes. Stroke 2013; 44:2821. 62. Wannamethee SG, Shaper AG, Whincup PH, Walker M. Smoking cessation and the risk of stroke in middle-aged men. JAMA 1995; 274:155. 63. Chomistek AK, Manson JE, Stefanick ML, et al. Relationship of sedentary behavior and physical activity to incident cardiovascular disease: results from the Women's Health Initiative. J Am Coll Cardiol 2013; 61:2346. 64. Gillum RF, Mussolino ME, Ingram DD. Physical activity and stroke incidence in women and men. The NHANES I Epidemiologic Follow-up Study. Am J Epidemiol 1996; 143:860. 65. Billinger SA, Arena R, Bernhardt J, et al. Physical activity and exercise recommendations for stroke survivors: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014; 45:2532. 66. English C, MacDonald-Wicks L, Patterson A, et al. The role of diet in secondary stroke prevention. Lancet Neurol 2021; 20:150. 67. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 129:S76. 68. Indave BI, Sordo L, Bravo MJ, et al. Risk of stroke in prescription and other amphetamine- type stimulants use: A systematic review. Drug Alcohol Rev 2018; 37:56. 69. Sordo L, Indave BI, Barrio G, et al. Cocaine use and risk of stroke: a systematic review. Drug Alcohol Depend 2014; 142:1. 70. Guo Y, Yue XJ, Li HH, et al. Overweight and Obesity in Young Adulthood and the Risk of Stroke: a Meta-analysis. J Stroke Cerebrovasc Dis 2016; 25:2995. 71. Bang OY, Ovbiagele B, Kim JS. Nontraditional Risk Factors for Ischemic Stroke: An Update. Stroke 2015; 46:3571. 72. Eikelboom JW, Hankey GJ, Anand SS, et al. Association between high homocyst(e)ine and ischemic stroke due to large- and small-artery disease but not other etiologic subtypes of https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 24/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate ischemic stroke. Stroke 2000; 31:1069. 73. Iso H, Moriyama Y, Sato S, et al. Serum total homocysteine concentrations and risk of stroke and its subtypes in Japanese. Circulation 2004; 109:2766. 74. Morris B, Partap S, Yeom K, et al. Cerebrovascular disease in childhood cancer survivors: A Children's Oncology Group Report. Neurology 2009; 73:1906. 75. Lam WW, Leung SF, So NM, et al. Incidence of carotid stenosis in nasopharyngeal carcinoma patients after radiotherapy. Cancer 2001; 92:2357. 76. Plummer C, Henderson RD, O'Sullivan JD, Read SJ. Ischemic stroke and transient ischemic attack after head and neck radiotherapy: a review. Stroke 2011; 42:2410. 77. Kasner SE. Treatment of "other" causes of stroke. In: Stroke: Pathophsyiology, Diagnosis, an d Management, 4th ed, Mohr JP, Choi DW, Grotta JC, et al (Eds), Churchill Livingstone, Philad elphia 2004. p.1059. Topic 1120 Version 65.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 25/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate GRAPHICS Known cardiovascular disease and similar risk Patients with the following are at high risk for a second (or first) cardiovascular disease event: Coronary heart disease Myocardial infarction Angina Coronary revascularization Cerebrovascular disease Stroke Transient ischemic attack Peripheral arterial disease Multiple risk factors that confer a 10-year risk of CVD >20% 2 Chronic kidney disease with estimated GFR <45 mL/min per 1.73 m * CVD: cardiovascular disease; GFR: glomerular filtration rate. Statin doses may require adjustment in patients with chronic kidney disease. Graphic 91576 Version 3.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 26/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate Antithrombotic therapy according to cause of acute ischemic stroke This algorithm is intended to provide basic guidance regarding the immediate use of antithrombotic therapy with an acute ischemic stroke. For further details, including scoring of the NIHSS and suggested dosing regim antithrombotic agents, refer to the relevant UpToDate topic reviews. https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 27/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate HTN: hypertension; SBP: systolic blood pressure; DBP: diastolic blood pressure; ICA: internal carotid artery; C endarterectomy; OA: oral anticoagulation; CAS: carotid artery stenting; DAPT: dual antiplatelet therapy (eg, a clopidogrel, or aspirin and ticagrelor); NIHSS: National Institutes of Health Stroke Scale; CT: computed tomog magnetic resonance imaging. Brain and neurovascular imaging, cardiac evaluation, and (for select patients) other laboratory tests. Indications for long-term oral anticoagulation include atrial fibrillation, ventricular thrombus, mechanical h treatment of venous thromboembolism. "Large" infarcts are defined as those that involve more than one-third of the middle cerebral artery territor one-half of the posterior cerebral artery territory based upon neuroimaging with CT or MRI. Though less relia infarct size can also be defined clinically (eg, NIHSS score >15). Long-term aspirin therapy is alternative (though less effective) if OA contraindicated or refused. Direct oral anticoagulant agents have a more rapid anticoagulant effect than warfarin, a factor that may inf choice of agent and timing of OA initiation. Some experts prefer DAPT, based upon observational evidence. Long-term single-agent antiplatelet therapy for secondary stroke prevention with aspirin, clopidogrel, or as release dipyridamole. Graphic 131701 Version 2.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 28/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate Immediate antithrombotic treatment of transient ischemic attack (TIA) This algorithm is intended to provide basic guidance regarding the use of immediate use of antithrombotic therapy for patients with a TIA. For further details, including suggested dosing regimens of antiplatelet and anticoagulant agents, refer to the relevant UpToDate topic reviews. 2 ABCD : age, blood pressure, clinical features, duration of symptoms, and diabetes; DAPT: dual antiplatelet therapy (eg, aspirin and clopidogrel, or aspirin and ticagrelor); BP: blood pressure; SBP: systolic blood pressure; DBP: diastolic blood pressure. Indications for long-term oral anticoagulation include embolism prevention for patients with atrial fibrillation, ventricular thrombus, mechanical heart valve, and treatment of venous thromboembolism. Graphic 131692 Version 1.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 29/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate Immediate antithrombotic treatment of acute ischemic stroke This algorithm is intended to provide basic guidance regarding the immediated use of antithrombotic therapy for patients with an acute ischemic stroke. For further details, including scoring of the NIHSS and suggested dosing regimens of antithrombotic agents, refer to the relevant UpToDate topic reviews. OA: oral anticoagulants; IVT: intravenous thrombolysis; MT: mechanical thrombectomy; NIHSS: National Institutes of Health Stroke Scale; DAPT: dual antiplatelet therapy (eg, aspirin and clopidogrel, or aspirin and ticagrelor). Refer to text and associated algorithm for details. Brain and large vessel imaging, cardiac evaluation, and (for select patients) other laboratory tests. https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 30/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate For severe systemic or symptomatic intracranial bleeding, withhold all anticoagulant and antiplatelet therapy for one to two weeks or until the patient is stable. Graphic 131697 Version 2.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 31/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate Stroke mortality related to blood pressure and age Stroke mortality rate, pictured on a log scale with 95% CI, in each decade of age in relation to the estimated usual systolic and diastolic blood pressure at the start of that decade. Stroke mortality increases with both higher pressures and older ages. For diastolic pressure, each age-specific regression line ignores the left-hand point (ie, at slightly less than 75 mmHg) for which the risk lies significantly above the fitted regression line (as indicated by the broken line below 75 mmHg). CI: confidence interval. Data from Prospective Studies Collaboration, Lancet 2002; 360:1903. Graphic 66793 Version 5.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 32/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate Coronary heart disease mortality related to blood pressure and age Coronary heart disease (CHD) mortality rate, pictured on a log scale with 95% confidence intervals (CI), in each decade of age in relation to the estimated usual systolic and diastolic blood pressure at the start of that decade. CHD mortality increases with both higher pressures and older ages. For diastolic pressure, each age- specific regression line ignores the left-hand point (ie, at slightly less than 75 mmHg) for which the risk lies significantly above the fitted regression line (as indicated by the broken line below 75 mmHg). IHD: ischemic heart disease. Reproduced from: Lewington S, Clarke R, Qizilbash N, et al. Age-speci c relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360:1903. Illustration used with the permission of Elsevier. All rights reserved. Graphic 75106 Version 9.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 33/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate Goal blood pressure according to baseline risk for cardiovascular disease and method of measuring blood pressure Routine/conventional office blood pressure Unattended AOBPM, (manual measurement daytime ABPM, or home with stethoscope or blood pressure oscillometric device)* Higher-risk population 125 to 130/<80 120 to 125/<80 Known ASCVD Heart failure Diabetes mellitus Chronic kidney disease Age 65 years Calculated 10-year risk of ASCVD event 10% Lower-risk 130 to 139/<90 125 to 135/<90 None of the above risk factors All target ranges presented above are in mmHg. On average, blood pressure readings are 5 to 10 mmHg lower with digital, unattended, or out-of- office methods of measurement (ie, AOBPM, daytime ABPM, home blood pressure) than with routine/standard methods of office measurement (ie, manual auscultatory or oscillometric measurement), presumably due to the "white coat effect." However, it is critical to realize that this average difference in blood pressures according to the methodology of measurement applies to the population and not the individual. Some patients do not experience a white coat effect, and, therefore, there is some uncertainty in setting goals that are specific to the method of measurement. When treating to these goals, a patient may (inadvertently) attain a blood pressure below the given target. Provided the patient does not develop symptoms, side effects, or adverse events as a result of the treatment regimen, then reducing or withdrawing antihypertensive medications is unnecessary. Less aggressive goals than those presented in the table may be appropriate for specific groups of patients, including those with postural hypotension, the frail older adult patient, and those with side effects to multiple antihypertensive medications. AOBPM: automated oscillometric blood pressure monitoring; ABPM: ambulatory blood pressure monitoring; ASCVD: atherosclerotic cardiovascular disease; ACC/AHA: American College of Cardiology/American Heart Association. https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 34/36 7/5/23, 11:42 AM Overview of secondary prevention of ischemic stroke - UpToDate Office blood pressure must be performed adequately in order to use such measurements to manage patients. Critical to an adequate office assessment of blood pressure are proper patient positioning (eg, seated in a chair, feet flat on the floor, arm supported, remove clothing covering the location of cuff placement) and proper technique (eg, calibrated device, proper-sized cuff). The average of multiple measurements should be used for management. Refer to UpToDate topics on measurement of blood pressure. Office readings should not be used to manage blood pressure unless it is performed adequately. Home blood pressure, like office blood pressure, must be performed adequately in order for the measurements to be used to manage patients. First, the accuracy of the home blood pressure device must be verified in the clinician's office. Second, the clinician should verify that the cuff and bladder that the patient will use are the appropriate size. Third, patients should measure their pressure after several minutes of rest and while seated in a chair (back supported and feet flat on the floor) with their arm supported (eg, resting on a table). Fourth, the blood pressure should be measured at different times per day and over multiple days. The average value of these multiple measurements is used for management. Home blood pressure readings should not be used to manage blood pressure unless it is performed adequately and in conjunction with office blood pressure or ambulatory blood pressure. The level of evidence supporting the lower goal in higher-risk individuals is stronger for some risk groups (eg, patients with known coronary heart disease, patients with a calculated 10-year risk 15%, chronic kidney disease) than for other risk groups (eg, patients with diabetes, patients with a prior stroke). Refer to UpToDate topics on goal blood pressure for a discussion of the evidence. Prior history of coronary heart disease (acute coronary syndrome or stable angina), prior stroke or transient ischemic attack, prior history of peripheral artery disease. In older adults with severe frailty, dementia, and/or a limited life expectancy, or in patients who are nonambulatory or institutionalized (eg, reside in a skilled nursing facility), we individualize goals and share decision-making with the patient, relatives, and caretakers, rather than targeting one of the blood pressure goals in the table. The 2013 ACC/AHA cardiovascular risk assessment calculator should be used to estimate 10-year cardiovascular disease risk. In the large subgroup of patients who have an initial (pretreatment) blood pressure 140/ 90 mmHg, but who do not have any of the other listed cardiovascular risk factors, some experts would set a more aggressive blood pressure goal of <130/<80 mmHg rather than those presented in the table. This more aggressive goal would likely reduce the chance of developing severe hypertension and ultimately lower the relative risk of cardiovascular events in these lower-risk patients over the long term. However, the absolute benefit of more aggressive blood pressure lowering in these patients is comparatively small, and a lower goal would require more intensive pharmacologic therapy and corresponding side effects. Graphic 117101 Version 3.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 35/36 7/5/23, 11:43 AM Overview of secondary prevention of ischemic stroke - UpToDate Contributor Disclosures Natalia S Rost, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Alexis Simpkins, MD, PhD, MSCR, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/overview-of-secondary-prevention-of-ischemic-stroke/print 36/36

7/5/23, 11:43 AM Percutaneous carotid artery stenting - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Percutaneous carotid artery stenting : Jeffrey Jim, MD, MPHS, FACS : John F Eidt, MD, Joseph L Mills, Sr, MD : Kathryn A Collins, MD, PhD, FACS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Sep 06, 2022. INTRODUCTION For patients with indications for carotid revascularization, treatment options include carotid endarterectomy or carotid artery stenting (CAS), which is most commonly accomplished with stent delivery using a transfemoral (ie, TF-CAS) approach, but other percutaneous approaches (transaxillary, transcervical, transradial) have also been described. Percutaneous CAS, and more specifically TF-CAS, has advantages and disadvantages and, as with other approaches to carotid artery revascularization, the patient's anatomy must meet specific anatomic requirements to undergo the procedure safely. The technical aspects and outcomes of primarily TF-CAS are reviewed, with aspects of other percutaneous approaches provided where relevant. Transcarotid artery revascularization (TCAR) requires a surgical cutdown to expose the common carotid artery for device placement and uses cerebral protection with flow reversal during introduction of a carotid stent. Because TCAR eliminates the risks associated with traversing the aortic arch, TCAR is gaining enthusiasm as an alternative approach to CAS among vascular clinicians and is reviewed separately. (See "Transcarotid artery revascularization".). A comparison of CAS techniques is also provided separately. (See "Overview of carotid artery stenting", section on 'Approach to carotid artery stenting'.) DEVICES USED FOR CAROTID REVASCULARIZATION https://www.uptodate.com/contents/percutaneous-carotid-artery-stenting/print 1/24 7/5/23, 11:43 AM Percutaneous carotid artery stenting - UpToDate CAS systems were developed in the 1990s as a less invasive alternative to carotid endarterectomy (CEA) for carotid artery stenosis [1]. An endovascular approach is associated with fewer perioperative complications compared with open surgery for other vascular diseases, and it was felt that the same would be the case for CEA. A reduced rate of complications would be especially pertinent for patients deemed to be at "high risk" for CEA related to specific anatomic or physiologic risk factors [2]. While the risk of some perioperative complications was reduced with CAS, the risk for stroke was increased for CAS in trials comparing CEA with predominantly transfemoral CAS (TF-CAS). Over time, stroke rates associated with TF-CAS have decreased but remain concerning for certain subsets of patients. In an effort to reduce the potential for embolization and the risk of periprocedural stroke, refinement in carotid stents, embolic protection devices, and techniques are ongoing. Carotid stent devices Carotid stents can be grossly divided into two groups: open-cell architecture and closed-cell architecture [3,4]. With closed-cell stents, the stent struts are all interconnected, which is not the case for open-cell stents. As such, this architectural difference makes open-cell stents more flexible, and they may be more often chosen for more complex, angulated lesions or tortuous anatomy that may make delivery of the stent challenging. While closed-cell stents may be less flexible, they do have smaller free cell area between the stent struts, leaving smaller gaps uncovered, and may be more resistant to particle penetration that can lead to embolization [5]. A novel dual layer stent, which is available for use outside of the United States, has reported good early results [6,7]. This "covered" stent is designed to minimize and control plaque prolapse, thereby preventing plaque-related embolism after stent placement. In one trial, this mesh stent appeared to reduce the number and volume of new lesions identified on diffusion-weighted magnetic resonance imaging (DW-MRI) performed 2 days and 30 days after the procedure [8]. However, longer follow-up is needed to determine whether there is any sustained benefit. Data from one trial, various retrospective studies, and registry reviews have failed to demonstrate any clinically important advantages for one stent type over another [9-12]. A systematic review that included nine predominantly retrospective studies did not find any significant differences in periprocedural (30-day) cerebrovascular complications comparing open- with closed-cell stent designs [9]. In a review of 740 patients who received carotid stents from the International Carotid Stenting Study (ICSS), the rate of ipsilateral stroke beyond 30 days was similar for each group [10]. However, the rate of restenosis 50 percent occurred in significantly fewer patients who received open- compared with closed-stent designs (36 versus 46 percent; hazard ratio [HR] 0.68, 95% CI 0.53-0.88), and there was a trend toward a reduced rate of severe stenosis ( 70 percent) or occlusion for the open-stent design (8.6 versus 12.7 percent; HR 0.63, 95% CI 0.37-1.05). https://www.uptodate.com/contents/percutaneous-carotid-artery-stenting/print 2/24 7/5/23, 11:43 AM Percutaneous carotid artery stenting - UpToDate The dual-layered stent combines a stent frame with a micromesh lattice to provide better coverage of the carotid plaque compared with conventional stent designs. In the SCAFFOLD trial, 265 patients were treated with a 30-day stroke rate of 1.1 percent [13]. In a meta-analysis looking at four single-arm prospective studies evaluating two different dual-layered stents, the 30-day stroke rate was 1.25 percent [14]. While the early results are promising, longer follow-up in these patients is needed to ensure that subsequent rates of stroke, stent thrombosis, or restenosis are not higher compared with other stents. There are no data supporting the use of drug-eluting stents or drug-coated balloons in treating carotid stenosis. The rate of restenosis following TF-CAS with bare metal stents is generally low. Embolic protection devices There are two basic types of embolic protection devices (EPDs): distal filters and proximal occlusion (flow arrest, flow reversal) [15-23]. Filter devices are used in the majority of percutaneous CAS procedures. In a review of over 24,000 patients undergoing CAS, 74 percent were performed using TF-CAS with distal embolic protection, 2.3 percent using TF-CAS with proximal balloon occlusion, and 22.9 percent using transcarotid artery revascularization (TCAR) with flow reversal [24]. Distal filters Distal filter designs allow continuous antegrade flow through the internal carotid artery during stent placement and are designed to catch debris dislodged during stent placement. Although filter devices are the most commonly used type of EPD for percutaneous CAS, they have several disadvantages [3,25-27]: They must pass unprotected across the stenosis, and tight lesions may require additional unprotected predilatation before the filter can be placed, a process that may dislodge emboli. There may be incomplete apposition of the filter device against the arterial wall, which may lead to incomplete capture of embolizing particles. The presence of the filter in the distal internal carotid artery may induce vasospasm that can severely compromise outflow and cause stroke if prolonged. Spasm can be treated with an intra-arterial vasodilator such as nitroglycerin or papaverine, but such treatment can lead to systemic hypotension. Filters can cause complications related to vessel wall injury or to difficulty in removal of the device once the carotid stent has been placed. By their inherent design that allows for flow through the filter, all filters allow some particles to pass into the internal carotid artery and cerebral circulation. In some instances, https://www.uptodate.com/contents/percutaneous-carotid-artery-stenting/print 3/24 7/5/23, 11:43 AM Percutaneous carotid artery stenting - UpToDate particles as large as 200 to 250 microns can pass, potentially resulting in small or minor stroke. Proximal occlusion Proximal occlusion devices redirect the flow of blood, including particulate matter, away from the internal carotid artery. Proximal occlusion is used in <5 percent of TF-CAS procedures [24]. Proponents of proximal devices emphasize that the embolic protection system is set up proximal to the lesion before intervention, which avoids unprotected engagement of the lesion as is necessary with distal filters. In a systematic review of proximal devices, the pooled rate of periprocedural adverse events was low at 1.7 percent [28]. There are two general categories of proximal occlusion. Flow arrest designs deploy occlusion balloons in the external carotid artery and common carotid artery, which results in cessation of flow in the internal carotid artery [29-31]. The proximal internal carotid artery is suctioned to remove debris prior to deflating the occlusion balloons. A single flow arrest system is commercially available (ie, MoMA). Flow reversal designs promote retrograde flow, with blood directed from the internal carotid artery through the device into the venous circulation. The flow reversal device originally used for TF-CAS has not been commercially available for several years. Of note, the flow reversal systems require traversing the aortic arch to access the carotid artery. One flow arrest or occlusion system (eg, MoMa) that has been used with TF-CAS requires traversing the aortic arch to access the common carotid artery, but the internal carotid lesion is not traversed with the wire platform until flow occlusion is established. Another flow reversal system (Gore) was withdrawn from the market and is no longer commercially available. The flow reversal system designed for use with TCAR provides flow reversal before the lesion is crossed and with delivery of the flow reversal system and carotid stent directly through a common carotid artery cutdown, embolization from an aortic arch source is eliminated. (See "Transcarotid artery revascularization", section on 'Transcarotid stenting system'.) Disadvantages associated with proximal embolic protection devices include [26]: They are larger than filter-type devices (6 French), requiring larger sheaths (9 French) to be placed into the femoral artery with potential higher risk of access-related complications. Cerebral ischemia can occur with proximal occlusion. Regardless of the design, some patients will be intolerant to the transient loss of flow up the internal carotid artery [32]. Using a flow arrest system, the rate of intolerance was as high as 30 percent in one study [32]. The rates of intolerance are much lower for flow reversal devices, ranging from <1 to 2.4 percent [31,33]. https://www.uptodate.com/contents/percutaneous-carotid-artery-stenting/print 4/24 7/5/23, 11:43 AM Percutaneous carotid artery stenting - UpToDate Injury to the common and external carotid arteries can occur with balloon inflation. Effectiveness of embolic protection A benefit for the use of EPDs during TF-CAS in preventing periprocedural stroke and death has not definitively been established, and the available evidence consisting of randomized trials, retrospective reviews, and registry studies has been conflicting. In addition, the clinical significance of any new microvascular lesions, which is often used to compare devices, has yet to be determined [25]. Nevertheless, many consider the use of an EPD to be standard of care. In the United States, the use of an EPD is mandatory for reimbursement for CAS. Stroke rates with versus without Data from some [34,35], but not all [36], carotid stent trials (predominantly TF-CAS) suggest that EPDs are not effective for preventing symptomatic stroke or new ischemic brain lesions. In a meta-analysis that included two trials (Stent-Protected Angioplasty versus Carotid Endarterectomy [SPACE], Endarterectomy versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis [EVA-3S]), the combined endpoint of death or any stroke was similar for CAS with compared to without cerebral protection (odds ratio 0.77, 95% CI 0.41-1.46) [37]. In the SPACE trial, the decision to use an EPD was left to the discretion of the enrolling center; only 27 percent of patients undergoing stenting received embolic protection. Four different EPDs were used. In a prespecified subgroup analysis, there was no significant difference in the 30-day outcome of ipsilateral stroke or death for those who underwent CAS with (n = 151) compared to without (n = 416) embolic protection (7.3 and 6.7 percent, respectively) [34]. In the EVA-3S trial, which began enrollment in 2000, embolic protection was initiated in 2003, but the study was stopped in 2005. The 30-day risk of stroke and death was lower for those undergoing CAS with protection compared with those undergoing CAS without protection (8 versus 25 percent) [38]. One explanation for the inability of EPDs to prevent all perioperative strokes is that they do not prevent all emboli from reaching the distal cerebral vessels. The risk of stroke may be related to embolic load. This was suggested in a study that analyzed aspirated debris from 54 patients who had CAS with proximal balloon occlusion [39]. The risk of a neurologic event was associated with higher numbers of relevant particles, larger maximum particle diameters, and larger maximum particle areas. Filter type EPDs may paradoxically increase the microembolic load by leading to disintegration of macroemboli into smaller microemboli that can pass through the https://www.uptodate.com/contents/percutaneous-carotid-artery-stenting/print 5/24 7/5/23, 11:43 AM Percutaneous carotid artery stenting - UpToDate micropores of the EPD or through gaps that exist between the EPD and the arterial wall [40]. In addition, thrombus may form on the distal filter surface or on the tip of the EPD wire or result from EPD-related microtrauma to the vascular wall. It is possible that some or all of the reduction in complication rates attributed to EPDs in observational studies is related to improvements in stent technology and the increasing experience of operators over time rather than the use of the EPDs [41,42]. In support of this hypothesis, a single-center case series of 528 patients who had CAS without protection over a five-year study period noted a significant reduction in the 30-day minor stroke rate in the fifth year compared with the first year (3.1 versus 7.1 percent, respectively) [41]. In a 2020 review of over 24,000 patients undergoing CAS, among 464 matched pairs undergoing TF-CAS with distal embolic protection or TF-CAS with proximal balloon occlusion, adverse event rates were low and outcomes were similar between the groups [24]. For distal embolic protection and proximal balloon occlusion these were, respectively: Stroke or death: 3.7 and 3.2 percent Stroke: 2.5 and 2.4 percent Death: 1.5 and 1.1 percent Transient ischemic attack: 1.5 and 1.7 percent Myocardial infarction (MI): 0.6 and 0.4 percent Microembolization There is increasing interest in quantifying microembolization events during and following CAS, but their clinical significance has yet to be established. Ischemic brain lesions discovered on DW-MRI after CAS may be associated with an increased risk for recurrent cerebrovascular events [43]. The number of events detected ranges widely between 33 and 72 percent and may be lower with use of EPDs [44]. Some have suggested that proximal flow reversal devices may cause less stent-related microembolization, but this is debated [45]. In a systematic review of observational studies that included nearly 700 patients, the rate of new ipsilateral lesions on DW-MRI was lower for CAS procedures using an EPD compared with those without an EPD (33 versus 45 percent) [46]. However, in a sub-study of the ICSS trial, more patients assigned to CAS at centers using EPDs had at least one new lesion on DW-MRI (largely asymptomatic) compared with those assigned to CAS at centers where EPDs were not used (37 of 51 [73 percent] versus 25 of 73 [34 percent]) [36,47,48]. A small review evaluated the number of microembolic signals detected by transcranial Doppler or the number of new lesions identified on DW-MRI in patients undergoing flow https://www.uptodate.com/contents/percutaneous-carotid-artery-stenting/print 6/24 7/5/23, 11:43 AM Percutaneous carotid artery stenting - UpToDate reversal compared with filter-type EPDs, or no filter [49]. Flow reversal was associated with fewer microembolic signals during the procedure relative to historic controls with filter protection. CAROTID REVASCULARIZATION Carotid artery stenosis most commonly results from atherosclerotic degeneration. Disease in the carotid arteries can lead to embolization or thrombosis, resulting in neurologic events (eg, transient ischemia attack, stroke). The treatment of carotid stenosis includes maximal medical therapy and carotid revascularization for patients with appropriate indications. (See "Management of symptomatic carotid atherosclerotic disease", section on 'Intensive medical management' and "Management of asymptomatic extracranial carotid atherosclerotic disease", section on 'Intensive medical therapy and follow-up'.) The general indications for carotid revascularization for stenotic atherosclerotic lesions are the same, regardless of revascularization approach (carotid endarterectomy [CEA], transfemoral CAS [TF-CAS], transcarotid artery revascularization [TCAR]). Indications in patients with asymptomatic or symptomatic carotid artery stenosis, whether to proceed with CEA or CAS, and whether one approach to CAS is preferable over another are discussed elsewhere. (See "Management of asymptomatic extracranial carotid atherosclerotic disease" and "Management of symptomatic carotid atherosclerotic disease" and "Overview of carotid artery stenting", section on 'Approach to carotid artery stenting'.) Contraindications for transfemoral approach Contraindications to CAS can be grouped into those that contraindicate the procedure, in general, and those that contraindicate a specific approach [50]: Absolute contraindications to CAS (regardless of approach) include the following (see "Overview of carotid artery stenting", section on 'Contraindications'): Visible thrombus within the lesion detected on preoperative or intraoperative imaging (eg, ultrasound, angiography) Inability to gain vascular access Active infection Relative complications to CAS include the following: Severe carotid plaque calcification, circumferential carotid plaque Severe carotid tortuosity https://www.uptodate.com/contents/percutaneous-carotid-artery-stenting/print 7/24 7/5/23, 11:43 AM Percutaneous carotid artery stenting - UpToDate Near occlusion of the carotid artery ( figure 1) [51,52] Small internal carotid artery (unable to accommodate available commercial carotid stents) For patients undergoing TF-CAS, the following may also preclude the ability to safely deliver the devices necessary to perform the procedure: Age >80 years (possibly a surrogate for a more heavily diseased aortic arch) Heavily calcified, severely ulcerated or thrombus-lined aortic arch Inability to track and deploy a cerebral protection device because of marked tortuosity of the proximal internal carotid artery Patients with marked truncal obesity; colonization of groins with bacteria or yeast Tortuous aortic arch (eg, type III arch) or aberrant arch anatomy (eg, bovine arch) PATIENT PREPARATION The preparatory management for CAS is similar regardless of technique. Preoperative imaging, considerations for anesthesia, and prophylactic measures (eg, antibiotics) are reviewed separately. Medication management specific to transfemoral CAS (TF-CAS) is reviewed below. (See "Overview of carotid artery stenting", section on 'Medication management'.) Antiplatelet/statin therapy Dual antiplatelet (DAPT) using aspirin and clopidogrel and statin therapy are recommended for all patients prior to undergoing TF-CAS. The efficacy of DAPT and statin therapy are reviewed separately. (See "Overview of carotid artery stenting", section on 'Dual antiplatelet therapy' and "Overview of carotid artery stenting", section on 'Statin therapy'.) We use the regimen from the Carotid Revascularization Endarterectomy versus Stent Trial (CREST) [53]: For those patients not on chronic aspirin therapy, we start aspirin (325 mg twice daily) at least 48 hours before the procedure, or, if within 48 hours of the procedure, we give a loading dose of aspirin 650 mg four or more hours before the procedure. For those patients not on chronic clopidogrel therapy, we start clopidogrel 75 mg twice daily at least 48 hours before the procedure, or if within 48 hours of the procedure, we give a loading dose of clopidogrel 450 mg four or more hours before the procedure. For those patients not on chronic statin therapy, we start atorvastatin 40 mg daily for seven days before the procedure or we give a loading dose of 80 mg 12 hours before the procedure. https://www.uptodate.com/contents/percutaneous-carotid-artery-stenting/print 8/24 7/5/23, 11:43 AM Percutaneous carotid artery stenting - UpToDate For TF-CAS, guidelines have supported a range of periprocedural aspirin therapy from 75 mg to 325 mg daily [54,55]. Following the CAS procedure, DAPT is continued for at least four weeks. We provide aspirin 325 mg daily plus clopidogrel 75 mg once daily. For patients with a history of neck irradiation, we continue DAPT indefinitely. For all other patients after CAS, we continue aspirin 325 mg daily (range 75 to 325 mg) indefinitely. TECHNIQUES Transfemoral CAS (TF-CAS) can be performed in an angiography suite or appropriately equipped operating room with a mobile fluoroscopy unit. Complications of CAS may be directly related to the length of the CAS procedure. CAS should be performed expeditiously; if technical roadblocks are encountered (such as challenging aortic arch anatomy or extreme tortuosity that makes it difficult to insert the platform), it is very appropriate to abort the procedure. (See 'Complications' below.) Percutaneous vascular access Percutaneous access is most commonly obtained via the right (or left) common femoral artery, but transaxillary, transbrachial, transradial, and transcervical percutaneous access have all been described [56-78]. Percutaneous access is obtained in the standard fashion using ultrasound guidance. (See "Percutaneous arterial access techniques for diagnostic or interventional procedures".) After obtaining access, an arch aortogram should be performed unless the arch anatomy is already known from preoperative imaging, such as computed tomographic (CT) angiography or magnetic resonance (MR) angiography. Older patients may have significant atherosclerotic disease of the aortic arch and origin vessels increasing their risk for atheroembolism. Selective cerebral arteriography is also performed. Cerebral arteriography following CAS is compared with that obtained before the stent is placed to evaluate for any distal embolic debris. Anticoagulation Before manipulation of the guidewires and catheters within the aortic arch and carotid artery, the patient should be anticoagulated (heparin or an alternative agent) to maintain the activated whole blood clotting time at 250 to 300 seconds. For patients who cannot receive heparin (eg, heparin-induced thrombocytopenia), bivalirudin is an alternative and may be associated with a lower incidence of bleeding compared with heparin [79-82]. (See "Heparin and LMW heparin: Dosing and adverse effects" and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Bivalirudin'.) https://www.uptodate.com/contents/percutaneous-carotid-artery-stenting/print 9/24 7/5/23, 11:43 AM Percutaneous carotid artery stenting - UpToDate Whether to reverse heparin with protamine at the end of the procedure is generally driven by issues pertaining to the percutaneous access site. The increased use of closure devices reduces the need for reversal; however, for patients in whom a closure device is not used at a femoral access site, reversal of anticoagulation reduces sheath dwell time and duration of bedrest. In a review from the Vascular Quality Initiative, among over 17,000 patients who underwent transfemoral carotid artery stenting, 15 percent received protamine [83]. The use of protamine was not associated with significant differences in perioperative complications (eg, bleeding requiring reintervention, blood transfusion, transient ischemic attack, stroke, myocardial infarction, death, others) compared with no protamine. For patients treated for symptomatic carotid disease, protamine was associated with lower risk of stroke or death (3 versus 4.3 percent; relative risk 0.69, 95% CI 0.47-0.99), a difference that was not seen for asymptomatic patients. Embolic protection device placement Following placement of a sheath into the common carotid artery, embolic protection devices (EPDs) are deployed and then removed once the carotid artery stent has been positioned, deployed, and expanded [84]. Two general types of EPDs (distal filter or proximal occlusion) are discussed above. (See 'Embolic protection devices' above.) For protection using a distal filter, the filter is either deployed over a wire that is placed across the lesion or the filter is built into the wire and deployed after it crosses the lesion. For protection using proximal occlusion and flow occlusion designs, the occlusion balloons are placed prior to crossing the lesion. Distal filter devices require "unprotected" tracking over a wire, through the stenotic lesion to be treated, and are deployed in the distal internal carotid artery. The most common technical problem associated with filter devices is maneuvering them up into a tortuous distal internal carotid artery. Various techniques can be used to assist in straightening the internal carotid artery (eg, use of a "buddy" wire). Another difficulty that may be encountered is passing a filter- type EPD through a severely stenotic internal carotid artery. Predilation of the lesion can be performed; however, without a filter in place, unprotected predilation is a recognized risk factor for periprocedural stroke. Vasospasm associated with the device can also be problematic. Stent positioning and dilation With the EPD in position, the carotid artery stenosis is predilated (if needed) and the carotid stent positioned and then deployed [85]. A post-stenting angioplasty is performed within the stent to ensure its full deployment and apposition against the arterial wall, though the need to do so routinely has been questioned [86-88]. Bradycardia due to baroreceptor activation can occur and lead to hypotension. The reaction is usually https://www.uptodate.com/contents/percutaneous-carotid-artery-stenting/print 10/24 7/5/23, 11:43 AM Percutaneous carotid artery stenting - UpToDate transient but may require the administration of atropine. Prophylactic administration of glycopyrrolate, an antimuscarinic anticholinergic agent, may prevent the hemodynamic response seen during carotid bulb manipulation. We give 0.2 mg glycopyrrolate intravenously prior to balloon dilation and provide a repeat dose of 0.2 mg, if necessary. (See "Anesthesia for carotid endarterectomy and carotid stenting", section on 'Hemodynamic monitoring'.) Completion arteriography Repeat carotid arteriography is performed before and after removal of the EPD, with attention not only to the carotid lesion but also the intracranial internal carotid vessels. Carotid arteriography should demonstrate brisk flow through the previously stenotic carotid artery. POSTPROCEDURE CARE AND FOLLOW-UP Many vascular surgeons will reverse heparin at the completion of a carotid endarterectomy (CEA); this can also be done at the completion of CAS. This allows normalization of activated whole blood clotting time to facilitate removing the access sheath(s). Alternatively, arterial closure devices can be used to reduce sheath dwell times and without the need for heparin reversal. (See 'Anticoagulation' above and "Percutaneous arterial access techniques for diagnostic or interventional procedures", section on 'Hemostasis at the access site'.) Postprocedure monitoring following CAS is similar to CEA. Following CAS, the patient is transferred to a monitored setting for frequent blood pressure and neurologic assessment. The importance of tight blood pressure control cannot be overemphasized. Dual antiplatelet and statin therapy should be continued postprocedure. (See 'Antiplatelet/statin therapy' above.) Routine duplex imaging is performed to identify restenosis. (See "Overview of carotid artery stenting", section on 'Postprocedure care and duplex surveillance'.) COMPLICATIONS The most serious acute complication associated with CAS is stroke. For transfemoral CAS (TF- CAS), the stroke rate is 3 to 4 percent and has steadily decreased with improvements in device technology and operator experience [89]. Stroke and other complications that are not specific to the approach to stenting, such as myocardial infarction, renal failure related to intravenous contrast, carotid thrombosis and restenosis, and stent fracture are reviewed separately. (See "Overview of carotid artery stenting", section on 'Complications'.) https://www.uptodate.com/contents/percutaneous-carotid-artery-stenting/print 11/24 7/5/23, 11:43 AM Percutaneous carotid artery stenting - UpToDate Access-related issues are the most common complications following TF-CAS and include hematoma, bleeding, pseudoaneurysm formation, and atheroembolization to the lower extremities. Following percutaneous access procedures, inadequate closure of the femoral artery puncture site may lead to bleeding, hematoma, or the formation of a pseudoaneurysm. In a review of the Vascular Quality Initiative, bleeding complications occurred in 3.8 percent; however, only 0.8 percent required intervention [89]. The incidence of femoral pseudoaneurysm is approximately 3 percent [90-92]. While the narrow profile of most carotid stenting devices requires a smaller sheath size compared with some vascular interventions (eg, iliac artery stenting), it might be expected that the incidence of pseudoaneurysm might lower; however, the concomitant administration of antiplatelet therapy and anticoagulation contributes to pseudoaneurysm formation. Risk factors associated with pseudoaneurysm include inadequate postprocedure compression of the puncture site, postprocedural anticoagulation, antiplatelet therapy during the intervention, age >65 years, obesity, hypertension, peripheral artery disease, and hemodialysis. The diagnosis and treatment of access site pseudoaneurysm are discussed elsewhere. (See "Femoral artery pseudoaneurysm following percutaneous intervention".) During any aortic catheterization procedure, atheromatous debris can become dislodged from the aortic wall. Clinical symptoms and signs are dependent upon the size of the debris and are reviewed in detail separately. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Occlusive carotid, aortic, renal, mesenteric, and peripheral atherosclerotic disease".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading https://www.uptodate.com/contents/percutaneous-carotid-artery-stenting/print 12/24 7/5/23, 11:43 AM Percutaneous carotid artery stenting - UpToDate level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Carotid artery disease (The Basics)") SUMMARY AND RECOMMENDATIONS Carotid revascularization to treat carotid atherosclerotic disease can be accomplished using open surgery (carotid endarterectomy) or using a carotid artery stent (CAS), with the most common CAS approach using a percutaneous approach. Transfemoral carotid artery stenting (TF-CAS) involves accessing the femoral artery percutaneously to place the necessary guidewires and sheaths, traversing the aortic arch to gain access to the carotid artery, deployment of an embolic protection device, and subsequently dilation of the artery and placement of the stent. (See 'Introduction' above and 'Carotid revascularization' above.) For patients in whom CAS is scheduled or anticipated, dual antiplatelet therapy (DAPT) using aspirin and clopidogrel is recommended. Furthermore, periprocedural statin therapy is also recommended. (See 'Patient preparation' above and "Overview of carotid artery stenting", section on 'Summary and recommendations'.) For percutaneous CAS (transfemoral or other percutaneous approach), we use the following regimen, which is generally consistent with multidisciplinary guidelines: For those patients not on chronic aspirin therapy, we start aspirin (325 mg twice daily) at least 48 hours before the procedure, or, if within 48 hours of the procedure, we give a loading dose of aspirin 650 mg four or more hours before the procedure. For those patients not on chronic clopidogrel therapy, we start clopidogrel 75 mg twice daily at least 48 hours before the procedure, or if within 48 hours of the procedure, we give a loading dose of clopidogrel 450 mg four or more hours before the procedure. For those patients not on chronic statin therapy, we start atorvastatin 40 mg daily for seven days before the procedure or we give a loading dose of 80 mg 12 hours before the procedure. https://www.uptodate.com/contents/percutaneous-carotid-artery-stenting/print 13/24 7/5/23, 11:43 AM Percutaneous carotid artery stenting - UpToDate Following percutaneous access and sheath placement, the patient is systemically anticoagulated, typically using heparin. Whether to reverse heparin with protamine is left to the discretion of the operator and generally based on issues pertaining to the percutaneous access site. For those in whom a vascular closure device will not be used at a femoral access site, we suggest reversal of anticoagulation (Grade 2C). Reversal of anticoagulation reduces sheath dwell time and duration of bedrest. (See 'Anticoagulation' above.) Following the CAS procedure, DAPT with aspirin (325 mg once daily) plus clopidogrel (75 mg once daily) is continued for at least four weeks. For patients with a history of neck irradiation, we continue DAPT indefinitely. For all other patients, after clopidogrel is discontinued, we continue aspirin 325 mg daily indefinitely. (See "Overview of carotid artery stenting", section on 'Dual antiplatelet therapy'.) Several types of embolic protection devices (EPDs) are available and are intended to prevent embolic complications of angioplasty and stenting. Filter devices are used in most percutaneous CAS procedures. Although a benefit for EPDs has not been definitively established, many consider the use of an EPD to be standard of care. In the United States, the use of an EPD is mandatory for reimbursement for CAS. (See 'Embolic protection devices' above.) The most serious acute complication associated with CAS is stroke, which can occur due to thromboembolism, hypoperfusion, hyperperfusion syndrome, or hemorrhage. The overall stroke rate for TF-CAS is 3 to 4 percent and has steadily decreased with improvements in device technology and operator experience. Other complications associated with CAS include access-related issues (eg, hematoma, bleeding, pseudoaneurysm formation, and distal atheroembolization), myocardial infarction, contrast-related renal failure, restenosis of the target lesion, and carotid stent fracture. (See 'Complications' above and "Overview of carotid artery stenting", section on 'Complications'.) ACKNOWLEDGMENT The editorial staff at UpToDate acknowledges Ronald M Fairman, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES https://www.uptodate.com/contents/percutaneous-carotid-artery-stenting/print 14/24 7/5/23, 11:43 AM Percutaneous carotid artery stenting - UpToDate 1. Yadav JS, Roubin GS, Iyer S, et al. Elective stenting of the extracranial carotid arteries. Circulation 1997; 95:376. 2. Jim J, Sicard GA. Who is unfit for carotid endarterectomy? Perspect Vasc Surg Endovasc Ther 2010; 22:40. 3. Giri J, Kennedy KF, Weinberg I, et al. Comparative effectiveness of commonly used devices for carotid artery stenting: an NCDR Analysis (National Cardiovascular Data Registry). JACC Cardiovasc Interv 2014; 7:171. 4. Nikas DN, Kompara G, Reimers B. Carotid stents: which is the best option? J Cardiovasc Surg (Torino) 2011; 52:779. 5. White CJ. Carotid artery stenting. J Am Coll Cardiol 2014; 64:722. 6. Wissgott C, Brandt-Wunderlich C, Kopetsch C, et al. Initial Clinical Results and In Vitro Testing of the New CGuard MicroNet-Covered "One-Size-Fits-All" Carotid Stent. J Endovasc Ther 2019; 26:578. 7. Schofer J, Musia ek P, Bijuklic K, et al. A Prospective, Multicenter Study of a Novel Mesh- Covered Carotid Stent: The CGuard CARENET Trial (Carotid Embolic Protection Using MicroNet). JACC Cardiovasc Interv 2015; 8:1229. 8. Karpenko A, Bugurov S, Ignatenko P, et al. Randomized Controlled Trial of Conventional Versus MicroNet-Covered Stent in Carotid Artery Revascularization. JACC Cardiovasc Interv 2021; 14:2377. 9. Kouvelos GN, Patelis N, Antoniou GA, et al. Meta-analysis of the Effect of Stent Design on 30-Day Outcome After Carotid Artery Stenting. J Endovasc Ther 2015; 22:789. 10. M ller MD, Gregson J, McCabe DJH, et al. Stent Design, Restenosis and Recurrent Stroke After Carotid Artery Stenting in the International Carotid Stenting Study. Stroke 2019; 50:3013. 11. Jim J, Rubin BG, Landis GS, et al. Society for Vascular Surgery Vascular Registry evaluation of stent cell design on carotid artery stenting outcomes. J Vasc Surg 2011; 54:71. 12. Tadros RO, Spyris CT, Vouyouka AG, et al. Comparing the embolic potential of open and closed cell stents during carotid angioplasty and stenting. J Vasc Surg 2012; 56:89. 13. Schneider PA, Levy E, Bacharach JM, et al. A First-in-Human Evaluation of a Novel Mesh- Covered Stent for Treatment of Carotid Stenosis in Patients at High Risk for Endarterectomy:

renal, mesenteric, and peripheral atherosclerotic disease".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading https://www.uptodate.com/contents/percutaneous-carotid-artery-stenting/print 12/24 7/5/23, 11:43 AM Percutaneous carotid artery stenting - UpToDate level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Carotid artery disease (The Basics)") SUMMARY AND RECOMMENDATIONS Carotid revascularization to treat carotid atherosclerotic disease can be accomplished using open surgery (carotid endarterectomy) or using a carotid artery stent (CAS), with the most common CAS approach using a percutaneous approach. Transfemoral carotid artery stenting (TF-CAS) involves accessing the femoral artery percutaneously to place the necessary guidewires and sheaths, traversing the aortic arch to gain access to the carotid artery, deployment of an embolic protection device, and subsequently dilation of the artery and placement of the stent. (See 'Introduction' above and 'Carotid revascularization' above.) For patients in whom CAS is scheduled or anticipated, dual antiplatelet therapy (DAPT) using aspirin and clopidogrel is recommended. Furthermore, periprocedural statin therapy is also recommended. (See 'Patient preparation' above and "Overview of carotid artery stenting", section on 'Summary and recommendations'.) For percutaneous CAS (transfemoral or other percutaneous approach), we use the following regimen, which is generally consistent with multidisciplinary guidelines: For those patients not on chronic aspirin therapy, we start aspirin (325 mg twice daily) at least 48 hours before the procedure, or, if within 48 hours of the procedure, we give a loading dose of aspirin 650 mg four or more hours before the procedure. For those patients not on chronic clopidogrel therapy, we start clopidogrel 75 mg twice daily at least 48 hours before the procedure, or if within 48 hours of the procedure, we give a loading dose of clopidogrel 450 mg four or more hours before the procedure. For those patients not on chronic statin therapy, we start atorvastatin 40 mg daily for seven days before the procedure or we give a loading dose of 80 mg 12 hours before the procedure. https://www.uptodate.com/contents/percutaneous-carotid-artery-stenting/print 13/24 7/5/23, 11:43 AM Percutaneous carotid artery stenting - UpToDate Following percutaneous access and sheath placement, the patient is systemically anticoagulated, typically using heparin. Whether to reverse heparin with protamine is left to the discretion of the operator and generally based on issues pertaining to the percutaneous access site. For those in whom a vascular closure device will not be used at a femoral access site, we suggest reversal of anticoagulation (Grade 2C). Reversal of anticoagulation reduces sheath dwell time and duration of bedrest. (See 'Anticoagulation' above.) Following the CAS procedure, DAPT with aspirin (325 mg once daily) plus clopidogrel (75 mg once daily) is continued for at least four weeks. For patients with a history of neck irradiation, we continue DAPT indefinitely. For all other patients, after clopidogrel is discontinued, we continue aspirin 325 mg daily indefinitely. (See "Overview of carotid artery stenting", section on 'Dual antiplatelet therapy'.) Several types of embolic protection devices (EPDs) are available and are intended to prevent embolic complications of angioplasty and stenting. Filter devices are used in most percutaneous CAS procedures. Although a benefit for EPDs has not been definitively established, many consider the use of an EPD to be standard of care. In the United States, the use of an EPD is mandatory for reimbursement for CAS. (See 'Embolic protection devices' above.) The most serious acute complication associated with CAS is stroke, which can occur due to thromboembolism, hypoperfusion, hyperperfusion syndrome, or hemorrhage. The overall stroke rate for TF-CAS is 3 to 4 percent and has steadily decreased with improvements in device technology and operator experience. Other complications associated with CAS include access-related issues (eg, hematoma, bleeding, pseudoaneurysm formation, and distal atheroembolization), myocardial infarction, contrast-related renal failure, restenosis of the target lesion, and carotid stent fracture. (See 'Complications' above and "Overview of carotid artery stenting", section on 'Complications'.) ACKNOWLEDGMENT The editorial staff at UpToDate acknowledges Ronald M Fairman, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES https://www.uptodate.com/contents/percutaneous-carotid-artery-stenting/print 14/24 7/5/23, 11:43 AM Percutaneous carotid artery stenting - UpToDate 1. Yadav JS, Roubin GS, Iyer S, et al. Elective stenting of the extracranial carotid arteries. Circulation 1997; 95:376. 2. Jim J, Sicard GA. Who is unfit for carotid endarterectomy? Perspect Vasc Surg Endovasc Ther 2010; 22:40. 3. Giri J, Kennedy KF, Weinberg I, et al. Comparative effectiveness of commonly used devices for carotid artery stenting: an NCDR Analysis (National Cardiovascular Data Registry). JACC Cardiovasc Interv 2014; 7:171. 4. Nikas DN, Kompara G, Reimers B. Carotid stents: which is the best option? J Cardiovasc Surg (Torino) 2011; 52:779. 5. White CJ. Carotid artery stenting. J Am Coll Cardiol 2014; 64:722. 6. Wissgott C, Brandt-Wunderlich C, Kopetsch C, et al. Initial Clinical Results and In Vitro Testing of the New CGuard MicroNet-Covered "One-Size-Fits-All" Carotid Stent. J Endovasc Ther 2019; 26:578. 7. Schofer J, Musia ek P, Bijuklic K, et al. A Prospective, Multicenter Study of a Novel Mesh- Covered Carotid Stent: The CGuard CARENET Trial (Carotid Embolic Protection Using MicroNet). JACC Cardiovasc Interv 2015; 8:1229. 8. Karpenko A, Bugurov S, Ignatenko P, et al. Randomized Controlled Trial of Conventional Versus MicroNet-Covered Stent in Carotid Artery Revascularization. JACC Cardiovasc Interv 2021; 14:2377. 9. Kouvelos GN, Patelis N, Antoniou GA, et al. Meta-analysis of the Effect of Stent Design on 30-Day Outcome After Carotid Artery Stenting. J Endovasc Ther 2015; 22:789. 10. M ller MD, Gregson J, McCabe DJH, et al. Stent Design, Restenosis and Recurrent Stroke After Carotid Artery Stenting in the International Carotid Stenting Study. Stroke 2019; 50:3013. 11. Jim J, Rubin BG, Landis GS, et al. Society for Vascular Surgery Vascular Registry evaluation of stent cell design on carotid artery stenting outcomes. J Vasc Surg 2011; 54:71. 12. Tadros RO, Spyris CT, Vouyouka AG, et al. Comparing the embolic potential of open and closed cell stents during carotid angioplasty and stenting. J Vasc Surg 2012; 56:89. 13. Schneider PA, Levy E, Bacharach JM, et al. A First-in-Human Evaluation of a Novel Mesh- Covered Stent for Treatment of Carotid Stenosis in Patients at High Risk for Endarterectomy: 30-Day Results of the SCAFFOLD Trial. JACC Cardiovasc Interv 2018; 11:2396. 14. Stabile E, de Donato G, Musialek P, et al. Use of Dual-Layered Stents in Endovascular Treatment of Extracranial Stenosis of the Internal Carotid Artery: Results of a Patient-Based Meta-Analysis of 4 Clinical Studies. JACC Cardiovasc Interv 2018; 11:2405. https://www.uptodate.com/contents/percutaneous-carotid-artery-stenting/print 15/24 7/5/23, 11:43 AM Percutaneous carotid artery stenting - UpToDate 15. Mousa AY, Campbell JE, Aburahma AF, Bates MC. Current update of cerebral embolic protection devices. J Vasc Surg 2012; 56:1429. 16. Bonati LH, Lyrer P, Ederle J, et al. Percutaneous transluminal balloon angioplasty and stenting for carotid artery stenosis. Cochrane Database Syst Rev 2012; :CD000515. 17. Bornak A, Milner R. Current debate on the role of embolic protection devices. Vasc Endovascular Surg 2012; 46:441. 18. Bijuklic K, Wandler A, Hazizi F, Schofer J. The PROFI study (Prevention of Cerebral Embolization by Proximal Balloon Occlusion Compared to Filter Protection During Carotid Artery Stenting): a prospective randomized trial. J Am Coll Cardiol 2012; 59:1383. 19. Matsumura JS, Gray W, Chaturvedi S, et al. Results of carotid artery stenting with distal embolic protection with improved systems: Protected Carotid Artery Stenting in Patients at High Risk for Carotid Endarterectomy (PROTECT) trial. J Vasc Surg 2012; 55:968. 20. Macdonald S. The evidence for cerebral protection: an analysis and summary of the literature. Eur J Radiol 2006; 60:20. 21. Garg N, Karagiorgos N, Pisimisis GT, et al. Cerebral protection devices reduce periprocedural strokes during carotid angioplasty and stenting: a systematic review of the current literature. J Endovasc Ther 2009; 16:412. 22. Macdonald S. New embolic protection devices: a review. J Cardiovasc Surg (Torino) 2011; 52:821. 23. Macdonald S. Embolic protection in carotid artery stenting: "a no-brainer"? J Cardiovasc Surg (Torino) 2010; 51:861. 24. Liang P, Soden P, Wyers MC, et al. The role of transfemoral carotid artery stenting with proximal balloon occlusion embolic protection in the contemporary endovascular management of carotid artery stenosis. J Vasc Surg 2020; 72:1701. 25. Stabile E, Sannino A, Schiattarella GG, et al. Cerebral embolic lesions detected with diffusion- weighted magnetic resonance imaging following carotid artery stenting: a meta-analysis of 8 studies comparing filter cerebral protection and proximal balloon occlusion. JACC Cardiovasc Interv 2014; 7:1177. 26. Brown MM. Carotid artery stenting evolution of a technique to rival carotid endarterectomy. Am J Med 2004; 116:273. 27. Scheinert D, Reimers B, Cremonesi A, et al. Independent Modular Filter for Embolic Protection in Carotid Stenting. Circ Cardiovasc Interv 2017; 10. 28. Bersin RM, Stabile E, Ansel GM, et al. A meta-analysis of proximal occlusion device outcomes in carotid artery stenting. Catheter Cardiovasc Interv 2012; 80:1072. https://www.uptodate.com/contents/percutaneous-carotid-artery-stenting/print 16/24 7/5/23, 11:43 AM Percutaneous carotid artery stenting - UpToDate 29. Alpaslan A, Wintermark M, Pint r L, et al. Transcarotid Artery Revascularization With Flow Reversal. J Endovasc Ther 2017; 24:265. 30. Ansel GM, Hopkins LN, Jaff MR, et al. Safety and effectiveness of the INVATEC MO.MA proximal cerebral protection device during carotid artery stenting: results from the ARMOUR pivotal trial. Catheter Cardiovasc Interv 2010; 76:1. 31. Clair DG, Hopkins LN, Mehta M, et al. Neuroprotection during carotid artery stenting using the GORE flow reversal system: 30-day outcomes in the EMPiRE Clinical Study. Catheter Cardiovasc Interv 2011; 77:420. 32. Giugliano G, Stabile E, Biamino G, et al. Predictors of carotid occlusion intolerance during proximal protected carotid artery stenting. JACC Cardiovasc Interv 2014; 7:1237. 33. Kwolek CJ, Jaff MR, Leal JI, et al. Results of the ROADSTER multicenter trial of transcarotid stenting with dynamic flow reversal. J Vasc Surg 2015; 62:1227. 34. SPACE Collaborative Group, Ringleb PA, Allenberg J, et al. 30 day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: a randomised non-inferiority trial. Lancet 2006; 368:1239. 35. Mas JL, Chatellier G, Beyssen B, et al. Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis. N Engl J Med 2006; 355:1660. 36. Bonati LH, Jongen LM, Haller S, et al. New ischaemic brain lesions on MRI after stenting or endarterectomy for symptomatic carotid stenosis: a substudy of the International Carotid Stenting Study (ICSS). Lancet Neurol 2010; 9:353. 37. Ederle J, Featherstone RL, Brown MM. Percutaneous transluminal angioplasty and stenting for carotid artery stenosis. Cochrane Database Syst Rev 2007; :CD000515. 38. Mas JL, Trinquart L, Leys D, et al. Endarterectomy Versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) trial: results up to 4 years from a randomised, multicentre trial. Lancet Neurol 2008; 7:885. 39. T bler T, Schl ter M, Dirsch O, et al. Balloon-protected carotid artery stenting: relationship of periprocedural neurological complications with the size of particulate debris. Circulation 2001; 104:2791. 40. Vos JA, van den Berg JC, Ernst SM, et al. Carotid angioplasty and stent placement: comparison of transcranial Doppler US data and clinical outcome with and without filtering cerebral protection devices in 509 patients. Radiology 2005; 234:493. 41. Roubin GS, New G, Iyer SS, et al. Immediate and late clinical outcomes of carotid artery stenting in patients with symptomatic and asymptomatic carotid artery stenosis: a 5-year prospective analysis. Circulation 2001; 103:532. https://www.uptodate.com/contents/percutaneous-carotid-artery-stenting/print 17/24 7/5/23, 11:43 AM Percutaneous carotid artery stenting - UpToDate 42. Badheka AO, Chothani A, Panaich SS, et al. Impact of symptoms, gender, co-morbidities, and operator volume on outcome of carotid artery stenting (from the Nationwide Inpatient Sample [2006 to 2010]). Am J Cardiol 2014; 114:933. 43. Gensicke H, van der Worp HB, Nederkoorn PJ, et al. Ischemic brain lesions after carotid artery stenting increase future cerebrovascular risk. J Am Coll Cardiol 2015; 65:521. 44. Rapp JH, Wakil L, Sawhney R, et al. Subclinical embolization after carotid artery stenting: new lesions on diffusion-weighted magnetic resonance imaging occur postprocedure. J Vasc Surg 2007; 45:867. 45. Castro-Afonso LH, Abud LG, Rolo JG, et al. Flow reversal versus filter protection: a pilot carotid artery stenting randomized trial. Circ Cardiovasc Interv 2013; 6:552. 46. Schnaudigel S, Gr schel K, Pilgram SM, Kastrup A. New brain lesions after carotid stenting versus carotid endarterectomy: a systematic review of the literature. Stroke 2008; 39:1911. 47. International Carotid Stenting Study investigators, Ederle J, Dobson J, et al. Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial. Lancet 2010; 375:985. 48. Bonati LH, Gregson J, Dobson J, et al. Restenosis and risk of stroke after stenting or endarterectomy for symptomatic carotid stenosis in the International Carotid Stenting Study (ICSS): secondary analysis of a randomised trial. Lancet Neurol 2018; 17:587. 49. Goode SD, Hoggard N, Macdonald S, et al. Assessment of reverse flow as a means of cerebral protection during carotid artery stent placement with diffusion-weighted and transcranial Doppler imaging. J Vasc Interv Radiol 2013; 24:528. 50. White CJ, Ramee SR, Collins TJ, et al. Carotid stents to prevent stroke: a nonsurgical option. Ochsner J 2003; 5:18. 51. Johansson E, Fox AJ. Carotid Near-Occlusion: A Comprehensive Review, Part 1 Definition, Terminology, and Diagnosis. AJNR Am J Neuroradiol 2016; 37:2. 52. Johansson E, Fox AJ. Carotid Near-Occlusion: A Comprehensive Review, Part 2 Prognosis and Treatment, Pathophysiology, Confusions, and Areas for Improvement. AJNR Am J Neuroradiol 2016; 37:200. 53. Brott TG, Hobson RW 2nd, Howard G, et al. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 2010; 363:11. 54. Liapis CD, Bell PR, Mikhailidis D, et al. ESVS guidelines. Invasive treatment for carotid stenosis: indications, techniques. Eur J Vasc Endovasc Surg 2009; 37:1. https://www.uptodate.com/contents/percutaneous-carotid-artery-stenting/print 18/24 7/5/23, 11:43 AM Percutaneous carotid artery stenting - UpToDate 55. Brott TG, Halperin JL, Abbara S, et al. 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease. Stroke 2011; 42:e464. 56. Pinter L, Ribo M, Loh C, et al. Safety and feasibility of a novel transcervical access neuroprotection system for carotid artery stenting in the PROOF Study. J Vasc Surg 2011; 54:1317. 57. Alvarez B, Matas M, Ribo M, et al. Transcervical carotid stenting with flow reversal is a safe technique for high-risk patients older than 70 years. J Vasc Surg 2012; 55:978. 58. Leal I, Orgaz A, Flores , et al. A diffusion-weighted magnetic resonance imaging-based study of transcervical carotid stenting with flow reversal versus transfemoral filter protection. J Vasc Surg 2012; 56:1585. 59. Sfyroeras GS, Moulakakis KG, Markatis F, et al. Results of carotid artery stenting with transcervical access. J Vasc Surg 2013; 58:1402. 60. Matsuda Y, Terada T, Masuo O, et al. The clinical results of transcervical carotid artery stenting and frequency chosen as the approach route of carotid artery stenting in 1,067 consecutive cases. Acta Neurochir (Wien) 2013; 155:1575. 61. Ortega G, lvarez B, Quintana M, et al. Cognitive improvement in patients with severe carotid artery stenosis after transcervical stenting with protective flow reversal. Cerebrovasc Dis 2013; 35:124. 62. Christopoulos D, Philippov E. The results of a simplified technique for safe carotid stenting in the elderly. J Vasc Surg 2011; 54:1637. 63. Palombo G, Stella N, Faraglia V, et al. Cervical access for filter-protected carotid artery stenting: a useful tool to reduce cerebral embolisation. Eur J Vasc Endovasc Surg 2010; 39:252. 64. Christopoulos D, Philippov E, Kallintzi M. Safe carotid artery angioplasty and stenting in patients unsuitable for transfemoral approach. Int Angiol 2010; 29:37. 65. Flores A, Doblas M, Criado E. Transcervical carotid artery stenting with flow reversal eliminates emboli during stenting: why does it work and what are the advantages with this approach. J Cardiovasc Surg (Torino) 2009; 50:745. 66. Faraglia V, Palombo G, Stella N, et al. Cerebral embolization during transcervical carotid stenting with flow reversal: a diffusion-weighted magnetic resonance study. Ann Vasc Surg 2009; 23:429. https://www.uptodate.com/contents/percutaneous-carotid-artery-stenting/print 19/24 7/5/23, 11:43 AM Percutaneous carotid artery stenting - UpToDate 67. Criado E, Fontcuberta J, Orgaz A, et al. Transcervical carotid stenting with carotid artery flow reversal: 3-year follow-up of 103 stents. J Vasc Surg 2007; 46:864. 68. Matas M, Alvarez B, Ribo M, et al. Transcervical carotid stenting with flow reversal protection: experience in high-risk patients. J Vasc Surg 2007; 46:49. 69. Alexandrescu V, Ngongang C, Proumen J, et al. Filter-protected carotid stenting via a minimal cervical access with transitory aspirated reversed flow during initial passage of the target lesion. J Endovasc Ther 2006; 13:196. 70. Lin JC, Kolvenbach RR, Pinter L. Protected carotid artery stenting and angioplasty via transfemoral versus transcervical approaches. Vasc Endovascular Surg 2005; 39:499. 71. Pipinos II, Johanning JM, Pham CN, et al. Transcervical approach with protective flow reversal for carotid angioplasty and stenting. J Endovasc Ther 2005; 12:446. 72. Lo CH, Doblas M, Criado E. Advantages and indications of transcervical carotid artery stenting with carotid flow reversal. J Cardiovasc Surg (Torino) 2005; 46:229. 73. Criado E, Doblas M, Fontcuberta J, et al. Transcervical carotid stenting with internal carotid artery flow reversal: feasibility and preliminary results. J Vasc Surg 2004; 40:476. 74. Chang DW, Schubart PJ, Veith FJ, Zarins CK. A new approach to carotid angioplasty and stenting with transcervical occlusion and protective shunting: Why it may be a better carotid artery intervention. J Vasc Surg 2004; 39:994. 75. Kedev S, Petkoska D, Zafirovska B, et al. Safety of Slender 5Fr Transradial Approach for Carotid Artery Stenting With a Novel Nitinol Double-Layer Micromesh Stent. Am J Cardiol 2015; 116:977. 76. Lorenzoni R, Roffi M. Transradial access for peripheral and cerebrovascular interventions. J Invasive Cardiol 2013; 25:529. 77. Etxegoien N, Rhyne D, Kedev S, et al. The transradial approach for carotid artery stenting. Catheter Cardiovasc Interv 2012; 80:1081. 78. Ruzsa Z, Nemes B, Pint r L, et al. A randomised comparison of transradial and transfemoral approach for carotid artery stenting: RADCAR (RADial access for CARotid artery stenting) study. EuroIntervention 2014; 10:381. 79. Stabile E, Sorropago G, Tesorio T, et al. Heparin versus bivalirudin for carotid artery stenting using proximal endovascular clamping for neuroprotection: results from a prospective randomized study. J Vasc Surg 2010; 52:1505. 80. Cogar BD, Wayangankar SA, Abu-Fadel M, et al. Clinical safety of bivalirudin in patients undergoing carotid stenting. J Invasive Cardiol 2012; 24:202. https://www.uptodate.com/contents/percutaneous-carotid-artery-stenting/print 20/24 7/5/23, 11:43 AM Percutaneous carotid artery stenting - UpToDate 81. Omran J, Abdullah O, Abu-Fadel M, et al. Hemorrhagic and ischemic outcomes of Heparin vs. Bivalirudin in carotid artery stenting: A meta-analysis of studies. Catheter Cardiovasc Interv 2017; 89:746. 82. Wayangankar SA, Abu-Fadel MS, Aronow HD, et al. Hemorrhagic and ischemic outcomes after bivalirudin versus unfractionated heparin during carotid artery stenting: a propensity score analysis from the NCDR. Circ Cardiovasc Interv 2013; 6:131. 83. Liang P, Motaganahalli R, Swerdlow NJ, et al. Protamine use in transfemoral carotid artery stenting is not associated with an increased risk of thromboembolic events. J Vasc Surg 2021; 73:142. 84. Zahn R, Mark B, Niedermaier N, et al. Embolic protection devices for carotid artery stenting: better results than stenting without protection? Eur Heart J 2004; 25:1550. 85. Endovascular versus surgical treatment in patients with carotid stenosis in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS): a randomised trial. Lancet 2001; 357:1729. 86. Spacek M, Zimolova P, Veselka J. Carotid artery stenting without post-dilation. J Interv Cardiol 2012; 25:190. 87. cal L, K p A, elik M, et al. What should be the Optimal Carotid Stent Opening Rate Without Post-Dilation? J Stroke Cerebrovasc Dis 2020; 29:105155. 88. Ogata A, Sonobe M, Kato N, et al. Carotid artery stenting without post-stenting balloon dilatation. J Neurointerv Surg 2014; 6:517. 89. Malas MB, Dakour-Aridi H, Wang GJ, et al. Transcarotid artery revascularization versus transfemoral carotid artery stenting in the Society for Vascular Surgery Vascular Quality Initiative. J Vasc Surg 2019; 69:92. 90. Jackson BM, English SJ, Fairman RM, et al. Carotid artery stenting: identification of risk factors for poor outcomes. J Vasc Surg 2008; 48:74. 91. Taha MM, Sakaida H, Asakura F, et al. Access site complications with carotid angioplasty and stenting. Surg Neurol 2007; 68:431. 92. Schermerhorn ML, Liang P, Eldrup-Jorgensen J, et al. Association of Transcarotid Artery Revascularization vs Transfemoral Carotid Artery Stenting With Stroke or Death Among Patients With Carotid Artery Stenosis. JAMA 2019; 322:2313. Topic 127412 Version 6.0 https://www.uptodate.com/contents/percutaneous-carotid-artery-stenting/print 21/24 7/5/23, 11:43 AM Percutaneous carotid artery stenting - UpToDate GRAPHICS Angiographic criteria for internal carotid near-occlusion The figures illustrate the four criteria for internal carotid near-occlusion on conventional angiography. In all figures, the intravenous contrast (gray color) is shown emanating from a catheter positioned in the CCA. (A) Delayed filling (B) Evidence of intracranial collaterals when the contralateral side is examined (C) Ipsilateral distal ICA diameter less than the contralateral distal ICA diameter (D) Ipsilateral distal ICA diameter equal to or less than the ipsilateral ECA diameter CCA: common carotid artery; ICA: internal carotid artery; ECA: external carotid artery. Modi ed with permission of the American Society of Neuroradiology, from: Johansson E, Fox AJ. Carotid Near- Occlusion: A Comprehensive Review, Part 1 De nition, Terminology, and Diagnosis. AJNR Am J Neuroradiol 2016; https://www.uptodate.com/contents/percutaneous-carotid-artery-stenting/print 22/24 7/5/23, 11:43 AM Percutaneous carotid artery stenting - UpToDate 37:2; permission conveyed through Copyright Clearance Center, Inc. Copyright 2016. Graphic 129242 Version 1.0 https://www.uptodate.com/contents/percutaneous-carotid-artery-stenting/print 23/24 7/5/23, 11:43 AM Percutaneous carotid artery stenting - UpToDate Contributor Disclosures Jeffrey Jim, MD, MPHS, FACS Consultant/Advisory Boards: Endospan [Aortic interventions]; Medtronic [Aortic interventions]; Silk Road Medical [Carotid stent]. All of the relevant financial relationships listed have been mitigated. John F Eidt, MD Grant/Research/Clinical Trial Support: Syntactx [Clinical events, data/safety monitoring for medical device trials]. All of the relevant financial relationships listed have been mitigated. Joseph L Mills, Sr, MD No relevant financial relationship(s) with ineligible companies to disclose. Kathryn A Collins, MD, PhD, FACS No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/percutaneous-carotid-artery-stenting/print 24/24

7/5/23, 11:43 AM Screening for asymptomatic carotid artery stenosis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Screening for asymptomatic carotid artery stenosis : Mark O McCarron, MD, FRCP, Larry B Goldstein, MD, FAAN, FANA, FAHA, David B Matchar, MD : Scott E Kasner, MD, Joann G Elmore, MD, MPH : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 01, 2023. INTRODUCTION Progression of atheromatous plaque at the cervical carotid artery bifurcation results in luminal narrowing, often accompanied by ulceration. This process can be asymptomatic but may lead to ischemic stroke or transient ischemic attack from embolization, thrombosis, or hemodynamic compromise. This topic will review the role of screening for asymptomatic carotid atherosclerotic disease. The management of asymptomatic carotid disease is discussed separately. (See "Management of asymptomatic extracranial carotid atherosclerotic disease".) Other aspects of carotid occlusive disease are reviewed elsewhere. (See "Evaluation of carotid artery stenosis" and "Management of symptomatic carotid atherosclerotic disease".) ASYMPTOMATIC CAROTID DISEASE Definitions Asymptomatic cervical carotid atherosclerotic disease refers to the presence of atherosclerotic narrowing of one or both of the extracranial internal carotid arteries in individuals without a history of carotid territory ischemic stroke or transient ischemic attack (TIA) [1-3]. Carotid stenosis is also often considered asymptomatic if the patient has not had an ipsilateral carotid territory ischemic stroke or TIA within the prior six months [4]. Symptomatic carotid disease is defined as focal neurologic symptoms (eg, amaurosis fugax, contralateral weakness or numbness of an extremity or the face, dysarthria or aphasia, spatial https://www.uptodate.com/contents/screening-for-asymptomatic-carotid-artery-stenosis/print 1/13 7/5/23, 11:43 AM Screening for asymptomatic carotid artery stenosis - UpToDate neglect, homonymous visual loss) in the distribution of a carotid artery with a significant stenosis. Importantly, nonspecific neurologic symptoms (eg, dizziness, lightheadedness) are not indicative of carotid stenosis. Therefore, patients with these symptoms in isolation should be considered as asymptomatic with regard to carotid disease even if they are found to have carotid artery stenosis. (See "Management of symptomatic carotid atherosclerotic disease", section on 'Definition of symptomatic disease'.) Prevalence The prevalence of asymptomatic cervical carotid stenosis is low in the general population, but increases with age, which is the most important risk factor. In a 2010 meta-analysis of four population-based studies (including the CHS) with individual data from over 23,000 participants, the prevalence estimates of asymptomatic cervical carotid stenosis varied according to age [5]. The prevalence of severe stenosis (defined as 70 percent of the lumen diameter) was quite low, ranging from <1 percent for men and women age <70 year up to approximately 3 percent for men and 1 percent for women age 80 years ( figure 1). The prevalence of at least moderate stenosis (defined as 50 percent of the lumen diameter) was somewhat higher. A 2020 meta-analysis of worldwide population-based studies identified 59 eligible studies and found that the global prevalence of 50 percent stenosis of the extracranial carotid artery was 1.5 percent (95% CI 1.1-2.1), increased with age from 30 to 79 years, and was higher in men than women [6]. A Chinese national cross sectional study not included in the 2020 meta-analysis reported that among people 40 years of age, the prevalence of a >50 percent carotid artery stenosis was 0.4 percent (95% CI 0.3-0.4%) [7]. Stroke risk The most feared consequence of carotid atherosclerosis is ischemic stroke. The estimated risk of ipsilateral stroke in prospective studies that followed patients with asymptomatic cervical internal carotid artery atherosclerosis (stenosis 50 percent) receiving optimal medical management is 1 percent annually, as discussed separately (see "Management of asymptomatic extracranial carotid atherosclerotic disease", section on 'Risk of stroke and cardiovascular events'). The risk of stroke may be higher in individuals with severe carotid artery stenosis (70 to 99 percent) compared with individuals with moderate (50 to 69 percent) carotid artery stenosis [8]. However, in a retrospective study of a community-based cohort of patients with asymptomatic severe (70 to 99 percent) carotid stenosis diagnosed between 2008 and 2012 who did not undergo carotid revascularization, the estimated annual rate of ipsilateral carotid- related acute ischemic stroke was 0.9 percent [9]. https://www.uptodate.com/contents/screening-for-asymptomatic-carotid-artery-stenosis/print 2/13 7/5/23, 11:43 AM Screening for asymptomatic carotid artery stenosis - UpToDate Asymptomatic carotid atherosclerosis is also a marker of increased risk for myocardial infarction and vascular death. Thus, asymptomatic carotid atherosclerosis is considered a risk equivalent for coronary heart disease. (See "Overview of established risk factors for cardiovascular disease", section on 'Noncoronary atherosclerotic disease'.) Therapeutic options All patients with carotid atherosclerotic disease should undergo intensive medical therapy, which includes several strategies to reduce their cardiovascular risk. Periodic clinical follow-up to evaluate compliance with medical therapies and to evaluate for symptoms and signs of TIA or stroke is also important. Medical management and the role of carotid revascularization with endarterectomy or stenting is reviewed in detail separately. (See "Management of asymptomatic extracranial carotid atherosclerotic disease".) SCREENING Our approach Consistent with national guidelines (see 'Recommendations of others' below), we suggest not screening asymptomatic individuals for carotid artery stenosis with vascular imaging tests. Although there have been no randomized controlled trials evaluating the utility of screening for carotid artery stenosis, general screening for carotid stenosis in asymptomatic individuals does not appear to be warranted based upon the following observations [10-12]: The prevalence of asymptomatic carotid stenosis in the population is low; for severe ( 70 percent) carotid stenosis, the prevalence increases with age from approximately 0 to 3 percent. (See 'Prevalence' above.) The annual risk of ipsilateral stroke in patients with asymptomatic carotid artery stenosis is relatively low ( 1 percent annually). (See 'Stroke risk' above.) There are no validated, reliable clinical characteristics or markers that identify a subset of asymptomatic individuals likely to have carotid stenosis who also would benefit from carotid revascularization. The routine use of duplex ultrasonography to detect asymptomatic carotid stenosis, a low- prevalence condition found in approximately 1 percent of the general population, would result in many more false-positive results than true-positive results, which in turn could lead to many unnecessary interventions, including additional testing and carotid revascularization, with its attendant morbidity and mortality [13,14]. As shown in data from large administrative databases and surgical registries, both carotid endarterectomy and carotid stenting for asymptomatic carotid stenosis are associated with an increased 30-day risk of stroke and death. These risks are variable between surgeons and centers, but are in https://www.uptodate.com/contents/screening-for-asymptomatic-carotid-artery-stenosis/print 3/13 7/5/23, 11:43 AM Screening for asymptomatic carotid artery stenosis - UpToDate the range of 1.5 to 3.5 percent for carotid endarterectomy and 2.6 to 5.1 percent for carotid artery stenting [15]. Complication rates may be higher in low-volume settings. For patients with asymptomatic carotid stenosis, the absolute reduction in stroke risk with carotid endarterectomy was small when compared with the now-outdated medical treatment employed in the randomized trials of the time (2004 and earlier). This small benefit of revascularization may have been reduced or eliminated with subsequent advances in medical therapy. (See "Management of asymptomatic extracranial carotid atherosclerotic disease", section on 'Intensive medical therapy and follow-up'.) Recommendations of others As already discussed (see 'Our approach' above), we suggest not screening asymptomatic individuals for carotid artery stenosis with vascular imaging tests. Our recommendation is in general agreement with most national and society guidelines, though there are some differences among them: The 2021 United States Preventive Services Task Force (USPSTF) statement, reaffirming its 2014 position [16], recommends against screening for asymptomatic carotid artery stenosis in the general population [17,18]. The 2014 guidelines for the primary prevention of stroke from the American Heart Association/American Stroke Association indicate that screening low-risk populations for asymptomatic carotid artery stenosis is not recommended [19]. Joint 2011 guidelines from multiple US societies (including the American College of Cardiology, American Heart Association, American Stroke Association, American College of Radiology, and the Society for Vascular Surgery) advise that carotid duplex ultrasonography "is not recommended for routine screening of asymptomatic patients who have no clinical manifestations of or risk factors for atherosclerosis" [20]. However, they note that it is reasonable to screen (with duplex ultrasonography) asymptomatic individuals who have a carotid bruit, and that duplex ultrasonography screening of the carotid arteries "may be considered" for patients who have symptomatic atherosclerotic disease in another vascular bed (ie, peripheral arterial disease, coronary disease, or aortic aneurysm), or have two or more risk factors for atherosclerotic disease. Benefits and harms of screening The potential benefit of carotid screening depends on identifying people with asymptomatic carotid stenosis whose stroke risk would be reduced with carotid revascularization or more intensive medical treatment [10]. The potential harms associated with screening include risks associated with the screening procedure itself and risks associated with carotid revascularization or other interventions [21]. The risks of screening studies also include false positive findings and the need for confirmatory testing. The reliability https://www.uptodate.com/contents/screening-for-asymptomatic-carotid-artery-stenosis/print 4/13 7/5/23, 11:43 AM Screening for asymptomatic carotid artery stenosis - UpToDate of carotid duplex screening is variable among laboratories and is operator-dependent [22]. False-positive tests cause patient anxiety and the potential for additional testing and unnecessary surgical procedures. Carotid tests In the absence of symptoms, screening patients for carotid artery stenosis has not been shown to be effective at a population level. As noted above, we suggest not screening asymptomatic individuals for carotid artery stenosis with vascular imaging tests (see 'Our approach' above). Screening studies for carotid artery stenosis have used two approaches: noninvasive imaging of the carotid artery (eg, carotid duplex ultrasonography [DUS], magnetic resonance angiography [MRA], or computed tomography angiography [CTA]) and auscultation for carotid bruits during the physical examination. Cerebral angiography is the gold standard for imaging the carotid arteries, but it is not appropriate for screening because of its invasive nature, attendant risk of complications, high cost, and risk of morbidity. (See "Evaluation of carotid artery stenosis", section on 'Catheter cerebral angiography'.) Noninvasive imaging There are many noninvasive techniques available to identify and quantify carotid stenosis, including carotid DUS, MRA, contrast-enhanced MRA (CEMRA), and CTA. (See "Evaluation of carotid artery stenosis".) The accuracy of these noninvasive imaging modalities is not well-studied in subjects with asymptomatic carotid stenosis, but all have high sensitivities and specificities for diagnosing 70 to 99 percent internal carotid artery stenosis in patients with ipsilateral carotid territory ischemic symptoms. (See "Evaluation of carotid artery stenosis", section on 'Choice of imaging test'.) Carotid auscultation A carotid bruit is an audible sound arising from turbulent blood flow. Interobserver agreement in detecting a carotid bruit by physicians is relatively high (kappa = 0.67) [23]. A meta-analysis suggested that the presence of a carotid bruit increases the risk of cerebrovascular disease [24]. However, a bruit alone is a poor predictor of either underlying carotid stenosis or stroke risk in asymptomatic patients, as reflected by the following: In a meta-analysis of symptomatic and asymptomatic patients, the sensitivity and specificity of a carotid bruit for a 70 to 99 percent stenosis carotid lesion were 53 percent and 83 percent, respectively [25]. The Framingham Heart Study found that an asymptomatic carotid bruit was associated with an approximate doubling of the expected stroke risk [26]. However, the majority of strokes occurred in a vascular territory different from the carotid bruit, suggesting that a carotid bruit is a marker of generalized atherosclerosis. https://www.uptodate.com/contents/screening-for-asymptomatic-carotid-artery-stenosis/print 5/13 7/5/23, 11:43 AM Screening for asymptomatic carotid artery stenosis - UpToDate The Systolic Hypertension in the Elderly Program (SHEP) found that the presence of a carotid bruit was associated with a nonsignificant overall relative risk of 1.29 for stroke over a mean follow-up of 4.2 years [27]. A study of 241 older nursing home residents (mean age 86 years) found that 12 percent had asymptomatic carotid bruits [28]. The three-year cumulative incidence of cerebrovascular events was similar for patients with and without bruits (10 and 9 percent, respectively). Furthermore, baseline carotid bruits disappeared in 60 percent of surviving residents; loss of the bruit was not due to a cerebrovascular event. The poor predictive value of carotid bruits in asymptomatic individuals is in part related to the low prevalence of significant carotid stenosis in this population. Bruits are a better indicator of general atherosclerotic disease than of stroke risk [26,29-31]. The rate of myocardial infarction and cardiovascular death in patients with carotid bruits is twice that of patients without carotid bruits [31]. Patients with carotid artery disease are more likely to die from cardiovascular than cerebrovascular disease [32,33]. Nonetheless, risk stratification to identify patients at high risk for cardiovascular disease is most commonly based upon the Framingham risk score, the pooled cardiovascular risk calculator (calculator 1) [34,35], or similar risk assessment tools and not the presence or absence of carotid bruits. (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach" and "Screening for coronary heart disease".) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults" and "Society guideline links: Occlusive carotid, aortic, renal, mesenteric, and peripheral atherosclerotic disease".) SUMMARY AND RECOMMENDATIONS Definition of asymptomatic carotid stenosis Asymptomatic cervical carotid atherosclerotic disease refers to the presence of atherosclerotic narrowing of the extracranial internal carotid artery in individuals without a history of recent ipsilateral carotid territory ischemic stroke or transient ischemic attack (TIA). The cutoff used to define clinically significant carotid artery stenosis varies among studies, ranging from 50 to 70 percent stenosis. (See 'Definitions' above.) https://www.uptodate.com/contents/screening-for-asymptomatic-carotid-artery-stenosis/print 6/13 7/5/23, 11:43 AM Screening for asymptomatic carotid artery stenosis - UpToDate Prevalence The prevalence of asymptomatic carotid stenosis is low in the general population, but increases with age, which is the most important risk factor, and is higher in men than in women. (See 'Prevalence' above.) Risk of stroke with asymptomatic disease The most important consequence of carotid atherosclerosis is ischemic stroke; however, the estimated risk of stroke directly attributable to an identified stenosis in patients with asymptomatic carotid atherosclerosis (stenosis 50 percent) is 1 percent annually. (See 'Stroke risk' above.) Screening not recommended In the absence of a practical strategy for targeting screening to individuals with high risk, we suggest not screening asymptomatic individuals for carotid artery stenosis (Grade 2B). This recommendation is based on the low prevalence of asymptomatic carotid stenosis, the low annual risk for stroke in patients with asymptomatic carotid stenosis, and the high estimated rate of false-positive results with noninvasive screening that could lead to unnecessary additional testing or interventions. (See 'Our approach' above and 'Benefits and harms of screening' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Endarterectomy for asymptomatic carotid artery stenosis. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. JAMA 1995; 273:1421. 2. Chambers BR, Donnan GA. Carotid endarterectomy for asymptomatic carotid stenosis. Cochrane Database Syst Rev 2005; :CD001923. 3. Halliday A, Mansfield A, Marro J, et al. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomised controlled trial. Lancet 2004; 363:1491. 4. Moresoli P, Habib B, Reynier P, et al. 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Ro ckville (MD): Agency for Healthcare Research and Quality (US); 2014 Jul. (Evidence Syntheses, No. 111.) Available at: https://www.ncbi.nlm.nih.gov/books/NBK223225/ (Accessed on Febru ary 05, 2021). 14. Matchar DB, Pauker SG. Endarterectomy in carotid artery disease. A decision analysis. JAMA 1987; 258:793. 15. Guirguis-Blake JM, Webber EM, Coppola EL. Final evidence review: Screening for asymptoma tic carotid artery stenosis. Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services. AHRQ Publication No. 20-05268-EF-1. February 2021. Available at: https://uspreventiveservicestaskforce.org/uspstf/document/final-evidence-review/caroti d-artery-stenosis-screening (Accessed on February 05, 2021). 16. LeFevre ML, U.S. Preventive Services Task Force. Screening for asymptomatic carotid artery stenosis: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2014; 161:356. 17. US Preventive Services Task Force, Krist AH, Davidson KW, et al. Screening for Asymptomatic Carotid Artery Stenosis: US Preventive Services Task Force Recommendation Statement. JAMA 2021; 325:476. 18. Guirguis-Blake JM, Webber EM, Coppola EL. Screening for Asymptomatic Carotid Artery Stenosis in the General Population: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA 2021; 325:487. https://www.uptodate.com/contents/screening-for-asymptomatic-carotid-artery-stenosis/print 8/13 7/5/23, 11:43 AM Screening for asymptomatic carotid artery stenosis - UpToDate 19. Meschia JF, Bushnell C, Boden-Albala B, et al. Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014; 45:3754. 20. Brott TG, Halperin JL, Abbara S, et al. 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease. Stroke 2011; 42:e464. 21. Keyhani S, Cheng EM. Screening for Asymptomatic Carotid Artery Stenosis in Adult Patients: Unclear Benefit but Downstream Risks. JAMA Intern Med 2021; 181:585. 22. Jahromi AS, Cin CS, Liu Y, Clase CM. Sensitivity and specificity of color duplex ultrasound measurement in the estimation of internal carotid artery stenosis: a systematic review and meta-analysis. J Vasc Surg 2005; 41:962. 23. Chambers BR, Norris JW. Clinical significance of asymptomatic neck bruits. Neurology 1985; 35:742. 24. Pickett CA, Jackson JL, Hemann BA, Atwood JE. Carotid bruits and cerebrovascular disease risk: a meta-analysis. Stroke 2010; 41:2295. 25. McColgan P, Bentley P, McCarron M, Sharma P. Evaluation of the clinical utility of a carotid bruit. QJM 2012; 105:1171. 26. Wolf PA, Kannel WB, Sorlie P, McNamara P. Asymptomatic carotid bruit and risk of stroke. The Framingham study. JAMA 1981; 245:1442. 27. Shorr RI, Johnson KC, Wan JY, et al. The prognostic significance of asymptomatic carotid bruits in the elderly. J Gen Intern Med 1998; 13:86. 28. Van Ruiswyk J, Noble H, Sigmann P. The natural history of carotid bruits in elderly persons. Ann Intern Med 1990; 112:340. 29. Bogousslavsky J, Despland PA, Regli F. Asymptomatic tight stenosis of the internal carotid artery: long-term prognosis. Neurology 1986; 36:861. 30. Autret A, Pourcelot L, Saudeau D, et al. Stroke risk in patients with carotid stenosis. Lancet 1987; 1:888. 31. Pickett CA, Jackson JL, Hemann BA, Atwood JE. Carotid bruits as a prognostic indicator of cardiovascular death and myocardial infarction: a meta-analysis. Lancet 2008; 371:1587. 32. Chambers BR, Norris JW. Outcome in patients with asymptomatic neck bruits. N Engl J Med 1986; 315:860. 33. Heyman A, Wilkinson WE, Heyden S, et al. Risk of stroke in asymptomatic persons with cervical arterial bruits: a population study in Evans County, Georgia. N Engl J Med 1980; https://www.uptodate.com/contents/screening-for-asymptomatic-carotid-artery-stenosis/print 9/13 7/5/23, 11:43 AM Screening for asymptomatic carotid artery stenosis - UpToDate 302:838. 34. Muntner P, Colantonio LD, Cushman M, et al. Validation of the atherosclerotic cardiovascular disease Pooled Cohort risk equations. JAMA 2014; 311:1406. 35. Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014; 63:2935. Topic 7571 Version 36.0 https://www.uptodate.com/contents/screening-for-asymptomatic-carotid-artery-stenosis/print 10/13 7/5/23, 11:43 AM Screening for asymptomatic carotid artery stenosis - UpToDate GRAPHICS Prevalence of asymptomatic carotid artery stenosis in the general population Age- and sex-specific prevalence estimates of moderate (A) and severe (B) asymptomatic carotid artery stenosis in men and women. From: de Weerd M, Greving JP, Hedblad B, et al. Prevalence of asymptomatic carotid artery stenosis in the general population: an individual participant data meta-analysis. Stroke 2010; 41:1294. DOI: 10.1161/STROKEAHA.110.581058. Copyright 2010 American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. https://www.uptodate.com/contents/screening-for-asymptomatic-carotid-artery-stenosis/print 11/13 7/5/23, 11:43 AM Screening for asymptomatic carotid artery stenosis - UpToDate Graphic 103097 Version 5.0 https://www.uptodate.com/contents/screening-for-asymptomatic-carotid-artery-stenosis/print 12/13 7/5/23, 11:43 AM Screening for asymptomatic carotid artery stenosis - UpToDate Contributor Disclosures Mark O McCarron, MD, FRCP No relevant financial relationship(s) with ineligible companies to disclose. Larry B Goldstein, MD, FAAN, FANA, FAHA No relevant financial relationship(s) with ineligible companies to disclose. David B Matchar, MD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Joann G Elmore, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/screening-for-asymptomatic-carotid-artery-stenosis/print 13/13

7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Atrial fibrillation in adults: Selection of candidates for anticoagulation : Warren J Manning, MD, Daniel E Singer, MD, Gregory YH Lip, MD, FRCPE, FESC, FACC : Peter J Zimetbaum, MD, Scott E Kasner, MD, Bradley P Knight, MD, FACC : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Sep 23, 2022. INTRODUCTION Atrial fibrillation (AF) is a major cause of morbidity and mortality in adults. While ischemic stroke due to embolization of left atrial thrombi is the most frequent clinical manifestation of embolization, embolization to other locations in the systemic circulation (and in the pulmonary circulation from right atrial thrombi) also occurs, but is less commonly recognized. Stroke associated with AF tends to be more extensive/larger than stroke related to carotid artery disease. Chronic oral anticoagulation (OAC) is recommended to reduce the risk of thromboembolism for most patients with AF. However, such therapy is associated with an increased risk of bleeding, and recommendations for its use must take both benefit and risk into account through shared decision-making with the patient. (See "Stroke in patients with atrial fibrillation".) This topic will focus on identifying which patients with AF require long-term/chronic OAC with either vitamin K antagonist (VKA; eg, warfarin) or direct oral anticoagulants (DOAC; also referred to as non-vitamin K oral anticoagulants [NOAC]). The discussion here excludes patients with 2 rheumatic mitral stenosis that is severe or clinically significant (mitral valve area 1.5 cm ), a bioprosthetic valve (surgical or bioprosthetic) within the first three to six months after implantation, or a mechanical heart valve. Management for patients with these valve conditions is briefly discussed in a section below that provides links to related topics. (See 'Patients with valvular heart disease' below.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 1/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Other potentially relevant topics to the reader include: Choice of OAC for AF (see "Atrial fibrillation in adults: Use of oral anticoagulants") (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) (See "Stroke in patients with atrial fibrillation".) (See "Atrial fibrillation: Left atrial appendage occlusion".) (Related Pathway(s): Atrial fibrillation: Anticoagulation for adults with atrial fibrillation.) APPROACH TO DECIDING WHETHER TO ANTICOAGULATE Decision-making based upon risk assessment A first step in deciding which patients with AF should receive long-term oral anticoagulation (OAC) is to assess the individual patient s risks of thromboembolism and bleeding along with patient preferences. Long-term anticoagulation lowers the risk of clinical embolization in patients with AF, but its use is associated with an increased risk of bleeding. The benefits and risks of OAC with respect to reduction in risk of stroke and increment in risk of bleeding must be carefully considered and discussed with each patient. The greater the estimated reduction in absolute stroke risk compared with the increase in absolute risk of life- threatening or severely debilitating bleeding (such as intracranial hemorrhage), the more likely a patient is to benefit from long-term OAC. The benefit generally outweighs the risk for all but those with the lowest risk of thromboembolism. In cases of more balanced stroke reduction and bleeding risks, OAC is less likely to provide a net benefit. Risk scores are commonly used to assess thromboembolic and bleeding risks, although these tools are subject to a number of limitations. (See 'CHA2DS2-VASc score' below and 'Bleeding risk' below.) (Related Pathway(s): Atrial fibrillation: Anticoagulation for adults with atrial fibrillation.) Our approach to deciding whether to prescribe anticoagulant therapy for patients with AF (without severe or clinically significant rheumatic mitral stenosis [mitral valve area 1.5 2 cm ], a bioprosthetic valve [surgical or bioprosthetic] within the first three to six months after implantation, or a mechanical valve) is as follows: For a CHA DS -VASc score 2 in males or 3 in females (calculator 1) ( table 1), we 2 2 recommend chronic OAC. For a CHA DS -VASc score of 1 in males and 2 in females (calculator 1) ( table 1), the 2 2 specific nonsex risk factor present and the documented burden of AF influences decision making: https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 2/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate For patients with CHA DS -VASc score of 1 in males and 2 in females based on age 2 2 65 to 74 years, we recommend chronic OAC. Age 65 to 74 years is a stronger risk factor than the other factors conferring one CHA DS -VASc score point [1]. 2 2 For patients with other risk factors, the decision to anticoagulate is based upon the specific nonsex risk factor and the burden of AF. For patients with very low burden of AF (eg, AF that is well documented as limited to an isolated episode that may have been due to a reversible cause such as recent surgery, heavy alcohol ingestion, or sleep deprivation), it may be reasonable to forgo chronic OAC and institute close surveillance for recurrent AF, although it may not be possible to reliably estimate AF burden from surveying symptoms or infrequent monitoring. The frequency and duration of AF episodes vary widely over time and episodes are often asymptomatic. (See "Atrial fibrillation in patients undergoing noncardiac surgery", section on 'Anticoagulation after surgery' and "Atrial fibrillation and flutter after cardiac surgery", section on 'Anticoagulation'.) For patients with a CHA DS -VASc of 0 in males or 1 in females (calculator 1)( table 1), 2 2 we suggest against anticoagulant therapy. Patient values and preferences may impact the decision. For example, a patient who is particularly stroke averse and is not at increased risk for bleeding (see 'Bleeding risk' below) may reasonably choose anticoagulation, particularly if the patient is a candidate for treatment with a direct oral anticoagulant (DOAC). For all potential candidates for OAC, bleeding risk and related possible contraindications to OAC should be reviewed ( table 2 and table 3). The appropriate use of bleeding risk assessment is to draw attention to modifiable bleeding risk factors that can be mitigated, and to flag patients with high bleeding risk for early review and follow-up and to identify potential candidates for left atrial appendage occlusion [2-6]. (See 'Bleeding risk' below and "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Mitigating bleeding risk' and "Risks and prevention of bleeding with oral anticoagulants", section on 'Risk factors for bleeding'.) Effects of anticoagulation In identifying which patients with AF are likely to benefit from OAC, the relative risk reduction in thromboembolism with OAC identified in randomized trials (see 'General efficacy' below) is combined with estimates of baseline risk using the CHA DS - 2 2 VASc score to estimate the expected absolute risk reduction from OAC (see 'CHA2DS2-VASc score' below). The estimated absolute risk reduction for thromboembolic events is weighed against the estimated increase in absolute risk of intracranial hemorrhage (ICH) and other major bleeding complications. (See 'Bleeding risk' below.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 3/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate General efficacy For patients with AF, randomized trials have shown that therapeutic OAC (vitamin K antagonist [VKA] or DOAC) reduces the risk of ischemic stroke and other embolic events by approximately two-thirds compared with placebo irrespective of baseline risk ( figure 1) [7-17]. A meta-analysis included six randomized trials comparing VKA (warfarin) with placebo or no treatment in a total of 2900 participants with AF (mean age at entry 69 years, 20 percent with prior stroke or transient ischemic attack) [14]. The overall rate of stroke was 2.2 percent/patient year in the warfarin group and 6.0 percent/patient year in the control group (relative risk reduction 0.64; 95% CI 0.49-0.74). The absolute risk reduction was 2.7 percent/year for primary prevention and 8.4 percent/year for secondary prevention. With warfarin therapy, all-cause mortality was reduced by 1.6 percent/year (relative risk reduction 0.26; 95% CI 0.03-0.43). While most of the evidence comparing OAC with placebo in patients involved treatment with VKA, a trial comparing edoxaban 15 mg daily with placebo in patients with AF 80 years old with low body weight found a similar relative reduction in risk of stroke or systemic embolism (2.3 versus 6.7 percent/year; hazard ratio 0.34, 95% CI 0.19-0.61) [18]. The possible implications of this study for edoxaban dose are discussed separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants" and "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'DOACs'.) CHA2DS2-VASc score Use We use the CHA DS -VASc score (calculator 1) to estimate thromboembolic risk in 2 2 patients with AF, while recognizing its limitations (see 'Potential alternatives' below and 'Limitations' below). This estimation of baseline thromboembolic risk is combined with the above information on relative risk reduction (see 'General efficacy' above) to estimate the expected absolute risk reduction. The annual risk of ischemic stroke in untreated patients is estimated to be 0.2, 0.6, and 2.2 percent for those with CHA DS -VASc scores of 0, 1, and 2 ( table 1) [19]. However, stroke 2 2 rates have varied substantially among studies, which may be due to differences in study populations and methodologies [2,20-24]. As an example, studies examining ischemic stroke rates in patients with a single risk factor have identified risks of <1 to 2.7 percent/year [25-27]. Among patients with AF, ischemic stroke is the dominant type of thromboembolic event. As an example, in a study including data on 39,973 participants in four randomized trials of anticoagulation, the incidence of nonstroke systemic embolic events (SEEs) was 0.23/100 person-years, and the incidence of cerebral embolism was 1.92/100 person-years [28]. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 4/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Among those with SEEs, 58 percent occurred in the lower extremities, 31 percent in the visceral-mesenteric system, and 11 percent in the upper extremities. Among patients with AF treated with OAC, annual stroke risk is lowered by approximately two-thirds to <0.1, 0.2, and 0.6 percent, respectively. In addition to the lowering of stroke risk, there is evidence that warfarin, compared with no anticoagulant therapy, leads to less severe stroke episodes and lower 30-day stroke mortality [14,29]. The annual risk of intracranial bleeding with warfarin is 0.2, 0.3, and 0.5 percent, respectively. The risk of ICH with DOAC is approximately half of that with VKA ( table 4). (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Choice of anticoagulant'.) Among adults with AF, females have a modestly higher risk of thromboembolism than males, but female sex is associated with increased risk primarily in patients with at least two CHA DS - 2 2 VASc score non-sex risk score points [1,30]. Thus, we focus on non-sex risk factors when deciding whether OAC is indicated. For CHA DS -VASc score 2 in males or 3 in females (when the risk score points are 2 2 from two or more non-sex risk factors), the benefit from OAC generally exceeds the risks of severe bleeding [19,31-33]. For CHA DS -VASc score of 1 in males or 2 in females (one non-sex risk factor with a 2 2 value of 1), the risk of thromboembolism varies depending upon the non-sex risk factor [1]. Among the risk factors with a one-point value, age 65 to 74 years and the presence of heart failure have the greatest effect on thromboembolic risk [1], and OAC is recommended in patients with any of these risk factors. For CHA DS - VASc score of 0 in males or 1 in females (zero nonsex risk factors), the 2 2 thromboembolic risk is low [27], so no OAC is suggested. (See 'Approach to deciding whether to anticoagulate' above.) The warfarin versus placebo or aspirin trials were reported in the early 1990s, raising concerns that the findings may not be applicable to contemporary clinical practice [31,34,35]. Studies evaluating more contemporary data have found that the absolute risk of stroke in untreated patients has fallen from approximately 8 percent/year to 4 or 5 percent/year ( table 1), but the relative risk reduction attributable to anticoagulant therapy is in the same range as earlier studies [36,37]. A two-thirds risk reduction in thromboembolism using the more contemporary lower absolute risks is clinically important for patients with two or more nonsex risk factors and for selected patients with one nonsex risk factor. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 5/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Comparisons of the effects of VKA and DOAC are presented separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants".) Potential alternatives A variety of risk scores, imaging methods, and biomarkers have been studied for their potential predictive value for thromboembolic risk in patients with AF [38]. The CHA DS -VASc score has been compared with potential alternatives including the CHADS 2 2 2 and ATRIA risk scores ( table 1 and table 5). The clinical utility of a risk score for individuals with AF hinges primarily on its accuracy in identifying those at lowest risk for thromboembolism, as anticoagulation is generally recommended for individuals with all but the lowest level of risk. Systematic reviews suggest that the CHA DS -VASc score generally performs better than the 2 2 CHADS and ATRIA scores in identifying low-risk patients, although there have been some 2 discrepant results for comparisons of CHA DS -VASc and ATRIA [38]. However, all these risk 2 2 scores are subject to the limitations discussed below. (See 'Limitations' below.) A potential alternative to the risk score approach is to calculate the risk for each patient based upon risk factors including age as a continuous variable using the Calculator of Absolute Stroke Risk (CARS) [1]. For patients with AF, there is no established role for routine cardiac imaging to assess thromboembolic risk. Transesophageal echocardiography (TEE) is used in patients with AF primarily to evaluate left and right atrial appendage anatomy/function to identify individuals who are free of atrial thrombi and are therefore candidates for early cardioversion (see "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation"). Thromboembolic risk is associated with cardiac imaging findings, including evidence of left atrial thrombus (generally assessed by TEE; less commonly assessed by cardiovascular magnetic resonance [CMR] or cardiac computed tomography [CCT]) and depressed left ventricular ejection fraction (which can be assessed by transthoracic echocardiography, TEE, CMR, CCT, or nuclear methods) [39]. However, imaging findings have not been shown to improve risk stratification in patients with AF [2]. Limitations Risk scores to estimate thromboembolic risk in patients with AF have limited predictive value when applied to individual patients. One limitation is that risk scores utilize point systems that do not reflect differences in risk among included risk factors. Risk factors assigned equal point values are associated with substantially different risks, as illustrated by the following examples for the CHA DS -VASc score 2 2 ( table 1) [1]: https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 6/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Age 65 to 74 years is associated with substantially greater stroke risk than other risk factors assigned one point. A history of prior stroke, transient ischemic attack, or thromboembolic event is assigned two points, but the risk associated with this risk factor is more than five times the risk associated with risk factors assigned one point. The continuous risk of age is lumped into categories, so that ages 65 years and 74 years each confer one point, despite the much higher actual risk associated with the older age. Another limitation is that the event rates observed in populations used to generate risk score may differ from those occurring in different clinical settings (eg, community versus hospitalized) and patient populations with differing risk profiles. Also, some clinical features or conditions may impact the risk of thromboembolism but are not included in risk models; these include the duration or frequency of episodes of paroxysmal AF and the presence of conditions such as chronic kidney disease and elevated troponin level. Prediabetes has also been implicated as a possible risk factor for stroke in patients with AF [40]. The potential role of troponin measurement in the assessment of the risk of embolization in patients with AF is discussed separately. (See 'Chronic kidney disease' below and "Elevated cardiac troponin concentration in the absence of an acute coronary syndrome", section on 'Atrial fibrillation'.) Bleeding risk When OAC is considered, the major safety concern is the increased risk of bleeding, especially major bleeding, which includes events that require hospitalization, transfusion, or surgery, or that involve particularly sensitive anatomic locations. Thus, bleeding risk and related contraindications to OAC should be reviewed ( table 2). A systematic review comparing various bleeding risk scores in patients with AF found that the HAS-BLED risk score ( table 3) was the best predictor of bleeding risk [2], although all bleeding risk scores provide imprecise estimates for individual patients, do not provide estimates for specific types of major bleeds, and are based upon bleeding risk with warfarin. Two more recent studies confirmed the efficacy of the HAS-BLED score was comparable to or better than ORBIT score in patients treated with DOACs [41,42]. Among patients with AF, the three most important predictors of major bleeding (including ICH) are overanticoagulation with warfarin (defined as an international normalized ratio greater than 3.0), prior stroke, and older patient age [31,43-45]. (See "Risks and prevention of bleeding with oral anticoagulants".) The risk of bleeding was evaluated in a cohort of over 16,000 patients diagnosed with AF between 2005 and 2010 [37]. The incidence of major bleeding with current, recent, past, or no https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 7/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate VKA (warfarin) exposure was 3.8, 4.5, 2.7, and 2.9/100 patient-years, respectively. However, major bleeding includes ICH and extracranial bleeding, particularly gastrointestinal bleeding. ICH is the most serious bleeding complication, since the likelihood of mortality or subsequent major disability is substantially higher than with bleeding at other sites [46]. In this study and others, the annual risk of ICH in patients with AF who are not anticoagulated is estimated to be 0.2 percent/year; that risk approximately doubles with OAC with VKA [34,37]. Randomized trials have shown that the risk of ICH with DOAC (both direct thrombin and factor Xa inhibitors) is approximately half of that with VKA ( table 4). (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Choice of anticoagulant'.) Given differences in morbidity associated with different types of bleeding, we think most patients would weigh the reduction in risk of ischemic stroke primarily against the increase in risk of ICH, with less weight given to the risk of gastrointestinal bleed or other less serious bleeding. While the incremental absolute risk of ICH with VKA (approximately 0.2 percent/year) is not trivial, it is substantially less than the expected absolute reduction in risk of ischemic stroke from OAC for most patients with AF and two or more nonsex CHA DS -VASc risk factors. 2 2 One problem with the bleeding risk scores is that they were developed from studies that included bleeds of differing severity. While any bleed can lead to death or severe disability, most do not; the major exception is ICH. The morbidity associated with ICH is similar to that for ischemic stroke, while the morbidity associated with gastrointestinal bleeding is generally not as severe. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Intracranial'.) For patients in the following clinical settings, the bleeding risk is significantly higher: Thrombocytopenia or known coagulation defect associated with bleeding Active bleeding or recent surgery with a concern for ongoing bleeding Prior severe bleeding (including ICH) while on an oral anticoagulant Aortic dissection Malignant hypertension Combined use of anticoagulant and antiplatelet (including regular use of nonsteroidal antiinflammatory) agents SPECIFIC PATIENT GROUPS Patients with valvular heart disease For patients with valvular heart disease (excluding those with rheumatic mitral stenosis that is severe or clinically significant [mitral valve area 1.5 2 cm ], a bioprosthetic valve [surgical or transcatheter] within the first three to six months after https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 8/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate implantation, or a mechanical heart valve), the above general approach to deciding on oral anticoagulation (OAC) applies, although the evidence in patients with severe native valve disease is more limited than for the general population of patients with AF [47]. (See 'Approach to deciding whether to anticoagulate' above.) Approaches to antithrombotic therapy (including anticoagulation) in patients with AF with specific valve conditions are discussed separately: 2 Rheumatic mitral stenosis that is severe or clinically significant (mitral valve area 1.5 cm ). (See "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism'.) Mechanical heart valve. (See "Antithrombotic therapy for mechanical heart valves".) Surgically implanted bioprosthetic valve. (See "Antithrombotic therapy for mechanical heart valves".) Transcatheter bioprosthetic valve. (See "Transcatheter aortic valve implantation: Antithrombotic therapy", section on 'General approach'.) AF type and management Paroxysmal AF Our approach to deciding whether to anticoagulate is generally similar for patients with paroxysmal AF (PAF; with or without symptoms) as for persistent, or permanent, AF, as described above (see 'Decision-making based upon risk assessment' above). However, the burden of AF (duration and frequency of episodes) is a factor for decision-making for selected patients in whom the balance of benefit versus risk of anticoagulation is uncertain, recognizing that it may not be possible to accurately estimate AF burden except in patients with cardiac implantable electronic devices that can measure AF burden. We consider the burden of AF in decision-making for patients aged <65 years and who have one nonsex CHA DS -VASc risk 2 2 factor. On the other hand, patients with AF with past history of embolic stroke are at high risk for a recurrent thromboembolic event, so the burden of AF would generally not impact the decision to anticoagulate. (See 'Decision-making based upon risk assessment' above.) As discussed separately, the risk of thromboembolism in patients with PAF appears to be lower than in patients with persistent AF, and thromboembolic risk is higher in those with greater AF burden (percentage of time in AF). (See "Paroxysmal atrial fibrillation", section on 'Risk of embolization'.) There are no definitive data to establish a threshold duration of AF episodes for the initiation of anticoagulant therapy. Some of our experts recommend a single threshold for duration of AF of https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 9/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate 30 seconds, and others use a threshold as long as 24 hours [48]. Those experts who do not routinely anticoagulate patients with shorter-duration AF believe that the benefit is small and potentially outweighed by the bleeding risk. However, the AF burden is likely to vary over time, so a patient with 30 seconds of AF in one monitoring period may well have 30 hours of AF in the next monitoring period. While a large proportion of patients with short episodes of AF will go on to experience longer episodes, it is also true that the reverse occurs in a sizable percentage of patients experiencing long episodes of AF [49]. Also, the extent to which thromboembolic risk may continue during periods of sinus rhythm is uncertain. (See "Paroxysmal atrial fibrillation", section on 'Risk of embolization'.) Rhythm versus rate control For patients with AF, the process of deciding whether to anticoagulate is generally the same regardless of the choice between rhythm control or rate control strategies. As discussed separately, the risk of thromboembolism is not reduced by clinical maintenance of sinus rhythm. (See "Management of atrial fibrillation: Rhythm control versus rate control", section on 'Thromboembolic risk'.) AF after surgery Approaches to OAC in patients with AF after cardiac surgery and after noncardiac surgery are discussed separately. (See "Atrial fibrillation and flutter after cardiac surgery", section on 'Our approach to postoperative anticoagulation' and "Atrial fibrillation in patients undergoing noncardiac surgery", section on 'Anticoagulation after surgery'.) Older adults For older adults, we follow the general approach described above, including careful assessment the relative benefits and risks of OAC (see 'Decision-making based upon risk assessment' above). The approach to chronic kidney disease is discussed below. (See 'Chronic kidney disease' below.) In patients with documented frequent falls but without prior trauma (eg, fracture, subdural), we weight the risks and benefits of OAC versus left atrial appendage occlusion. In this clinical setting, we often recommend OAC and work to reduce the risk of falls. The risk of falls leading to subdural hematomas is increased in older adult patients taking oral anticoagulants independent of the agent chosen. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Age, race, and sex' and "Atrial fibrillation: Left atrial appendage occlusion".) A Taiwanese database study compared 15,756 older ( 90 years of age) adults with AF (11,064 receiving no antithrombotic therapy, 4075 receiving antiplatelet therapy, and 617 on warfarin) with 14,658 older adult patients without AF and without antithrombotic therapy [50]: Patients with AF had a greater risk of ischemic stroke (5.75 versus 3.00 percent/year; hazard ratio [HR] 1.93, 95% CI 1.74-2.14) and a similar risk of intracranial hemorrhage (ICH; 0.97 versus 0.54 percent/year; HR 0.85, 95% CI 0.66-1.09) compared with those without AF. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 10/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Among patients with AF, warfarin use was associated with a lower stroke risk (3.83 versus 5.75 percent/year; HR 0.69, 95% CI 0.49-0.96) compared with no antithrombotic therapy. There was a nominal but nonsignificant increase in risk of ICH (HR 1.26, 95% CI 0.70-2.25). In a second, later cohort of patients 90 years of age with AF, 768 patients treated with warfarin were compared with 978 patients treated with a direct oral anticoagulant (DOAC) [50]. DOACs were associated with a lower risk of ICH compared with warfarin (0.42 versus 1.63 percent/year; HR 0.32, 95% CI 0.10-0.97) and similar rate of ischemic stroke (4.07 versus 4.59 percent/year; HR 1.16; 95% CI 0.61 2.22). (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Older adults'.) Potential use of reduced-dose DOAC (edoxaban) in selected older adults with AF with low body weight is discussed separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'DOACs'.) Chronic kidney disease For most patients with AF and chronic kidney disease (CKD), we follow the general approach to selection of candidates for OAC described above (see 'Approach to deciding whether to anticoagulate' above). However, some of our authors consider anticoagulation for the very uncommon CKD patient with a CHA DS -VASc score of 0 in males or 2 2 1 in females. For patients with CKD and AF, the following is our approach for deciding whether to anticoagulate ( figure 2): Stages 2, 3, and 4 and 5 (not on dialysis) For patients with estimated glomerular 2 filtration rate (eGFR) of 15 to 89 mL/min/1.73 m , our approach is similar to the general approach described above (see 'Decision-making based upon risk assessment' above), although there are very limited data for patients with end-stage kidney disease. Individualized risk assessment is performed to carefully weigh the benefits and risks of anticoagulation, with special attention to the bleeding risk associated with CKD. (See "Overview of the management of chronic kidney disease in adults", section on 'Uremic bleeding'.) Stage 5 on dialysis Among patients with end-stage kidney disease on dialysis, we anticoagulate some higher-risk individuals (based on the CHA DS VASc score) after shared 2 2- decision-making and discussion of risks and benefits between the clinician and the patient. However, it is reasonable to not anticoagulate the following groups of individuals with AF and eGFR <30 mL/min (stages 4 and 5) given our uncertainty of the benefit-to-risk ratio for antithrombotic therapy in these patients: https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 11/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Patients with high frailty Patients with prior life-threatening bleeding or recurrent bleeding Patients with poorly controlled hypertension AF is common in patients with CKD [51-56], with prevalence between 8 and 35 percent in patients on hemodialysis and approximately 7 percent in patients undergoing peritoneal dialysis [57-59]. This rate is significantly higher than in the general population [60-63]. Rates are even higher in studies which used prolonged/continuous monitoring for identifying AF ( figure 3) [51,52,64]. CKD significantly increases thromboembolic risk above baseline and is also associated with increased risk of bleeding [65-68]. Studies assessing the independent predictive value of presence of CKD for thromboembolic risk beyond the CHA DS -VASc score have yielded 2 2 mixed results [65,69,70]. The thromboembolic risk associated with CKD may be due to alterations in the normal hemostatic mechanisms. The increased bleeding risk, particularly from the gastrointestinal tract, is due to pathophysiologic mechanisms including impairment of normal platelet function secondary to factors such as uremic toxins, abnormal platelet arachidonic acid metabolism, altered von Willebrand factor, and reduction in intracellular adenosine diphosphate and serotonin, as well as an increase in the frequency of the need for invasive procedures [60]. (See "Uremic platelet dysfunction".) The evidence to support OAC (vitamin K antagonist [VKA] or DOAC) is less robust in individuals with creatinine clearance <30 mL/min, as many such patients were excluded from the important randomized trials [71]. However, we believe that the benefit outweighs the risk in most cases. The efficacy and safety of warfarin in patients with AF and CKD have been evaluated in observational studies which have come to differing conclusions [66,72-77]. A 2020 meta-analysis of 15 studies (with a total of 47,480 patients with AF and end-stage renal disease) found no difference in the risk of ischemic stroke (HR 0.96, 95% CI 0.82-1.13), a higher risk of hemorrhage stroke (HR 1.46, 95% CI 1.05-2.04), and no significant difference in mortality (HR 0.95, 95% CI 0.83-1.09) or major bleeding (HR 1.20, 95% CI 0.99-1.47) in comparing warfarin users with those not taking warfarin [78]. Many of the observational cohorts did not evaluate the quality of the OAC with warfarin, such as the time in the therapeutic range (TTR). This may be relevant since evidence suggests that higher TTR is associated with better outcomes. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Monitoring (PT/INR)'.) Hyperthyroidism The role of anticoagulant therapy is less well defined in patients in whom the underlying disease associated with AF can be corrected, as in hyperthyroidism. (See "Epidemiology, risk factors, and prevention of atrial fibrillation" and "Cardiovascular effects of hyperthyroidism", section on 'Atrial fibrillation'.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 12/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate For patients with AF attributable to hyperthyroidism, we follow the general approach described above for identifying candidates for OAC. (See 'Approach to deciding whether to anticoagulate' above.) After successful treatment of the disorder, and after documentation that AF has not been present for at least three months, most of our experts suggest discontinuing anticoagulant treatment with periodic reassessment of the patient for recurrence of AF. We consider the absence of symptoms or signs of AF and two-week continuous monitoring showing no AF as adequate documentation. Some experts prefer additional documentation. However, some of our experts make a decision about continuing anticoagulant therapy based on the CHA DS -VASc 2 2 score independent of monitored rhythm in these patients. Hypertrophic cardiomyopathy The role of OAC in patients with hypertrophic cardiomyopathy and AF is discussed separately. (See "Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation", section on 'Long-term management'.) Patients with cancer on chemotherapy Several chemotherapy drugs have been associated with AF and atrial flutter. Depending on severity, dose reduction or discontinuation of the offending chemotherapy agent may be indicated. (See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines".) For most patients with AF and cancer who are on chemotherapy, we follow the general approach to selection of candidates for OACs described above. (See 'Approach to deciding whether to anticoagulate' above.). For patients who have AF in the setting of chemotherapy-related thrombocytopenia, OACs may require a dose reduction in order to prevent bleeding. (See "Anticoagulation in individuals with thrombocytopenia", section on 'Atrial fibrillation and acute coronary syndromes'.) ALTERNATIVES TO ANTICOAGULATION Left atrial appendage occlusion As discussed separately, left atrial appendage occlusion is the primary alternative for patients with AF (excluding those with severe or clinically significant rheumatic stenosis, a bioprosthetic valve [surgical or bioprosthetic] within the first three to six months after implantation, or a mechanical valve) who have an indication for anticoagulation but have a contraindication for long-term anticoagulation. (See 'Decision-making based upon risk assessment' above and "Atrial fibrillation: Left atrial appendage occlusion".) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 13/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Pharmacologic agents For patients with AF, no other antithrombotic regimen is an effective and safe alternative to standard therapeutic oral anticoagulation (OAC). In this setting, other antithrombotic regimens are less effective in lowering thromboembolic risk than standard therapeutic OAC and some antithrombotic regimens entail a bleeding risk similar to or greater than standard therapeutic OAC: Aspirin plus clopidogrel Dual antiplatelet therapy is preferred to aspirin alone in the occasional high-risk patient with AF who cannot be treated with any OAC for a reason other than risk of bleeding. Given the availability of the direct oral anticoagulant (DOAC) agents as alternatives to vitamin K antagonists (VKAs), this situation should be extremely uncommon. One possible example is a patient with contraindications to DOAC agents who cannot receive effective international normalized ratio (INR) monitoring for VKA. Of note, dual antiplatelet therapy and OAC have similar bleeding risks. Thus, a patient who would not be a candidate for OAC because of bleeding risk is also not a candidate for dual antiplatelet therapy. In patients with AF, dual antiplatelet therapy (with aspirin plus clopidogrel) reduces the risk of thromboembolism compared with aspirin monotherapy but offers less protection against thromboembolism than OAC (with VKA or DOAC). The safety and efficacy of dual antiplatelet therapy in patients with AF were investigated in the ACTIVE W and ACTIVE A trials. All patients in the two trials had AF and one or more risk factors for stroke. The primary endpoint in both trials was a composite outcome (the first occurrence of stroke, systemic [non-central nervous system] embolization, myocardial infarction, or vascular death). The ACTIVE W trial included 6706 patients who were randomly assigned to combined therapy with clopidogrel (75 mg/day) and aspirin (75 to

11/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Patients with high frailty Patients with prior life-threatening bleeding or recurrent bleeding Patients with poorly controlled hypertension AF is common in patients with CKD [51-56], with prevalence between 8 and 35 percent in patients on hemodialysis and approximately 7 percent in patients undergoing peritoneal dialysis [57-59]. This rate is significantly higher than in the general population [60-63]. Rates are even higher in studies which used prolonged/continuous monitoring for identifying AF ( figure 3) [51,52,64]. CKD significantly increases thromboembolic risk above baseline and is also associated with increased risk of bleeding [65-68]. Studies assessing the independent predictive value of presence of CKD for thromboembolic risk beyond the CHA DS -VASc score have yielded 2 2 mixed results [65,69,70]. The thromboembolic risk associated with CKD may be due to alterations in the normal hemostatic mechanisms. The increased bleeding risk, particularly from the gastrointestinal tract, is due to pathophysiologic mechanisms including impairment of normal platelet function secondary to factors such as uremic toxins, abnormal platelet arachidonic acid metabolism, altered von Willebrand factor, and reduction in intracellular adenosine diphosphate and serotonin, as well as an increase in the frequency of the need for invasive procedures [60]. (See "Uremic platelet dysfunction".) The evidence to support OAC (vitamin K antagonist [VKA] or DOAC) is less robust in individuals with creatinine clearance <30 mL/min, as many such patients were excluded from the important randomized trials [71]. However, we believe that the benefit outweighs the risk in most cases. The efficacy and safety of warfarin in patients with AF and CKD have been evaluated in observational studies which have come to differing conclusions [66,72-77]. A 2020 meta-analysis of 15 studies (with a total of 47,480 patients with AF and end-stage renal disease) found no difference in the risk of ischemic stroke (HR 0.96, 95% CI 0.82-1.13), a higher risk of hemorrhage stroke (HR 1.46, 95% CI 1.05-2.04), and no significant difference in mortality (HR 0.95, 95% CI 0.83-1.09) or major bleeding (HR 1.20, 95% CI 0.99-1.47) in comparing warfarin users with those not taking warfarin [78]. Many of the observational cohorts did not evaluate the quality of the OAC with warfarin, such as the time in the therapeutic range (TTR). This may be relevant since evidence suggests that higher TTR is associated with better outcomes. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Monitoring (PT/INR)'.) Hyperthyroidism The role of anticoagulant therapy is less well defined in patients in whom the underlying disease associated with AF can be corrected, as in hyperthyroidism. (See "Epidemiology, risk factors, and prevention of atrial fibrillation" and "Cardiovascular effects of hyperthyroidism", section on 'Atrial fibrillation'.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 12/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate For patients with AF attributable to hyperthyroidism, we follow the general approach described above for identifying candidates for OAC. (See 'Approach to deciding whether to anticoagulate' above.) After successful treatment of the disorder, and after documentation that AF has not been present for at least three months, most of our experts suggest discontinuing anticoagulant treatment with periodic reassessment of the patient for recurrence of AF. We consider the absence of symptoms or signs of AF and two-week continuous monitoring showing no AF as adequate documentation. Some experts prefer additional documentation. However, some of our experts make a decision about continuing anticoagulant therapy based on the CHA DS -VASc 2 2 score independent of monitored rhythm in these patients. Hypertrophic cardiomyopathy The role of OAC in patients with hypertrophic cardiomyopathy and AF is discussed separately. (See "Hypertrophic cardiomyopathy in adults: Supraventricular tachycardias including atrial fibrillation", section on 'Long-term management'.) Patients with cancer on chemotherapy Several chemotherapy drugs have been associated with AF and atrial flutter. Depending on severity, dose reduction or discontinuation of the offending chemotherapy agent may be indicated. (See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines".) For most patients with AF and cancer who are on chemotherapy, we follow the general approach to selection of candidates for OACs described above. (See 'Approach to deciding whether to anticoagulate' above.). For patients who have AF in the setting of chemotherapy-related thrombocytopenia, OACs may require a dose reduction in order to prevent bleeding. (See "Anticoagulation in individuals with thrombocytopenia", section on 'Atrial fibrillation and acute coronary syndromes'.) ALTERNATIVES TO ANTICOAGULATION Left atrial appendage occlusion As discussed separately, left atrial appendage occlusion is the primary alternative for patients with AF (excluding those with severe or clinically significant rheumatic stenosis, a bioprosthetic valve [surgical or bioprosthetic] within the first three to six months after implantation, or a mechanical valve) who have an indication for anticoagulation but have a contraindication for long-term anticoagulation. (See 'Decision-making based upon risk assessment' above and "Atrial fibrillation: Left atrial appendage occlusion".) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 13/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Pharmacologic agents For patients with AF, no other antithrombotic regimen is an effective and safe alternative to standard therapeutic oral anticoagulation (OAC). In this setting, other antithrombotic regimens are less effective in lowering thromboembolic risk than standard therapeutic OAC and some antithrombotic regimens entail a bleeding risk similar to or greater than standard therapeutic OAC: Aspirin plus clopidogrel Dual antiplatelet therapy is preferred to aspirin alone in the occasional high-risk patient with AF who cannot be treated with any OAC for a reason other than risk of bleeding. Given the availability of the direct oral anticoagulant (DOAC) agents as alternatives to vitamin K antagonists (VKAs), this situation should be extremely uncommon. One possible example is a patient with contraindications to DOAC agents who cannot receive effective international normalized ratio (INR) monitoring for VKA. Of note, dual antiplatelet therapy and OAC have similar bleeding risks. Thus, a patient who would not be a candidate for OAC because of bleeding risk is also not a candidate for dual antiplatelet therapy. In patients with AF, dual antiplatelet therapy (with aspirin plus clopidogrel) reduces the risk of thromboembolism compared with aspirin monotherapy but offers less protection against thromboembolism than OAC (with VKA or DOAC). The safety and efficacy of dual antiplatelet therapy in patients with AF were investigated in the ACTIVE W and ACTIVE A trials. All patients in the two trials had AF and one or more risk factors for stroke. The primary endpoint in both trials was a composite outcome (the first occurrence of stroke, systemic [non-central nervous system] embolization, myocardial infarction, or vascular death). The ACTIVE W trial included 6706 patients who were randomly assigned to combined therapy with clopidogrel (75 mg/day) and aspirin (75 to 100 mg/day) or to OAC with a VKA (target INR 2.0 to 3.0) [79]. The trial was stopped at an interim analysis after a median follow-up of 1.3 years because VKA lowered the annual rate of the primary endpoint compared with combined antiplatelet therapy (3.9 versus 5.6 percent; relative risk [RR] 0.69, 95% CI 0.57-0.85). The ACTIVE A trial included 7554 patients with AF who were not candidates for warfarin OAC and were randomly assigned to combined therapy with clopidogrel (75 mg/day) and aspirin (75 to 100 mg/day) or to aspirin alone at the same dose [80]. After a median follow- up period of 3.6 years, patients treated with clopidogrel plus aspirin had a significantly lower annual rate of the primary combined endpoint (6.8 versus 7.8 percent; RR 0.89, 95% CI 0.81-0.98), which was primarily driven by a reduction in stroke (2.4 versus 3.3 percent; RR 0.72, 95% CI 0.62-0.83). On the other hand, dual antiplatelet therapy resulted in a higher rate of major bleeding (2.0 versus 1.3 percent/year; RR 1.57, 95% CI 1.29-1.92). https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 14/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Aspirin monotherapy Aspirin (or other antiplatelet agent) is not an effective therapy for preventing thromboembolic events in patients with AF. In patients with AF, some but not all meta-analyses of clinical trials comparing aspirin with placebo have found that aspirin reduced the risk of stroke and systemic embolism ( table 6) [14,38,81]. In contrast, clinical trials have demonstrated that OAC (with VKA or DOAC) lowers the risk of thromboembolism compared with aspirin ( table 6) [9,14-17,82-84]. Aspirin plus low-dose warfarin In contrast to therapeutic adjusted-dose warfarin (target INR 2.0 to 3.0), low-dose warfarin (1.25 mg/day or target INR between 1.2 and 1.5) in combination with aspirin (300 to 325 mg/day) should not be used to reduce stroke risk in patients with nonvalvular AF [17,85,86]. In the SPAF-III trial of 1044 patients with AF who were at high risk for embolism, low-dose warfarin plus aspirin had a much higher rate of ischemic stroke and systemic embolism than therapeutic adjusted-dose warfarin ( figure 4A-B) [85]. Aspirin plus full-dose warfarin Limited available data suggest that there is no benefit from adding aspirin to therapeutic OAC in patients with AF. In a post-hoc analysis of the SPORTIF trials in patients with AF, among patients taking aspirin plus warfarin (or aspirin plus the factor Xa inhibitor ximelagatran) experienced similar rates of stroke and systemic embolism as those taking warfarin alone (or ximelagatran alone) [87]. The risk of major bleeding was higher with aspirin plus warfarin compared with warfarin alone (3.9 versus 2.3 percent/year). The management of antithrombotic therapy for patients with AF treated with OAC who have a concurrent indication for antiplatelet therapy is discussed separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Concomitant antiplatelet therapy'.) RECOMMENDATIONS OF OTHERS Recommendations for choosing which patients with atrial fibrillation should be anticoagulated are available from the American Heart Association/American College of Cardiology/Heart Rhythm Society, the European Society of Cardiology, and the American College of Chest Physicians [38,88-90]. In general, we agree with relevant recommendations made in these guidelines. SOCIETY GUIDELINE LINKS https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 15/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults" and "Society guideline links: Anticoagulation".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topics (see "Patient education: Atrial fibrillation (The Basics)" and "Patient education: Medicines for atrial fibrillation (The Basics)" and "Patient education: Choosing an oral medicine for blood clots (The Basics)" and "Patient education: Taking oral medicines for blood clots (The Basics)") Beyond the Basics topics (see "Patient education: Atrial fibrillation (Beyond the Basics)" and "Patient education: Warfarin (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Role of oral anticoagulation (OAC) in atrial fibrillation (AF) In patients with AF, OAC reduces the risk of thromboembolism by approximately two-thirds across clinical risk factor profiles but also entails an increased risk of major bleeding. Deciding whether to anticoagulate For each patient, their estimated absolute risk reduction for thromboembolic events is weighed against their estimated increase in absolute risk of intracranial hemorrhage and other life-threatening or severely debilitating bleeding complications. (See 'Approach to deciding whether to anticoagulate' above.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 16/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate CHA DS -VASc risk score Our approach to deciding whether to prescribe anticoagulant 2 2 therapy for patients with AF (excluding those with rheumatic mitral stenosis that is severe 2 or clinically significant [mitral valve area 1.5 cm ], a bioprosthetic valve [surgical or transcatheter] within the first three to six months after implantation, or a mechanical heart valve) is as follows (see 'Approach to deciding whether to anticoagulate' above): For a CHA DS -VASc score 2 in males or 3 in females (calculator 1) ( table 1), we 2 2 recommend chronic OAC (Grade 1A). For a CHA DS -VASc score of 1 in males and 2 in females (calculator 1) ( table 1): 2 2 For patients with CHA DS -VASc score of 1 in males and 2 in females based on age 2 2 65 to 74 years, we recommend chronic OAC (Grade 1A). Age 65 to 74 years is a stronger risk factor than the other factors conferring one CHA DS -VASc score 2 2 point. For patients with other risk factors, the decision to anticoagulate is based upon the specific nonsex risk factor and the burden of AF. For patients with very low burden of AF (eg, AF that is well documented as limited to an isolated episode that may have been due to a reversible cause such as recent surgery, heavy alcohol ingestion, or sleep deprivation), it may be reasonable to forgo chronic OAC and institute close surveillance for recurrent AF, although it may not be possible to reliably estimate AF burden from surveying symptoms or infrequent monitoring. (See "Atrial fibrillation in patients undergoing noncardiac surgery", section on 'Anticoagulation after surgery' and "Atrial fibrillation and flutter after cardiac surgery", section on 'Anticoagulation'.) For patients with a CHA DS -VASc of 0 in males or 1 in females (calculator 1) ( table 1), 2 2 we suggest against OAC (Grade 2C). Patient values and preferences may impact the decision. For example, a patient who is particularly stroke averse and is not at increased risk for bleeding (see 'Bleeding risk' above) may reasonably choose anticoagulation, particularly if the patient is a candidate for treatment with a direct oral anticoagulant (DOAC). Bleeding risk For all potential candidates for OAC, bleeding risk and related possible contraindications to OAC should be reviewed ( table 2 and table 3). (See 'Bleeding risk' above.) The appropriate use of bleeding risk assessment is to draw attention to modifiable bleeding risk factors that can be mitigated to flag high-bleeding-risk patients for early https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 17/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate review and follow-up. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Bleeding risk scores' and "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Mitigating bleeding risk'.) Specific patient groups Our approach to OAC for patients with AF who are older, have chronic kidney disease, hyperthyroidism, and hypertrophic cardiomyopathy can sometimes differ for patients who are younger or do not have these conditions. (See 'Specific patient groups' above.) Contraindication to OAC For patients with AF (excluding those with severe or clinically significant rheumatic stenosis, a surgical bioprosthetic valve within the first three to six months after implantation, or a mechanical valve) with an indication for OAC but who have a contraindication for long-term OAC, the primary alternative is left atrial appendage occlusion. For such patients, no other antithrombotic regimen is an effective and safe alternative to standard therapeutic OAC. (See 'Alternatives to anticoagulation' above and "Atrial fibrillation: Left atrial appendage occlusion".) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Lee CJ, Toft-Petersen AP, Ozenne B, et al. Assessing absolute stroke risk in patients with atrial fibrillation using a risk factor-based approach. Eur Heart J Cardiovasc Pharmacother 2021; 7:f3. 2. Borre ED, Goode A, Raitz G, et al. Predicting Thromboembolic and Bleeding Event Risk in Patients with Non-Valvular Atrial Fibrillation: A Systematic Review. Thromb Haemost 2018; 118:2171. 3. Lip GY, Lane DA. Bleeding risk assessment in atrial fibrillation: observations on the use and misuse of bleeding risk scores. J Thromb Haemost 2016; 14:1711. 4. Lip GY, Lane DA. Assessing bleeding risk in atrial fibrillation with the HAS-BLED and ORBIT scores: clinical application requires focus on the reversible bleeding risk factors. Eur Heart J 2015; 36:3265. 5. Guo Y, Lane DA, Chen Y, et al. Regular Bleeding Risk Assessment Associated with Reduction in Bleeding Outcomes: The mAFA-II Randomized Trial. Am J Med 2020; 133:1195. 6. Fang MC, Go AS, Chang Y, et al. A new risk scheme to predict warfarin-associated hemorrhage: The ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study. 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Ezekowitz MD, Bridgers SL, James KE, et al. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. N Engl J Med 1992; 327:1406. 12. Connolly SJ, Laupacis A, Gent M, et al. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol 1991; 18:349. 13. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994; 154:1449. 14. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007; 146:857. 15. van Walraven C, Hart RG, Singer DE, et al. Oral anticoagulants vs aspirin in nonvalvular atrial fibrillation: an individual patient meta-analysis. JAMA 2002; 288:2441. 16. Cooper NJ, Sutton AJ, Lu G, Khunti K. Mixed comparison of stroke prevention treatments in individuals with nonrheumatic atrial fibrillation. Arch Intern Med 2006; 166:1269. 17. McNamara RL, Tamariz LJ, Segal JB, Bass EB. Management of atrial fibrillation: review of the evidence for the role of pharmacologic therapy, electrical cardioversion, and echocardiography. Ann Intern Med 2003; 139:1018. 18. Okumura K, Akao M, Yoshida T, et al. Low-Dose Edoxaban in Very Elderly Patients with Atrial Fibrillation. N Engl J Med 2020; 383:1735. 19. Friberg L, Rosenqvist M, Lip GY. Net clinical benefit of warfarin in patients with atrial fibrillation: a report from the Swedish atrial fibrillation cohort study. Circulation 2012; 125:2298. 20. Nielsen PB, Chao TF. The risks of risk scores for stroke risk assessment in atrial fibrillation. Thromb Haemost 2015; 113:1170. 21. Nielsen PB, Larsen TB, Skj th F, et al. Stroke and thromboembolic event rates in atrial fibrillation according to different guideline treatment thresholds: A nationwide cohort study. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 19/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Sci Rep 2016; 6:27410. 22. Quinn GR, Severdija ON, Chang Y, Singer DE. Wide Variation in Reported Rates of Stroke Across Cohorts of Patients With Atrial Fibrillation. Circulation 2017; 135:208. 23. Quinn GR, Severdija ON, Chang Y, et al. Methodologic Differences Across Studies of Patients With Atrial Fibrillation Lead to Varying Estimates of Stroke Risk. J Am Heart Assoc 2018; 7. 24. Shah SJ, Eckman MH, Aspberg S, et al. Effect of Variation in Published Stroke Rates on the Net Clinical Benefit of Anticoagulation for Atrial Fibrillation. Ann Intern Med 2018; 169:517. 25. Friberg L, Skeppholm M, Ter nt A. Benefit of anticoagulation unlikely in patients with atrial fibrillation and a CHA2DS2-VASc score of 1. J Am Coll Cardiol 2015; 65:225. 26. Chao TF, Liu CJ, Wang KL, et al. Using the CHA2DS2-VASc score for refining stroke risk stratification in 'low-risk' Asian patients with atrial fibrillation. J Am Coll Cardiol 2014; 64:1658. 27. Lip GY, Skj th F, Rasmussen LH, Larsen TB. Oral anticoagulation, aspirin, or no therapy in patients with nonvalvular AF with 0 or 1 stroke risk factor based on the CHA2DS2-VASc score. J Am Coll Cardiol 2015; 65:1385. 28. Bekwelem W, Connolly SJ, Halperin JL, et al. Extracranial Systemic Embolic Events in Patients With Nonvalvular Atrial Fibrillation: Incidence, Risk Factors, and Outcomes. Circulation 2015; 132:796. 29. Johnsen SP, Svendsen ML, Hansen ML, et al. Preadmission oral anticoagulant treatment and clinical outcome among patients hospitalized with acute stroke and atrial fibrillation: a nationwide study. Stroke 2014; 45:168. 30. Nielsen PB, Skj th F, Overvad TF, et al. Female Sex Is a Risk Modifier Rather Than a Risk Factor for Stroke in Atrial Fibrillation: Should We Use a CHA2DS2-VA Score Rather Than CHA2DS2-VASc? Circulation 2018; 137:832. 31. Singer DE, Chang Y, Fang MC, et al. The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Ann Intern Med 2009; 151:297. 32. Olesen JB, Lip GY, Lindhardsen J, et al. Risks of thromboembolism and bleeding with thromboprophylaxis in patients with atrial fibrillation: A net clinical benefit analysis using a 'real world' nationwide cohort study. Thromb Haemost 2011; 106:739. 33. Banerjee A, Lane DA, Torp-Pedersen C, Lip GY. Net clinical benefit of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus no treatment in a 'real world' atrial fibrillation population: a modelling analysis based on a nationwide cohort study. Thromb Haemost 2012; 107:584. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 20/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate 34. Go AS, Hylek EM, Chang Y, et al. Anticoagulation therapy for stroke prevention in atrial fibrillation: how well do randomized trials translate into clinical practice? JAMA 2003; 290:2685. 35. Hart RG, Pearce LA. Current status of stroke risk stratification in patients with atrial fibrillation. Stroke 2009; 40:2607. 36. Agarwal S, Hachamovitch R, Menon V. Current trial-associated outcomes with warfarin in prevention of stroke in patients with nonvalvular atrial fibrillation: a meta-analysis. Arch Intern Med 2012; 172:623. 37. Gallagher AM, van Staa TP, Murray-Thomas T, et al. Population-based cohort study of warfarin-treated patients with atrial fibrillation: incidence of cardiovascular and bleeding outcomes. BMJ Open 2014; 4:e003839. 38. Lip GYH, Banerjee A, Boriani G, et al. Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report. Chest 2018; 154:1121. 39. Provid ncia R, Trigo J, Paiva L, Barra S. The role of echocardiography in thromboembolic risk assessment of patients with nonvalvular atrial fibrillation. J Am Soc Echocardiogr 2013; 26:801. 40. Kezerle L, Tsadok MA, Akriv A, et al. Pre-Diabetes Increases Stroke Risk in Patients With Nonvalvular Atrial Fibrillation. J Am Coll Cardiol 2021; 77:875. 41. Proietti M, Romiti GF, Vitolo M, et al. Comparison of HAS-BLED and ORBIT bleeding risk scores in atrial fibrillation patients treated with non-vitamin K antagonist oral anticoagulants: a report from the ESC-EHRA EORP-AF General Long-Term Registry. Eur Heart J Qual Care Clin Outcomes 2022; 8:778. 42. Wattanaruengchai P, Nathisuwan S, Karaketklang K, et al. Comparison of the HAS-BLED versus ORBIT scores in predicting major bleeding among Asians receiving direct-acting oral anticoagulants. Br J Clin Pharmacol 2022; 88:2203. 43. Poli D, Antonucci E, Grifoni E, et al. Bleeding risk during oral anticoagulation in atrial fibrillation patients older than 80 years. J Am Coll Cardiol 2009; 54:999. 44. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). J Am Coll Cardiol. 2006; 48:e149. 45. Hughes M, Lip GY, Guideline Development Group for the NICE national clinical guideline for management of atrial fibrillation in primary and secondary care. Risk factors for https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 21/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate anticoagulation-related bleeding complications in patients with atrial fibrillation: a systematic review. QJM 2007; 100:599. 46. Fang MC, Go AS, Chang Y, et al. Death and disability from warfarin-associated intracranial and extracranial hemorrhages. Am J Med 2007; 120:700. 47. Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2021; 143:e72. 48. Van Gelder IC, Healey JS, Crijns HJGM, et al. Duration of device-detected subclinical atrial fibrillation and occurrence of stroke in ASSERT. Eur Heart J 2017; 38:1339. 49. Diederichsen SZ, Haugan KJ, Brandes A, et al. Natural History of Subclinical Atrial Fibrillation Detected by Implanted Loop Recorders. J Am Coll Cardiol 2019; 74:2771. 50. Chao TF, Liu CJ, Lin YJ, et al. Oral Anticoagulation in Very Elderly Patients With Atrial Fibrillation: A Nationwide Cohort Study. Circulation 2018; 138:37. 51. V zquez E, S nchez-Perales C, Borrego F, et al. Influence of atrial fibrillation on the morbido- mortality of patients on hemodialysis. Am Heart J 2000; 140:886. 52. Genovesi S, Pogliani D, Faini A, et al. Prevalence of atrial fibrillation and associated factors in a population of long-term hemodialysis patients. Am J Kidney Dis 2005; 46:897. 53. Vazquez E, Sanchez-Perales C, Garcia-Garcia F, et al. Atrial fibrillation in incident dialysis patients. Kidney Int 2009; 76:324. 54. Wetmore JB, Mahnken JD, Rigler SK, et al. The prevalence of and factors associated with chronic atrial fibrillation in Medicare/Medicaid-eligible dialysis patients. Kidney Int 2012; 81:469. 55. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001; 285:2370. 56. Pokorney SD, Black-Maier E, Hellkamp AS, et al. Oral Anticoagulation and Cardiovascular Outcomes in Patients With Atrial Fibrillation and End-Stage Renal Disease. J Am Coll Cardiol 2020; 75:1299. 57. US Renal Data System: USRDS 2005 Annual Data Report: Atlas of End-Stage Renal Disease in the United States. Bethesda, National Institutes of Health, National Institute of Diabetes, an d Digestive and Kidney Diseases, 2005. 58. Winkelmayer WC, Patrick AR, Liu J, et al. The increasing prevalence of atrial fibrillation among hemodialysis patients. J Am Soc Nephrol 2011; 22:349. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 22/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate 59. Yang F, Chou D, Schweitzer P, Hanon S. Warfarin in haemodialysis patients with atrial fibrillation: what benefit? Europace 2010; 12:1666. 60. Marinigh R, Lane DA, Lip GY. Severe renal impairment and stroke prevention in atrial fibrillation: implications for thromboprophylaxis and bleeding risk. J Am Coll Cardiol 2011; 57:1339. 61. Atar I, Kona D, A ikel S, et al. Frequency of atrial fibrillation and factors related to its development in dialysis patients. Int J Cardiol 2006; 106:47. 62. Abbott KC, Trespalacios FC, Taylor AJ, Agodoa LY. Atrial fibrillation in chronic dialysis patients in the United States: risk factors for hospitalization and mortality. BMC Nephrol 2003; 4:1. 63. K/DOQI Workgroup. K/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients. Am J Kidney Dis 2005; 45:S1. 64. Bozbas H, Atar I, Yildirir A, et al. Prevalence and predictors of arrhythmia in end stage renal disease patients on hemodialysis. Ren Fail 2007; 29:331. 65. Go AS, Fang MC, Udaltsova N, et al. Impact of proteinuria and glomerular filtration rate on risk of thromboembolism in atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Circulation 2009; 119:1363. 66. Olesen JB, Lip GY, Kamper AL, et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med 2012; 367:625. 67. Limdi NA, Beasley TM, Baird MF, et al. Kidney function influences warfarin responsiveness and hemorrhagic complications. J Am Soc Nephrol 2009; 20:912. 68. Nakayama M, Metoki H, Terawaki H, et al. Kidney dysfunction as a risk factor for first symptomatic stroke events in a general Japanese population the Ohasama study. Nephrol Dial Transplant 2007; 22:1910. 69. Rold n V, Mar n F, Manzano-Fernandez S, et al. Does chronic kidney disease improve the predictive value of the CHADS2 and CHA2DS2-VASc stroke stratification risk scores for atrial fibrillation? Thromb Haemost 2013; 109:956. 70. Kornej J, Hindricks G, Kosiuk J, et al. Renal dysfunction, stroke risk scores (CHADS2, CHA2DS2-VASc, and R2CHADS2), and the risk of thromboembolic events after catheter ablation of atrial fibrillation: the Leipzig Heart Center AF Ablation Registry. Circ Arrhythm Electrophysiol 2013; 6:868. 71. Ha JT, Neuen BL, Cheng LP, et al. Benefits and Harms of Oral Anticoagulant Therapy in Chronic Kidney Disease: A Systematic Review and Meta-analysis. Ann Intern Med 2019; 171:181. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 23/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate 72. Chan KE, Lazarus JM, Thadhani R, Hakim RM. Warfarin use associates with increased risk for stroke in hemodialysis patients with atrial fibrillation. J Am Soc Nephrol 2009; 20:2223. 73. Wizemann V, Tong L, Satayathum S, et al. Atrial fibrillation in hemodialysis patients: clinical features and associations with anticoagulant therapy. Kidney Int 2010; 77:1098. 74. Winkelmayer WC, Liu J, Setoguchi S, Choudhry NK. Effectiveness and safety of warfarin initiation in older hemodialysis patients with incident atrial fibrillation. Clin J Am Soc Nephrol 2011; 6:2662. 75. Shah M, Avgil Tsadok M, Jackevicius CA, et al. Warfarin use and the risk for stroke and bleeding in patients with atrial fibrillation undergoing dialysis. Circulation 2014; 129:1196. 76. Carrero JJ, Evans M, Szummer K, et al. Warfarin, kidney dysfunction, and outcomes following acute myocardial infarction in patients with atrial fibrillation. JAMA 2014; 311:919. 77. Bonde AN, Lip GY, Kamper AL, et al. Net clinical benefit of antithrombotic therapy in patients with atrial fibrillation and chronic kidney disease: a nationwide observational cohort study. J Am Coll Cardiol 2014; 64:2471. 78. Randhawa MS, Vishwanath R, Rai MP, et al. Association Between Use of Warfarin for Atrial Fibrillation and Outcomes Among Patients With End-Stage Renal Disease: A Systematic Review and Meta-analysis. JAMA Netw Open 2020; 3:e202175. 79. ACTIVE Writing Group of the ACTIVE Investigators, Connolly S, Pogue J, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006; 367:1903. 80. ACTIVE Investigators, Connolly SJ, Pogue J, et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009; 360:2066. 81. Tereshchenko LG, Henrikson CA, Cigarroa J, Steinberg JS. Comparative Effectiveness of Interventions for Stroke Prevention in Atrial Fibrillation: A Network Meta-Analysis. J Am Heart Assoc 2016; 5. 82. Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994; 120:897. 83. Sj lander S, Sj lander A, Svensson PJ, Friberg L. Atrial fibrillation patients do not benefit from acetylsalicylic acid. Europace 2014; 16:631. 84. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364:806. 85. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 24/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate trial. Lancet 1996; 348:633. 86. Gull v AL, Koefoed BG, Petersen P, et al. Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation: Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study. Arch Intern Med 1998; 158:1513. 87. Flaker GC, Gruber M, Connolly SJ, et al. Risks and benefits of combining aspirin with anticoagulant therapy in patients with atrial fibrillation: an exploratory analysis of stroke prevention using an oral thrombin inhibitor in atrial fibrillation (SPORTIF) trials. Am Heart J 2006; 152:967. 88. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 89. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. 90. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. Topic 128998 Version 11.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 25/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate GRAPHICS Comparison of the CHADS and CHA DS -VASc risk stratification scores for 2 patients with nonvalvular AF 2 2 Definition and scores for CHADS and Stroke risk stratification with the 2 CHA DS -VASc CHADS and CHA DS -VASc scores 2 2 2 2 2 Unadjusted ischemic stroke rate [1] CHADS acronym Score CHADS acronym 2 2 (% per year) Congestive HF 1 0 0.6 Hypertension 1 1 3.0 Age 75 years 1 2 4.2 Diabetes mellitus 1 3 7.1 Stroke/TIA/TE 2 4 11.1 Maximum score 6 5 12.5 6 13.0 Unadjusted ischemic stroke rate CHA DS -VASc 2 2 [2] CHA DS -VASc acronym Score 2 2 acronym (% per year) Congestive HF 1 0 0.2 Hypertension 1 1 0.6 Age 75 years 2 2 2.2 Diabetes mellitus 1 3 3.2 Stroke/TIA/TE 2 4 4.8 Vascular disease (prior MI, PAD, or 1 5 7.2 aortic plaque) Age 65 to 74 years 1 6 9.7 Sex category (ie, female sex) 1 7 11.2 Maximum score 9 8 10.8 9 12.2

63. K/DOQI Workgroup. K/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients. Am J Kidney Dis 2005; 45:S1. 64. Bozbas H, Atar I, Yildirir A, et al. Prevalence and predictors of arrhythmia in end stage renal disease patients on hemodialysis. Ren Fail 2007; 29:331. 65. Go AS, Fang MC, Udaltsova N, et al. Impact of proteinuria and glomerular filtration rate on risk of thromboembolism in atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Circulation 2009; 119:1363. 66. Olesen JB, Lip GY, Kamper AL, et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N Engl J Med 2012; 367:625. 67. Limdi NA, Beasley TM, Baird MF, et al. Kidney function influences warfarin responsiveness and hemorrhagic complications. J Am Soc Nephrol 2009; 20:912. 68. Nakayama M, Metoki H, Terawaki H, et al. Kidney dysfunction as a risk factor for first symptomatic stroke events in a general Japanese population the Ohasama study. Nephrol Dial Transplant 2007; 22:1910. 69. Rold n V, Mar n F, Manzano-Fernandez S, et al. Does chronic kidney disease improve the predictive value of the CHADS2 and CHA2DS2-VASc stroke stratification risk scores for atrial fibrillation? Thromb Haemost 2013; 109:956. 70. Kornej J, Hindricks G, Kosiuk J, et al. Renal dysfunction, stroke risk scores (CHADS2, CHA2DS2-VASc, and R2CHADS2), and the risk of thromboembolic events after catheter ablation of atrial fibrillation: the Leipzig Heart Center AF Ablation Registry. Circ Arrhythm Electrophysiol 2013; 6:868. 71. Ha JT, Neuen BL, Cheng LP, et al. Benefits and Harms of Oral Anticoagulant Therapy in Chronic Kidney Disease: A Systematic Review and Meta-analysis. Ann Intern Med 2019; 171:181. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 23/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate 72. Chan KE, Lazarus JM, Thadhani R, Hakim RM. Warfarin use associates with increased risk for stroke in hemodialysis patients with atrial fibrillation. J Am Soc Nephrol 2009; 20:2223. 73. Wizemann V, Tong L, Satayathum S, et al. Atrial fibrillation in hemodialysis patients: clinical features and associations with anticoagulant therapy. Kidney Int 2010; 77:1098. 74. Winkelmayer WC, Liu J, Setoguchi S, Choudhry NK. Effectiveness and safety of warfarin initiation in older hemodialysis patients with incident atrial fibrillation. Clin J Am Soc Nephrol 2011; 6:2662. 75. Shah M, Avgil Tsadok M, Jackevicius CA, et al. Warfarin use and the risk for stroke and bleeding in patients with atrial fibrillation undergoing dialysis. Circulation 2014; 129:1196. 76. Carrero JJ, Evans M, Szummer K, et al. Warfarin, kidney dysfunction, and outcomes following acute myocardial infarction in patients with atrial fibrillation. JAMA 2014; 311:919. 77. Bonde AN, Lip GY, Kamper AL, et al. Net clinical benefit of antithrombotic therapy in patients with atrial fibrillation and chronic kidney disease: a nationwide observational cohort study. J Am Coll Cardiol 2014; 64:2471. 78. Randhawa MS, Vishwanath R, Rai MP, et al. Association Between Use of Warfarin for Atrial Fibrillation and Outcomes Among Patients With End-Stage Renal Disease: A Systematic Review and Meta-analysis. JAMA Netw Open 2020; 3:e202175. 79. ACTIVE Writing Group of the ACTIVE Investigators, Connolly S, Pogue J, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006; 367:1903. 80. ACTIVE Investigators, Connolly SJ, Pogue J, et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009; 360:2066. 81. Tereshchenko LG, Henrikson CA, Cigarroa J, Steinberg JS. Comparative Effectiveness of Interventions for Stroke Prevention in Atrial Fibrillation: A Network Meta-Analysis. J Am Heart Assoc 2016; 5. 82. Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994; 120:897. 83. Sj lander S, Sj lander A, Svensson PJ, Friberg L. Atrial fibrillation patients do not benefit from acetylsalicylic acid. Europace 2014; 16:631. 84. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364:806. 85. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 24/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate trial. Lancet 1996; 348:633. 86. Gull v AL, Koefoed BG, Petersen P, et al. Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation: Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study. Arch Intern Med 1998; 158:1513. 87. Flaker GC, Gruber M, Connolly SJ, et al. Risks and benefits of combining aspirin with anticoagulant therapy in patients with atrial fibrillation: an exploratory analysis of stroke prevention using an oral thrombin inhibitor in atrial fibrillation (SPORTIF) trials. Am Heart J 2006; 152:967. 88. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 89. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. 90. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. Topic 128998 Version 11.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 25/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate GRAPHICS Comparison of the CHADS and CHA DS -VASc risk stratification scores for 2 patients with nonvalvular AF 2 2 Definition and scores for CHADS and Stroke risk stratification with the 2 CHA DS -VASc CHADS and CHA DS -VASc scores 2 2 2 2 2 Unadjusted ischemic stroke rate [1] CHADS acronym Score CHADS acronym 2 2 (% per year) Congestive HF 1 0 0.6 Hypertension 1 1 3.0 Age 75 years 1 2 4.2 Diabetes mellitus 1 3 7.1 Stroke/TIA/TE 2 4 11.1 Maximum score 6 5 12.5 6 13.0 Unadjusted ischemic stroke rate CHA DS -VASc 2 2 [2] CHA DS -VASc acronym Score 2 2 acronym (% per year) Congestive HF 1 0 0.2 Hypertension 1 1 0.6 Age 75 years 2 2 2.2 Diabetes mellitus 1 3 3.2 Stroke/TIA/TE 2 4 4.8 Vascular disease (prior MI, PAD, or 1 5 7.2 aortic plaque) Age 65 to 74 years 1 6 9.7 Sex category (ie, female sex) 1 7 11.2 Maximum score 9 8 10.8 9 12.2 AF: atrial fibrillation; CHADS : Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, prior Stroke or TIA or thromboembolism (doubled); CHA DS -VASc: Congestive heart failure, Hypertension, Age 75 years (doubled), Diabetes mellitus, prior Stroke or TIA or thromboembolism 2 2 2 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 26/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate (doubled), Vascular disease, Age 65 to 74 years, Sex category; HF: heart failure; TIA: transient ischemic attack; TE: thromboembolism; MI: myocardial infarction; PAD: peripheral artery disease. [3] These unadjusted (not adjusted for possible use of aspirin) stroke rates were published in 2012 . Actual rates of stroke in contemporary cohorts might vary from these estimates. References: 1. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classi cation schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001; 285:2864. 2. Lip GYH, Nieuwlaat R, Pisters R, et al. Re ning clinical risk strati cation for predicting stroke and thromboembolism in atrial brillation using a novel risk factor-based approach: the euro heart survey on atrial brillation. Chest 2010; 137:263. 3. Friberg L, Rosenqvist M, Lip GY. Evaluation of risk strati cation schemes for ischaemic stroke and bleeding in 182 678 patients with atrial brillation: the Swedish Atrial Fibrillation cohort study. Eur Heart J 2012; 33:1500. Original table and unadjusted ischemic stroke rates, as noted above, have been modi ed for this publication. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64:e1. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 94752 Version 14.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 27/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Possible contraindications to anticoagulation Possible contraindication Factors to consider Active, clinically significant Site and degree of bleeding (eg, nosebleeds and menses generally bleeding are not a contraindication; active intracerebral bleeding is almost always an absolute contraindication), interval since bleeding stopped Severe bleeding diathesis Nature, severity, and reversibility of bleeding diathesis Severe thrombocytopenia (platelet count <50,000/microL) Absolute platelet count, platelet count trend, and platelet function (eg, some individuals with ITP and a platelet count in the range of 30,000 to 50,000 may tolerate anticoagulation if needed) Major trauma Site and extent of trauma, time interval since event (eg, for a patient with a mechanical heart valve it may be appropriate to anticoagulate sooner after trauma than a patient with a lesser indication) Invasive procedure or obstetric delivery (recent, emergency, or planned) Type of procedure and associated bleeding risk, interval between procedure and anticoagulation Previous intracranial hemorrhage Time interval since hemorrhage and underlying cause (eg, trauma or uncontrolled hypertension) Intracranial or spinal tumor Site and type of tumor, other comorbidities Neuraxial anesthesia Interval since spinal/epidural puncture or catheter removal, other alternatives for anesthesia; traumatic procedures are more concerning Severe, uncontrolled hypertension Absolute blood pressure and blood pressure trend This list does not take the place of clinical judgment in deciding whether or not to administer an anticoagulant. In any patient, the risk of bleeding from an anticoagulant must be weighed against the risk of thrombosis and its consequences. The greater the thromboembolic risk, the greater the tolerance for the possibility of bleeding and for shortening the time interval between an episode of bleeding and anticoagulant initiation. Refer to UpToDate content on the specific indication for the anticoagulant and the specific possible contraindication for discussions of these risks. ITP: immune thrombocytopenia. Graphic 107527 Version 4.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 28/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Clinical characteristics comprising the HAS-BLED bleeding risk score Letter Clinical characteristic* Points H Hypertension (ie, uncontrolled blood pressure) 1 A Abnormal renal and liver function (1 point each) 1 or 2 S Stroke 1 B Bleeding tendency or predisposition 1 L Labile INRs (for patients taking warfarin) 1 E Elderly (age greater than 65 years) 1 D Drugs (concomitant aspirin or NSAIDs) or excess alcohol use (1 point each) 1 or 2 Maximum 9 points HAS-BLED score (total points) Bleeds per 100 patient-years 0 1.13 1 1.02 2 1.88 3 3.74 4 8.70 5 to 9 Insufficient data The HAS-BLED bleeding risk score has only been validated in patients with atrial fibrillation receiving warfarin. Refer to UpToDate topics on anticoagulation in patients with atrial fibrillation and on specific anticoagulants for further information and other bleeding risk scores and their performance relative to clinical judgment. INR: international normalized ratio; NSAIDs: nonsteroidal antiinflammatory drugs. Hypertension is defined as systolic blood pressure >160 mmHg. Abnormal renal function is defined as the presence of chronic dialysis, renal transplantation, or serum creatinine 200 micromol/L. Abnormal liver function is defined as chronic hepatic disease (eg, cirrhosis) or biochemical evidence of significant hepatic derangement (eg, bilirubin more than 2 times the upper limit of normal, plus 1 or more of aspartate transaminase, alanine transaminase, and/or alkaline phosphatase more than 3 times the upper limit of normal). Bleeding predisposition includes chronic bleeding disorder or https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 29/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate previous bleeding requiring hospitalization or transfusion. Labile INRs for a patient on warfarin include unstable INRs, excessively high INRs, or <60% time in therapeutic range. Based on initial validation cohort from Pisters R. A novel-user-friendly score (HAS-BLED) to assess 1- year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010; 138:1093. Actual rates of bleeding in contemporary cohorts may vary from these estimates. Original gure modi ed for this publication. Lip GY. Implications of the CHA2DS2-VASc and HAS-BLED Scores for thromboprophylaxis in atrial brillation. Am J Med 2011; 124:111. Table used with the permission of Elsevier Inc. All rights reserved. Graphic 75259 Version 16.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 30/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Benefit of warfarin in chronic atrial fibrillation Efficacy of anticoagulation with warfarin to prevent ischemic stroke and other thromboemboli in 4 major studies. An intention to treat approach was used, and transient ischemic attack and hemorrhage were excluded. The numbers at the top represent the risk reduction with warfarin therapy, which ranged from 45 to 82%. SPAF: Stroke Prevention in Atrial Fibrillation; AFASAK: Copenhagen AFASAK Study; BAATAF: Boston Area Anticoagulation Trial for Atrial Fibrillation; CAFA: Canadian Atrial Fibrillation Anticoagulation Study. The data in the warfarin group in the SPAF assumes that half of the events were attributable to warfarin toxicity. Data from: Connolly SJ, Laupacis AN, Gent M, et al. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol 1991; 18:349. Graphic 79839 Version 4.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 31/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Trials comparing direct oral anticoagulants versus warfarin in atrial fibrillation Baseline characteristics Trial details of trial participants Trial N Percent Mean CHADS score Study drug (DOAC) and dose 2 on aspirin Compariso RE-LY 18,113 2.1 40% Dabigatran 110 mg twice Warfarin (target IN daily or 150 mg twice daily 3.0) ROCKET- 14,264 3.5 36% Rivaroxaban 20 mg once Warfarin (target IN AF daily* 3.0) ARISTOTLE 18,201 2.1 31% Apixaban 5 mg twice daily Warfarin (target IN 3.0) ENGAGE AF-TIMI 48 21,105 2.8 29% Edoxaban 30 mg once daily or 60 mg once daily Warfarin (target IN 3.0) Event rates for key outcomes Stroke or systemic Death Hemorrhagic s embolic event Trial Relative effect (95% CI) Relative effect (95% CI) DOAC Warfarin DOAC Warfarin DOAC Warfarin RE-LY 110 3.75 4.13 RR 0.91 1.53 1.69 RR 0.91 0.12 0.38 mg (0.8- 1.03) (0.74- 1.11) 150 3.64 4.13 RR 0.88 1.11 1.69 RR 0.66 0.10 0.38 mg (0.77- (0.53- 1.00) 0.82) ROCKET-AF 4.5 4.9 HR 0.92 (0.82- 2.1 2.4 HR 0.88 (0.75- 0.26 0.44 1.03) 1.03) ARISTOTLE 3.52 3.94 HR 0.89 (0.80- 1.27 1.60 HR 0.79 (0.66- 0.24 0.47 0.998) 0.95) ENGAGE 30 mg 3.80 4.35 HR 0.87 2.04 1.80 HR 1.13 0.16 0.47 AF-TIMI 48 (0.79- 0.96) (0.96- 1.34) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 32/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate ENGAGE AF-TIMI 48 60 mg 3.99 4.35 HR 0.92 (0.83- 1.57 1.80 HR 0.87 (0.73- 0.26 0.47 1.01) 1.04) Combined results 6.90 7.68 RR 0.90 (0.85- 3.11 3.79 RR 0.81 (0.73- 0.44 0.90 0.95) 0.91) DOAC: direct oral anticoagulant; AF: atrial fibrillation; N: number of trial participants; CHADS : score 2 to estimate risk of stroke with 1 point assigned for each of the following clinical features: history of congestive heart failure, hypertension, age 75 years, or diabetes mellitus, and 2 points assigned for prior stroke or transient ischemic attack; INR: international normalized ratio; HR: hazard ratio; RR: relative risk. Dose of rivaroxaban was adjusted to 15 mg once daily for renal insufficiency (creatinine clearance 30 to 49 mL/minute [0.5 to 0.82 mL/second]). Dose of apixaban was adjusted to 2.5 mg twice daily for patients with two or more of: age 80 years, body weight 60 kg, or renal insufficiency (serum creatinine level 1.5 mg/dL [133 micromol/L]). For patients in either dose group, the dose of edoxaban was reduced by 50% if any of the following characteristics were present: estimated creatinine clearance 30 to 50 mL/minute, body weight 60 kg, or concomitant use of verapamil, quinidine, or dronedarone. For the individual trials, the annual event rate (expressed as %/year) is presented for each outcome. For the meta-analysis, the table provides the absolute event rates (%) during the total study duration, which varied between studies (median follow-up 1.8 to 2.8 years). Major bleeding was variably defined. In RE-LY, it was defined as a reduction in hemoglobin of at least 2 g/dL [20 g/L], transfusion of 2 units of blood, or symptomatic bleeding in a critical area or organ. In ROCKET-AF, ARISTOTLE, and ENGAGE AF-TIMI 48, it was defined as fatal bleeding, bleeding at a critical site, or overt bleeding plus fall in hemoglobin of at least 2 g/dL [20 g/L] or transfusion of 2 units of blood. For ROCKET-AF, the results for hemorrhagic stroke and for bleeding are based on an as-treated safety population. These combined results include data for dabigatran 150 mg twice daily, rivaroxaban 20 mg once daily, apixaban 5 mg twice daily, and edoxaban 60 mg once daily. Data from: 1. Connolly SJ, Ezekowitz MD, Eikelbloom YS, et al. Dabigatran versus warfarin in patients with atrial brillation; N Engl J Med 2009; 361:1139. 2. Patel MR, Maha ey KE, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial brillation; N Engl J Med 2011; 365:883. 3. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial brillation; N Engl J Med 2011; 365:981. 4. Giugliano RP, Ru CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial brillation. N Engl J Med 2013; 369:2093. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 33/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate 5. Ru CT, Giugliano RP, Braunwald E, et al. Comparison of the e cacy and safety of new oral anticoagulants with warfarin in patients with atrial brillation: a meta-analysis of randomised trials. Lancet 2014; 383:955. Graphic 131871 Version 2.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 34/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate ATRIA stroke risk model point scoring system Points without prior Risk factor Points with prior stroke stroke Age, y 85 6 9 75 to 84 5 7 65 to 74 3 7 <65 0 8 Female 1 1 Diabetes 1 1 CHF 1 1 Hypertension 1 1 Proteinuria 1 1 eGFR <45 or ESRD 1 1 Possible point scores range from 0 to 12 for those without a prior stroke and from 7 to 15 for those with a prior stroke. ATRIA: Anticoagulation and Risk Factors in Atrial Fibrillation; CHF: congestive heart failure; eGFR: estimated glomerular filtration rate; ESRD: end-stage renal disease. Reprinted with permission. J Am Heart Assoc 2013; 2:e000250. Copyright 2013 American Heart Association, Inc. Graphic 90032 Version 1.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 35/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Staging of patients who meet the definition of CKD GFR and albuminuria grid to reflect the risk of progression by intensity of coloring (green, yellow, orange, red, deep red). The numbers in the boxes are a guide to the frequency of monitoring (number of times per year). GFR: glomerular filtration rate. Reprinted by permission from: Macmillan Publishers Ltd: Kidney International. KDIGO. Summary of recommendation statements. Kidney Int 2013; 3(Suppl):5. Copyright 2013. http://www.nature.com/ki/index.html. Graphic 59716 Version 7.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 36/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Prevalence of atrial fibrillation in chronic kidney disease patients The prevalence (percent) of atrial fibrillation in the general population and different cohorts of patients with CKD are shown: While patients with peritoneal dialysis appear to suffer less frequently from atrial fibrillation, in those on hemodialysis, the prevalence was observed to be 10- to 20-fold higher than in the general population. Age was in all groups a key factor. CKD: chronic kidney disease. Reproduced with permission from: Reinecke H, Brand E, Mesters R, et al. Dilemmas in the management of atrial brillation in chronic kidney disease. J Am Soc Nephrol 2009; 20:705. Copyright 2009 American Society of Nephrology. Graphic 55373 Version 6.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 37/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Meta-analysis of randomized controlled trials of warfarin and aspirin for primary prevention of stroke in atrial fibrillation Stroke Major bleeding Comparison Odds ratio, p Odds ratio, 95 p 95% CI value percent CI value Conventional dose warfarin versus placebo 0.31 (0.19 to 0.50) <0.001 1.88 (0.88 to 4.0) 0.10 Aspirin versus placebo 0.68 (0.46 to 0.06 0.82 (0.37 to 1.78) >0.2 1.02) Conventional dose warfarin versus aspirin 0.66 (0.45 to 0.04 1.61 (0.75 to 3.44) >0.2 0.99) Conventional dose warfarin versus low dose warfarin 0.52 (0.25 to 1.08) 0.08 2.21 (0.67 to 7.25) 0.19 Conventional dose warfarin versus low dose warfarin plus aspirin 0.44 (0.14 to 1.39) 0.16 1.14 (0.55 to 2.36) >0.2 Low dose warfarin versus aspirin 1.01 (0.49 to 2.06) >0.2 1.04 (0.43 to 2.48) >0.2 NOTE: The data in this table cannot be directly applied to clinical practice (an individual patient) since the decision to use warfarin or aspirin is importantly related to a patient's estimated risk of embolic events. Adapted from McNamara RL, Tamariz LJ, Segal JB, Bass EB. Ann Intern Med 2004; 139:1018. Graphic 66736 Version 2.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 38/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Low-dose warfarin plus aspirin is not optimal in high-risk AF Cumulative event rate of patients with AF at high risk for thromboembolism in the SPAF III trial. High risk was defined as the presence of at least 1 of the following: previous thromboembolism, female older than 75 years of age, heart failure or severe left ventricular systolic dysfunction, and systolic pressure >160 mmHg. There was a much lower incidence of events with standard adjusted- dose warfarin therapy (INR 2 to 3) compared with treatment with aspirin and low-dose warfarin (INR 1.2 to 1.5; p<0.0001). AF: atrial fibrillation; INR: international normalized ratio. Data from Stroke Prevention in Atrial Fibrillation Investigators. Lancet 1996; 348:633. Graphic 72790 Version 3.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 39/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Increased stroke risk with low-dose warfarin plus aspirin in AF Results from the SPAF III trial of high-risk patients showing significantly higher event rates for intracranial hemorrhage and ischemic stroke in patients treated with fixed low-dose warfarin plus aspirin compared with standard adjusted-dose warfarin. The risk was greater in those with a previous thromboembolic event. AF: atrial fibrillation. Data from Stroke Prevention in Atrial Fibrillation Investigators. Lancet 1996; 348:633. Graphic 62833 Version 2.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 40/41 7/5/23, 11:45 AM Atrial fibrillation in adults: Selection of candidates for anticoagulation - UpToDate Contributor Disclosures Warren J Manning, MD Equity Ownership/Stock Options: Pfizer [Anticoagulants]. All of the relevant financial relationships listed have been mitigated. Daniel E Singer, MD Grant/Research/Clinical Trial Support: Bristol-Myers Squibb [Screening for atrial fibrillation]. Consultant/Advisory Boards: Bristol-Myers Squibb [Atrial fibrillation and stroke]; Fitbit [Screening for atrial fibrillation]; Medtronic [Atrial fibrillation and stroke]. All of the relevant financial relationships listed have been mitigated. Gregory YH Lip, MD, FRCPE, FESC, FACC Consultant/Advisory Boards: BMS/Pfizer [Atrial fibrillation and thrombosis]; Boehringer Ingelheim [Atrial fibrillation and thrombosis]; Daiichi-Sankyo [Atrial fibrillation and thrombosis]. Speaker's Bureau: BMS/Pfizer [Atrial fibrillation and thrombosis]; Boehringer Ingelheim [Atrial fibrillation and thrombosis]; Daiichi-Sankyo [Atrial fibrillation and thrombosis]. All of the relevant financial relationships listed have been mitigated. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/atrial-fibrillation-in-adults-selection-of-candidates-for-anticoagulation/print 41/41

7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Atrial fibrillation in adults: Use of oral anticoagulants : Warren J Manning, MD, Daniel E Singer, MD, Gregory YH Lip, MD, FRCPE, FESC, FACC : Peter J Zimetbaum, MD, Scott E Kasner, MD, Bradley P Knight, MD, FACC : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 16, 2022. INTRODUCTION Most patients with atrial fibrillation (AF) should receive long-term oral anticoagulation to decrease the risk of ischemic stroke and other embolic events. For most patients, the benefit from anticoagulation outweighs the associated increase in the risk of bleeding. The use of anticoagulant therapy for patients with AF who are not pregnant (excluding those 2 with rheumatic mitral stenosis that is moderate or severe [mitral valve area 1.5 cm ], a bioprosthetic valve within three to six months of implantation, or a mechanical heart valve) will be reviewed here. Management for patients with valve disease is briefly discussed in a section below that provides links to related topics on these specific valve conditions. (See 'Patients with valvular heart disease' below.) Related topics include: (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) Anticoagulation for atrial fibrillation during pregnancy. (See "Supraventricular arrhythmias during pregnancy", section on 'Atrial fibrillation and flutter' and "Use of anticoagulants during pregnancy and postpartum".) (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) (See "Stroke in patients with atrial fibrillation".) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 1/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate (See "Atrial fibrillation: Left atrial appendage occlusion".) (Related Pathway(s): Atrial fibrillation: Anticoagulation for adults with atrial fibrillation.) APPROACH TO ANTICOAGULATION Choice of anticoagulant For patients with AF, we suggest the following sequential steps (related Pathway(s): Atrial fibrillation: Anticoagulation for adults with atrial fibrillation): Determine if anticoagulation is indicated. The identification of patients who should receive long-term oral anticoagulation is discussed separately. Prior to initiation of anticoagulant therapy, possible contraindications should be weighed ( table 1). (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) Select an anticoagulant. The following discussion applies to patients who are not pregnant. Selection of anticoagulant for use during pregnancy is discussed separately. (See "Supraventricular arrhythmias during pregnancy", section on 'Anticoagulation' and "Use of anticoagulants during pregnancy and postpartum".) For most patients with AF with an indication for anticoagulation, we recommend a direct oral anticoagulant (DOAC) rather than vitamin K antagonist (VKA; eg, warfarin). For most patients with AF who have been treated with warfarin with an annual time in the therapeutic range (TTR) of at least 70 percent, we suggest consideration of switching to a DOAC. However, it is reasonable to continue VKA in these patients for financial or other preferences. Exceptions to the general preference for use of DOAC rather than VKA in patients with AF with an indication for anticoagulation include: Clinical settings in which VKA (eg, warfarin; target international normalized ratio [INR] 2.0 to 3.0; TTR 70 percent) is the agent of choice and in which DOAC should not be used (see 'Patients with valvular heart disease' below): Patients with a mechanical heart valve of any type and location. (See "Antithrombotic therapy for mechanical heart valves".) Patients with rheumatic mitral stenosis that is severe or clinically significant (mitral 2 valve area 1.5 cm ). (See "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism'.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 2/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Patients for whom the DOAC agents are avoided due to drug interactions (eg, those receiving P-glycoprotein drug efflux pump [P-gp] inducers, which can decrease the anticoagulant effect of DOACs and chronic antiviral agents, which may increase the anticoagulant effect of DOACs) ( table 2A-C) [1]. (See 'Drug interactions' below and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".) Clinical settings in which VKA is reasonable or preferable to DOAC: For patients who are not likely to comply with the twice daily dosing of dabigatran or apixaban and who are unable to take once-a-day rivaroxaban or edoxaban due to intolerance. For patients for whom the DOAC agents will lead to an unacceptable increase in patient cost. For patients with chronic severe kidney disease whose creatinine clearance (CrCl by Cockcroft-Gault equation) is less than 25 to 30 mL/min. VKA is generally preferred in this setting, although some clinicians prescribe apixaban for selected patients in this setting, as described below. (See 'Chronic kidney disease' below.) Evidence supporting this approach comes from randomized trials in patients with nonvalvular AF in which DOAC use resulted in similar or lower rates of both ischemic stroke and major bleeding compared with treatment with adjusted-dose warfarin (INR of 2.0 to 3.0) ( table 3) [2-8]. Important additional advantages of the DOAC agents include a high relative but small absolute reduction in the risk of intracranial hemorrhage (ICH), convenience (no requirement for routine testing of the INR), lack of susceptibility to dietary interactions, and markedly reduced susceptibility to drug interactions [3-6]. Disadvantages of DOAC include lack of efficacy and safety data in patients with severe chronic kidney disease, lack of easily available monitoring of blood levels and compliance, and higher patient cost in some health care settings. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Chronic kidney disease'.) A meta-analysis including the RE-LY (dabigatran) [3,9], ARISTOTLE (apixaban) [5], ROCKET AF (rivaroxaban) [4], and ENGAGE AF-TIMI 48 (edoxaban) [10] trials supports the broad conclusion that DOAC agents are preferable to adjusted-dose VKA for most patients [2]. Compared with VKA (warfarin), DOAC reduced rates of mortality, stroke or systemic embolic event, and hemorrhagic stroke ( table 3). https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 3/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Regarding the relative efficacy and safety of the DOAC agents, no randomized controlled trials (RCTs) directly comparing the DOACs have been published. Published observational studies have many limitations and are no substitute for head to head RCTs [11-16]. Initiation DOAC For patients with AF starting DOAC, effective anticoagulation is achieved within a few hours. We do not use heparin to bridge patients starting DOAC. For patients prescribed one of the DOACs, we suggest that clinicians review dosing recommendations from regulatory agencies and available in drug information compendia such as Lexicomp. (See 'Dosing' below.) Vitamin K antagonist Protocols for initiating VKA (eg, warfarin) are discussed separately. All patients should have an INR measured before starting therapy. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Warfarin administration' and 'Dosing' below.) For patients with AF starting VKA (eg, warfarin): With no intracardiac thrombus or prior history of thromboembolism, the risk of a thromboembolic event during the several days typically required to achieve therapeutic anticoagulation with warfarin is generally very low. Thus, it is reasonable for outpatients to initiate warfarin without low molecular weight heparin bridging. (See "Warfarin and other VKAs: Dosing and adverse effects".) With high risk of thromboembolism (eg, prior cerebrovascular event/transient ischemic attack or current intracardiac thrombus) and low risk of ICH, initiation of warfarin with a heparin bridging regimen may be reasonable in some clinical settings (eg, patient who is hospitalized for another condition such as heart failure and has no acute stroke) although there is no high quality evidence to support this approach. Management for patients with acute stroke is discussed below. (See 'Acute stroke' below.) Dosing DOACs Dosing recommendations for DOACs are largely derived from the doses tested in the randomized clinical trials ( table 3) [3-5,10,17,18]. Given differences in the characteristics and availability of DOACs, it is important for practitioners to develop familiarity with the clinical use of multiple DOAC agents. DOACs are generally administered at fixed doses without laboratory monitoring. Use in patients with chronic kidney disease is discussed below. (See 'Chronic kidney disease' below.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 4/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Use of these agents including drug interactions ( table 2A-C) and dosing in patients with chronic renal insufficiency is presented separately. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Direct factor Xa inhibitors' and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Direct thrombin inhibitors'.): Apixaban The dose of apixaban is 5 mg twice daily (approximately 12 hours apart) unless the patient has two or more of the following: age 80 years, body weight 60 kg, or serum creatinine level 1.5 mg/dL [133 micromol/L]). Then the dose of apixaban is 2.5 mg twice daily. This dose adjustment is for moderate renal impairment. Data are lacking to inform use in patients with CrCL <15 mL/min or on dialysis. (See 'Chronic kidney disease' below.) Dabigatran For patients with CrCl >30 mL/min, the dose is 150 mg twice daily (approximately 12 hours apart). For most patients prescribed dabigatran, we suggest the 150 mg twice daily dose, as opposed to the 110 mg dose, based upon the results of the RE-LY trial. Where available, the 110 mg twice daily dose may be preferred in patients assessed to be at increased risk of bleeding or who are particularly concerned about the risk of bleeding. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".) For patients with CrCL 15 to 30 mL/min, the dose is 75 mg orally, twice daily. Concomitant use of a P-gp inhibitor or antiviral should be avoided. We generally avoid use of dabigatran in this setting. (See 'Choice of anticoagulant' below.) For patients with CrCl <15 mL/min or on dialysis, no dosing recommendations are available. We avoid use of dabigatran in this setting. (See 'Choice of anticoagulant' below.) Edoxaban dosing varies according to the estimated glomerular filtration rate: For patients with a Cockcroft-Gault equation CrCl >95 mL/min, edoxaban should not be used due to lesser efficacy compared with warfarin in preventing stroke in this group due to high renal clearance. For such patients, another DOAC is an alternative. For patients with a CrCl of >50 to 95 mL/min, an edoxaban dose of 60 mg once daily is used. For patients with a CrCl of 15 to 50 mL/min, the dose is 30 mg once daily. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 5/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate For patients with a CrCl of <15 mL/min, there are limited data, so edoxaban is avoided in these patients. For patients 65 years of age and with at least one of the following characteristics, the dose is 30 mg once daily: weight 60 kg or concomitant use of potent P-glycoprotein inhibitors (eg, verapamil, quinidine). For patients with advanced age ( 80 years) and low body weight (ie, 45 kg or 60 kg plus an additional risk factor), a lower dose of edoxaban (15 mg once daily) may be safe and effective. This approach is supported by the results of the ELDERCARE-AF trial in which 984 Japanese patients age 80 years or older were randomly assigned to receive edoxaban 15 mg or placebo daily [19]. The mean body weight of participants was low (50.6 11 kg). All patients were considered inappropriate candidates for standard oral anticoagulant regimens due to one or more of the following concerns: a low CrCL ( 15 and <30 mL/min), a history of bleeding, low body weight ( 45 kg), or use of a nonsteroidal antiinflammatory drug or an antiplatelet drug. The annualized rate of stroke or systemic embolism was 2.3 and 6.7 percent in the two groups, respectively (hazard ratio [HR] 0.34, 95% CI 0.19-0.61), and the rate of major bleeding was 3.3 and 1.8 percent, respectively (HR 1.87, 95% CI 0.90-3.89). ICH was rare in both groups (0.3 and 0.6 percent). In a prespecified subanalysis of this trial, findings were largely similar across different categories of renal dysfunction (ie, mild, moderate, and severe) [20]. (See 'Older adults' below.) Rivaroxaban If the CrCl is >50 mL/min, the rivaroxaban dose is 20 mg once daily with the largest meal of the day (>500 calories), usually the evening meal. If the CrCl is 15 to 50 mL/min, the rivaroxaban dose is 15 mg once daily with the largest meal of the day (>500 calories). If the CrCl <15 mL/min, avoid use of rivaroxaban. (See 'Chronic kidney disease' below.) Vitamin K antagonist For patients with AF treated with VKA (eg, warfarin), an INR between 2.0 and 3.0 is recommended with an average annual TTR >70 percent [21,22]. This is based upon the increased risk of stroke observed with INR values significantly below 2 (four- to sixfold at an INR of 1.3 compared with an INR of 2 or above) and the increased risk of bleeding associated with INR above 3.0 ( figure 1) [23-27]. Dosing of warfarin is discussed in detail separately. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Warfarin administration'.) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 6/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Advanced age (over 74 years) is an independent risk factor for bleeding during anticoagulation as well as a risk factor for stroke. However, we recommend an INR between 2.0 and 3.0 for these patients as well [27]. Temporary interruption of anticoagulation Temporary interruption of oral anticoagulation for reasons of bleeding or urgent/elective surgery/invasive procedure results in an increased risk of thromboembolism after the period of effective anticoagulation has ended [28]. The optimal approach to such patients is unclear and likely depends on issues such as baseline thromboembolic risk, duration of anticoagulant interruption, and bleeding risk. These issues are discussed in detail separately. (See "Perioperative management of patients receiving anticoagulants" and "Management of anticoagulants in patients undergoing endoscopic procedures" and "Use of anticoagulants during pregnancy and postpartum" and "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Urgent surgery/procedure'.) The discussion of the management of anticoagulant therapy in the patient undergoing percutaneous coronary intervention is found separately [29,30]. (See "Periprocedural management of antithrombotic therapy in patients receiving long-term oral anticoagulation and undergoing percutaneous coronary intervention", section on 'Elective patients'.) The reversal of the anticoagulant effect of warfarin and DOAC agents is discussed separately. (See "Management of warfarin-associated bleeding or supratherapeutic INR" and "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Anticoagulant reversal'.) Anticoagulant failure Thromboembolic events occur despite adequate anticoagulation in patients with AF. Predictors of these events include (see "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Atrial fibrillation'): Transesophageal echocardiographic (TEE) evidence of dense spontaneous echo contrast and low left atrial appendage ejection velocity [31]. TEE evidence of complex aortic plaque [31]. TEE-detected thrombi can be related to clinical risk factors [32]. (See "Pathophysiology of ischemic stroke", section on 'Stroke subtypes'.) Subtherapeutic INR on VKA [33] or noncompliance in patients taking DOAC agents. Elevated D-dimer levels. In a single-center, prospective, observational study of 269 patients, D-dimer levels were elevated (at least 0.5 mcg/mL) in 23 percent, and elevated levels were significantly associated with a higher rate of thromboembolism (HR 15.8, 95% CI 3.33-75.5) [34]. Similarly, in a study of 829 patients with AF, elevated von Willebrand factor levels were associated with risk of thrombotic events [35]. However, we do not recommend routine https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 7/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate testing of D-dimer or von Willebrand factor in patients with AF, as incorporating such testing in anticoagulation decision-making has not been shown to alter outcomes in this setting. There are no studies of the optimal anticoagulation strategy for those experiencing a thromboembolic event. For those patients with a subtherapeutic INR with warfarin at the time of the event, an attempt should be made to identify the cause (compliance, drug/food interaction) and to consider switching to a DOAC if the annual TTR has been less than 70 percent [36]. For those on a twice-a-day DOAC, consideration of a once-a-day DOAC should be made if noncompliance is an issue. For those on a once-a-day DOAC, a different once-daily agent may be considered (eg, another once-daily DOAC or possibly warfarin because the INR can be followed). Though reasonable, none of these approaches is of proven benefit. Ischemic strokes with nonembolic causes occur in patients with AF as in patients without AF. These are not the target of anticoagulants. Occurrence of such a stroke is not a "failure" of anticoagulation. Other reasons for switching agents Some patients with AF may need to be switched from DOAC agent to VKA, from VKA to DOAC, or between DOAC agents for reasons other than anticoagulant failure (which is discussed above). (See 'Anticoagulant failure' above.) Reasons for switching from VKA to DOAC: As discussed above, most patients with AF treated with VKA should be switched to DOAC. (See 'Choice of anticoagulant' above.) Need for repeated invasive procedures, annual TTR <70 percent, convenience. Possible reasons for switching from DOAC to VKA: Out-of-pocket cost Development of severe kidney disease (see 'Chronic kidney disease' below) Development of a contraindication to DOAC use, as discussed above (see 'Choice of anticoagulant' above) Information on switching oral agents is provided separately ( table 4). (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Transitioning between anticoagulants'.) Recommendations for transitioning between DOACs and parenteral anticoagulants, including unfractionated heparin and low molecular weight heparin, are available in the individual drug https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 8/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate monographs for each DOAC. Drug interactions The individual DOACs are in varying degrees eliminated by CYP3A4 metabolism or are substrates of P-glycoprotein (P-gp) efflux pump and subject to pharmacokinetic drug interactions, although fewer in number than warfarin interactions. Drugs that inhibit CYP3A4 metabolism or P-gp efflux can increase DOAC levels (ie, greater anticoagulant effect and bleeding), whereas drugs that are inducers can decrease DOAC effect, which can lead to therapeutic failure. A detailed review of the different drug interactions can be found in tables ( table 2A-C) and the Lexicomp drug interaction program within UpToDate. Additional related content is discussed separately. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".) SPECIFIC PATIENT GROUPS Patients with valvular heart disease The above general considerations regarding choice of anticoagulant (DOAC versus VKA) apply to patients with valvular heart disease (excluding patients with rheumatic mitral stenosis that is severe or clinically significant [mitral valve area 2 1.5 cm ], a bioprosthetic valve within three to six months of implantation, or a mechanical heart valve in any location), although the evidence in patients with severe native valve disease is more limited than for the general population of AF patients [37]. (See 'Choice of anticoagulant' above.) Some patients with valvular lesions (without heart failure), such as mitral valve prolapse, nonrheumatic moderate or severe mitral regurgitation, mitral valve repair (except for the first three to six months postoperatively), or moderate or less aortic valvular conditions, have been enrolled in clinical trials of the DOACs. These trials also included a few patients (with or without heart failure) with severe native valvular conditions who were not scheduled to undergo valve replacement. As an example, in the ARISTOTLE trial, which compared apixaban with warfarin ( table 3), approximately 26 percent of the patients had a history of moderate or severe valvular heart disease or previous valve surgery (not including placement of a mechanical heart valve) [38]. While these patients had higher rates of stroke and systemic embolism than those without, the benefits of a lower rate of stroke/systemic embolism and major bleeding with apixaban (compared with warfarin) were similar to those without valvular heart disease. Approaches to antithrombotic therapy (including anticoagulation) in patients with AF with the following specific valve conditions are discussed separately: https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 9/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate 2 Rheumatic mitral stenosis that is severe or clinically significant (mitral valve area 1.5 cm ). (See "Antithrombotic therapy for mechanical heart valves" and "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism'.) Mechanical heart valve in any location. (See "Antithrombotic therapy for mechanical heart valves".) Surgically implanted bioprosthetic valve. The choice of anticoagulant after surgical valve procedures is discussed separately. (See "Antithrombotic therapy for mechanical heart valves" and 'Choice of anticoagulant' above.) Transcatheter bioprosthetic valve. The choice of anticoagulant after transcatheter valve procedures is discussed separately. (See 'Choice of anticoagulant' above and "Transcatheter aortic valve implantation: Antithrombotic therapy", section on 'General approach' and "Transcatheter mitral valve repair", section on 'Antithrombotic therapy'.) Older adults For most older patients, including those over the age of 75 years, we prefer DOACs (also referred to as non-vitamin K oral anticoagulants [NOACs]) to warfarin because of the reduced risk of intracranial hemorrhage versus warfarin. Since there are no head to head randomized trials comparing DOACs in this patient group, we do not have a preference for a specific DOAC. Dose adjustment should be made if the patient meets relevant criteria such as renal function for the DOAC. The results of the ELDERCARE-AF trial are discussed separately. (See 'Dosing' above and 'Chronic kidney disease' below.) Chronic kidney disease Who to anticoagulate Our approach to deciding which AF patients with chronic kidney disease (CKD) to anticoagulate is presented separately. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Chronic kidney disease'.) Choice of anticoagulant For patients with AF and CKD stage G2 or G3 ( figure 2) treated with oral anticoagulation, most of our contributors choose a DOAC rather than VKA. However, the evidence to support this choice in patients with CKD is limited [39-43]. One contributor prefers VKA in this setting given wider clinical experience. For patients with AF and severe kidney disease (stage G4 or G5; estimated glomerular filtration 2 rate <30 mL/min/1.73 m ), on dialysis, or with acute renal injury, DOAC is generally avoided and VKA is generally the preferred long-term anticoagulant. Patients with stage 4 and 5 CKD are at higher risk of having unpredictable sudden deterioration in renal function than patients with https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 10/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate normal renal function, and such deterioration could cause an abrupt reduction in clearance of a DOAC that depends on renal metabolism. In such a setting, use of an agent such as warfarin that allows for therapeutic drug monitoring may be preferred. An annual time in the therapeutic range of >70 percent is desirable. (See "Direct oral anticoagulants (DOACs) and parenteral direct- acting anticoagulants: Dosing and adverse effects", section on 'Chronic kidney disease' and "Warfarin and other VKAs: Dosing and adverse effects", section on 'Monitoring (PT/INR)'.) If a DOAC is chosen for a patient with stage 4 or 5 CKD or on dialysis, our contributors prefer apixaban, in part because apixaban is less dependent on kidney function for clearance than other DOACs available in the US ( table 2A). The support for use of apixaban in these patients is largely based upon our clinical experience and observational studies [40,41]. In a subgroup analysis of the ARISTOTLE trial in patients with creatinine clearance (CrCl) 25 to 30 mL/min, the risk of major bleeding was significantly less with apixaban compared with warfarin (hazard ratio [HR] 0.34, 95% CI 0.14-0.80) [41]. We avoid dabigatran in patients with stage 4 or 5 CKD because a high percentage of the drug is renally cleared. These issues are discussed further separately. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Chronic kidney disease'.) Based upon pharmacokinetic modeling, the US Food and Drug Administration approved DOAC dosing for use in selected patients with CKD based upon Cockcroft-Gault CrCl as described above (see 'Dosing' above). Patients at risk for gastrointestinal bleeding Risk factors for gastrointestinal bleeding in patients on oral anticoagulants have been identified. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Gastrointestinal'.) Choosing apixaban or dabigatran over rivaroxaban or warfarin may be prudent to prevent major bleeding outcomes in AF patients at high risk of gastrointestinal bleeding. In a subgroup analysis of the ARISTOPHANES observational study, 381,054 individuals anticoagulated for nonvalvular AF and who were at high risk of gastrointestinal bleeding were followed for major bleeding outcomes [44]. Compared with warfarin, apixaban and dabigatran were associated with a lower risk of major bleeding (apixaban: HR 0.59, 95% CI 0.56-0.63; dabigatran: HR 0.78, 95% CI 0.70-0.86), whereas rivaroxaban was associated with a higher gastrointestinal bleeding risk (HR 1.11, 95% CI 1.05-1.16). Acute stroke Recommendations for the management (including the role of antithrombotic therapy) of patients with AF with an acute stroke are presented separately. Patients with AF for whom anticoagulant therapy is being considered and who have had an ischemic stroke within 30 days should be referred to a neurologist or other clinician who is experienced in managing https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 11/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate antithrombotic care in such patients. Although once widely practiced, early treatment with heparin for patients with AF who have an acute cardioembolic stroke is generally avoided as studies have shown that such treatment causes more harm than good (See "Stroke in patients with atrial fibrillation" and "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Atrial fibrillation'.) AF after surgery Approaches to OAC in patients with AF after cardiac surgery and after noncardiac surgery are discussed separately. (See "Atrial fibrillation and flutter after cardiac surgery", section on 'Our approach to postoperative anticoagulation' and "Atrial fibrillation in patients undergoing noncardiac surgery", section on 'Anticoagulation after surgery'.) Concomitant antiplatelet therapy For patients with indications for both anticoagulant for AF and for antiplatelet therapy (for a concurrent condition), any potential benefit must take into account an increased risk of bleeding with concomitant antiplatelet and anticoagulant therapy. The combination of antiplatelet and anticoagulant increases the risk of bleeding compared with either alone [45]. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Alternatives to anticoagulation'.) The potential use of both anticoagulant and antiplatelet therapies in patients with AF is discussed separately. (See "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy", section on 'Efficacy and safety' and "Acute coronary syndrome: Oral anticoagulation in medically treated patients" and "Periprocedural management of antithrombotic therapy in patients receiving long-term oral anticoagulation and undergoing percutaneous coronary intervention", section on 'Elective patients'.) The issue of whether aspirin is necessary for secondary prevention of cardiovascular disease in patients treated with anticoagulant for AF is discussed in detail separately. (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".) The impact of antiplatelet therapy on bleeding (and efficacy) outcomes in patients taking either warfarin or dabigatran was evaluated in a post-hoc subgroup analysis of the RE-LY trial (see 'Choice of anticoagulant' above) in which approximately 40 percent of patients were taking concomitant aspirin or clopidogrel at some point during the study [46]. Very few patients were taking two antiplatelet agents and individuals taking prasugrel or ticagrelor were not enrolled. The following findings were noted: In the comparison of dabigatran 110 mg twice daily with warfarin for the prevention of ischemic events, antiplatelet therapy did not significantly change the relative risk (dabigatran noninferior to warfarin) of stroke and systemic embolism. With regard to the outcome of major bleeding, the relative risk did not change significantly, but the crude https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 12/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate rates of bleeding were higher in those receiving antiplatelet therapy (2.2 versus 2.8 and 3.8 versus 4.8 percent, comparing dabigatran 110 mg with warfarin in the no antiplatelet and antiplatelet groups, respectively). In the comparison of dabigatran 150 mg twice daily with warfarin for the endpoint of ischemic events, there was a nonsignificant decrease in the relative superiority of dabigatran compared with warfarin with the use of antiplatelet therapy (HR 0.52, 95% CI 0.38-0.72 and HR 0.80, 95% CI 0.59-1.08, comparing dabigatran with warfarin in the no antiplatelet and antiplatelet groups, respectively). With regard to the outcome of major bleeding, the relative risk did not change significantly comparing dabigatran 150 mg twice daily with warfarin, but the crude rates of bleeding were higher in those receiving antiplatelet therapy (2.7 versus 2.8 and 4.4 versus 4.8 percent, respectively). Concomitant use of a single antiplatelet agent significantly increased the risk of major bleeding (HR 1.6), while dual antiplatelet therapy further increased this risk (HR 2.3). This subgroup analysis from RE-LY raises the possibility that in patients with AF treated with both oral anticoagulant and antiplatelet therapy, dabigatran might be preferred to warfarin to reduce the absolute risk of major bleeding. As discussed separately, neither aspirin alone nor in combination with clopidogrel is as effective as warfarin in preventing stroke in patients with AF. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation" and "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Alternatives to anticoagulation'.) RECOMMENDATIONS OF OTHERS Recommendations for the use of antithrombotic agents in patients with AF are available from the American Heart Association/American College of Cardiology/Heart Rhythm Society, the European Society of Cardiology, and the American College of Chest Physicians [22,47-50]. In general, we agree with relevant recommendations made in these guidelines. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults" and "Society guideline links: Anticoagulation".) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 13/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topics (see "Patient education: Atrial fibrillation (The Basics)" and "Patient education: Medicines for atrial fibrillation (The Basics)" and "Patient education: Choosing an oral medicine for blood clots (The Basics)" and "Patient education: Taking oral medicines for blood clots (The Basics)") Beyond the Basics topics (see "Patient education: Atrial fibrillation (Beyond the Basics)" and "Patient education: Warfarin (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Type of anticoagulation For most patients with atrial fibrillation (AF) with an indication for anticoagulation, we recommend a direct oral anticoagulant (DOAC) rather than a vitamin K antagonist (VKA; eg, warfarin) (Grade 1A). (See 'Choice of anticoagulant' above.) Reasons to switch to a DOAC For patients with AF who have been treated with warfarin and are comfortable with periodic international normalized ratio (INR) measurement with an annual time in the therapeutic range (TTR) of at least 70 percent, we suggest consideration of switching to DOAC (Grade 2B). However, it is reasonable to continue VKA in these patients for issues of patient cost and preference. When to use a VKA Exceptions to the general preference for use of DOAC rather than VKA in patients with AF with an indication for anticoagulation include (see 'Choice of anticoagulant' above): https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 14/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Definite reasons to use a VKA Clinical settings in which VKA (eg, warfarin; target INR 2.0 to 3.0; annual TTR 70 percent) is the agent of choice and in which DOAC should not be used (see 'Patients with valvular heart disease' above): Patients with rheumatic mitral stenosis that is severe or clinically significant (mitral 2 valve area 1.5 cm ). (See "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism'.) Patients with mechanical heart valves of any type and any location. (See "Antithrombotic therapy for mechanical heart valves".) Patients with a (surgical or transcatheter) bioprosthetic valve implanted within the prior three to six months. (See "Transcatheter aortic valve implantation: Periprocedural and postprocedural management" and "Antithrombotic therapy for surgical bioprosthetic valves and surgical valve repair", section on 'Approach for surgical bioprosthetic valves'.) Patients for whom the DOAC agents are avoided due to drug interactions (eg, those receiving P-glycoprotein drug efflux pump inducers, which can decrease the anticoagulant effect of DOACs) ( table 2A-C) or antivirals that may increase the anticoagulant effect of DOACs. (See 'Drug interactions' above and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".) Possible reasons to use a VKA Clinical settings in which VKA is reasonable or preferable to DOAC: For patients who are not likely to comply with the twice daily dosing of dabigatran or apixaban and who are unable to take once-a-day rivaroxaban or edoxaban due to intolerance. For patients for whom the DOAC agents will lead to an unacceptable increase in patient cost. For patients with chronic severe kidney disease whose estimated glomerular filtration rate (Cockcroft-Gault creatinine clearance) is less than 30 mL/min/. VKA is generally preferred in this setting, although some clinicians prescribe apixaban for selected patients in this setting. (See 'Chronic kidney disease' above.) Types of DOACs DOACs include the oral direct thrombin inhibitor dabigatran and direct

taking two antiplatelet agents and individuals taking prasugrel or ticagrelor were not enrolled. The following findings were noted: In the comparison of dabigatran 110 mg twice daily with warfarin for the prevention of ischemic events, antiplatelet therapy did not significantly change the relative risk (dabigatran noninferior to warfarin) of stroke and systemic embolism. With regard to the outcome of major bleeding, the relative risk did not change significantly, but the crude https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 12/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate rates of bleeding were higher in those receiving antiplatelet therapy (2.2 versus 2.8 and 3.8 versus 4.8 percent, comparing dabigatran 110 mg with warfarin in the no antiplatelet and antiplatelet groups, respectively). In the comparison of dabigatran 150 mg twice daily with warfarin for the endpoint of ischemic events, there was a nonsignificant decrease in the relative superiority of dabigatran compared with warfarin with the use of antiplatelet therapy (HR 0.52, 95% CI 0.38-0.72 and HR 0.80, 95% CI 0.59-1.08, comparing dabigatran with warfarin in the no antiplatelet and antiplatelet groups, respectively). With regard to the outcome of major bleeding, the relative risk did not change significantly comparing dabigatran 150 mg twice daily with warfarin, but the crude rates of bleeding were higher in those receiving antiplatelet therapy (2.7 versus 2.8 and 4.4 versus 4.8 percent, respectively). Concomitant use of a single antiplatelet agent significantly increased the risk of major bleeding (HR 1.6), while dual antiplatelet therapy further increased this risk (HR 2.3). This subgroup analysis from RE-LY raises the possibility that in patients with AF treated with both oral anticoagulant and antiplatelet therapy, dabigatran might be preferred to warfarin to reduce the absolute risk of major bleeding. As discussed separately, neither aspirin alone nor in combination with clopidogrel is as effective as warfarin in preventing stroke in patients with AF. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation" and "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Alternatives to anticoagulation'.) RECOMMENDATIONS OF OTHERS Recommendations for the use of antithrombotic agents in patients with AF are available from the American Heart Association/American College of Cardiology/Heart Rhythm Society, the European Society of Cardiology, and the American College of Chest Physicians [22,47-50]. In general, we agree with relevant recommendations made in these guidelines. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults" and "Society guideline links: Anticoagulation".) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 13/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topics (see "Patient education: Atrial fibrillation (The Basics)" and "Patient education: Medicines for atrial fibrillation (The Basics)" and "Patient education: Choosing an oral medicine for blood clots (The Basics)" and "Patient education: Taking oral medicines for blood clots (The Basics)") Beyond the Basics topics (see "Patient education: Atrial fibrillation (Beyond the Basics)" and "Patient education: Warfarin (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Type of anticoagulation For most patients with atrial fibrillation (AF) with an indication for anticoagulation, we recommend a direct oral anticoagulant (DOAC) rather than a vitamin K antagonist (VKA; eg, warfarin) (Grade 1A). (See 'Choice of anticoagulant' above.) Reasons to switch to a DOAC For patients with AF who have been treated with warfarin and are comfortable with periodic international normalized ratio (INR) measurement with an annual time in the therapeutic range (TTR) of at least 70 percent, we suggest consideration of switching to DOAC (Grade 2B). However, it is reasonable to continue VKA in these patients for issues of patient cost and preference. When to use a VKA Exceptions to the general preference for use of DOAC rather than VKA in patients with AF with an indication for anticoagulation include (see 'Choice of anticoagulant' above): https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 14/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Definite reasons to use a VKA Clinical settings in which VKA (eg, warfarin; target INR 2.0 to 3.0; annual TTR 70 percent) is the agent of choice and in which DOAC should not be used (see 'Patients with valvular heart disease' above): Patients with rheumatic mitral stenosis that is severe or clinically significant (mitral 2 valve area 1.5 cm ). (See "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism'.) Patients with mechanical heart valves of any type and any location. (See "Antithrombotic therapy for mechanical heart valves".) Patients with a (surgical or transcatheter) bioprosthetic valve implanted within the prior three to six months. (See "Transcatheter aortic valve implantation: Periprocedural and postprocedural management" and "Antithrombotic therapy for surgical bioprosthetic valves and surgical valve repair", section on 'Approach for surgical bioprosthetic valves'.) Patients for whom the DOAC agents are avoided due to drug interactions (eg, those receiving P-glycoprotein drug efflux pump inducers, which can decrease the anticoagulant effect of DOACs) ( table 2A-C) or antivirals that may increase the anticoagulant effect of DOACs. (See 'Drug interactions' above and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".) Possible reasons to use a VKA Clinical settings in which VKA is reasonable or preferable to DOAC: For patients who are not likely to comply with the twice daily dosing of dabigatran or apixaban and who are unable to take once-a-day rivaroxaban or edoxaban due to intolerance. For patients for whom the DOAC agents will lead to an unacceptable increase in patient cost. For patients with chronic severe kidney disease whose estimated glomerular filtration rate (Cockcroft-Gault creatinine clearance) is less than 30 mL/min/. VKA is generally preferred in this setting, although some clinicians prescribe apixaban for selected patients in this setting. (See 'Chronic kidney disease' above.) Types of DOACs DOACs include the oral direct thrombin inhibitor dabigatran and direct factor Xa inhibitors (eg, apixaban, edoxaban, and rivaroxaban). DOACs are generally https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 15/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate administered at fixed doses without laboratory monitoring. Given differences in the characteristics and availability of DOACs, it is important for clinicians to be familiar with the clinical use of multiple DOAC agents ( table 2A and table 3). (See 'DOACs' above and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Clinician familiarity with dosing'.) Target INR For patients with AF treated with VKA (eg, warfarin), the target INR is between 2.0 and 3.0 with an average annual TTR 70 percent. This is based upon the increased risk of stroke observed with INR values significantly below 2 (four- to sixfold at an INR of 1.3 compared with an INR of 2 or above) and the increased risk of bleeding associated with INR above 3.0 ( figure 1). (See 'Vitamin K antagonist' above and "Warfarin and other VKAs: Dosing and adverse effects", section on 'Warfarin administration'.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Bellesini M, Bianchin M, Corradi C, et al. Drug-Drug Interactions between Direct Oral Anticoagulants and Hepatitis C Direct-Acting Antiviral Agents: Looking for Evidence Through a Systematic Review. Clin Drug Investig 2020; 40:1001. 2. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383:955. 3. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139. 4. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365:883. 5. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365:981. 6. Chatterjee S, Sardar P, Biondi-Zoccai G, Kumbhani DJ. New oral anticoagulants and the risk of intracranial hemorrhage: traditional and Bayesian meta-analysis and mixed treatment comparison of randomized trials of new oral anticoagulants in atrial fibrillation. JAMA Neurol 2013; 70:1486. 7. Salazar CA, del Aguila D, Cordova EG. Direct thrombin inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in people with non-valvular atrial fibrillation. Cochrane Database Syst Rev 2014; :CD009893. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 16/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate 8. Bruins Slot KM, Berge E. Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients with atrial fibrillation. Cochrane Database Syst Rev 2018; 3:CD008980. 9. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2014/022512Orig1s025ltr.pdf (Ac cessed on December 05, 2018). 10. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369:2093. 11. Schneeweiss S, Gagne JJ, Patrick AR, et al. Comparative efficacy and safety of new oral anticoagulants in patients with atrial fibrillation. Circ Cardiovasc Qual Outcomes 2012; 5:480. 12. Lip GYH, Keshishian A, Li X, et al. Effectiveness and Safety of Oral Anticoagulants Among Nonvalvular Atrial Fibrillation Patients. Stroke 2018; 49:2933. 13. Graham DJ, Baro E, Zhang R, et al. Comparative Stroke, Bleeding, and Mortality Risks in Older Medicare Patients Treated with Oral Anticoagulants for Nonvalvular Atrial Fibrillation. Am J Med 2019; 132:596. 14. Andersson NW, Svanstr m H, Lund M, et al. Comparative effectiveness and safety of apixaban, dabigatran, and rivaroxaban in patients with non-valvular atrial fibrillation. Int J Cardiol 2018; 268:113. 15. Fralick M. Effectiveness and safety of apixaban. Ann Intern Med 2020; :463. 16. Ray WA, Chung CP, Stein CM, et al. Association of Rivaroxaban vs Apixaban With Major Ischemic or Hemorrhagic Events in Patients With Atrial Fibrillation. JAMA 2021; 326:2395. 17. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Newly identified events in the RE-LY trial. N Engl J Med 2010; 363:1875. 18. Connolly SJ, Wallentin L, Ezekowitz MD, et al. The Long-Term Multicenter Observational Study of Dabigatran Treatment in Patients With Atrial Fibrillation (RELY-ABLE) Study. Circulation 2013; 128:237. 19. Okumura K, Akao M, Yoshida T, et al. Low-Dose Edoxaban in Very Elderly Patients with Atrial Fibrillation. N Engl J Med 2020; 383:1735. 20. Yoshida T, Nakamura A, Funada J, et al. Efficacy and Safety of Edoxaban 15 mg According to Renal Function in Very Elderly Patients With Atrial Fibrillation: A Subanalysis of the ELDERCARE-AF Trial. Circulation 2022; 145:718. 21. Fuster V, Ryd n LE, Asinger RW, et al. ACC/AHA/ESC Guidelines for the Management of Patients With Atrial Fibrillation: Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 17/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the North American Society of Pacing and Electrophysiology. Circulation 2001; 104:2118. 22. You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e531S. 23. Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:546S. 24. Hylek EM, Skates SJ, Sheehan MA, Singer DE. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med 1996; 335:540. 25. Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003; 349:1019. 26. European Atrial Fibrillation Trial Study Group. Optimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and recent cerebral ischemia. N Engl J Med 1995; 333:5. 27. Singer DE, Chang Y, Fang MC, et al. Should patient characteristics influence target anticoagulation intensity for stroke prevention in nonvalvular atrial fibrillation?: the ATRIA study. Circ Cardiovasc Qual Outcomes 2009; 2:297. 28. Sherwood MW, Douketis JD, Patel MR, et al. Outcomes of temporary interruption of rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: results from the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF). Circulation 2014; 129:1850. 29. Faxon DP, Eikelboom JW, Berger PB, et al. Consensus document: antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting. A North-American perspective. Thromb Haemost 2011; 106:572. 30. Huber K, Airaksinen KJ, Cuisset T, et al. Antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting: similarities and dissimilarities between North America and Europe. Thromb Haemost 2011; 106:569. 31. Bernhardt P, Schmidt H, Hammerstingl C, et al. Patients with atrial fibrillation and dense spontaneous echo contrast at high risk a prospective and serial follow-up over 12 months with transesophageal echocardiography and cerebral magnetic resonance imaging. J Am Coll Cardiol 2005; 45:1807. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 18/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate 32. Tang RB, Dong JZ, Liu XP, et al. Is CHA2DS2-VASc score a predictor of left atrial thrombus in patients with paroxysmal atrial fibrillation? Thromb Haemost 2011; 105:1107. 33. Reynolds MW, Fahrbach K, Hauch O, et al. Warfarin anticoagulation and outcomes in patients with atrial fibrillation: a systematic review and metaanalysis. Chest 2004; 126:1938. 34. Sadanaga T, Sadanaga M, Ogawa S. Evidence that D-dimer levels predict subsequent thromboembolic and cardiovascular events in patients with atrial fibrillation during oral anticoagulant therapy. J Am Coll Cardiol 2010; 55:2225. 35. Rold n V, Mar n F, Mui a B, et al. Plasma von Willebrand factor levels are an independent risk factor for adverse events including mortality and major bleeding in anticoagulated atrial fibrillation patients. J Am Coll Cardiol 2011; 57:2496. 36. Lip GYH, Banerjee A, Boriani G, et al. Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report. Chest 2018; 154:1121. 37. Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2021; 143:e72. 38. Avezum A, Lopes RD, Schulte PJ, et al. Apixaban in Comparison With Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease: Findings From the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial. Circulation 2015; 132:624. 39. Ha JT, Neuen BL, Cheng LP, et al. Benefits and Harms of Oral Anticoagulant Therapy in Chronic Kidney Disease: A Systematic Review and Meta-analysis. Ann Intern Med 2019; 171:181. 40. Siontis KC, Zhang X, Eckard A, et al. Outcomes Associated With Apixaban Use in Patients With End-Stage Kidney Disease and Atrial Fibrillation in the United States. Circulation 2018; 138:1519. 41. Stanifer JW, Pokorney SD, Chertow GM, et al. Apixaban Versus Warfarin in Patients With Atrial Fibrillation and Advanced Chronic Kidney Disease. Circulation 2020; 141:1384. 42. Weir MR, Ashton V, Moore KT, et al. Rivaroxaban versus warfarin in patients with nonvalvular atrial fibrillation and stage IV-V chronic kidney disease. Am Heart J 2020; 223:3. 43. Su X, Yan B, Wang L, et al. Oral Anticoagulant Agents in Patients With Atrial Fibrillation and CKD: A Systematic Review and Pairwise Network Meta-analysis. Am J Kidney Dis 2021; 78:678. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 19/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate 44. Lip GYH, Keshishian AV, Zhang Y, et al. Oral Anticoagulants for Nonvalvular Atrial Fibrillation in Patients With High Risk of Gastrointestinal Bleeding. JAMA Netw Open 2021; 4:e2120064. 45. Lamberts M, Olesen JB, Ruwald MH, et al. Bleeding after initiation of multiple antithrombotic drugs, including triple therapy, in atrial fibrillation patients following myocardial infarction and coronary intervention: a nationwide cohort study. Circulation 2012; 126:1185. 46. Dans AL, Connolly SJ, Wallentin L, et al. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. Circulation 2013; 127:634. 47. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014; 130:e199. 48. Heidbuchel H, Verhamme P, Alings M, et al. Updated European Heart Rhythm Association practical guide on the use of non-vitamin-K antagonist anticoagulants in patients with non- valvular atrial fibrillation: Executive summary. Eur Heart J 2016. 49. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42:373. 50. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019; 140:e125. Topic 1031 Version 139.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 20/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate GRAPHICS Possible contraindications to anticoagulation Possible contraindication Factors to consider Active, clinically significant Site and degree of bleeding (eg, nosebleeds and menses generally bleeding are not a contraindication; active intracerebral bleeding is almost always an absolute contraindication), interval since bleeding stopped Severe bleeding diathesis Nature, severity, and reversibility of bleeding diathesis Severe thrombocytopenia Absolute platelet count, platelet count trend, and platelet function (platelet count <50,000/microL) (eg, some individuals with ITP and a platelet count in the range of 30,000 to 50,000 may tolerate anticoagulation if needed) Major trauma Site and extent of trauma, time interval since event (eg, for a patient with a mechanical heart valve it may be appropriate to anticoagulate sooner after trauma than a patient with a lesser indication) Invasive procedure or obstetric delivery (recent, emergency, or Type of procedure and associated bleeding risk, interval between procedure and anticoagulation planned) Previous intracranial Time interval since hemorrhage and underlying cause (eg, trauma hemorrhage or uncontrolled hypertension) Intracranial or spinal tumor Site and type of tumor, other comorbidities Neuraxial anesthesia Interval since spinal/epidural puncture or catheter removal, other alternatives for anesthesia; traumatic procedures are more concerning Severe, uncontrolled Absolute blood pressure and blood pressure trend hypertension This list does not take the place of clinical judgment in deciding whether or not to administer an anticoagulant. In any patient, the risk of bleeding from an anticoagulant must be weighed against the risk of thrombosis and its consequences. The greater the thromboembolic risk, the greater the tolerance for the possibility of bleeding and for shortening the time interval between an episode of bleeding and anticoagulant initiation. Refer to UpToDate content on the specific indication for the anticoagulant and the specific possible contraindication for discussions of these risks. ITP: immune thrombocytopenia. Graphic 107527 Version 4.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 21/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Pharmacokinetics and drug interactions of direct oral anticoagulants Potential for Metabolism pharmacokinetic Anticoagulant Bioavailability and Half-life drug clearance* interactions* Dabigatran 3 to 7% bioavailable Over 80% cleared by the 12 to 17 hours P-gp inhibitors can increase (Pradaxa) kidney dabigatran effect Unaffected by Prolonged food P-gp with kidney P-gp inducers can substrate* impairment and in older decrease dabigatran Capsule must be taken intact and requires adults effect gastric acidity for absorption Avoidance of some combinations or dose adjustment may be needed Apixaban (Eliquis) 50% bioavailable 27% cleared by the kidney 12 hours Strong dual CYP3A4 and P-gp inhibitors can increase apixaban effect Prolonged in older adults Unaffected by food Metabolized, primarily by CYP3A4 Strong CYP3A4 P-gp substrate* inducers and/or P-gp inducers can decrease apixaban effect Avoidance of some combinations or dose adjustment may be needed Edoxaban 62% bioavailable 50% cleared by the kidney 10 to 14 hours P-gp inhibitors can increase (Savaysa, Lixiana) edoxaban effect Unaffected by Reduced Prolonged in food efficacy in renal P-gp inducers can patients with nonvalvular impairment decrease edoxaban effect atrial fibrillation Avoidance of some combinations or https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 22/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate and CrCl >95 dose adjustment mL/minute may be needed Undergoes minimal CYP metabolism P-gp substrate* Rivaroxaban (Xarelto) 10 mg dose: 36% cleared by the kidney 5 to 9 hours Strong dual CYP3A4 and P-gp 80 to 100% bioavailable Prolonged to 11 to 13 inhibitors can increase Metabolized, primarily by CYP3A4 hours in older adults Unaffected rivaroxaban effect by food P-gp substrate* 20 mg dose: Strong CYP3A4 66% inducers and/or P-gp inducers can decrease rivaroxaban bioavailable if taken when fasting; increased if taken with food effect Avoidance of some combinations or dose adjustment may be needed Refer to UpToDate for dosing in specific clinical settings, including nonvalvular AF, VTE treatment, and VTE prophylaxis. Data on clearance may help assess the potential for accumulation in patients with kidney impairment. Data on metabolism may help assess potential drug interactions through alteration of CYP3A4 metabolism and/or P-gp-mediated drug efflux. Refer to Lexi-Interact, the drug interactions tool included with UpToDate, for specific drug interactions. Tables of P-gp inhibitors and inducers and CYP3A4 inhibitors and inducers are available separately in UpToDate. P-gp: P-glycoprotein drug efflux pump; CYP3A4: cytochrome p450 3A4 isoform; CrCl: creatinine clearance estimated by the Cockcroft-Gault equation; AF: atrial fibrillation; VTE: venous thromboembolism, includes deep vein thrombosis and pulmonary embolism; DOAC: direct oral anticoagulant. Examples of P-gp inhibitors that reduce metabolism of DOACs, leading to increased DOAC levels, include clarithromycin, ombitasvir- or ritonavir-containing combinations, and verapamil. Examples of P-gp inducers that increase DOAC metabolism, leading to lower DOAC levels, include phenytoin, rifampin, and St. John's wort. Refer to list available as a separate table in UpToDate. Examples of strong CYP3A4 inhibitors that reduce metabolism of some DOACs, leading to increased DOAC levels, include clarithromycin and ombitasvir- or ritonavir-containing combinations. Examples of strong CYP3A4 inducers that increase metabolism of some DOACs, leading to lower https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 23/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate DOAC levels, include carbamazepine, phenytoin, and rifampin. Refer to list available as a separate table in UpToDate. In patients with AF, combined use of levetiracetam or valproate with dabigatran, apixaban, or rivaroxaban was associated with an increased risk of ischemic stroke or systemic embolism. The mechanism of this interaction is unknown. [1] Inhibition of CYP3A4 (ie, without P-gp inhibition) may also increase apixaban and rivaroxaban effect, but to a lesser extent than dual inhibition of CYP3A4 and P-gp. Examples of CYP3A4 inhibitors that do not also inhibit P-gp include diltiazem, fluconazole, and voriconazole. Increased monitoring is advised. Blood levels of edoxaban were reduced and a higher rate of ischemic stroke was observed in patients with AF and CrCl >95 mL/minute who were treated with edoxaban compared with those receiving warfarin. Refer to the UpToDate topic on anticoagulation in AF for additional information. Reference: 1. Gronich N, Stein N, Muszkat M. Association between use of pharmacokinetic-interacting drugs and e ectiveness and safety of direct acting oral anticoagulants: Nested case-control study. Clin Pharmacol Ther 2021; 110:1526. Prepared with data from: 1. Lexicomp Online. Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. 2. Drugs@FDA: FDA-Approved Drugs. U.S. Food and Drug Administration. Available at: https://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm (Accessed on December 9, 2021). Graphic 112756 Version 19.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 24/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Cytochrome P450 3A (including 3A4) inhibitors and inducers Strong inhibitors Moderate Strong inducers Moderate inducers inhibitors Adagrasib Amiodarone Apalutamide Bexarotene Atazanavir Aprepitant Carbamazepine Bosentan Ceritinib Berotralstat Enzalutamide Cenobamate Clarithromycin Cimetidine Fosphenytoin Dabrafenib Cobicistat and cobicistat- Conivaptan Lumacaftor Dexamethasone Crizotinib Lumacaftor- ivacaftor Dipyrone containing coformulations Cyclosporine Efavirenz Mitotane Diltiazem Elagolix, estradiol, Darunavir Phenobarbital and norethindrone therapy pack Duvelisib Idelalisib Phenytoin Dronedarone Indinavir Eslicarbazepine Primidone Erythromycin Itraconazole Etravirine Rifampin (rifampicin) Fedratinib Ketoconazole Lorlatinib Fluconazole Levoketoconazole Mitapivat Fosamprenavir Lonafarnib Modafinil Fosaprepitant Lopinavir Nafcillin Fosnetupitant- palonosetron Mifepristone* Pexidartinib Nefazodone Rifabutin Grapefruit juice Nelfinavir Rifapentine Imatinib Nirmatrelvir- ritonavir Sotorasib Isavuconazole (isavuconazonium sulfate) St. John's wort Ombitasvir- paritaprevir- ritonavir Lefamulin Letermovir Ombitasvir- paritaprevir- Netupitant Nilotinib ritonavir plus dasabuvir Ribociclib Schisandra Posaconazole Verapamil Ritonavir and ritonavir-containing coformulations Saquinavir Telithromycin Tucatinib Voriconazole https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 25/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate For drug interaction purposes, the inhibitors and inducers of CYP3A metabolism listed above can alter serum concentrations of drugs that are dependent upon the CYP3A subfamily of liver enzymes, including CYP3A4, for elimination or activation. [1,2] These classifications are based upon US Food and Drug Administration (FDA) guidance. sources may use a different classification system resulting in some agents being classified Other differently. Data are for systemic drug forms. Degree of inhibition or induction may be altered by dose, method, and timing of administration. Weak inhibitors and inducers are not listed in this table with exception of a few examples. Clinically significant interactions can occasionally occur due to weak inhibitors and inducers (eg, target drug is highly dependent on CYP3A4 metabolism and has a narrow therapeutic index). Accordingly, specific interactions should be checked using a drug interaction program such as the Lexicomp drug interactions program included within UpToDate. Refer to UpToDate topics on specific agents and indications for further details. Mifepristone is a significant inhibitor of CYP3A4 when used chronically (eg, for hyperglycemia in patients with Cushing syndrome); not in single-dose use. [1] Classified as a weak inhibitor of CYP3A4 according to FDA system. [1] Classified as a weak inducer of CYP3A4 according to FDA system. The fixed-dose combination therapy pack taken in the approved regimen has moderate CYP3A4 induction effects. When elagolix is used as a single agent, it is a weak CYP3A4 inducer. Norethindrone and estradiol are not CYP3A4 inducers. Data from: Lexicomp Online (Lexi-Interact). Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. References: 1. Clinical Drug Interaction Studies Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry (January 2020) available at: https://www.fda.gov/regulatory-information/search-fda-guidance- documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions. 2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website. Graphic 76992 Version 90.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 26/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Inhibitors and inducers of P-glycoprotein (P-gp) drug efflux pump (P-gp multidrug resistance transporter) Inhibitors of P-gp Inducers of P-gp Abrocitinib Lapatinib Apalutamide Adagrasib* Ledipasvir Carbamazepine Amiodarone Levoketoconazole Fosphenytoin Azithromycin (systemic) Mifepristone Green tea (Camellia sinensis) Cannabidiol and cannabidiol- Neratinib Lorlatinib containing coformulations Nirmatrelvir-ritonavir Phenytoin Capmatinib Ombitasvir-paritaprevir- ritonavir (Technivie) Rifampin (rifampicin) Carvedilol St. John's wort Clarithromycin Osimertinib Cobicistat and cobicistat- containing coformulations Pirtobrutinib Posaconazole Cyclosporine (systemic) Propafenone Daclatasvir Quinidine Diosmin (a plant flavonoid sold as dietary supplement) Quinine Ranolazine Dronedarone Ritonavir and ritonavir- containing coformulations Elagolix Elagolix-estradiol- norethindrone Rolapitant Selpercatinib Eliglustat Simeprevir Elexacaftor-tezacaftor- ivacaftor Tamoxifen* Tepotinib Enzalutamide Tezacaftor-ivacaftor Erythromycin (systemic) Ticagrelor* Flibanserin Tucatinib Fostamatinib Velpatasvir Glecaprevir-pibrentasvir Vemurafenib Isavuconazole Verapamil (isavuconazonium sulfate) Voclosporin Itraconazole Ivacaftor Ketoconazole (systemic) Inhibitors of the P-gp drug efflux pump (also known as P-gp multidrug resistance transporter) listed above may increase serum concentrations of drugs that are substrates of P-gp, whereas inducers of P-gp drug efflux may decrease serum concentrations of substrates of P-gp. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 27/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Examples of drugs that are substrates of P-gp efflux pump include: Apixaban, colchicine, cyclosporine, dabigatran, digoxin, edoxaban, rivaroxaban, and tacrolimus. The degree of effect on P-gp substrate serum concentration may be altered by dose and timing of orally administered P-gp inhibitor or inducer. [1,2] These classifications are based upon US FDA guidance. classification system resulting in some agents being classified differently. Other sources may use a different Specific drug interaction effects may be determined by using the Lexicomp drug interactions program included with UpToDate. Refer to UpToDate clinical topics on specific agents and conditions for further details. P-gp: P-glycoprotein; US FDA: US Food and Drug Administration. Minor clinical effect or supportive data are limited to in vitro effects (ie, clinical effect is unknown). Mifepristone is a significant inhibitor of P-gp when used chronically (eg, for hyperglycemia in patients with Cushing syndrome); not in single-dose use. The combination of ombitasvir-paritaprevir-ritonavir plus dasabuvir (Viekira Pak) is not a significant inhibitor of P-gp efflux pump. [3] Data from: Lexicomp Online (Lexi-Interact). Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. References: 1. US Food and Drug Administration. Clinical drug interaction studies Cytochrome P450 enzyme- and transporter- mediated drug interactions guidance for industry, January 2020. Available at: https://www.fda.gov/regulatory- information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and- transporter-mediated-drug-interactions (Accessed on June 5, 2020). 2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website. 3. Menon RM, Badri PS, Wang T, et al. Drug-drug interaction pro le of the all-oral anti-hepatitis C virus regimen of paritaprevir/ritonavir, ombitasvir, and dasabuvir. J Hepatol 2015; 63:20. Graphic 73326 Version 76.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 28/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Trials comparing direct oral anticoagulants versus warfarin in atrial fibrillation Baseline characteristics Trial details of trial participants Trial N Percent Mean CHADS score Study drug (DOAC) and dose 2 on aspirin Compariso RE-LY 18,113 2.1 40% Dabigatran 110 mg twice Warfarin (target IN daily or 150 mg twice daily 3.0) ROCKET- 14,264 3.5 36% Rivaroxaban 20 mg once Warfarin (target IN AF daily* 3.0) ARISTOTLE 18,201 2.1 31% Apixaban 5 mg twice daily Warfarin (target IN 3.0) ENGAGE AF-TIMI 48 21,105 2.8 29% Edoxaban 30 mg once daily or 60 mg once daily Warfarin (target IN 3.0) Event rates for key outcomes Stroke or systemic Death Hemorrhagic s embolic event Trial Relative effect (95% CI) Relative effect (95% CI) DOAC Warfarin DOAC Warfarin DOAC Warfarin RE-LY 110 3.75 4.13 RR 0.91 1.53 1.69 RR 0.91 0.12 0.38 mg (0.8- 1.03) (0.74- 1.11) 150 3.64 4.13 RR 0.88 1.11 1.69 RR 0.66 0.10 0.38 mg (0.77- (0.53- 1.00) 0.82) ROCKET-AF 4.5 4.9 HR 0.92 (0.82- 2.1 2.4 HR 0.88 (0.75- 0.26 0.44 1.03) 1.03) ARISTOTLE 3.52 3.94 HR 0.89 (0.80- 1.27 1.60 HR 0.79 (0.66- 0.24 0.47 0.998) 0.95) ENGAGE 30 mg 3.80 4.35 HR 0.87 2.04 1.80 HR 1.13 0.16 0.47 AF-TIMI 48 (0.79- 0.96) (0.96- 1.34) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 29/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate ENGAGE AF-TIMI 48 60 mg 3.99 4.35 HR 0.92 (0.83- 1.57 1.80 HR 0.87 (0.73- 0.26 0.47 1.01) 1.04) Combined results 6.90 7.68 RR 0.90 (0.85- 3.11 3.79 RR 0.81 (0.73- 0.44 0.90 0.95) 0.91) DOAC: direct oral anticoagulant; AF: atrial fibrillation; N: number of trial participants; CHADS : score 2 to estimate risk of stroke with 1 point assigned for each of the following clinical features: history of congestive heart failure, hypertension, age 75 years, or diabetes mellitus, and 2 points assigned for prior stroke or transient ischemic attack; INR: international normalized ratio; HR: hazard ratio; RR: relative risk. Dose of rivaroxaban was adjusted to 15 mg once daily for renal insufficiency (creatinine clearance 30 to 49 mL/minute [0.5 to 0.82 mL/second]).

Lexicomp drug interactions program included within UpToDate. Refer to UpToDate topics on specific agents and indications for further details. Mifepristone is a significant inhibitor of CYP3A4 when used chronically (eg, for hyperglycemia in patients with Cushing syndrome); not in single-dose use. [1] Classified as a weak inhibitor of CYP3A4 according to FDA system. [1] Classified as a weak inducer of CYP3A4 according to FDA system. The fixed-dose combination therapy pack taken in the approved regimen has moderate CYP3A4 induction effects. When elagolix is used as a single agent, it is a weak CYP3A4 inducer. Norethindrone and estradiol are not CYP3A4 inducers. Data from: Lexicomp Online (Lexi-Interact). Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. References: 1. Clinical Drug Interaction Studies Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry (January 2020) available at: https://www.fda.gov/regulatory-information/search-fda-guidance- documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions. 2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website. Graphic 76992 Version 90.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 26/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Inhibitors and inducers of P-glycoprotein (P-gp) drug efflux pump (P-gp multidrug resistance transporter) Inhibitors of P-gp Inducers of P-gp Abrocitinib Lapatinib Apalutamide Adagrasib* Ledipasvir Carbamazepine Amiodarone Levoketoconazole Fosphenytoin Azithromycin (systemic) Mifepristone Green tea (Camellia sinensis) Cannabidiol and cannabidiol- Neratinib Lorlatinib containing coformulations Nirmatrelvir-ritonavir Phenytoin Capmatinib Ombitasvir-paritaprevir- ritonavir (Technivie) Rifampin (rifampicin) Carvedilol St. John's wort Clarithromycin Osimertinib Cobicistat and cobicistat- containing coformulations Pirtobrutinib Posaconazole Cyclosporine (systemic) Propafenone Daclatasvir Quinidine Diosmin (a plant flavonoid sold as dietary supplement) Quinine Ranolazine Dronedarone Ritonavir and ritonavir- containing coformulations Elagolix Elagolix-estradiol- norethindrone Rolapitant Selpercatinib Eliglustat Simeprevir Elexacaftor-tezacaftor- ivacaftor Tamoxifen* Tepotinib Enzalutamide Tezacaftor-ivacaftor Erythromycin (systemic) Ticagrelor* Flibanserin Tucatinib Fostamatinib Velpatasvir Glecaprevir-pibrentasvir Vemurafenib Isavuconazole Verapamil (isavuconazonium sulfate) Voclosporin Itraconazole Ivacaftor Ketoconazole (systemic) Inhibitors of the P-gp drug efflux pump (also known as P-gp multidrug resistance transporter) listed above may increase serum concentrations of drugs that are substrates of P-gp, whereas inducers of P-gp drug efflux may decrease serum concentrations of substrates of P-gp. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 27/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Examples of drugs that are substrates of P-gp efflux pump include: Apixaban, colchicine, cyclosporine, dabigatran, digoxin, edoxaban, rivaroxaban, and tacrolimus. The degree of effect on P-gp substrate serum concentration may be altered by dose and timing of orally administered P-gp inhibitor or inducer. [1,2] These classifications are based upon US FDA guidance. classification system resulting in some agents being classified differently. Other sources may use a different Specific drug interaction effects may be determined by using the Lexicomp drug interactions program included with UpToDate. Refer to UpToDate clinical topics on specific agents and conditions for further details. P-gp: P-glycoprotein; US FDA: US Food and Drug Administration. Minor clinical effect or supportive data are limited to in vitro effects (ie, clinical effect is unknown). Mifepristone is a significant inhibitor of P-gp when used chronically (eg, for hyperglycemia in patients with Cushing syndrome); not in single-dose use. The combination of ombitasvir-paritaprevir-ritonavir plus dasabuvir (Viekira Pak) is not a significant inhibitor of P-gp efflux pump. [3] Data from: Lexicomp Online (Lexi-Interact). Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. References: 1. US Food and Drug Administration. Clinical drug interaction studies Cytochrome P450 enzyme- and transporter- mediated drug interactions guidance for industry, January 2020. Available at: https://www.fda.gov/regulatory- information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and- transporter-mediated-drug-interactions (Accessed on June 5, 2020). 2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: FDA.gov website. 3. Menon RM, Badri PS, Wang T, et al. Drug-drug interaction pro le of the all-oral anti-hepatitis C virus regimen of paritaprevir/ritonavir, ombitasvir, and dasabuvir. J Hepatol 2015; 63:20. Graphic 73326 Version 76.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 28/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Trials comparing direct oral anticoagulants versus warfarin in atrial fibrillation Baseline characteristics Trial details of trial participants Trial N Percent Mean CHADS score Study drug (DOAC) and dose 2 on aspirin Compariso RE-LY 18,113 2.1 40% Dabigatran 110 mg twice Warfarin (target IN daily or 150 mg twice daily 3.0) ROCKET- 14,264 3.5 36% Rivaroxaban 20 mg once Warfarin (target IN AF daily* 3.0) ARISTOTLE 18,201 2.1 31% Apixaban 5 mg twice daily Warfarin (target IN 3.0) ENGAGE AF-TIMI 48 21,105 2.8 29% Edoxaban 30 mg once daily or 60 mg once daily Warfarin (target IN 3.0) Event rates for key outcomes Stroke or systemic Death Hemorrhagic s embolic event Trial Relative effect (95% CI) Relative effect (95% CI) DOAC Warfarin DOAC Warfarin DOAC Warfarin RE-LY 110 3.75 4.13 RR 0.91 1.53 1.69 RR 0.91 0.12 0.38 mg (0.8- 1.03) (0.74- 1.11) 150 3.64 4.13 RR 0.88 1.11 1.69 RR 0.66 0.10 0.38 mg (0.77- (0.53- 1.00) 0.82) ROCKET-AF 4.5 4.9 HR 0.92 (0.82- 2.1 2.4 HR 0.88 (0.75- 0.26 0.44 1.03) 1.03) ARISTOTLE 3.52 3.94 HR 0.89 (0.80- 1.27 1.60 HR 0.79 (0.66- 0.24 0.47 0.998) 0.95) ENGAGE 30 mg 3.80 4.35 HR 0.87 2.04 1.80 HR 1.13 0.16 0.47 AF-TIMI 48 (0.79- 0.96) (0.96- 1.34) https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 29/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate ENGAGE AF-TIMI 48 60 mg 3.99 4.35 HR 0.92 (0.83- 1.57 1.80 HR 0.87 (0.73- 0.26 0.47 1.01) 1.04) Combined results 6.90 7.68 RR 0.90 (0.85- 3.11 3.79 RR 0.81 (0.73- 0.44 0.90 0.95) 0.91) DOAC: direct oral anticoagulant; AF: atrial fibrillation; N: number of trial participants; CHADS : score 2 to estimate risk of stroke with 1 point assigned for each of the following clinical features: history of congestive heart failure, hypertension, age 75 years, or diabetes mellitus, and 2 points assigned for prior stroke or transient ischemic attack; INR: international normalized ratio; HR: hazard ratio; RR: relative risk. Dose of rivaroxaban was adjusted to 15 mg once daily for renal insufficiency (creatinine clearance 30 to 49 mL/minute [0.5 to 0.82 mL/second]). Dose of apixaban was adjusted to 2.5 mg twice daily for patients with two or more of: age 80 years, body weight 60 kg, or renal insufficiency (serum creatinine level 1.5 mg/dL [133 micromol/L]). For patients in either dose group, the dose of edoxaban was reduced by 50% if any of the following characteristics were present: estimated creatinine clearance 30 to 50 mL/minute, body weight 60 kg, or concomitant use of verapamil, quinidine, or dronedarone. For the individual trials, the annual event rate (expressed as %/year) is presented for each outcome. For the meta-analysis, the table provides the absolute event rates (%) during the total study duration, which varied between studies (median follow-up 1.8 to 2.8 years). Major bleeding was variably defined. In RE-LY, it was defined as a reduction in hemoglobin of at least 2 g/dL [20 g/L], transfusion of 2 units of blood, or symptomatic bleeding in a critical area or organ. In ROCKET-AF, ARISTOTLE, and ENGAGE AF-TIMI 48, it was defined as fatal bleeding, bleeding at a critical site, or overt bleeding plus fall in hemoglobin of at least 2 g/dL [20 g/L] or transfusion of 2 units of blood. For ROCKET-AF, the results for hemorrhagic stroke and for bleeding are based on an as-treated safety population. These combined results include data for dabigatran 150 mg twice daily, rivaroxaban 20 mg once daily, apixaban 5 mg twice daily, and edoxaban 60 mg once daily. Data from: 1. Connolly SJ, Ezekowitz MD, Eikelbloom YS, et al. Dabigatran versus warfarin in patients with atrial brillation; N Engl J Med 2009; 361:1139. 2. Patel MR, Maha ey KE, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial brillation; N Engl J Med 2011; 365:883. 3. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial brillation; N Engl J Med 2011; 365:981. 4. Giugliano RP, Ru CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial brillation. N Engl J Med 2013; 369:2093. https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 30/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate 5. Ru CT, Giugliano RP, Braunwald E, et al. Comparison of the e cacy and safety of new oral anticoagulants with warfarin in patients with atrial brillation: a meta-analysis of randomised trials. Lancet 2014; 383:955. Graphic 131871 Version 2.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 31/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Optimal INR to minimize both bleeding and thromboembo lism in patients with atrial fibrillation (A) ORs for TE (396 cases, 1581 controls) and ICH (164 cases, 656 controls) by INR level in adults with nonvalvular AF, with 8 INR categories using INR 2.0 to 2.5 as the referent. Vertical bars indicate 95% CI. The numbers of cases and controls for each INR category are given below the figure. (B) ORs for TE (396 cases, 1581 controls) and ICH (164 cases, 656 controls) by INR level in adults with nonvalvular AF, with 6 INR categories using INR 2.0 to https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 32/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate 2.5 as the referent. Vertical bars indicate 95% CI. The numbers of cases and controls for each INR category are given below the figure. AF: atrial fibrillation; INR: international normalized ratio; OR: odds ratio; TE: thromboembolism; ICH: intracranial hemorrhage; CI: confidence interval. Reproduced with permission from: Singer DE, Chang Y, Fang MC, et al. Should patient characteristics in uence target anticoagulation intensity for stroke prevention in nonvalvular atrial brillation? The ATRIA study. Circ Cardiovasc Qual Outcomes 2009; 2:297. Copyright 2009 Lippincott Williams & Wilkins. Graphic 65373 Version 13.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 33/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Switching between oral anticoagulants Switching from a DOAC to warfarin Dabigatran Overlap warfarin with dabigatran for 3 days (normal renal function); 2 days (CrCl 30 to 50 mL/min); or 1 day (CrCl 15 to 30 mL/min); note that dabigatran can contribute to INR elevation. or- Overlap warfarin with dabigatran until the INR is therapeutic on warfarin (ASH).* Apixaban If continuous anticoagulation is needed, discontinue apixaban and start a parenteral anticoagulant with warfarin; continue the parenteral agent until the INR is therapeutic on warfarin (PI). Note that apixaban can contribute to INR elevation. or- Overlap warfarin with apixaban until the INR is therapeutic on warfarin, testing right before the next apixaban dose to minimize the effect of apixaban on INR elevation (ASH).* Edoxaban Reduce dose by half (eg, from 60 to 30 mg daily or from 30 to 15 mg daily) and begin warfarin concurrently (PI). Discontinue edoxaban when the INR is 2; note that edoxaban can contribute to INR elevation. or- Discontinue edoxaban and start a parenteral anticoagulant with warfarin; continue the parenteral agent until the INR is therapeutic on warfarin (PI). or- Overlap warfarin with edoxaban until the INR is therapeutic on warfarin, testing right before the next edoxaban dose to minimize the effect of edoxaban on INR elevation (ASH).* Rivaroxaban Discontinue rivaroxaban and start a parenteral anticoagulant with warfarin; continue the parenteral agent until the INR is therapeutic on warfarin (PI). Note that rivaroxaban can contribute to INR elevation. or- Overlap warfarin with rivaroxaban until the INR is therapeutic on warfarin, testing right before the next rivaroxaban dose to minimize the effect of rivaroxaban on INR elevation (ASH).* Switching from warfarin to a DOAC Dabigatran Stop warfarin, monitor the PT/INR, and start dabigatran when the INR https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 34/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate is <2 (PI). Apixaban Stop warfarin, monitor the PT/INR, and start apixaban when the INR is <2 (PI). Edoxaban Stop warfarin, monitor the PT/INR, and start edoxaban when the INR is 2.5 (PI). Rivaroxaban Stop warfarin, monitor the PT/INR, and start rivaroxaban when the INR is <3 (PI). Switching from one DOAC to a different DOAC Any DOAC Start the second DOAC when the next dose of the first DOAC would have been due; do not overlap. This table presents a reasonable approach to switching between oral anticoagulants. It does not substitute for clinical judgment regarding individual patient risks of thrombosis and bleeding. Individuals switching from a DOAC to warfarin are more likely to require continuous anticoagulation if they have had a recent thromboembolic event or if they are at especially high risk of thromboembolism. Refer to UpToDate topics on specific indications, perioperative management, and the use of DOACs and warfarin for further details. DOAC: direct oral anticoagulant; CrCl: creatinine clearance; INR: international normalized ratio; ASH: American Society of Hematology clinical practice guideline; PI: package insert; PT: prothrombin time. Two to three days of overlap after the INR becomes therapeutic may be needed in individuals with higher thrombosis risk, because the PT/INR will enter the therapeutic range before full anticoagulation occurs. In individuals overlapping warfarin and a DOAC, the DOAC may contribute to INR elevation. Prepared with information from: 1. Witt DM, Nieuwlaat R, Clark NP, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: Optimal management of anticoagulation therapy. Blood Adv 2018; 2:3257. 2. PRADAXA (dabigatran etexilate mesylate) capsules. US FDA approval 2010. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022512s035lbl.pdf (Accessed on April 25, 2019). 3. ELIQUIS (apixaban) tablets. US FDA approval 2012. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202155s020lbl.pdf (Accessed on April 25, 2019). 4. SAVAYSA (edoxaban) tablets. US FDA approval 2015. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/206316s012lbl.pdf (Accessed on April 25, 2019). 5. XARELTO (rivaroxaban) tablets. US FDA approval 2011. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022406s030s032lbledt.pdf (Accessed on April 25, 2019). Graphic 120639 Version 4.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 35/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Staging of patients who meet the definition of CKD GFR and albuminuria grid to reflect the risk of progression by intensity of coloring (green, yellow, orange, red, deep red). The numbers in the boxes are a guide to the frequency of monitoring (number of times per year). GFR: glomerular filtration rate. Reprinted by permission from: Macmillan Publishers Ltd: Kidney International. KDIGO. Summary of recommendation statements. Kidney Int 2013; 3(Suppl):5. Copyright 2013. http://www.nature.com/ki/index.html. Graphic 59716 Version 7.0 https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 36/37 7/5/23, 11:46 AM Atrial fibrillation in adults: Use of oral anticoagulants - UpToDate Contributor Disclosures Warren J Manning, MD Equity Ownership/Stock Options: Pfizer [Anticoagulants]. All of the relevant financial relationships listed have been mitigated. Daniel E Singer, MD Grant/Research/Clinical Trial Support: Bristol-Myers Squibb [Screening for atrial fibrillation]. Consultant/Advisory Boards: Bristol-Myers Squibb [Atrial fibrillation and stroke]; Fitbit [Screening for atrial fibrillation]; Medtronic [Atrial fibrillation and stroke]. All of the relevant financial relationships listed have been mitigated. Gregory YH Lip, MD, FRCPE, FESC, FACC Consultant/Advisory Boards: BMS/Pfizer [Atrial fibrillation and thrombosis]; Boehringer Ingelheim [Atrial fibrillation and thrombosis]; Daiichi-Sankyo [Atrial fibrillation and thrombosis]. Speaker's Bureau: BMS/Pfizer [Atrial fibrillation and thrombosis]; Boehringer Ingelheim [Atrial fibrillation and thrombosis]; Daiichi-Sankyo [Atrial fibrillation and thrombosis]. All of the relevant financial relationships listed have been mitigated. Peter J Zimetbaum, MD Consultant/Advisory Boards: Abbott Medical [Lead extraction]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Bradley P Knight, MD, FACC Grant/Research/Clinical Trial Support: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; MDT [Electrophysiology]; Philips [Electrophysiology]. Consultant/Advisory Boards: Abbott [Electrophysiology]; Atricure [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Electrophysiology]; BSCI [Electrophysiology]; CVRx [Heart failure]; MDT [Electrophysiology]; Philips [Electrophysiology]; Sanofi [Arrhythmias]. Speaker's Bureau: Abbott [Electrophysiology]; Biosense Webster [Electrophysiology]; Biotronik [Electrophysiology]; Boston Scientific [Transeptal catheterization]; BSCI [Electrophysiology]; MDT [Electrophysiology]. All of the relevant financial relationships listed have been mitigated. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/atrial-fibrillation-in-adults-use-of-oral-anticoagulants/print 37/37

7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults : Steven R Mess , MD, Naser M Ammash, MD : Scott E Kasner, MD, Heidi M Connolly, MD, FACC, FASE : John F Dashe, MD, PhD, Susan B Yeon, MD, JD, FACC All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 10, 2023. INTRODUCTION Stroke can be associated with abnormalities of the atrial septum, specifically patent foramen ovale (PFO), atrial septal defect (ASD), and atrial septal aneurysm (ASA). The relationship between PFO, ASD, or ASA and ischemic neurologic complications will be reviewed here. Treatment is reviewed separately. (See "Stroke associated with patent foramen ovale (PFO): Evaluation".) PFO AND ASD The foramen ovale and its flap-like valve between the right and left atrium are important components of the fetal circulation. In the developing fetus, oxygenated blood from the umbilical vein enters the right atrium via the inferior vena cava and is shunted into the left atrium, circumventing the noninflated lungs. After birth, a relative increase in left atrial pressure closes the flap, and adhesions frequently result in a structurally intact atrial septum. However, in approximately 25 percent of adults, the foramen ovale remains patent and acts as a potential interatrial shunt ( movie 1 and movie 2). (See "Patent foramen ovale".) Less commonly, an open communication called an ASD persists between the atria after septation. The majority of these are secundum ASD defects caused by deficiency in the septum https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 1/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate primum. This may be visualized on transthoracic ( movie 3 and movie 4) or transesophageal echocardiography ( movie 5). The pathophysiology and clinical features of PFOs and ASDs are discussed in detail separately. (See "Clinical manifestations and diagnosis of atrial septal defects in adults", section on 'Embryology and classification'.) SOURCES OF EMBOLI Some patients with ischemic stroke and no other evident source cause for stroke have a PFO, ASD, or an ASA that can be identified by transthoracic echocardiography (TTE) or transesophageal echocardiography (TEE). Alternatively, a right-to-left shunt (RLS; most of which are caused by PFO) can be identified by contrast-enhanced transcranial Doppler (TCD). (See "Echocardiography in detection of cardiac and aortic sources of systemic embolism" and "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)".) These structures have been implicated in the pathogenesis of embolic events, primarily by causing paradoxical embolization from the systemic venous circulation. However, identification of one or more of these atrial septal abnormalities in a patient with an ischemic event does not prove a causal relationship since other, more common, sources or conduits of embolism may also be present. Paradoxical emboli A paradoxical embolus originates in the systemic venous circulation and enters the systemic arterial circulation through a PFO, ASD, ventricular septal defect, or extracardiac communication such as a pulmonary arteriovenous malformation [1-6]. Paradoxical embolism is a potential cause of embolic stroke of undetermined source (ESUS), which is defined as a nonlacunar brain infarct without proximal arterial stenosis or cardioembolic source. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Embolic stroke of undetermined source'.) Case reports have described patients with an "impending" paradoxical embolus due to a trapped embolus in a PFO [7-9]. Increased risk of decompression sickness complicating SCUBA diving in individuals at risk for paradoxical emboli (including those with PFO or ASD) is discussed separately. (See "Complications of SCUBA diving", section on 'Right-to-left shunt'.) Right-sided sources Thromboemboli can originate from lower extremity or pelvic veins, right-sided valve (tricuspid) vegetations, a papillary fibroelastoma or other cardiac tumor, an https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 2/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate ASA, or thrombi (in transit or in situ) within the PFO [10,11]. Air emboli can arise from intravenous lines. Fat emboli can complicate trauma or orthopedic procedures. Thromboembolism from a right-sided source can result in concurrent pulmonary embolism and stroke. (See "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults", section on 'Early'.) Transvenous cardiac device (pacemaker or defibrillator) leads, which are most commonly placed in right-sided heart chambers, are another potential nidus for the formation of mobile thrombi that can be a source of pulmonary emboli [12] or, via paradoxical embolization, can result in cerebral or other systemic emboli [13,14]. Small mobile thrombi are frequently observed by echocardiography attached to the right atrial segments of these leads. Although data are limited, a retrospective study of patients with transvenous cardiac device leads in the right atrium or right ventricle found that the presence of PFO was associated with a significantly increased risk of cardioembolic stroke [15]. Further data are needed to confirm this finding and determine how this compares with the risk of cardioembolic stroke in patients with PFO who do not have intracardiac device leads. Right-to-left shunting Right-to-left shunting through a PFO or an ASD can result in a paradoxical embolus (see 'Paradoxical emboli' above). Since a transient right-to-left atrial pressure gradient is sufficient to induce right-to-left shunting across a PFO (or ASD), such shunts commonly occur in individuals with no significant net right- to-left shunting between the atria (ie, those with no net intracardiac shunt or with a net left-to- right shunt). Chronic elevation in right heart pressures (eg, Eisenmenger syndrome) is not required for paradoxical embolism to occur. Transient right-to-left shunting across a PFO is a dynamic phenomenon given the significant variability of both right and left atrial pressures. Transient increases in right atrial pressure occur in normal individuals during early ventricular systole ( movie 1 and movie 2), during the Valsalva maneuver, and with repetitive cough [16]. In addition, a persistent, large Eustachian valve or a Chiari network may direct inferior vena caval blood toward the atrial septum where a PFO or ASD is located and potentially into the left atrium and systemic circulation. (See "Patent foramen ovale", section on 'Eustachian valve and Chiari network'.) With the Valsalva maneuver, transient right-to-left shunting in patients with a PFO or an ASD can be induced particularly during Valsalva release. During the straining phase, the right atrial pressure rises disproportionately, and during release there is a sudden increase in systemic venous return into the right atrium. Physiologic conditions associated with a Valsalva maneuver include straining to defecate, lifting or pushing heavy objects, and vigorous repetitive cough. In https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 3/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate one series of 148 patients with a PFO, 84 (57 percent) had right-to-left shunting at rest, and 136 (92 percent) had right-to-left shunting with straining or coughing [17]. (See "Contrast echocardiography: Clinical applications", section on 'Shunt detection' and "Clinical manifestations and diagnosis of atrial septal defects in adults", section on 'Agitated saline contrast'.) An uncommon consequence of intermittent right-to-left shunting is the platypnea-orthodeoxia syndrome [5]. This disorder is defined as an orthostatic right-to-left shunt across an ASD or PFO resulting in decreases in oxygen saturation when changing position from prone to upright, leading to significant positional dyspnea. (See "Patent foramen ovale", section on 'Platypnea- orthodeoxia syndrome'.) ASA An ASA is defined as redundant and mobile interatrial septal tissue in the region of the fossa ovalis with phasic excursion of at least 10 to 15 mm during the cardiorespiratory cycle. ASAs have been classified according to their oscillation (intrusion) into the left or right atrium and according to their motion during the respiratory cycle [18]. Most investigators have defined an ASA as an excursion of at least 10 or 15 mm. The aneurysm may either bulge persistently into the right or left atrium or exhibit striking oscillations from right atrium to left atrium during respiration, in response to fluctuating pressure gradients between the atria [18-20]. ASA is most commonly an incidental finding. However, some patients with ASA present with systemic thromboembolism and some present with symptoms and signs of significant intracardiac shunting via one or more associated ASDs. (See "Clinical manifestations and diagnosis of atrial septal defects in adults".) The diagnosis of ASA can sometimes be established by TTE7 ( movie 6), but TEE is more sensitive since the interatrial septum is visualized more consistently ( movie 7). In the review of 195 cases cited above, 47 percent were missed with TTE [21]. The prevalence of ASA varies with the method of identification and the population studied. ASAs have been found in 1 percent of necropsies [22] and 0.2 to 2 percent of patients undergoing TTE [23,24]. With TEE, ASAs were detected in 2.2 percent of population controls [25], 4 percent of patients referred for TEE for a reason other than detection of a source of embolic stroke [18], and 4.9 percent of patients undergoing cardiac surgery [26]. There is an increased prevalence of ASAs among patients with cerebral ischemic events [18,25,27]. As an example, ASA was observed in 7.9 to 15 percent of patients with a possible embolic stroke [18,25] and 28 percent of those with a cerebral ischemic event and normal carotid arteries [27]. Two mechanisms have been proposed to explain the association between ASA and cryptogenic stroke. Since ASA is commonly associated with PFO and ASD, paradoxical https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 4/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate embolism may occur via the septal defect. In patients with ASA without an intracardiac shunt, it has been hypothesized that fibrin-platelet particles adhere to the left atrial side of the aneurysm and are dislodged by oscillations of the aneurysm, causing systemic embolism. An intracardiac shunt has been reported in up to 78 percent of patients with an ASA [18- 21,25,27]. Most patients (54 to 84 percent) with cerebral ischemic events and an ASA also have an interatrial shunt, usually via a PFO [3,21,25,27]. In a multicenter review of 195 cases in which ASA was detected by TEE, ASA was the only defect in 32 percent and was associated with an interatrial shunt in 54 percent, most often a PFO (33 percent) or ASD (19 percent) [21]. Some ASAs are associated with multiple atrial septal fenestrations (perforations) [28]. Left-sided sources A common source of cerebral emboli originating in the systemic arterial circulation in patients with atrial septal abnormalities is the left atrium (particularly left atrial appendage), especially in those with atrial fibrillation. Patients with a hemodynamically significant ASD causing volume overload of the atria and right ventricle are at risk for atrial fibrillation, especially after age 50 years. Although evidence is more limited, patients with PFO or ASA may also be predisposed to atrial fibrillation [23,29]. However, whereas ASD can cause volume overload of the right heart chambers, an isolated PFO is not associated with volume overload of any cardiac chamber. Other potential sources of emboli are left-sided tumors, such as atrial myxoma and papillary fibroelastoma, left-sided prosthetic valve thrombosis, and vegetations caused by infective endocarditis or other disorders. (See "Complications and outcome of infective endocarditis", section on 'Metastatic infection'.) RISK OF EMBOLIC STROKE Approximately 25 to 40 percent of ischemic strokes are cryptogenic, including embolic stroke of undetermined source (ESUS; defined as a brain infarct without an identified cardioembolic or large vessel source and with a distribution that is not consistent with small vessel disease). The causes of cryptogenic stroke are likely heterogeneous with embolism a dominant etiology. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)".) There is an increased prevalence of PFO and ASA in patients who have an embolic-appearing ischemic stroke and no other evident source of stroke, suggesting that paradoxical embolism and/or other mechanisms related to PFO and ASA are the cause of some ischemic strokes. However, the detection of an atrial septal abnormality in a patient with an embolic stroke does not prove a cause-and-effect relationship given how common they are in the general population and the likelihood of other potential source when properly investigated. As an example, in a https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 5/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate report of 134 patients with cerebral embolic events, an ASA was found in 45, but 41 of these 45 patients had other potential sources for embolization [30]. PFO may be a risk factor for perioperative stroke, but the quality of the evidence is low [31]. One study found that a preoperative diagnosis of PFO was associated with an increased risk of perioperative ischemic stroke within 30 days after noncardiac surgery [32], and meta-analyses of observational studies have also found an association of PFO with an increased risk of stroke at 30 days after noncardiac surgery [31,33]. The strength of these findings is limited by the largely retrospective nature of the data, since patients with prior cardiac disease, including coronary artery disease and atrial fibrillation, were more likely to have a PFO identified. Nevertheless, patients, especially those 60 years of age, with an embolic-appearing ischemic stroke in the setting of a PFO with a right-to-left interatrial shunt and no other source of stroke despite a comprehensive evaluation are now recognized as most likely having a PFO-associated stroke [34]. Data on the risk of stroke in patients with PFO and pulmonary embolism is discussed separately. (See "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults", section on 'Early'.) Prevalence of PFO in cryptogenic stroke A number of case-control and population-based studies have reported an increased prevalence of PFO and/or ASA in patients who have had a cryptogenic stroke [18,19,21,25,35-39]. A 2007 prospective case-control study examined 503 consecutive patients with ischemic stroke using transesophageal echocardiography (TEE), and compared 227 patients who had cryptogenic stroke (classified before TEE was performed) with 276 control patients who had stroke of known cause [38]. The prevalence of PFO was significantly higher among those with cryptogenic stroke compared with those with known cause of stroke in both the younger (<55 years of age; 43.9 versus 14.3 percent) and older ( 55 years of age; 28.3 versus 11.9 percent) groups. In multivariate analysis, the presence of a PFO was independently associated with cryptogenic stroke in both the younger (odds ratio [OR] 3.7, 95% CI 1.42-9.65) and older age groups (OR 3.0, 95% CI 1.73-5.23). Similarly, a 2018 prospective population-based study found that the prevalence of right-to-left shunt (RLS, which is known to be caused mainly by PFO) identified by contrast-enhanced transcranial Doppler (TCD) was significantly higher among patients with cryptogenic events (transient ischemic attack [TIA] or ischemic stroke) compared with those who had a known cause of stroke, both in the overall population (OR 1.93, 95% CI 1.32-2.82) and in those >60 years of age (OR 2.06, 95% CI 1.32-3.23) [39]. https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 6/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate In a meta-analysis that included 9 studies (including both of the above prospective studies) of PFO prevalence (as assessed by TEE, transthoracic echocardiography [TTE], or TCD), a significant association between PFO and cryptogenic events was identified for all three screening modalities [39]. A significant association between PFO and cryptogenic events was also identified among older patients (patients greater than 40 to 60 years old in various studies) for each of the three screening modalities, although the results of the TEE studies were heterogeneous. Even in a patient with a cryptogenic stroke, the presence of an atrial septal abnormality does not establish the stroke etiology. A 2009 meta-analysis of case-control studies evaluating the prevalence of PFO in patients with cryptogenic stroke suggested that approximately one-third of PFOs detected in such patients are incidental findings [40]. In a 2021 meta-analysis of individual patient data from six randomized controlled trials of PFO closure for patients with PFO- associated stroke, the risk reduction for recurrent stroke with PFO closure varied among subgroups with different probabilities that the stroke was causally related to the PFO, as determined by the Risk of Paradoxical Embolism (RoPE) score ( table 1A) and a modified PFO- associated stroke causal likelihood (PASCAL) classification ( table 2) [41]. The RoPE score and PASCAL classification are discussed in detail separately. (See "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'RoPE score' and "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'PASCAL classification'.) Risk factors In patients with PFO, some retrospective analyses have suggested that certain factors may increase the likelihood of initial and recurrent stroke [42]. These include a history of Valsalva maneuver (eg, straining) preceding the cerebral embolic event, a history of multiple strokes in different vascular distributions, and possibly a transient or chronic hypercoagulable state [17,43-45]. By contrast, one study found that these factors were not associated with radiologic markers of stroke recurrence [46]. The association of an ASD with cerebral embolic events has been less well studied [4,21]. In one series of 103 patients (mean age 52 years) with a presumed paradoxical embolism and an atrial septal abnormality undergoing percutaneous closure, a PFO alone was present in 81, an ASD alone in 12, and both a PFO and ASD in 10 [4]. PFO characteristics PFO characteristics possibly associated with an increased risk of recurrent stroke include large PFO, large right-to-left shunt, spontaneous right-to-left shunt, greater PFO flap mobility, prominent Eustachian valve or Chiari network, and the presence of an ASA [41,42,47-53]. However, characteristics such as concurrent ASA or shunt size were not associated with increased recurrent stroke risk in some studies [54-57]. https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 7/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate An analysis of individual patient data on 898 patients with recent PFO-associated stroke from two prospective observational studies and the medical arms of two randomized trials (CLOSE and DEFENSE-PFO) assessed risk factors for recurrent stroke with medical therapy [53]. During a median follow-up of 3.8 years, 47 patients (5 percent) experienced a recurrent stroke. In a multivariate model incorporating age, hypertension, antithrombotic therapy and PFO anatomy, presence of an ASA was associated with recurrent stroke (adjusted HR 3.27; 95% CI 1.82-5.86), whereas large PFO was not (adjusted HR 1.43; 95% CI 0.50-4.03). Prospective studies Prospective observational and therapeutic studies of the risk of cryptogenic stroke with PFO and ASA have yielded variable results [3,26,38,49,54,55,58]. However, there is good evidence that PFO as a sole risk factor for stroke is associated with a low risk of recurrent stroke. The Risk of Paradoxical Embolism (RoPE) study performed a patient level meta-analysis of 12 cryptogenic stroke cohorts [59,60]. The following observations were noted: Among 3023 patients with cryptogenic stroke, the prevalence of PFO, and the likelihood that PFO was the cause of the stroke (the PFO-attributable fraction), correlated with the absence of vascular risk factors (ie, hypertension, diabetes, smoking, prior stroke or TIA, older age) and the presence of a cortical (as opposed to subcortical) cryptogenic infarct on imaging [59]. Using multivariate modeling, the investigators devised the RoPE score [( table 1A) and (calculator 1)], which estimates the probability that a PFO is incidental or pathogenic in a patient with cryptogenic stroke [59]. High RoPE scores, as found in younger patients who lack vascular risk factors and have a cortical infarct on neuroimaging, suggest pathogenic PFOs, while low RoPE scores, as found in older patients with vascular risk factors, suggest incidental PFOs. For each RoPE score stratum, the corresponding PFO prevalence was used to estimate the PFO-attributable fraction ( table 1B) (ie, the probability that the index event was related to the PFO). Patients with the highest PFO-attributable fraction (ie, those whose PFO was most likely to have caused the cryptogenic stroke) were at the lowest risk for stroke recurrence. As an example, a patient less than 30 years of age with none of the vascular risk factors noted above had a PFO-attributable fraction of 88 percent and an estimated two-year stroke recurrence rate of 1 percent (95% CI 0-2 percent), while a patient 70 years of age or older with all of the vascular risk factors noted above had a PFO-attributable fraction of 0 percent and an estimated two-year stroke recurrence rate of 16 percent (95% CI 9- 24 percent). https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 8/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate In a subsequent analysis, stroke recurrence was associated with the following three variables only in the high RoPE score group: a history of stroke or TIA (hazard ratio [HR] 3.79, 95% CI 1.43-10.09), a hypermobile interatrial septum (HR 2.31, 95% CI 1.05-5.05), and a small shunt (HR 3.26, 95% CI 1.59-6.67) [60]. In a meta-analysis of 14 prospective studies reporting recurrent cerebrovascular events in 4241 medically treated patients, patients with a PFO had no increased risk of recurrent cryptogenic stroke compared with those without a PFO (annual rate 2.0 versus 2.4 percent, risk ratio 0.85, 95% CI 0.59-1.22) [61]. Furthermore, PFO size was not associated with the risk of recurrent stroke or TIA. Among several of the cryptogenic stroke cohorts included in the RoPE analysis cited above, the presence of PFO together with an ASA was a significant predictor of an increased risk of recurrent stroke, but this was not the case in PICSS, the German Stroke Study, or CODICIA studies [54,55,62]. Population-based studies Two prospective population-based cohort studies [56,63] and one population-based case-control study [57] suggest that PFO and large PFO are not independent risk factors for ischemic stroke in patients without prior stroke. These results could be due to study populations composed largely of older adults and therefore a low average RoPE score (ie, a low PFO-attributable fraction of stroke). In the NOMAS study of 1100 stroke-free subjects 40 years of age or older (mean age 69 years), PFO was not associated with a statistically significant increase in stroke risk (HR 1.64, 95% CI 0.87-3.09), nor was the coexistence of PFO and ASA (HR 1.25, 95% CI 0.17-9.24) or the presence of an isolated ASA (HR 3.66, 95% CI 0.88-15.3), although the confidence intervals for these HRs do not exclude clinically important associations [56]. In the SPARC study of 585 randomly sampled subjects 45 years of age or older, PFO was not a significant independent predictor of cerebrovascular events after adjustment for age and comorbid conditions (HR 1.46; 95% CI 0.74-2.88) [63]. Furthermore, there was no association of large PFO size with risk of cerebrovascular events. ASA was associated with a nearly fourfold increase in the risk of cerebrovascular events, but this risk did not achieve statistical significance (HR 3.72; 95% CI 0.88-15.71), possibly because ASA was present in only 11 subjects, of whom only two had cerebrovascular events. In a population-based, case-control study, PFO and large PFO were not independent risk factors for cryptogenic stroke in the entire study population, which was generally older than age 65 [57]. The small number of patients younger than age 55 led to wide confidence intervals in the analysis of that subgroup, and the study does not refute the contention https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 9/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate that PFO is associated with an increased ischemic stroke risk in children or young adults [64]. Conclusions The true risk of primary or recurrent ischemic stroke associated with PFO and ASA remains uncertain. However, available data can be summarized as follows (see 'Prevalence of PFO in cryptogenic stroke' above and 'Prospective studies' above and 'Population-based studies' above): Multiple case-control trials have reported an increased prevalence of PFO in younger patients who have had a cryptogenic stroke, suggesting that PFO is frequent cause of cryptogenic stroke. By contrast, population-based cohort studies, which enrolled predominantly older subjects, have found no statistically significant association between the risk of first ischemic stroke and presence of a PFO. The PFO-attributable fraction of stroke varies widely and decreases with age and the presence of vascular risk factors. Differences in the PFO-attributable fraction of stroke likely explain, at least in part, the discrepant findings of the case-control and population-based studies. Subjects with cryptogenic stroke are generally younger and more likely to have a higher PFO-attributable fraction of stroke than the older subjects enrolled in the population-based studies. Additionally, it is possible that patients with PFO-associated stroke have other risk factors that may predispose to paradoxical embolism, such as a hypercoagulable condition [65]. For patients with cryptogenic stroke and PFO, the risk of stroke recurrence is inversely related to the likelihood that the PFO was responsible for the index stroke. Large-shunt PFO and the presence of an ASA with a PFO are probably risk factors for recurrent PFO-associated stroke. DIAGNOSIS The diagnosis of ischemic stroke or transient ischemic attack (TIA) due to paradoxical embolism through a PFO (ie, a PFO-associated stroke) or ASD is usually one of exclusion. A PFO or ASD should be considered as a potential cause of embolic stroke or TIA in patients with no other identifiable cause, particularly in younger patients (eg, 60 years of age). When evaluating whether an ischemic stroke is related to PFO or to another mechanism, the assessment should look for features that increase the probability that a PFO is the cause of the https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 10/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate stroke. These include [34]: Factors that increase right-to-left shunt flow (eg, large PFO size, chronic right atrial hypertension, or a Valsalva maneuver) Presence of embolic stroke Presence of associated ASA Risk for current or prior venous thrombosis Absence of atherosclerotic risk factors or other likely causes of ischemic stroke, including atrial fibrillation The diagnostic evaluation and treatment of PFO-associated stroke is discussed in detail separately. (See "Stroke associated with patent foramen ovale (PFO): Evaluation".) TREATMENT Therapeutic options for secondary prevention of PFO-associated stroke include medical therapy with antithrombotic agents or percutaneous closure of the defect. These options are discussed separately. (See "Stroke associated with patent foramen ovale (PFO): Evaluation".) No specific treatment is needed for incidentally discovered PFO, small ASD and/or ASA in asymptomatic patients. The available evidence from population-based studies suggests that PFO and large PFO are not independent risk factors for ischemic stroke in otherwise asymptomatic individuals. However, given the potential risk of paradoxical embolism in patients with PFO or small ASD, it is reasonable to educate the patient on how to prevent deep venous thrombosis by avoiding prolonged period of immobilization and dehydration. (See 'Population-based studies' above.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 11/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Patent foramen ovale (The Basics)") SUMMARY Embolic sources Emboli leading to stroke or to transient ischemic attack (TIA) can originate in either the systemic venous circulation (paradoxical emboli) or in the systemic arterial circulation. Some patients with an embolic-appearing ischemic stroke and no other evident source of stroke have a patent foramen ovale (PFO), an atrial septal defect (ASD), and/or an atrial septal aneurysm (ASA) that can be best identified by transesophageal echocardiography (TEE). These structures have been implicated in the pathogenesis of embolic events. However, identification of one or more of these atrial septal abnormalities in a patient with an ischemic event does not prove a causal relationship since other sources or conduits of embolism may also be present. (See 'Sources of emboli' above.) Cryptogenic stroke Approximately 25 to 40 percent of ischemic strokes are cryptogenic (ie, without an identified cardioembolic or large vessel source and with a distribution that is not consistent with small vessel disease). The causes of cryptogenic stroke are likely heterogeneous, with embolism a dominant etiology. (See 'Risk of embolic stroke' above and "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)".) Risk of stroke from a PFO The true risk of primary or recurrent ischemic stroke associated with PFO and ASA remains uncertain. However, available data can be summarized as follows (see 'Conclusions' above): Multiple case-control trials have reported an increased prevalence of PFO in patients who have had a cryptogenic stroke, suggesting that PFO is frequent cause of cryptogenic stroke. By contrast, population-based cohort studies, which enrolled predominantly older subjects, have found no statistically significant association between the risk of first https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 12/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate ischemic stroke and presence of a PFO. The PFO-attributable fraction of stroke varies widely and decreases with age and the presence of vascular risk factors, as shown in the table ( table 1A-B) and calculator (calculator 1) for the RoPE score. Differences in the PFO-attributable fraction of stroke probably explain the discrepant findings of the case-control and population-based studies. Subjects with an embolic-appearing cryptogenic stroke are generally younger and more likely to have a higher PFO-attributable fraction of stroke than the older subjects enrolled in the population-based studies. For patients with cryptogenic stroke, the risk of stroke recurrence is inversely related to the likelihood that the PFO was responsible for the index stroke. Large-shunt PFO and the presence of an ASA with a PFO are probably a risk factors for recurrent PFO-associated stroke. PFO-associated stroke Patients with an embolic-appearing ischemic stroke in the setting of a PFO with a right-to-left interatrial shunt and no other source of stroke or other risk factors for stroke despite a comprehensive evaluation are now recognized as having a PFO- associated stroke. Select patients with PFO-associated stroke may benefit from PFO closure. (See 'Risk of embolic stroke' above and "Stroke associated with patent foramen ovale (PFO): Evaluation" and "Stroke associated with patent foramen ovale (PFO): Management".) ACKNOWLEDGMENTS The editorial staff at UpToDate, Inc. acknowledge Joseph K Perloff, MD (deceased), Thomas Graham Jr, MD and Robert S Schwartz, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Cardiogenic brain embolism. Cerebral Embolism Task Force. Arch Neurol 1986; 43:71. 2. CORRIN B. PARADOXICAL EMBOLISM. Br Heart J 1964; 26:549. 3. Lamy C, Giannesini C, Zuber M, et al. Clinical and imaging findings in cryptogenic stroke patients with and without patent foramen ovale: the PFO-ASA Study. Atrial Septal Aneurysm. https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 13/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate Stroke 2002; 33:706. 4. Khositseth A, Cabalka AK, Sweeney JP, et al. Transcatheter Amplatzer device closure of atrial septal defect and patent foramen ovale in patients with presumed paradoxical embolism. Mayo Clin Proc 2004; 79:35. 5. Kerut EK, Norfleet WT, Plotnick GD, Giles TD. Patent foramen ovale: a review of associated conditions and the impact of physiological size. J Am Coll Cardiol 2001; 38:613. 6. Harvey JR, Teague SM, Anderson JL, et al. Clinically silent atrial septal defects with evidence for cerebral embolization. Ann Intern Med 1986; 105:695. 7. Caes FL, Van Belleghem YV, Missault LH, et al. Surgical treatment of impending paradoxical embolism through patent foramen ovale. Ann Thorac Surg 1995; 59:1559. 8. Falk V, Walther T, Krankenberg H, Mohr FW. Trapped thrombus in a patent foramen ovale. Thorac Cardiovasc Surg 1997; 45:90. 9. Meacham RR 3rd, Headley AS, Bronze MS, et al. Impending paradoxical embolism. Arch Intern Med 1998; 158:438. 10. d'audiffret A, Pillai L, Dryjski M. Paradoxical emboli: the relationship between patent foramen ovale, deep vein thrombosis and ischaemic stroke. Eur J Vasc Endovasc Surg 1999; 17:468. 11. Yan C, Li H. Preliminary Investigation of In situ Thrombus Within Patent Foramen Ovale in Patients With and Without Stroke. JAMA 2021; 325:2116. 12. Supple GE, Ren JF, Zado ES, Marchlinski FE. Mobile thrombus on device leads in patients undergoing ablation: identification, incidence, location, and association with increased pulmonary artery systolic pressure. Circulation 2011; 124:772. 13. DeSimone CV, DeSimone DC, Patel NA, et al. Implantable cardiac devices with patent foramen ovale a risk factor for cardioembolic stroke? J Interv Card Electrophysiol 2012; 35:159. 14. DeSimone CV, DeSimone DC, Hagler DJ, et al. Cardioembolic stroke in patients with patent foramen ovale and implanted cardiac leads. Pacing Clin Electrophysiol 2013; 36:50. 15. DeSimone CV, Friedman PA, Noheria A, et al. Stroke or transient ischemic attack in patients with transvenous pacemaker or defibrillator and echocardiographically detected patent foramen ovale. Circulation 2013; 128:1433. 16. Langholz D, Louie EK, Konstadt SN, et al. Transesophageal echocardiographic demonstration of distinct mechanisms for right to left shunting across a patent foramen ovale in the absence of pulmonary hypertension. J Am Coll Cardiol 1991; 18:1112. https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 14/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate 17. Meissner I, Whisnant JP, Khandheria BK, et al. Prevalence of potential risk factors for stroke assessed by transesophageal echocardiography and carotid ultrasonography: the SPARC study. Stroke Prevention: Assessment of Risk in a Community. Mayo Clin Proc 1999; 74:862. 18. Pearson AC, Nagelhout D, Castello R, et al. Atrial septal aneurysm and stroke: a transesophageal echocardiographic study. J Am Coll Cardiol 1991; 18:1223. 19. Cabanes L, Mas JL, Cohen A, et al. Atrial septal aneurysm and patent foramen ovale as risk factors for cryptogenic stroke in patients less than 55 years of age. A study using

medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Patent foramen ovale (The Basics)") SUMMARY Embolic sources Emboli leading to stroke or to transient ischemic attack (TIA) can originate in either the systemic venous circulation (paradoxical emboli) or in the systemic arterial circulation. Some patients with an embolic-appearing ischemic stroke and no other evident source of stroke have a patent foramen ovale (PFO), an atrial septal defect (ASD), and/or an atrial septal aneurysm (ASA) that can be best identified by transesophageal echocardiography (TEE). These structures have been implicated in the pathogenesis of embolic events. However, identification of one or more of these atrial septal abnormalities in a patient with an ischemic event does not prove a causal relationship since other sources or conduits of embolism may also be present. (See 'Sources of emboli' above.) Cryptogenic stroke Approximately 25 to 40 percent of ischemic strokes are cryptogenic (ie, without an identified cardioembolic or large vessel source and with a distribution that is not consistent with small vessel disease). The causes of cryptogenic stroke are likely heterogeneous, with embolism a dominant etiology. (See 'Risk of embolic stroke' above and "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)".) Risk of stroke from a PFO The true risk of primary or recurrent ischemic stroke associated with PFO and ASA remains uncertain. However, available data can be summarized as follows (see 'Conclusions' above): Multiple case-control trials have reported an increased prevalence of PFO in patients who have had a cryptogenic stroke, suggesting that PFO is frequent cause of cryptogenic stroke. By contrast, population-based cohort studies, which enrolled predominantly older subjects, have found no statistically significant association between the risk of first https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 12/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate ischemic stroke and presence of a PFO. The PFO-attributable fraction of stroke varies widely and decreases with age and the presence of vascular risk factors, as shown in the table ( table 1A-B) and calculator (calculator 1) for the RoPE score. Differences in the PFO-attributable fraction of stroke probably explain the discrepant findings of the case-control and population-based studies. Subjects with an embolic-appearing cryptogenic stroke are generally younger and more likely to have a higher PFO-attributable fraction of stroke than the older subjects enrolled in the population-based studies. For patients with cryptogenic stroke, the risk of stroke recurrence is inversely related to the likelihood that the PFO was responsible for the index stroke. Large-shunt PFO and the presence of an ASA with a PFO are probably a risk factors for recurrent PFO-associated stroke. PFO-associated stroke Patients with an embolic-appearing ischemic stroke in the setting of a PFO with a right-to-left interatrial shunt and no other source of stroke or other risk factors for stroke despite a comprehensive evaluation are now recognized as having a PFO- associated stroke. Select patients with PFO-associated stroke may benefit from PFO closure. (See 'Risk of embolic stroke' above and "Stroke associated with patent foramen ovale (PFO): Evaluation" and "Stroke associated with patent foramen ovale (PFO): Management".) ACKNOWLEDGMENTS The editorial staff at UpToDate, Inc. acknowledge Joseph K Perloff, MD (deceased), Thomas Graham Jr, MD and Robert S Schwartz, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Cardiogenic brain embolism. Cerebral Embolism Task Force. Arch Neurol 1986; 43:71. 2. CORRIN B. PARADOXICAL EMBOLISM. Br Heart J 1964; 26:549. 3. Lamy C, Giannesini C, Zuber M, et al. Clinical and imaging findings in cryptogenic stroke patients with and without patent foramen ovale: the PFO-ASA Study. Atrial Septal Aneurysm. https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 13/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate Stroke 2002; 33:706. 4. Khositseth A, Cabalka AK, Sweeney JP, et al. Transcatheter Amplatzer device closure of atrial septal defect and patent foramen ovale in patients with presumed paradoxical embolism. Mayo Clin Proc 2004; 79:35. 5. Kerut EK, Norfleet WT, Plotnick GD, Giles TD. Patent foramen ovale: a review of associated conditions and the impact of physiological size. J Am Coll Cardiol 2001; 38:613. 6. Harvey JR, Teague SM, Anderson JL, et al. Clinically silent atrial septal defects with evidence for cerebral embolization. Ann Intern Med 1986; 105:695. 7. Caes FL, Van Belleghem YV, Missault LH, et al. Surgical treatment of impending paradoxical embolism through patent foramen ovale. Ann Thorac Surg 1995; 59:1559. 8. Falk V, Walther T, Krankenberg H, Mohr FW. Trapped thrombus in a patent foramen ovale. Thorac Cardiovasc Surg 1997; 45:90. 9. Meacham RR 3rd, Headley AS, Bronze MS, et al. Impending paradoxical embolism. Arch Intern Med 1998; 158:438. 10. d'audiffret A, Pillai L, Dryjski M. Paradoxical emboli: the relationship between patent foramen ovale, deep vein thrombosis and ischaemic stroke. Eur J Vasc Endovasc Surg 1999; 17:468. 11. Yan C, Li H. Preliminary Investigation of In situ Thrombus Within Patent Foramen Ovale in Patients With and Without Stroke. JAMA 2021; 325:2116. 12. Supple GE, Ren JF, Zado ES, Marchlinski FE. Mobile thrombus on device leads in patients undergoing ablation: identification, incidence, location, and association with increased pulmonary artery systolic pressure. Circulation 2011; 124:772. 13. DeSimone CV, DeSimone DC, Patel NA, et al. Implantable cardiac devices with patent foramen ovale a risk factor for cardioembolic stroke? J Interv Card Electrophysiol 2012; 35:159. 14. DeSimone CV, DeSimone DC, Hagler DJ, et al. Cardioembolic stroke in patients with patent foramen ovale and implanted cardiac leads. Pacing Clin Electrophysiol 2013; 36:50. 15. DeSimone CV, Friedman PA, Noheria A, et al. Stroke or transient ischemic attack in patients with transvenous pacemaker or defibrillator and echocardiographically detected patent foramen ovale. Circulation 2013; 128:1433. 16. Langholz D, Louie EK, Konstadt SN, et al. Transesophageal echocardiographic demonstration of distinct mechanisms for right to left shunting across a patent foramen ovale in the absence of pulmonary hypertension. J Am Coll Cardiol 1991; 18:1112. https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 14/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate 17. Meissner I, Whisnant JP, Khandheria BK, et al. Prevalence of potential risk factors for stroke assessed by transesophageal echocardiography and carotid ultrasonography: the SPARC study. Stroke Prevention: Assessment of Risk in a Community. Mayo Clin Proc 1999; 74:862. 18. Pearson AC, Nagelhout D, Castello R, et al. Atrial septal aneurysm and stroke: a transesophageal echocardiographic study. J Am Coll Cardiol 1991; 18:1223. 19. Cabanes L, Mas JL, Cohen A, et al. Atrial septal aneurysm and patent foramen ovale as risk factors for cryptogenic stroke in patients less than 55 years of age. A study using transesophageal echocardiography. Stroke 1993; 24:1865. 20. Belkin RN, Kisslo J. Atrial septal aneurysm: recognition and clinical relevance. Am Heart J 1990; 120:948. 21. M gge A, Daniel WG, Angermann C, et al. Atrial septal aneurysm in adult patients. A multicenter study using transthoracic and transesophageal echocardiography. Circulation 1995; 91:2785. 22. Silver MD, Dorsey JS. Aneurysms of the septum primum in adults. Arch Pathol Lab Med 1978; 102:62. 23. Hanley PC, Tajik AJ, Hynes JK, et al. Diagnosis and classification of atrial septal aneurysm by two-dimensional echocardiography: report of 80 consecutive cases. J Am Coll Cardiol 1985; 6:1370. 24. Olivares-Reyes A, Chan S, Lazar EJ, et al. Atrial septal aneurysm: a new classification in two hundred five adults. J Am Soc Echocardiogr 1997; 10:644. 25. Agmon Y, Khandheria BK, Meissner I, et al. Frequency of atrial septal aneurysms in patients with cerebral ischemic events. Circulation 1999; 99:1942. 26. Burger AJ, Sherman HB, Charlamb MJ. Low incidence of embolic strokes with atrial septal aneurysms: A prospective, long-term study. Am Heart J 2000; 139:149. 27. Mattioli AV, Aquilina M, Oldani A, et al. Atrial septal aneurysm as a cardioembolic source in adult patients with stroke and normal carotid arteries. A multicentre study. Eur Heart J 2001; 22:261. 28. Ewert P, Berger F, Vogel M, et al. Morphology of perforated atrial septal aneurysm suitable for closure by transcatheter device placement. Heart 2000; 84:327. 29. Djaiani G, Phillips-Bute B, Podgoreanu M, et al. The association of patent foramen ovale and atrial fibrillation after coronary artery bypass graft surgery. Anesth Analg 2004; 98:585. 30. Ilercil A, Meisner JS, Vijayaraman P, et al. Clinical significance of fossa ovalis membrane aneurysm in adults with cardioembolic cerebral ischemia. Am J Cardiol 1997; 80:96. https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 15/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate 31. Hobbes B, Akseer S, Pikula A, et al. Risk of Perioperative Stroke in Patients With Patent Foramen Ovale: A Systematic Review and Meta-analysis. Can J Cardiol 2022; 38:1189. 32. Ng PY, Ng AK, Subramaniam B, et al. Association of Preoperatively Diagnosed Patent Foramen Ovale With Perioperative Ischemic Stroke. JAMA 2018; 319:452. 33. Rais G, Vassallo P, Schorer R, et al. Patent foramen ovale and perioperative stroke in noncardiac surgery: a systematic review and meta-analysis. Br J Anaesth 2022; 129:898. 34. Elgendy AY, Saver JL, Amin Z, et al. Proposal for Updated Nomenclature and Classification of Potential Causative Mechanism in Patent Foramen Ovale-Associated Stroke. JAMA Neurol 2020; 77:878. 35. Webster MW, Chancellor AM, Smith HJ, et al. Patent foramen ovale in young stroke patients. Lancet 1988; 2:11. 36. Lechat P, Mas JL, Lascault G, et al. Prevalence of patent foramen ovale in patients with stroke. N Engl J Med 1988; 318:1148. 37. Di Tullio M, Sacco RL, Gopal A, et al. Patent foramen ovale as a risk factor for cryptogenic stroke. Ann Intern Med 1992; 117:461. 38. Handke M, Harloff A, Olschewski M, et al. Patent foramen ovale and cryptogenic stroke in older patients. N Engl J Med 2007; 357:2262. 39. Mazzucco S, Li L, Binney L, et al. Prevalence of patent foramen ovale in cryptogenic transient ischaemic attack and non-disabling stroke at older ages: a population-based study, systematic review, and meta-analysis. Lancet Neurol 2018; 17:609. 40. Alsheikh-Ali AA, Thaler DE, Kent DM. Patent foramen ovale in cryptogenic stroke: incidental or pathogenic? Stroke 2009; 40:2349. 41. Kent DM, Saver JL, Kasner SE, et al. Heterogeneity of Treatment Effects in an Analysis of Pooled Individual Patient Data From Randomized Trials of Device Closure of Patent Foramen Ovale After Stroke. JAMA 2021; 326:2277. 42. Wu LA, Malouf JF, Dearani JA, et al. Patent foramen ovale in cryptogenic stroke: current understanding and management options. Arch Intern Med 2004; 164:950. 43. Dearani JA, Ugurlu BS, Danielson GK, et al. Surgical patent foramen ovale closure for prevention of paradoxical embolism-related cerebrovascular ischemic events. Circulation 1999; 100:II171. 44. Bogousslavsky J, Garazi S, Jeanrenaud X, et al. Stroke recurrence in patients with patent foramen ovale: the Lausanne Study. Lausanne Stroke with Paradoxal Embolism Study Group. Neurology 1996; 46:1301. https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 16/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate 45. Pezzini A, Grassi M, Zotto ED, et al. Do common prothrombotic mutations influence the risk of cerebral ischaemia in patients with patent foramen ovale? Systematic review and meta- analysis. Thromb Haemost 2009; 101:813. 46. Kitsios GD, Lasker A, Singh J, Thaler DE. Recurrent stroke on imaging and presumed paradoxical embolism: a cross-sectional analysis. Neurology 2012; 78:993. 47. Schuchlenz HW, Weihs W, Horner S, Quehenberger F. The association between the diameter of a patent foramen ovale and the risk of embolic cerebrovascular events. Am J Med 2000; 109:456. 48. Homma S, Di Tullio MR, Sacco RL, et al. Characteristics of patent foramen ovale associated with cryptogenic stroke. A biplane transesophageal echocardiographic study. Stroke 1994; 25:582. 49. De Castro S, Cartoni D, Fiorelli M, et al. Morphological and functional characteristics of patent foramen ovale and their embolic implications. Stroke 2000; 31:2407. 50. Stone DA, Godard J, Corretti MC, et al. Patent foramen ovale: association between the degree of shunt by contrast transesophageal echocardiography and the risk of future ischemic neurologic events. Am Heart J 1996; 131:158. 51. Hanna JP, Sun JP, Furlan AJ, et al. Patent foramen ovale and brain infarct. Echocardiographic predictors, recurrence, and prevention. Stroke 1994; 25:782. 52. Rigatelli G, Dell'avvocata F, Braggion G, et al. Persistent venous valves correlate with increased shunt and multiple preceding cryptogenic embolic events in patients with patent foramen ovale: an intracardiac echocardiographic study. Catheter Cardiovasc Interv 2008; 72:973. 53. Turc G, Lee JY, Brochet E, et al. Atrial Septal Aneurysm, Shunt Size, and Recurrent Stroke Risk in Patients With Patent Foramen Ovale. J Am Coll Cardiol 2020; 75:2312. 54. Serena J, Marti-F bregas J, Santamarina E, et al. Recurrent stroke and massive right-to-left shunt: results from the prospective Spanish multicenter (CODICIA) study. Stroke 2008; 39:3131. 55. Homma S, Sacco RL, Di Tullio MR, et al. Effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in Cryptogenic Stroke Study. Circulation 2002; 105:2625. 56. Di Tullio MR, Sacco RL, Sciacca RR, et al. Patent foramen ovale and the risk of ischemic stroke in a multiethnic population. J Am Coll Cardiol 2007; 49:797. 57. Petty GW, Khandheria BK, Meissner I, et al. Population-based study of the relationship between patent foramen ovale and cerebrovascular ischemic events. Mayo Clin Proc 2006; https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 17/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate 81:602. 58. Mas JL, Arquizan C, Lamy C, et al. Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. N Engl J Med 2001; 345:1740. 59. Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology 2013; 81:619. 60. Thaler DE, Ruthazer R, Weimar C, et al. Recurrent stroke predictors differ in medically treated patients with pathogenic vs. other PFOs. Neurology 2014; 83:221. 61. Katsanos AH, Spence JD, Bogiatzi C, et al. Recurrent stroke and patent foramen ovale: a systematic review and meta-analysis. Stroke 2014; 45:3352. 62. Weimar C, Holle DN, Benemann J, et al. Current management and risk of recurrent stroke in cerebrovascular patients with right-to-left cardiac shunt. Cerebrovasc Dis 2009; 28:349. 63. Meissner I, Khandheria BK, Heit JA, et al. Patent foramen ovale: innocent or guilty? Evidence from a prospective population-based study. J Am Coll Cardiol 2006; 47:440. 64. Adams HP Jr. Cardiac disease and stroke: will history repeat itself? Mayo Clin Proc 2006; 81:597. 65. Chiasakul T, De Jesus E, Tong J, et al. Inherited Thrombophilia and the Risk of Arterial Ischemic Stroke: A Systematic Review and Meta-Analysis. J Am Heart Assoc 2019; 8:e012877. Topic 1092 Version 30.0 https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 18/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate GRAPHICS Risk of Paradoxical Embolism (RoPE) score RoPE score Characteristic Points No history of hypertension 1 No history of diabetes 1 No history of stroke or TIA 1 Nonsmoker 1 Cortical infarct on imaging 1 Age, years 18 to 29 5 30 to 39 4 40 to 49 3 50 to 59 2 60 to 69 1 70 0 Total score (sum of individual points) Maximum score (a patient <30 years with no hypertension, no 10 diabetes, no history of stroke or TIA, nonsmoker, and cortical infarct) Minimum score (a patient 70 years with hypertension, diabetes, prior stroke, current smoker, and no cortical infarct) 0 TIA: transient ischemic attack. From: Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology 2013; 81:619. DOI: 10.1212/WNL.0b013e3182a08d59. Reproduced with permission from Lippincott Williams & Wilkins. Copyright 2013 American Academy of Neurology. Unauthorized reproduction of this material is prohibited. Graphic 97895 Version 5.0 https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 19/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate Proposed flexible clinical practice approach to classifying patent foramen ovale causal association in patients with embolic infarct topography and without other major stroke sources* RoPE score Risk source Features Low High Very high A PFO and a straddling thrombus Definite Definite High (1) Concomitant pulmonary embolism Probable Highly probable or deep venous thrombosis preceding an index infarct combined with either (2a) a PFO and an atrial septal aneurysm or (2b) a large-shunt PFO Medium Either (1) a PFO and an atrial septal aneurysm or (2) a large-shunt PFO Possible Probable Low A small-shunt PFO without an atrial septal aneurysm Unlikely Possible RoPE: Risk of Paradoxical Embolism; PFO: patent foramen ovale. The algorithm in this table is proposed for use in flexible clinical practice when application of an entire formal classification system is not being conducted. The RoPE score includes points for 5 age categories, cortical infarct, absence of hypertension, diabetes, prior stroke or transient ischemic attack, and smoking. A higher RoPE score ( 7 points) increases probability of causal association. Reproduced with permission from: Elgendy AY, Saver JL, Amin Z, et al. Proposal for updated nomenclature and classi cation of potential causative mechanism in patent foramen ovale-associated Stroke. JAMA Neurol 2020; 77:878. Copyright 2020 American Medical Association. All rights reserved. Graphic 134674 Version 3.0 https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 20/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate PFO prevalence, attributable fraction, and estimated two-year risk of stroke/TIA CS patients with PFO (n = Cryptogenic stroke (n = 3023) 1324) Estimated two-year stroke/TIA Prevalence of PFO- RoPE patients with a PFO, attributable fraction, Number of CS patients with score Number of patients recurrence rate (Kaplan- percent (95% CI)* percent (95% CI)* PFO* Meier), percent (95% CI) 0 to 3 613 23 (19 to 26) 0 (0 to 4) 108 20 (12 to 28) 4 511 35 (31 to 39) 38 (25 to 48) 148 12 (6 to 18) 5 516 34 (30 to 38) 34 (21 to 45) 186 7 (3 to 11) 6 482 47 (42 to 51) 62 (54 to 68) 236 8 (4 to 12) 7 434 54 (49 to 59) 72 (66 to 76) 263 6 (2 to 10) 8 287 67 (62 to 73) 84 (79 to 87) 233 6 (2 to 10) 9 to 10 180 73 (66 to 79) 88 (83 to 91) 150 2 (0 to 4) CI: confidence interval; CS: cryptogenic stroke; PFO: patent foramen ovale; RoPE: Risk of Paradoxical Embolism; TIA: transient ischemic attack. NOTE: 95% CI for PFO prevalence and attributable fraction based on normal approximation to the binomial distribution. From: Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology 2013; 81:619. DOI: 10.1212/WNL.0b013e3182a08d59. Reproduced with permission from Lippincott Williams & Wilkins. Copyright 2013 American Academy of Neurology. Unauthorized reproduction of this material is prohibited. Graphic 97896 Version 5.0 https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 21/22 7/5/23, 11:47 AM Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults - UpToDate Contributor Disclosures Steven R Mess , MD Equity Ownership/Stock Options: Neuralert Technologies [Stroke monitoring]. Grant/Research/Clinical Trial Support: Biogen [Hemispheric ischemic stroke]; Mallinkrodt, Inc [Nitric oxide and cerebral perfusion]; Novartis [Intracerebral hemorrhage]; WL Gore & Associates [PFO closure for secondary stroke prevention, neurologic outcomes from proximal aortic repair]. Consultant/Advisory Boards: Boston Scientific [steering committee for PROTECTED-TAVR trial of embolic protection during TAVR]; EmStop [embolic protection during TAVR]; WL Gore [DSMB for post marketing study of PFO closure for secondary stroke prevention]. Other Financial Interest: Novo Nordisk [ONWARDS trial event adjudication committee]; Terumo [Patient selection committee, Relay Branch trial]. All of the relevant financial relationships listed have been mitigated. Naser M Ammash, MD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Heidi M Connolly, MD, FACC, FASE No relevant financial relationship(s) with ineligible companies to disclose. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/atrial-septal-abnormalities-pfo-asd-and-asa-and-risk-of-cerebral-emboli-in-adults/print 22/22

7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) : Muhamed Saric, MD, PhD, FACC, FASE : Catherine M Otto, MD, Jos Biller, MD, FACP, FAAN, FAHA, John F Eidt, MD, Joseph L Mills, Sr, MD : Kathryn A Collins, MD, PhD, FACS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Mar 31, 2021. INTRODUCTION Aortic atherosclerotic plaques are a manifestation of systemic atherosclerosis. They are associated with general risk factors for atherosclerotic disease, including age, hypertension, and hypercholesterolemia, and are more common in patients with coronary artery disease [1,2]. Aortic atherosclerotic plaques are an important source of emboli, leading to cerebral (eg, transient ischemic attack, stroke), extremity, or visceral embolization ( picture 1) [3-6]. Embolic events can occur spontaneously or can be induced by interventions, including cardiac catheterization, arteriography, peripheral interventions, intraaortic balloon pumping, and cardiac or vascular surgery [7,8]. The general manifestations and treatment of cholesterol crystal embolism, diagnosis, and medical and surgical management will be reviewed. Thromboembolism from unstable aortic plaques is discussed elsewhere. (See "Thromboembolism from aortic plaque".) Specific considerations related to end-organ ischemia (kidney, gut, extremity) that may result from cholesterol crystal embolus are discussed in separate topic reviews. ATHEROEMBOLISM VERSUS THROMBOEMBOLISM https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 1/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate Two types of emboli originate from atherosclerotic plaques: thromboemboli and atheroemboli (cholesterol crystal emboli). Although the underlying risk factors may be similar, the two can often be differentiated based upon associated conditions and clinical manifestations. This is an important distinction, since the prognosis and treatment differ. Thromboembolism from complex aortic plaques is common, particularly from thoracic aortic plaques. In comparison, cholesterol crystal embolism is fairly rare but is probably underrecognized given its diverse presentations. (See 'Epidemiology and risk factors' below and "Thromboembolism from aortic plaque".) Although there is some overlap, these two disorders can be distinguished from each other. Thromboembolism occurs when thrombus, which is usually superimposed on an atherosclerotic plaque, dislodges due to plaque rupture or other forces. The thromboemboli tend to be single and lodge in medium or large arteries. Thromboemboli from aortic atherosclerotic plaque most often result in transient ischemic attack or stroke [3-6]. Acute ischemia of the extremities, intestines, or solid organs (eg, kidney, spleen) can also occur [9]. The term cholesterol crystal embolism is used synonymously with cholesterol embolism or atheroembolism [10]. Cholesterol crystal embolism occurs when atherosclerotic plaque is disrupted and cholesterol crystals within the plaque or portions of the plaque embolize distally. The debris showers into the circulation, partially or totally occluding arterioles that are <200 micrometers in diameter, leading to a myriad of occlusions that typically affect multiple organs. These characteristic sizes of atheroemboli were illustrated in an experimental study using human aortorenal endarterectomy specimens. Following ex vivo "angioplasty" of these specimens, thousands of fragments 20 to 40 micrometers in size, the approximate size of the human afferent arteriole, and hundreds >100 micrometers in size, were collected [11]. EPIDEMIOLOGY AND RISK FACTORS Cholesterol embolization is most likely to occur in the male patient >50 years of age, with risk factors for atherosclerosis following cardiac catheterization or a vascular procedure. Cholesterol crystal embolism is strongly associated with older age, with the average age being 66 years in a review of 221 published cases [12]. Lighter-skinned individuals may be more often affected, but it is more likely that subtle skin manifestations are not recognized in patients with darker skin tones. (See 'Skin' below.) The incidence and prevalence of cholesterol crystal embolism are unknown. The published estimates are limited by suboptimal or unclear diagnostic criteria (such as solely relying on https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 2/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate elevation of serum creatinine concentration after a procedure) and infrequent biopsy data. The full manifestations of the syndrome are probably rare. (See 'Clinical manifestations' below.) Cholesterol crystal embolization may arise spontaneously or as the result of instrumentation of the vasculature (eg, cardiac catheterization, arteriography, vascular surgery). The following observations are from some of the studies that have evaluated the incidence or prevalence of cholesterol crystal embolism: In a review of 519 patients with extensive thoracic aortic plaque on transesophageal echocardiography, cholesterol crystal embolism occurred in 1 percent of patients during a follow-up of more than three years [13]. In a series of 1011 patients who underwent infrarenal aortic and infrainguinal vascular surgery or angiographic manipulation, clinical and pathologic evidence of cholesterol crystal embolism was found in 2.9 percent [14]. Lower rates are seen after cardiac surgery (0.2 percent) [15]. In a prospective observational study of 1786 patients undergoing cardiac catheterization, definite cholesterol crystal embolism was observed in 0.8 percent [16]. In a retrospective review of 493 patients who underwent aortoiliac stent placements, 72 bilateral, the incidence of atheroembolism was 1.6 percent [17]. Many cases of cholesterol crystal embolism are not recognized clinically [18]. This issue was addressed in a prospective study of 60 patients with an acute myocardial infarction, one half of whom were treated with thrombolytic therapy [19]. All patients underwent coronary artery bypass graft surgery (CABG) within one month, and two muscle biopsy specimens and one skin biopsy specimen were obtained at the time of surgery. Seven patients (12 percent) had pathologic evidence of cholesterol crystal emboli in the muscle biopsy specimens, only one of whom had clinically evident disease. This finding of asymptomatic disease is consistent with the prevalence of cholesterol crystal embolism in autopsy studies in unselected patients that range from 0.7 to 4 percent [15,20]. Even higher rates of cholesterol embolization (up to 75 percent) are reported in retrospective autopsy studies in patients selected for atherosclerotic risk factors or following surgery or instrumentation, but these studies may overestimate the incidence of cholesterol crystal embolism due to selection bias [21]. In addition to asymptomatic disease, it is probable that clinical manifestations of cholesterol crystal embolism are ascribed to other causes. This may be most likely with acute renal failure, where acute kidney injury is much more common than cholesterol crystal embolism, which will https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 3/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate not be diagnosed unless tissue is available for pathology if there are no other manifestations of this syndrome [22]. (See 'Renal' below.) Risk factors for aortic atherosclerosis Risk factors for developing cholesterol crystal embolism are largely those associated with developing general atherosclerotic disease such as smoking, hypercholesterolemia, hypertension, obesity, and diabetes. The data supporting these associations are discussed in detail separately. (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach".) The "classic" risk factors of hypertension, age, and smoking have been correlated with severe atherosclerotic plaque in the thoracic aorta. This relationship was demonstrated with transesophageal echocardiography (TEE) in a population-based study [23]. Among those with aortic plaque, the odds of having complex plaque increased as systolic blood pressure increased (odds ratio [OR] 1.43 for each 10 mmHg increase, 95% CI 1.10-1.87). Complex aortic plaque also correlated with hypertension treatment, controlling for age and history of smoking. Risk factors for embolization The risk of cholesterol crystal embolization is directly related to the severity of atherosclerosis. Any factor that destabilizes atherosclerotic plaque can result in cholesterol crystal embolism. Embolization may be spontaneous or iatrogenic precipitated by vascular manipulation during arteriography or surgery. It was previously estimated that 50 to 60 percent of cases of cholesterol crystal embolization were spontaneous [14,24]. However, the increasing frequency of endovascular manipulations (eg, coronary, aortoiliac, renal) has increased the incidence of iatrogenic embolization [24,25]. In one retrospective review, spontaneous embolism occurred in only 25 percent of patients [26]. Abdominal aortic aneurysms are a known source of cholesterol emboli. In a prospective study of 660 patients with abdominal aortic aneurysm who were followed for 1 to 60 months (mean 15 months), cholesterol crystal embolization was diagnosed in 2.9 percent of the patients [27]. (See "Clinical features and diagnosis of abdominal aortic aneurysm", section on 'Limb ischemia'.) Plaque characteristics and location The risk of cholesterol crystal embolism in patients with aortic atherosclerosis is markedly increased if transesophageal echocardiography reveals protruding plaques, particularly if 4 mm in thickness; ulceration; or superimposed mobile thrombi [5,9,28-33]. A correlation between complex plaque seen on two-dimensional transesophageal echocardiography (2D-TEE) and embolization phenomena was first noted in 1990 [31]. Subsequent 2D-TEE studies found that complex plaques may give rise to either cholesterol crystal emboli or thromboemboli ( image 1 and movie 1). In a few case reports, cholesterol crystal embolism to the skin and kidneys was proven by biopsy in patients with complex plaques https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 4/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate in the descending thoracic aorta on 2D-TEE [32,33]. In another report, transesophageal echocardiography demonstrated mobile particulate matter in transit from a complex plaque in a patient who subsequently died after multisystem involvement from cholesterol crystal embolism ( image 2) [34]. Plaque in the aortic arch is implicated as a risk factor for cerebral embolization. However, data are conflicting. In longitudinal population-based studies in nonselected individuals, complex aortic atherosclerosis does not appear to be associated with an increased risk of primary stroke [35]. However, most reports evaluating secondary stroke risk have found that complex aortic atherosclerosis is a risk factor for recurrent stroke. This may be due to selection bias as the studies linking aortic atheroma and secondary stroke were usually performed in patients referred for TEE to evaluate a cardiac source of emboli rather than in a random population sample. Mechanistically, aortic plaque may be both a source of cerebral emboli and a marker of generalized atherosclerosis. Studies of aortic arch plaque have found a 12 to 14 percent risk of cerebral embolization, particularly when the plaque is ulcerated or mobile. On the other hand, aortic plaque may be a marker of aging, and age is an independent predictor of cerebrovascular events [36]. Atherosclerotic plaque in the thoracic aorta is typically associated with distal embolization (abdominal organs, lower extremities). However, retrograde flow from complex descending thoracic aortic plaques may be a source of cranial or upper extremity embolization. In a study of 94 patients using transesophageal echocardiography, retrograde diastolic flow reached the left subclavian artery in 60 percent, the left common carotid artery in 26 percent, and the brachiocephalic trunk in 14 percent [37]. The abdominal aorta and iliac arteries are commonly identified as a source for lower extremity cholesterol crystal embolization. In one surgical series of 62 patients, the aorta or iliac arteries were identified angiographically as the embolic source in 80 percent of patients [24]. Atherosclerotic plaque in the femoral, popliteal, or subclavian arteries may also be a source of extremity embolization. Instrumentation Iatrogenic embolism is typically related to cardiovascular manipulation during arteriography, stenting, or surgery [38,39]. Surgical procedures may disrupt atherosclerotic plaque as vessels are dissected, cross-clamped, or as an arteriotomy is made. Trauma is an unusual cause [24]. https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 5/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate Arteriography is a more common iatrogenic cause than surgery, accounting for as many as 85 percent of iatrogenic cases [14]. The source of the emboli in a review of 29 patients was the abdominal aorta (16 patients), iliac arteries (7 patients), and femoropopliteal arteries (6 patients) [14]. Patients with atherosclerotic renal artery stenosis often have diffuse atherosclerosis and are at a relatively high risk for cholesterol crystal embolism after renal arteriography, with an overall incidence of approximately 2 percent [40]. The effect of arterial manipulation has been illustrated in several studies [16,41-43]. In a prospective series of 1000 patients who underwent percutaneous coronary interventions, guiding catheter placement was associated with visible scraping of debris from the walls of the aorta in more than one half of the patients [43]. Clinical cholesterol crystal embolism was not seen, however, as ischemic events were not associated with visualization of debris in the catheter. Similarly, in reviews of renal artery angioplasty and stenting, grossly visible material (cholesterol crystals, atheromatous material, and thrombus) was retrieved from the embolic protection filter in 45 to 60 percent of cases [44,45]. (See "Clinical presentation, evaluation, and treatment of renal atheroemboli".) Anticoagulation/thrombolytic therapy Cholesterol crystal embolism has been reported after the use of thrombolytic agents or anticoagulants (eg, heparin, warfarin, direct factor Xa inhibitors, direct oral anticoagulants) [46,47]. However, a causal relationship between the use of these medications and cholesterol crystal embolism has not been established, and, based on available evidence, the overall risk appears to be low. In the 40 years since the introduction of thrombolytic therapy, a total of 30 cases as a complication of thrombolysis have been reported; 28 patients received a thrombolytic agent for acute myocardial infarction and 2 patients for deep venous thrombosis [48,49]. These case reports gave the impression that there might be a causal relationship between thrombolysis and cholesterol crystal embolism. However, there is no evidence to suggest that lysis of thrombus overlying atherosclerotic plaque leads to plaque destabilization and atheroembolism. There are no large-scale clinical trials that specifically addressed the issue of cholesterol crystal embolism in the setting of thrombolytic therapy. One small study of 60 patients found no differences in the rate of cholesterol crystal embolism between the patients who received thrombolysis and those who did not. The presence or absence of cholesterol crystal embolism in this study was based upon skin and muscle biopsies [19]. However, given the low incidence of embolism and the small number of patients in the study, a significant difference may not have been detectable. Cholesterol crystal embolism has also been blamed on therapy with anticoagulant drugs, particularly heparin or warfarin, with plaque hemorrhage as the putative precipitating factor [50,51]. However, it is unclear if cholesterol crystal embolism was caused by anticoagulants or it https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 6/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate simply occurred in patients who happened to be on anticoagulation therapy. Trials that have randomly assigned patients with documented aortic plaque identified by transesophageal echocardiography to anticoagulant therapy have not identified an increased risk for atheroembolism [13,16,52,53]. Thus, the putative risk associated with anticoagulation therapy appears to be low. CLINICAL MANIFESTATIONS The variability in clinical manifestation is related to the location of the embolic source, extent of embolization, whether there is partial or complete occlusion of the affected vessels, and the presence or absence of preexisting disease in the affected vascular bed (eg, peripheral artery disease). Atheroemboli from the aortic arch typically embolize to the brain, eye, or upper extremity while descending thoracic or abdominal aortic plaque causes gastrointestinal or lower extremity symptoms and signs. Retrograde embolization from the thoracic aorta can also occur. (See 'Plaque characteristics and location' above.) The presenting symptoms of cholesterol crystal embolism may be subtle and nonspecific. As an example, 21 percent of patients in a review of 221 cases presented with systemic symptoms of fever, myalgias, headache, and weight loss [12]. Often there is a delay between the embolic event and subsequent symptoms. In a review of histologically proven cholesterol embolization, skin signs developed more than 30 days after a precipitating event in 50 percent of patients [54]. More dramatic clinical presentations are generally due to a diffuse showering of larger, atheromatous debris originating from usually aortic plaque. The emboli may lodge into the renal, mesenteric, pelvic, carotid, coronary, or extremity vascular beds [55]. Classic manifestations include "blue toe syndrome," livedo reticularis, acute or subacute renal failure, and intestinal ischemia. Other manifestations include gastrointestinal bleeding and pancreatitis. Skin Skin findings are the most common clinical sign of cholesterol crystal embolism, occurring in 34 percent of patients in one systematic review [12]. In this study, the most frequent findings included livedo reticularis (16 percent), gangrene (12 percent), cyanosis (10 percent), skin ulcer (6 percent), purpura or petechiae (5 percent), and firm, painful erythematous nodules (3 percent) [12]. Splinter hemorrhages have also been described as a possible cutaneous manifestation of cholesterol crystal embolization [56]. Gangrene and ulcerations typically affect the toes but may extend to more proximal portions of the lower extremities. (See "Management of chronic limb-threatening ischemia".) https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 7/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate These classic skin findings in cholesterol crystal embolism commonly occur in areas where the arterial pulse is palpable since the embolization is to smaller arteries [12,54,57]. However, the arterial pulse may not be palpable in patients who also have underlying peripheral artery disease. (See "Noninvasive diagnosis of upper and lower extremity arterial disease" and 'Treatment' below.) Cholesterol crystal embolization to the skin of the genitalia is rare but, when it occurs, can lead to severe scrotal or penile skin loss [58-60]. This devastating complication has been reported following open and, more recently, endovascular repair of abdominal aortic aneurysm [60]. Livedo reticularis Livedo reticularis is a reticulated, mottled, or erythematous skin discoloration that blanches on pressure ( picture 2). It may be red or blue, and even ulcerated, depending on the degree of blood flow compromise and oxygen desaturation through the affected area. Livedo reticularis is not specific for atheroembolism and has an extensive differential diagnosis. In patients with cholesterol crystal embolization, livedo reticularis is usually bilateral and is typically found on the feet and lower legs but may extend toward the thighs, buttocks, and back. Upper extremities are less commonly involved. Atheroembolism involving the breast has also been reported [61]. In patients undergoing abdominal aortic aneurysm repair, livedo reticularis may appear on the back and the buttocks due to cholesterol embolization into the branches of the internal iliac arteries. Blue toe syndrome Although cholesterol crystal embolization is often referred to as the "blue toe syndrome" ( picture 3), blue skin discoloration is less common than other skin findings. In the overall population of patients with cholesterol embolization syndrome, skin manifestations are seen in only approximately one third of such patients, and of these, blue toes are present in 10 to 15 percent [12,18,54]. The blue toe syndrome may be considered as a specific manifestation of retiform purpura ( picture 4 and picture 5). (See "Approach to the patient with retiform (angulated) purpura".) In a retrospective review of 78 patients with cutaneous manifestations of cholesterol crystal embolization, blue toes were noted in 14 percent of the patients. More common skin manifestations were livedo reticularis (49 percent), gangrene (35 percent), cyanosis (28 percent), and ulceration (17 percent) [54]. In another study of 221 patients, skin manifestations were present in 75 patients. Of these 75, blue toes were observed in 11 patients [12]. https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 8/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate Renal Acute kidney injury is a common manifestation of cholesterol crystal embolism [26,62]. Acute kidney injury is present in 25 to 50 percent of cases [12,15,24,63]. Renal disease most often occurs after invasive vascular procedures but can occur spontaneously. In such patients, the diagnosis may be difficult to establish without biopsy unless other manifestations of crystal embolism are present. Because the cholesterol crystal emboli are irregularly shaped and nondistensible and typically do not completely occlude larger vessels, the renal manifestations are those of distal parenchymal ischemia usually manifested as a bland sediment rather than renal infarction as seen with thromboemboli, which present with flank pain, hematuria that may be gross, and markedly elevated serum lactate dehydrogenase ( image 3). The characteristics of renal involvement are discussed in detail separately ( picture 6A-B). (See "Clinical presentation, evaluation, and treatment of renal atheroemboli".) When acute kidney injury occurs after arteriography, the primary differential diagnosis is contrast nephropathy and cholesterol crystal embolism. Unless there are other signs of cholesterol crystal embolism, the two disorders are distinguished by differences in the clinical course. Contrast nephropathy typically begins to recover within three to five days, while cholesterol crystal embolism shows at best an incomplete recovery, and there may be a stuttering course with further showers of cholesterol crystals. (See "Contrast-associated and contrast-induced acute kidney injury: Clinical features, diagnosis, and management".) Although not a common manifestation of cholesterol crystal embolism, rhabdomyolysis has been reported in association with massive cholesterol crystal embolism and can lead to heme-pigment-associated acute kidney injury [64]. Rhabdomyolysis presents with elevated serum muscle enzymes (including creatine kinase), red to brown urine due to myoglobinuria if there is persistent renal function, and electrolyte abnormalities. Peak serum creatine kinase levels depend upon the volume of muscle breakdown and the muscle mass of the patient. (See "Clinical features and diagnosis of heme pigment-induced acute kidney injury".) Gastrointestinal Atheroembolism to the mesenteric circulation most commonly involves the colon, small bowel, and stomach [65-68]. The pancreas, liver, and gallbladder also may be affected [69]. (See "Overview of intestinal ischemia in adults" and "Colonic ischemia".) Gastrointestinal manifestations include abdominal pain, diarrhea, and, in approximately 10 percent of patients, bleeding [12,68,70]. Bleeding may originate from any site in the gastrointestinal tract, including the stomach [71]. Other manifestations of cholesterol crystal embolism include necrotizing pancreatitis, focal hepatic cell necrosis, and acalculous necrotizing https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 9/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate cholecystitis. Intestinal infarction has a poor prognosis, with reported mortality rates ranging from 38 to 81 percent [12,72]. Upper endoscopic findings of nonspecific entities such as gastritis may be erroneously diagnosed [71]. A definitive diagnosis can only be established by examination of a biopsy specimen. Central nervous system Central nervous system manifestations of atheroembolism may include amaurosis fugax, transient ischemic attack (TIA), stroke, confusional state, headache, dizziness, or organic brain syndrome. Embolization to the spinal cord is rare but can lead to lower extremity paralysis Transient ischemic attack/stroke Transient ischemic attack due to atheroembolic debris is more commonly associated with carotid atherosclerotic disease, and carotid thrombosis or thromboembolism can lead to hemispheric stroke. (See "Stroke: Etiology, classification, and epidemiology", section on 'Embolism'.) There are conflicting data regarding the stroke risk associated with aortic atherosclerosis [4,5,35,73-78]. Large protruding plaques in the aortic arch, particularly mobile plaques, in our opinion, are an important cause of brain pathology. In one retrospective review of 29 patients with cholesterol emboli in the brain identified on autopsy, encephalopathy presumably due to ischemia was the predominant clinical finding and was most likely due to bilateral diffuse embolization from the identified aortic plaque disease [79]. In clinical longitudinal population studies in unselected patients, complex aortic atherosclerosis does not appear to be associated with an increased risk for primary ischemic stroke [35,75,76]. However, most studies have found that complex aortic atherosclerosis is a risk factor for recurrent stroke [4,5,77,78]. The range of findings is illustrated by the following studies: A prospective study examined the frequency and thickness of atherosclerotic plaques in the ascending aorta and proximal arch in 250 patients admitted to the hospital with ischemic stroke and 250 consecutive controls, all over the age of 60 years [5]. Atherosclerotic plaques 4 mm in thickness were found in 14 percent of patients compared with 2 percent of controls, and the odds ratio for ischemic stroke among patients with such plaques was 9.1 after adjustment for atherosclerotic risk factors. In addition, aortic atherosclerotic plaques 4 mm were much more common in patients with brain infarcts of unknown cause (relative risk 4.7). https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 10/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate In contrast, a population-based study of 1135 subjects who had transesophageal echocardiography (TEE) found that complex atherosclerotic plaque (>4 mm with or without mobile debris) in the ascending and transverse aortic arch was not a significant risk factor for cryptogenic ischemic stroke or TIA after adjusting for age, sex, and other clinical risk factors [75]. However, there was an association between complex aortic plaque and non- cryptogenic stroke. The investigators concluded that complex aortic arch debris is a marker for the presence of generalized atherosclerosis. Methodologic differences are a potential explanation for the discrepant results of these reports assessing the risk of ischemic stroke related to aortic atherosclerosis, as the earlier case-control studies may have been skewed by selection and referral bias. However, many patients with aortic atherosclerosis also have cardiac or large artery lesions, a problem that may confound purely epidemiologic studies. Ocular signs Hollenhorst plaques are bright, refractile lesions in the retina indicative of cholesterol crystal embolization from a proximal atherosclerotic source ( picture 7) [80,81]. The most common proximal source is the carotid artery [82,83]. In a review of 130 patents with Hollenhorst plaque or retinal artery occlusion (amaurosis excluded), 61 percent complained of ocular symptoms, including eye pain, blurred vision, or other atypical visual symptoms [84]. Of the 98 patients who underwent carotid duplex, all had some evidence of carotid stenosis ipsilateral to the ocular findings, but the degree of stenosis was less than 60 percent in 90 of the 130 patients. Over a mean of 22 months, no patient suffered from a transient ischemic attack (including amaurosis fugax) or stroke. Evaluation of the more central vasculature was performed in approximately 20 percent of the patients, and, although some minor valvular problems were found, a cardiac or aortic source for the retinal findings was not found. Cholesterol embolization resulting in Hollenhorst plaques can occur following arteriography or cardiac catheterization, vascular surgery, or trauma. The mere finding of Hollenhorst plaques in a patient presenting with suspected cholesterol embolization syndrome should not be used to confirm that the acute clinical presentation is due to cholesterol emboli. A finding of Hollenhorst plaque may represent a prior event [85,86]. In one study, serial funduscopic examination found persistence of Hollenhorst plaques for over one year [83]. Moreover, approximately one third of patients who have Hollenhorst plaques are asymptomatic. Thus, additional evaluation may be needed to confirm the diagnosis of acute cholesterol embolization syndrome. (See 'Diagnosis' below.) Other Other vascular beds including coronary, pulmonary, prostate, thyroid, and adrenal glands may rarely be affected with diagnosis often established at autopsy [87]. https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 11/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate DIAGNOSIS A diagnosis of cholesterol crystal embolization should be highly suspected in a patient with known atherosclerotic disease and a classic history: the development of renal failure, abdominal pain or diarrhea, typical skin findings or a finding of Hollenhorst plaques of the retina following arteriography, cardiac catheterization, vascular surgery, or trauma to the abdomen. (See 'Clinical manifestations' above.) Laboratory testing is generally nonspecific and may show elevations in the white blood cell count, decreased red blood cell count, or thrombocytopenia. Inflammation markers including elevated erythrocyte sedimentation rate, C-reactive protein and fibrinogen have been associated with atheroembolism [16]. Other abnormalities may include transient hypocomplementemia and eosinophilia. Because there is an association between occlusive diseases in large peripheral arteries and cholesterol crystal embolization to smaller arteries, patients with extremity embolism should undergo noninvasive vascular testing to identify the presence of hemodynamically significant proximal peripheral artery disease. Even when a stenotic peripheral artery may not be the source of cholesterol crystal embolism, arterial revascularization may improve clinical outcomes. (See 'Revascularization' below.) Specific abnormalities may indicate end-organ dysfunction such as increased creatinine or eosinophiluria if the kidneys are involved [88-91], increased amylase with pancreatic (and possibly bowel) involvement, elevated transaminases with hepatic involvement, or elevated creatine kinase and myoglobinuria with sufficient muscle involvement. Imaging Plaques in the aorta can be visualized, characterized, and quantified by a variety of imaging techniques; however, the index plaque that is the cause of the cholesterol crystal embolization is rarely determined. The diagnosis is more difficult in patients without typical clinical features, particularly if cholesterol crystal embolism has occurred spontaneously. However, the identification of complex aortic plaque or multiple ischemic strokes on imaging studies may permit a presumptive diagnosis to be made [5,29,30]. Plaques can be simple or complex ( image 4). Simple plaques are characterized by wall thickness <4 mm and the absence of mobile components. Complex plaques are 4 mm in thickness and may exhibit irregular borders, ulceration, and mobile components that represent superimposed thrombus. Complex plaques are associated with an increased propensity for embolization. (See 'Plaque characteristics and location' above.) https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 12/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate Transesophageal echocardiography, primarily two-dimensional (2D) transesophageal echocardiography (TEE), is the first-line diagnostic modality to identify a thoracic aortic source of atheroembolism. Real-time three-dimensional transesophageal echocardiography (3D-TEE) provides very detailed information on aortic plaque location and morphology ( picture 8 and movie 2). Transthoracic echocardiography, abdominal ultrasound, and endoscopic ultrasound ( image 5) of the upper gastrointestinal tract have occasionally incidentally identified atherosclerotic plaques in the thoracic or abdominal aorta. Compared with TEE, computed tomography (CT) ( image 6 and movie 3) and magnetic resonance imaging (MRI) ( image 7) are less invasive and more complete evaluations of the extent of atherosclerosis in the aorta. CT and MRI have several advantages over TEE [92,93]. These radiologic techniques are better than TEE for imaging aortic branches. In addition, they can image the entire abdominal aorta. In comparison, only the very proximal abdominal aorta between the diaphragm and the ostium of the superior mesenteric artery can be seen with TEE. Conventional arteriography has low sensitivity for detection of plaques and often fails to identify plaques detected by other imaging techniques and should be avoided given the potential disruption of atherosclerotic debris with instrumentation [94]. (See 'Instrumentation' above.) Radiologic studies of the brain may help suggest the diagnosis in demonstrating multiple small ischemic lesions. (See "Neuroimaging of acute stroke".) Biopsy and pathologic findings Biopsy is the only definitive means of confirming the diagnosis of cholesterol embolization syndrome. Thus, biopsy should be performed whenever the diagnosis is in doubt and when the specimen can safely be obtained from the patient. Histopathologic examination of amputated body parts or embolectomy specimens for cholesterol emboli pose no additional risk to the patient and should be performed if the diagnosis is suspected. Skin and skeletal biopsies are less invasive than renal and gastrointestinal biopsies. The histologic hallmark of cholesterol crystal embolism is the presence of "ghosts" of cholesterol crystals or cholesterol clefts within arterioles, since the cholesterol crystals are dissolved during tissue fixation ( picture 6A-B). The cholesterol clefts are crescentic (with pointed ends) or elongated ovoid spaces present in small or medium-sized arteries or arterioles. Inflammatory or fibrous intimal proliferation develops rapidly and may be the cause for vascular occlusion and resultant ischemic tissue damage [95]. Cholesterol clefts have also been demonstrated in the pulmonary arteries of patients with cholesterol crystal embolism. Since pulmonary arterial atherosclerosis is rare (eg, in end-stage Eisenmenger syndrome), the crystals presumably pass through the systemic capillary bed into https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 13/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate the venous system and lungs. In a case report, cholesterol crystal emboli were seen in 25 percent of the small pulmonary arteries in a patient with atheroembolic disease [96]. Differential diagnosis The diagnosis is often difficult to establish when the presenting symptoms and signs of cholesterol crystal embolism are subtle and nonspecific. Cholesterol crystal embolism needs to be distinguished from thromboembolism given differences in treatment. (See "Thromboembolism from aortic plaque", section on 'Clinical manifestations'.) Because of its many differing effects, cholesterol crystal embolism may be included as one of the "great imitators," (such as tuberculosis, brucellosis) given its often nonspecific symptoms, leading it to be confused with a number of other diseases, including vascular diseases such aortic dissection, and tumors such as left atrial myxoma, lymphoma, and renal cell carcinoma [55]. The differential diagnosis includes many systemic illnesses, including cyanotic congenital heart disease, secondary syphilis, and pheochromocytoma [72]. There is also an extensive differential diagnosis of livedo reticularis that includes Raynaud's phenomenon, vasculitis (polyarteritis nodosa, systemic lupus, dermatomyositis, leukocytoclastic

patients who have Hollenhorst plaques are asymptomatic. Thus, additional evaluation may be needed to confirm the diagnosis of acute cholesterol embolization syndrome. (See 'Diagnosis' below.) Other Other vascular beds including coronary, pulmonary, prostate, thyroid, and adrenal glands may rarely be affected with diagnosis often established at autopsy [87]. https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 11/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate DIAGNOSIS A diagnosis of cholesterol crystal embolization should be highly suspected in a patient with known atherosclerotic disease and a classic history: the development of renal failure, abdominal pain or diarrhea, typical skin findings or a finding of Hollenhorst plaques of the retina following arteriography, cardiac catheterization, vascular surgery, or trauma to the abdomen. (See 'Clinical manifestations' above.) Laboratory testing is generally nonspecific and may show elevations in the white blood cell count, decreased red blood cell count, or thrombocytopenia. Inflammation markers including elevated erythrocyte sedimentation rate, C-reactive protein and fibrinogen have been associated with atheroembolism [16]. Other abnormalities may include transient hypocomplementemia and eosinophilia. Because there is an association between occlusive diseases in large peripheral arteries and cholesterol crystal embolization to smaller arteries, patients with extremity embolism should undergo noninvasive vascular testing to identify the presence of hemodynamically significant proximal peripheral artery disease. Even when a stenotic peripheral artery may not be the source of cholesterol crystal embolism, arterial revascularization may improve clinical outcomes. (See 'Revascularization' below.) Specific abnormalities may indicate end-organ dysfunction such as increased creatinine or eosinophiluria if the kidneys are involved [88-91], increased amylase with pancreatic (and possibly bowel) involvement, elevated transaminases with hepatic involvement, or elevated creatine kinase and myoglobinuria with sufficient muscle involvement. Imaging Plaques in the aorta can be visualized, characterized, and quantified by a variety of imaging techniques; however, the index plaque that is the cause of the cholesterol crystal embolization is rarely determined. The diagnosis is more difficult in patients without typical clinical features, particularly if cholesterol crystal embolism has occurred spontaneously. However, the identification of complex aortic plaque or multiple ischemic strokes on imaging studies may permit a presumptive diagnosis to be made [5,29,30]. Plaques can be simple or complex ( image 4). Simple plaques are characterized by wall thickness <4 mm and the absence of mobile components. Complex plaques are 4 mm in thickness and may exhibit irregular borders, ulceration, and mobile components that represent superimposed thrombus. Complex plaques are associated with an increased propensity for embolization. (See 'Plaque characteristics and location' above.) https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 12/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate Transesophageal echocardiography, primarily two-dimensional (2D) transesophageal echocardiography (TEE), is the first-line diagnostic modality to identify a thoracic aortic source of atheroembolism. Real-time three-dimensional transesophageal echocardiography (3D-TEE) provides very detailed information on aortic plaque location and morphology ( picture 8 and movie 2). Transthoracic echocardiography, abdominal ultrasound, and endoscopic ultrasound ( image 5) of the upper gastrointestinal tract have occasionally incidentally identified atherosclerotic plaques in the thoracic or abdominal aorta. Compared with TEE, computed tomography (CT) ( image 6 and movie 3) and magnetic resonance imaging (MRI) ( image 7) are less invasive and more complete evaluations of the extent of atherosclerosis in the aorta. CT and MRI have several advantages over TEE [92,93]. These radiologic techniques are better than TEE for imaging aortic branches. In addition, they can image the entire abdominal aorta. In comparison, only the very proximal abdominal aorta between the diaphragm and the ostium of the superior mesenteric artery can be seen with TEE. Conventional arteriography has low sensitivity for detection of plaques and often fails to identify plaques detected by other imaging techniques and should be avoided given the potential disruption of atherosclerotic debris with instrumentation [94]. (See 'Instrumentation' above.) Radiologic studies of the brain may help suggest the diagnosis in demonstrating multiple small ischemic lesions. (See "Neuroimaging of acute stroke".) Biopsy and pathologic findings Biopsy is the only definitive means of confirming the diagnosis of cholesterol embolization syndrome. Thus, biopsy should be performed whenever the diagnosis is in doubt and when the specimen can safely be obtained from the patient. Histopathologic examination of amputated body parts or embolectomy specimens for cholesterol emboli pose no additional risk to the patient and should be performed if the diagnosis is suspected. Skin and skeletal biopsies are less invasive than renal and gastrointestinal biopsies. The histologic hallmark of cholesterol crystal embolism is the presence of "ghosts" of cholesterol crystals or cholesterol clefts within arterioles, since the cholesterol crystals are dissolved during tissue fixation ( picture 6A-B). The cholesterol clefts are crescentic (with pointed ends) or elongated ovoid spaces present in small or medium-sized arteries or arterioles. Inflammatory or fibrous intimal proliferation develops rapidly and may be the cause for vascular occlusion and resultant ischemic tissue damage [95]. Cholesterol clefts have also been demonstrated in the pulmonary arteries of patients with cholesterol crystal embolism. Since pulmonary arterial atherosclerosis is rare (eg, in end-stage Eisenmenger syndrome), the crystals presumably pass through the systemic capillary bed into https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 13/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate the venous system and lungs. In a case report, cholesterol crystal emboli were seen in 25 percent of the small pulmonary arteries in a patient with atheroembolic disease [96]. Differential diagnosis The diagnosis is often difficult to establish when the presenting symptoms and signs of cholesterol crystal embolism are subtle and nonspecific. Cholesterol crystal embolism needs to be distinguished from thromboembolism given differences in treatment. (See "Thromboembolism from aortic plaque", section on 'Clinical manifestations'.) Because of its many differing effects, cholesterol crystal embolism may be included as one of the "great imitators," (such as tuberculosis, brucellosis) given its often nonspecific symptoms, leading it to be confused with a number of other diseases, including vascular diseases such aortic dissection, and tumors such as left atrial myxoma, lymphoma, and renal cell carcinoma [55]. The differential diagnosis includes many systemic illnesses, including cyanotic congenital heart disease, secondary syphilis, and pheochromocytoma [72]. There is also an extensive differential diagnosis of livedo reticularis that includes Raynaud's phenomenon, vasculitis (polyarteritis nodosa, systemic lupus, dermatomyositis, leukocytoclastic angiitis, rheumatoid vasculitis, thromboangiitis obliterans), infection (syphilis or tuberculosis), cryoglobulinemia, antiphospholipid syndrome, and polycythemia vera. A familial form called Sneddon's syndrome is seen in association with cerebrovascular disease. There is also an extensive differential diagnosis for retiform purpura. (See "Approach to the patient with retiform (angulated) purpura".) Among patients who develop acute kidney injury, particularly if the sediment is relatively bland, the differential renal diagnosis includes contrast nephropathy and acute kidney injury, both of which are typically reversible. (See "Clinical presentation, evaluation, and treatment of renal atheroemboli".) TREATMENT Treatment for cholesterol embolization comprises managing cardiovascular risk factors, management of end-organ ischemia, and prevention of recurrent embolization. Cardiovascular risk factor management Patients with cholesterol crystal embolism should be aggressively treated for secondary prevention of cardiovascular disease [97]. These modalities include aspirin, statins, blood pressure control, cessation of smoking, and, in patients with diabetes, glycemic control. (See 'Lipid-lowering therapy' below and "Prevention of https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 14/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".) Managing ischemic manifestations The management of the microvascular obstruction leading to end-organ ischemia varies depending upon the vascular bed affected but is primarily supportive with measures to control pain and lessen inflammation. The inflammatory reaction that results from cholesterol crystal embolization is essentially a foreign body reaction to the cholesterol crystals that are resistant to breakdown by macrophages. Arterioles that are not immediately occluded may occlude as a chronic inflammatory infiltrate fills the lumen. Given this pathologic mechanism, various anti- inflammatory and antithrombotic agents have been used to lessen the inflammatory reaction and to prevent thrombosis. There are no large trials evaluating anti-inflammatory therapies for treating cholesterol crystal embolism. Isolated reports in small numbers of patients using steroids [98-103], iloprost [104,105], and LDL apheresis [106-108] have shown modest success. The inflammatory nature of cholesterol crystal embolism results in pain that is often out of proportion to the apparent degree of tissue ischemia, and pain management is of critical importance. (See "Pain control in the critically ill adult patient" and "Approach to the management of chronic non-cancer pain in adults".) For patients with significant muscle inflammation, aggressive saline hydration is important to reduce the risk of acute kidney injury associated with myoglobinuria. Other treatments may include bicarbonate or mannitol. The prevention and treatment of heme-pigment-induced acute kidney injury is discussed in detail elsewhere. (See "Prevention and treatment of heme pigment- induced acute kidney injury (including rhabdomyolysis)".) Preventing recurrent embolization The optimal treatment to prevent recurrent cholesterol crystal embolization is not clear. Secondary prevention seems warranted, particularly since aortic plaques 4 mm in size appear to be associated with an increased risk of recurrent stroke [6,109,110]. In patients whose cholesterol embolization syndrome was precipitated by instrumentation (such as arteriography, cardiac catheterization, or vascular surgery), any further invasive imaging or treatment should be avoided unless absolutely necessary. Noninvasive ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI) should replace the invasive techniques whenever possible. When arterial cannulation is absolutely necessary, alternative access routes should be considered (eg, cardiac catheterization via radial artery approach in a patient with extensive plaques in the descending thoracic aorta). https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 15/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate Lipid-lowering therapy Statin therapy may decrease the risk of future embolization. Statins lower LDL cholesterol and have a variety of other effects, one of which appears to be plaque stabilization. In a retrospective study of 519 patients with severe thoracic aortic plaque cited, statin therapy was associated with a significantly lower rate of recurrent stroke and thromboembolization [13]. However, the number of patients with atheroembolization was too small (five) for subset analysis. On multivariate analysis, the protective effect seen with statin therapy was not present for patients taking warfarin or antiplatelet agents. Specific lipid- lowering therapy regimens may affect atherosclerotic plaque in the thoracic versus the abdominal aorta differently [111]. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk", section on 'Dyslipidemia' and "Thromboembolism from aortic plaque", section on 'Statin therapy'.) Antithrombotic therapy Anticoagulant therapy for the treatment of cholesterol crystal embolism remains controversial [112]. Although it seems intuitive that anticoagulation would improve arterial patency, the obstruction is mostly due to the atheroembolic debris and the inflammatory reaction it incites, and not thrombus. Another important consideration is the association between anticoagulant and antithrombotic therapy and the development of cholesterol crystal embolism; however, due to paucity of data, a causal relationship between cholesterol crystal embolism and anticoagulation and/or thrombolytic therapy can be neither proven nor refuted with certainty. (See 'Anticoagulation/thrombolytic therapy' above.) There are no randomized trials that have evaluated the role of antithrombotic therapy in patients with aortic atheroma [109,113]. Nonrandomized retrospective studies have shown a benefit of oral anticoagulation over aspirin in patients with mobile thrombi in the aortic arch. Based on this low-quality evidence, the 2012 American College of Chest Physicians (ACCP) guidelines panel suggested oral anticoagulation or antiplatelet agents for patients with cryptogenic stroke and mobile aortic arch thrombi [113]. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Treatment'.) However, the 2012 ACCP guidelines stated that the hemorrhagic complications may outweigh the benefits of anticoagulation [113]. Other studies have not shown a benefit to anticoagulation. In a retrospective review of 519 patients with complex plaque, cholesterol crystal embolism occurred in only 5 (1 percent) during a follow-up of more than three years [13]. The risk was similar in the patients treated (2 of 206) and not treated with warfarin (3 of 313). This rate is similar to that noted in the Stroke Prevention in Atrial Fibrillation (SPAF-III) trial (1 of 134 warfarin-treated patients), most of whom had severe atherosclerotic plaques on transesophageal echocardiography [52,53]. https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 16/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate In our practice, we do not routinely use anticoagulants in patients who are diagnosed with cholesterol crystal embolism unless they have other indications for anticoagulation (such as atrial fibrillation or mechanical prosthetic valve). Definitive recommendations regarding the use of anticoagulant in this context should await the results of an ongoing randomized trial comparing oral anticoagulant with antiplatelet therapy in patients with thoracic aortic plaque. It is important to emphasize that the package insert for warfarin explicitly states that warfarin therapy may increase the risk of cholesterol crystal embolism and that discontinuation of warfarin is recommended when cholesterol crystal embolism is observed [114]. Plaque removal or exclusion Given the poor outcomes associated with cholesterol crystal embolism, surgical plaque removal (endarterectomy) or exclusion of the plaque (ligation and bypass, endovascular exclusion) may be indicated if a clear embolic source is identified, the source is surgically accessible, and the patient is an appropriate candidate for surgery. Patients with lower extremity symptoms and an infrarenal source for embolism may have more favorable outcomes [115]. In a prospective study of 100 patients who underwent surgery over a 12 year period following identification of the embolic source, occlusive aortoiliac disease (47 patients) and small aortic aneurysms (20 patients) were the most commonly identified embolic sources [116]. The most common surgical treatment was aortic bypass. Other procedures included aortoiliac endarterectomy with patching, femoral or popliteal endarterectomy, and infrainguinal or upper extremity bypass. (See "Management of chronic limb-threatening ischemia" and "Overview of upper extremity peripheral artery disease" and "Lower extremity surgical bypass techniques".) In this study, the reported outcomes were: Postoperative mortality 11 percent (all had a suprarenal aortic thrombus preoperatively) Survival rates at one, three, and five years 89, 83, and 73 percent, respectively Toe and leg amputations 9 and 10 percent, respectively Hemodialysis 10 percent Recurrent emboli 5 percent within eight months of surgery with no further emboli over the next three years In another surgical series of 62 patients who underwent surgery at one institution, bypass grafts were inserted in 42 patients after exclusion of the native diseased artery, 20 had endarterectomies (6 of them with bypass grafts), and 5 were treated medically [24]. The 30 day https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 17/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate mortality rate was 5 percent. "Minor" amputation was required in 19 patients (31 percent), and leg amputation in 2 patients. Limb salvage was possible in 86 of 88 limbs. There were no postoperative embolic incidents in the involved limbs during a mean follow-up of 20 months. Covered stents More recently, covered stents and endografts have been used to exclude the involved arterial segment in a small number of patients with aortic or iliac artery sources of cholesterol crystal embolism [27,117]. The disadvantage of this technique compared with open surgery is a greater risk for recurrent embolization related to the intraluminal manipulation of guidewires [17]. Definitive recommendations for the use of covered stents are not possible at this time. Revascularization For patients with lower extremity cholesterol embolism and a hemodynamically significant proximal stenosis (that may or may not be the source of embolism), arterial revascularization can restore normal pressures, improve distal perfusion, and may improve pain. (See 'Managing ischemic manifestations' above.) Surgical (eg, bypass) or endovascular (eg, stent) management may be appropriate depending on the location of the obstruction. Percutaneous angioplasty and stenting, mostly of the iliac and femoral arteries, have been performed in a small number of patients without causing recurrent embolization [116,118]. The decision on whether to perform revascularization in patients with cholesterol embolization syndrome should also take into account the severity and duration of ischemic symptoms. (See "Approach to revascularization for claudication due to peripheral artery disease".) PROGNOSIS The prognosis in medically treated patients with cholesterol crystal emboli is poor, in part because of severe underlying atherosclerosis [119]. Acute, in-hospital mortality was 16 percent (4 of 25) in one series [16], but mortality rates may be as high as 80 percent when cases that are diagnosed post-mortem are included [12]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute extremity ischemia".) https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 18/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate SUMMARY AND RECOMMENDATIONS Atheroembolism, also known as cholesterol crystal embolism or cholesterol embolism, refers to arterio-arterial embolism of cholesterol crystals or small pieces of atheromatous material originating from an atherosclerotic plaque usually from the aorta but occasionally from other arteries. Cholesterol crystal embolism results in partial or total occlusion of small arteries, leading to tissue or organ ischemia. (See 'Introduction' above.) Risk factors for atheroembolism include patient factors such as hypertension, advancing age, smoking, hypercholesterolemia, obesity, and diabetes. Anatomic factors associated with the aortic atherosclerotic plaque, such as plaque thickness 4 mm, plaque ulceration, or the presence of mobile debris, increase the risk for embolization. (See 'Epidemiology and risk factors' above.) The clinical diagnosis of cholesterol crystal embolism should be suspected in patients with known atherosclerotic disease and the development of renal failure; transient ischemic attack; cerebral infarction; signs of intestinal ischemia; digital ischemia; typical skin findings or Hollenhorst plaques in the retina, particularly following arteriography; cardiac catheterization; vascular surgery; or trauma to the abdomen. The diagnosis is more difficult in patients who do not have these features, particularly if cholesterol crystal embolism has occurred spontaneously. (See 'Clinical manifestations' above.) The presence of complex aortic plaque on imaging studies supports the diagnosis. Atherosclerotic plaques can also be seen using transthoracic echocardiography, abdominal ultrasound, and endoscopic ultrasound of the upper gastrointestinal tract. (See 'Imaging' above.) Laboratory testing is generally nonspecific but may indicate the effects of end-organ ischemia. A definitive diagnosis depends upon pathologic specimens. Biopsy should be performed whenever the diagnosis is in doubt and when the specimen can safely be obtained from the patient; debrided or amputated tissue and thrombectomy specimens should be sent for pathologic examination since these represent no risk to the patient. The histologic hallmark of cholesterol crystal embolism is the presence of "ghosts" of cholesterol crystals or cholesterol clefts within arterioles. (See 'Biopsy and pathologic findings' above.) The treatment of cholesterol crystal embolism is primarily medical, consisting of risk factor reduction. Statin therapy is indicated as part of risk factor reduction and appears to reduce the rate of recurrent embolism. (See 'Lipid-lowering therapy' above.) https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 19/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate Surgical or endovascular treatment may be indicated if a clear embolic source is identified, the source is anatomically suitable, and the patient is an appropriate candidate for surgery. For patients who meet these criteria, we suggest surgical or endovascular treatment to remove or exclude the embolic source (Grade 2C). (See 'Treatment' above.) We suggest not routinely anticoagulating patients who are diagnosed with cholesterol crystal embolism (Grade 2C). Anticoagulation with heparin, warfarin, and use of thrombolytic therapy are all associated with the development of cholesterol embolism, although a causal relationship has never been demonstrated. However, patients with another indication for anticoagulation, such as thromboembolism or deep vein thrombosis, should be treated. (See 'Managing ischemic manifestations' above.) The prognosis in patients with cholesterol crystal embolism correlates with the degree of the underlying atherosclerosis and is overall poor. (See 'Prognosis' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Itzhak Kronzon, MD, FACC, FAHA, FASE, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Fazio GP, Redberg RF, Winslow T, Schiller NB. Transesophageal echocardiographically detected atherosclerotic aortic plaque is a marker for coronary artery disease. J Am Coll Cardiol 1993; 21:144. 2. Matsuzaki M, Ono S, Tomochika Y, et al. 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Freedberg RS, Tunick PA, Kronzon I. Emboli in transit: the missing link. J Am Soc Echocardiogr 1998; 11:826. 35. Meissner I, Khandheria BK, Sheps SG, et al. Atherosclerosis of the aorta: risk factor, risk marker, or innocent bystander? A prospective population-based transesophageal echocardiography study. J Am Coll Cardiol 2004; 44:1018. https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 22/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate 36. Tunick PA, Kronzon I. Atherosclerosis of the aorta: a risk factor, risk marker, or an innocent bystander? J Am Coll Cardiol 2005; 45:1907; author reply 1907. 37. Harloff A, Simon J, Brendecke S, et al. Complex plaques in the proximal descending aorta: an underestimated embolic source of stroke. Stroke 2010; 41:1145. 38. Tanaka H, Yamana H, Matsui H, et al. Proportion and risk factors of cholesterol crystal embolization after cardiovascular procedures: a retrospective national database study. Heart Vessels 2020; 35:1250. 39. Pandit AK, Ohshima T, Kawaguchi R, et al. Cholesterol Embolization Syndrome After Carotid Artery Stenting Associated with Delayed Cerebral Hyperperfusion Intracerebral Hemorrhage. World Neurosurg 2020; 142:274. 40. Rudnick MR, Berns JS, Cohen RM, Goldfarb S. Nephrotoxic risks of renal angiography: contrast media-associated nephrotoxicity and atheroembolism a critical review. Am J Kidney Dis 1994; 24:713. 41. Nishi T, Tokuda Y, Tanaka A, et al. Cholesterol Crystal Embolization After Transcatheter Aortic Valve Replacement. Circ Rep 2020; 2:701. 42. Khan AM, Jacobs S. Trash feet after coronary angiography. Heart 2003; 89:e17. 43. Keeley EC, Grines CL. Scraping of aortic debris by coronary guiding catheters: a prospective evaluation of 1,000 cases. J Am Coll Cardiol 1998; 32:1861. 44. Holden A, Hill A, Jaff MR, Pilmore H. Renal artery stent revascularization with embolic protection in patients with ischemic nephropathy. Kidney Int 2006; 70:948. 45. Edwards MS, Craven BL, Stafford J, et al. Distal embolic protection during renal artery angioplasty and stenting. J Vasc Surg 2006; 44:128. 46. Muller-Hansma AHG, Daemen-Gubbels CRGM, Schut NH. Cholesterol embolisms as possible adverse drug reaction of direct oral anticoagulants. Neth J Med 2018; 76:125. 47. Oka H, Kamimura T, Hiramatsu Y, et al. Cholesterol Crystal Embolism Induced by Direct Factor Xa Inhibitor: A First Case Report. Intern Med 2018; 57:71. 48. Glassock RJ, Ritz E, Bommer J, et al. Acute renal failure, hypertension and skin necrosis in a patient with streptokinase therapy. Am J Nephrol 1984; 4:193. 49. Hitti WA, Wali RK, Weinman EJ, et al. Cholesterol embolization syndrome induced by thrombolytic therapy. Am J Cardiovasc Drugs 2008; 8:27. 50. Nevelsteen A, Kutten M, Lacroix H, Suy R. Oral anticoagulant therapy: a precipitating factor in the pathogenesis of cholesterol embolization? Acta Chir Belg 1992; 92:33. 51. Hyman BT, Landas SK, Ashman RF, et al. Warfarin-related purple toes syndrome and cholesterol microembolization. Am J Med 1987; 82:1233. https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 23/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate 52. Transesophageal echocardiographic correlates of thromboembolism in high-risk patients with nonvalvular atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators Committee on Echocardiography. Ann Intern Med 1998; 128:639. 53. Blackshear JL, Zabalgoitia M, Pennock G, et al. Warfarin safety and efficacy in patients with thoracic aortic plaque and atrial fibrillation. SPAF TEE Investigators. Stroke Prevention and Atrial Fibrillation. Transesophageal echocardiography. Am J Cardiol 1999; 83:453. 54. Falanga V, Fine MJ, Kapoor WN. The cutaneous manifestations of cholesterol crystal embolization. Arch Dermatol 1986; 122:1194. 55. Olin JW. Other Peripheral Arterial Diseases. In: Goldman: Cecil Textbook of Medicine, 21st e d, WB Saunders, Philadelphia 2000. p.362. 56. Turakhia AK, Khan MA. Splinter hemorrhages as a possible clinical manifestation of cholesterol crystal embolization. J Rheumatol 1990; 17:1083. 57. Donohue KG, Saap L, Falanga V. Cholesterol crystal embolization: an atherosclerotic disease with frequent and varied cutaneous manifestations. J Eur Acad Dermatol Venereol 2003; 17:504. 58. Rosansky SJ. Multiple cholesterol emboli syndrome. South Med J 1982; 75:677. 59. Quintart C, Treille S, Lefebvre P, Pontus T. Penile necrosis following cholesterol embolism. Br J Urol 1997; 80:347. 60. Zhang WW, Chauvapun JP, Dosluoglu HH. Scrotal necrosis following endovascular abdominal aortic aneurysm repair. Vascular 2007; 15:113. 61. Zaveri S, Price LZ, Tupper H, Tadros RO. Atheroembolism to the Breast. Ann Vasc Surg 2020; 64:411.e17. 62. Mittal BV, Alexander MP, Rennke HG, Singh AK. Atheroembolic renal disease: a silent masquerader. Kidney Int 2008; 73:126. 63. Scolari F, Ravani P. Atheroembolic renal disease. Lancet 2010; 375:1650. 64. Sarwar S, Al-Absi A, Wall BM. Catastrophic cholesterol crystal embolization after endovascular stent placement for peripheral vascular disease. Am J Med Sci 2008; 335:403. 65. Grassia R, Manotti L, Pasin F. An Unusual Storm Within the Gastroduodenal Tract. Gastroenterology 2016; 151:243. 66. Tian M, Matsukuma KE. Cholesterol crystal embolism to the gastrointestinal tract: a catastrophic case. Autops Case Rep 2019; 9:e2018082. 67. Kadoya Y, Zen K, Takigami M, et al. Multiple Small Bowel Perforations Associated With Cholesterol Crystal Embolization After Transcatheter Aortic Valve Replacement. JACC Cardiovasc Interv 2020; 13:1831. https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 24/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate 68. Ben-Horin S, Bardan E, Barshack I, et al. Cholesterol crystal embolization to the digestive system: characterization of a common, yet overlooked presentation of atheroembolism. Am J Gastroenterol 2003; 98:1471. 69. Moolenaar W, Lamers CB. Cholesterol crystal embolization to liver, gallbladder, and pancreas. Dig Dis Sci 1996; 41:1819. 70. Moolenaar W, Lamers CB. Gastrointestinal blood loss due to cholesterol crystal embolization. J Clin Gastroenterol 1995; 21:220. 71. Bourdages R, Prentice RS, Beck IT, et al. Atheromatous embolization to the stomach: an unusual cause of gastrointestinal bleeding. Am J Dig Dis 1976; 21:889. 72. Abdelmalek MF, Spittell PC. 79-year-old woman with blue toes. Mayo Clin Proc 1995; 70:292. 73. Maekawa K, Shibata M, Nakajima H, et al. Cholesterol Crystals in Embolic Debris are Associated with Postoperative Cerebral Embolism after Carotid Artery Stenting. Cerebrovasc Dis 2018; 46:242. 74. Caplan LR. The aorta as a donor source of brain embolism. In: Brain embolism, Caplan, LR, Manning, WJ (Eds), Informa Healthcare, New York 2006. p.187. 75. Petty GW, Khandheria BK, Meissner I, et al. Population-based study of the relationship between atherosclerotic aortic debris and cerebrovascular ischemic events. Mayo Clin Proc 2006; 81:609. 76. Russo C, Jin Z, Rundek T, et al. Atherosclerotic disease of the proximal aorta and the risk of vascular events in a population-based cohort: the Aortic Plaques and Risk of Ischemic Stroke (APRIS) study. Stroke 2009; 40:2313. 77. Cohen A, Tzourio C, Bertrand B, et al. Aortic plaque morphology and vascular events: a follow-up study in patients with ischemic stroke. FAPS Investigators. French Study of Aortic Plaques in Stroke. Circulation 1997; 96:3838. 78. Di Tullio MR, Russo C, Jin Z, et al. Aortic arch plaques and risk of recurrent stroke and death. Circulation 2009; 119:2376. 79. Ezzeddine MA, Primavera JM, Rosand J, et al. Clinical characteristics of pathologically proved cholesterol emboli to the brain. Neurology 2000; 54:1681. 80. Gonzalez-Castellon M, Kadakia P, Willey J, et al. Teaching video neuroimages: Hollenhorst plaque. Neurology 2013; 81:e60. 81. HOLLENHORST RW. Significance of bright plaques in the retinal arterioles. JAMA 1961; 178:23. 82. Chawluk JB, Kushner MJ, Bank WJ, et al. Atherosclerotic carotid artery disease in patients with retinal ischemic syndromes. Neurology 1988; 38:858. https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 25/45 7/5/23, 11:47 AM

37. Harloff A, Simon J, Brendecke S, et al. Complex plaques in the proximal descending aorta: an underestimated embolic source of stroke. Stroke 2010; 41:1145. 38. Tanaka H, Yamana H, Matsui H, et al. Proportion and risk factors of cholesterol crystal embolization after cardiovascular procedures: a retrospective national database study. Heart Vessels 2020; 35:1250. 39. Pandit AK, Ohshima T, Kawaguchi R, et al. Cholesterol Embolization Syndrome After Carotid Artery Stenting Associated with Delayed Cerebral Hyperperfusion Intracerebral Hemorrhage. World Neurosurg 2020; 142:274. 40. Rudnick MR, Berns JS, Cohen RM, Goldfarb S. Nephrotoxic risks of renal angiography: contrast media-associated nephrotoxicity and atheroembolism a critical review. Am J Kidney Dis 1994; 24:713. 41. Nishi T, Tokuda Y, Tanaka A, et al. Cholesterol Crystal Embolization After Transcatheter Aortic Valve Replacement. Circ Rep 2020; 2:701. 42. Khan AM, Jacobs S. Trash feet after coronary angiography. Heart 2003; 89:e17. 43. Keeley EC, Grines CL. Scraping of aortic debris by coronary guiding catheters: a prospective evaluation of 1,000 cases. J Am Coll Cardiol 1998; 32:1861. 44. Holden A, Hill A, Jaff MR, Pilmore H. Renal artery stent revascularization with embolic protection in patients with ischemic nephropathy. Kidney Int 2006; 70:948. 45. Edwards MS, Craven BL, Stafford J, et al. Distal embolic protection during renal artery angioplasty and stenting. J Vasc Surg 2006; 44:128. 46. Muller-Hansma AHG, Daemen-Gubbels CRGM, Schut NH. Cholesterol embolisms as possible adverse drug reaction of direct oral anticoagulants. Neth J Med 2018; 76:125. 47. Oka H, Kamimura T, Hiramatsu Y, et al. Cholesterol Crystal Embolism Induced by Direct Factor Xa Inhibitor: A First Case Report. Intern Med 2018; 57:71. 48. Glassock RJ, Ritz E, Bommer J, et al. Acute renal failure, hypertension and skin necrosis in a patient with streptokinase therapy. Am J Nephrol 1984; 4:193. 49. Hitti WA, Wali RK, Weinman EJ, et al. Cholesterol embolization syndrome induced by thrombolytic therapy. Am J Cardiovasc Drugs 2008; 8:27. 50. Nevelsteen A, Kutten M, Lacroix H, Suy R. Oral anticoagulant therapy: a precipitating factor in the pathogenesis of cholesterol embolization? Acta Chir Belg 1992; 92:33. 51. Hyman BT, Landas SK, Ashman RF, et al. Warfarin-related purple toes syndrome and cholesterol microembolization. Am J Med 1987; 82:1233. https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 23/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate 52. Transesophageal echocardiographic correlates of thromboembolism in high-risk patients with nonvalvular atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators Committee on Echocardiography. Ann Intern Med 1998; 128:639. 53. Blackshear JL, Zabalgoitia M, Pennock G, et al. Warfarin safety and efficacy in patients with thoracic aortic plaque and atrial fibrillation. SPAF TEE Investigators. Stroke Prevention and Atrial Fibrillation. Transesophageal echocardiography. Am J Cardiol 1999; 83:453. 54. Falanga V, Fine MJ, Kapoor WN. The cutaneous manifestations of cholesterol crystal embolization. Arch Dermatol 1986; 122:1194. 55. Olin JW. Other Peripheral Arterial Diseases. In: Goldman: Cecil Textbook of Medicine, 21st e d, WB Saunders, Philadelphia 2000. p.362. 56. Turakhia AK, Khan MA. Splinter hemorrhages as a possible clinical manifestation of cholesterol crystal embolization. J Rheumatol 1990; 17:1083. 57. Donohue KG, Saap L, Falanga V. Cholesterol crystal embolization: an atherosclerotic disease with frequent and varied cutaneous manifestations. J Eur Acad Dermatol Venereol 2003; 17:504. 58. Rosansky SJ. Multiple cholesterol emboli syndrome. South Med J 1982; 75:677. 59. Quintart C, Treille S, Lefebvre P, Pontus T. Penile necrosis following cholesterol embolism. Br J Urol 1997; 80:347. 60. Zhang WW, Chauvapun JP, Dosluoglu HH. Scrotal necrosis following endovascular abdominal aortic aneurysm repair. Vascular 2007; 15:113. 61. Zaveri S, Price LZ, Tupper H, Tadros RO. Atheroembolism to the Breast. Ann Vasc Surg 2020; 64:411.e17. 62. Mittal BV, Alexander MP, Rennke HG, Singh AK. Atheroembolic renal disease: a silent masquerader. Kidney Int 2008; 73:126. 63. Scolari F, Ravani P. Atheroembolic renal disease. Lancet 2010; 375:1650. 64. Sarwar S, Al-Absi A, Wall BM. Catastrophic cholesterol crystal embolization after endovascular stent placement for peripheral vascular disease. Am J Med Sci 2008; 335:403. 65. Grassia R, Manotti L, Pasin F. An Unusual Storm Within the Gastroduodenal Tract. Gastroenterology 2016; 151:243. 66. Tian M, Matsukuma KE. Cholesterol crystal embolism to the gastrointestinal tract: a catastrophic case. Autops Case Rep 2019; 9:e2018082. 67. Kadoya Y, Zen K, Takigami M, et al. Multiple Small Bowel Perforations Associated With Cholesterol Crystal Embolization After Transcatheter Aortic Valve Replacement. JACC Cardiovasc Interv 2020; 13:1831. https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 24/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate 68. Ben-Horin S, Bardan E, Barshack I, et al. Cholesterol crystal embolization to the digestive system: characterization of a common, yet overlooked presentation of atheroembolism. Am J Gastroenterol 2003; 98:1471. 69. Moolenaar W, Lamers CB. Cholesterol crystal embolization to liver, gallbladder, and pancreas. Dig Dis Sci 1996; 41:1819. 70. Moolenaar W, Lamers CB. Gastrointestinal blood loss due to cholesterol crystal embolization. J Clin Gastroenterol 1995; 21:220. 71. Bourdages R, Prentice RS, Beck IT, et al. Atheromatous embolization to the stomach: an unusual cause of gastrointestinal bleeding. Am J Dig Dis 1976; 21:889. 72. Abdelmalek MF, Spittell PC. 79-year-old woman with blue toes. Mayo Clin Proc 1995; 70:292. 73. Maekawa K, Shibata M, Nakajima H, et al. Cholesterol Crystals in Embolic Debris are Associated with Postoperative Cerebral Embolism after Carotid Artery Stenting. Cerebrovasc Dis 2018; 46:242. 74. Caplan LR. The aorta as a donor source of brain embolism. In: Brain embolism, Caplan, LR, Manning, WJ (Eds), Informa Healthcare, New York 2006. p.187. 75. Petty GW, Khandheria BK, Meissner I, et al. Population-based study of the relationship between atherosclerotic aortic debris and cerebrovascular ischemic events. Mayo Clin Proc 2006; 81:609. 76. Russo C, Jin Z, Rundek T, et al. Atherosclerotic disease of the proximal aorta and the risk of vascular events in a population-based cohort: the Aortic Plaques and Risk of Ischemic Stroke (APRIS) study. Stroke 2009; 40:2313. 77. Cohen A, Tzourio C, Bertrand B, et al. Aortic plaque morphology and vascular events: a follow-up study in patients with ischemic stroke. FAPS Investigators. French Study of Aortic Plaques in Stroke. Circulation 1997; 96:3838. 78. Di Tullio MR, Russo C, Jin Z, et al. Aortic arch plaques and risk of recurrent stroke and death. Circulation 2009; 119:2376. 79. Ezzeddine MA, Primavera JM, Rosand J, et al. Clinical characteristics of pathologically proved cholesterol emboli to the brain. Neurology 2000; 54:1681. 80. Gonzalez-Castellon M, Kadakia P, Willey J, et al. Teaching video neuroimages: Hollenhorst plaque. Neurology 2013; 81:e60. 81. HOLLENHORST RW. Significance of bright plaques in the retinal arterioles. JAMA 1961; 178:23. 82. Chawluk JB, Kushner MJ, Bank WJ, et al. Atherosclerotic carotid artery disease in patients with retinal ischemic syndromes. Neurology 1988; 38:858. https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 25/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate 83. Bunt TJ. The clinical significance of the asymptomatic Hollenhorst plaque. J Vasc Surg 1986; 4:559. 84. Dunlap AB, Kosmorsky GS, Kashyap VS. The fate of patients with retinal artery occlusion and Hollenhorst plaque. J Vasc Surg 2007; 46:1125. 85. Wijman CA, Babikian VL, Matjucha IC, et al. Cerebral microembolism in patients with retinal ischemia. Stroke 1998; 29:1139. 86. Babikian V, Wijman CA, Koleini B, et al. Retinal ischemia and embolism. Etiologies and outcomes based on a prospective study. Cerebrovasc Dis 2001; 12:108. 87. Kitamura N, Sasabe E, Kitaoka H, Yamamoto T. Unilateral necrosis of the tongue caused by embolisation of cholesterol crystals. Br J Oral Maxillofac Surg 2018; 56:340. 88. Thadhani RI, Camargo CA Jr, Xavier RJ, et al. Atheroembolic renal failure after invasive procedures. Natural history based on 52 histologically proven cases. Medicine (Baltimore) 1995; 74:350. 89. Cosio FG, Zager RA, Sharma HM. Atheroembolic renal disease causes hypocomplementaemia. Lancet 1985; 2:118. 90. Kasinath BS, Lewis EJ. Eosinophilia as a clue to the diagnosis of atheroembolic renal disease. Arch Intern Med 1987; 147:1384. 91. Wilson DM, Salazer TL, Farkouh ME. Eosinophiluria in atheroembolic renal disease. Am J Med 1991; 91:186. 92. Tunick PA, Krinsky GA, Lee VS, Kronzon I. Diagnostic imaging of thoracic aortic atherosclerosis. AJR Am J Roentgenol 2000; 174:1119. 93. Tenenbaum A, Garniek A, Shemesh J, et al. Dual-helical CT for detecting aortic atheromas as a source of stroke: comparison with transesophageal echocardiography. Radiology 1998; 208:153. 94. Khatri IA, Mian N, Alkawi A, et al. 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Elinav E, Chajek-Shaul T, Stern M. Improvement in cholesterol emboli syndrome after iloprost therapy. BMJ 2002; 324:268. 105. Minatohara K. Renal failure associated with blue toe syndrome: effective treatment with intravenous prostaglandin E-1. Acta Derm Venereol 2006; 86:364. 106. Hasegawa M, Sugiyama S. Apheresis in the treatment of cholesterol embolic disease. Ther Apher Dial 2003; 7:435. 107. Tamura K, Umemura M, Yano H, et al. Acute renal failure due to cholesterol crystal embolism treated with LDL apheresis followed by corticosteroid and candesartan. Clin Exp Nephrol 2003; 7:67. 108. Muso E, Mune M, Fujii Y, et al. Significantly rapid relief from steroid-resistant nephrotic syndrome by LDL apheresis compared with steroid monotherapy. Nephron 2001; 89:408. 109. Kronzon I, Tunick PA. Aortic atherosclerotic disease and stroke. Circulation 2006; 114:63. 110. Fujimoto S, Yasaka M, Otsubo R, et al. Aortic arch atherosclerotic lesions and the recurrence of ischemic stroke. 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Topic 8184 Version 24.0 https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 28/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate GRAPHICS Autopsy specimen of atherosclerosis Autopsy specimen from a patient with cholesterol crystal embolism demonstrates severe atherosclerosis of the aorta. Courtesy of Dr. Amy Rapkiewicz. Graphic 54250 Version 1.0 https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 29/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate Complex atherosclerotic plaque in the thoracic aorta Complex atherosclerotic plaque in the thoracic aorta visualized by 2D TEE. (A) Ulcerated plaque in the aortic arch. (B) Plaque with a mobile component representing superimposed thrombus (arrow) in the descending thoracic aorta. Courtesy of Dr. Muhamed Saric. Graphic 63285 Version 4.0 https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 30/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate Emboli in transit Transesophageal echocardiogram of the descending thoracic aorta in a patient who later died from cholesterol crystal embolization syndrome, with intestinal infarction and renal failure. Note the massive atherosclerotic plaque. The pictures on the right (1A, 2A, 3A) were taken one or two seconds after their respective pictures on the left. The arrows point to small particles of embolic material moving in transit in the aortic lumen. Reproduced with permission from: Freedberg, RS, Tunick, PA, Kronzon, I. Emboli in Transit: The Missing Link. J Am Soc Echocardiogr 1998, 11:826. Copyright 1998 Elsevier. Graphic 64740 Version 2.0 https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 31/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate Livedo reticularis Patient with lupus and anti-phospholipid antibodies with livedo reticularis (manifested by a reddish-cyanotic, reticular pattern of the skin) which has resulted in ulcer formation (arrows). Courtesy of Samuel Moschella, MD. Graphic 71860 Version 1.0 https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 32/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate Blue toe syndrome Blue toes are a classic manifestation of peripheral embolization of atheromatous material from proximal arterial sources (eg, aorta); the pedal pulses are often normal. This patient, who has a 30-year history of type 1 diabetes and severe peripheral vascular disease, presented with foot pain and discoloration. Cholesterol microemboli from the aorta were suspected to be the cause. Reproduced with permission from Lawrence B Stack, MD. Copyright Lawrence B Stack, MD. Graphic 58761 Version 2.0 https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 33/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate Cholesterol emboli Acral retiform purpura involving the left foot. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 123032 Version 1.0 https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 34/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate Retiform purpura due to cholesterol emboli Retiform purpura (purpura in a pattern reminiscent of livedo reticularis) are present on the buttocks. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved. Graphic 69150 Version 6.0 https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 35/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate Cholesterol emboli to the kidney on CT scan A axial CT scan through the kidneys (A) shows punctate perfusion defects in the renal parenchyma (arrows) and regions of diffuse thinning of the cortex (arrowheads). Image B is a magnified view showing tiny perfusion defects (arrows), as well as larger regions of parenchymal thinning (arrowheads). CT: computed tomography. Graphic 98920 Version 1.0 https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 36/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate Renal atheroembolus histology Light micrograph of an atheroembolus in a muscular renal artery showing cleft-like spaces (arrow) due to washout of the cholesterol crystals during histologic processing. Courtesy of Helmut Rennke, MD. Graphic 56672 Version 2.0 https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 37/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate Renal atheroembolus toluidine blue Thin section, toluidine blue stain shows the characteristic cholesterol clefts of an atheroembolus in the small renal artery. Courtesy of Helmut Rennke, MD. Graphic 68445 Version 2.0 https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 38/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate Hollenhorst plaque retinal artery Reproduced with permission from: Digital Reference of Opthalmology, Edward S. Harkness Eye Institute, Columbia University, NY. Graphic 63740 Version 2.0 https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 39/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate Thoracic aortic plaque Three transesophageal echocardiograms of the thoracic aorta: left: normal; middle: moderate (3 mm) plaque; and right: severe (7 mm) plaque. Reproduced with permission from: Tunick, PA, Kronzon, I. Atheroembolism. In: Vascular Medicine. A Companion to Braunwald's Heart Disease, 1st edition, Dzau, VJ, Creager, M, Loscalzo, J, et al (Eds), WB Saunders 2005. Copyright 2005 Elsevier. Graphic 72777 Version 2.0 https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 40/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate Atherosclerotic plaque visualized by 3D TEE (A) Protruding plaque in the aortic arch. (B) Ulcerated plaque in the descending thoracica aorta. Courtesy of Dr. Muhamed Saric. Graphic 56112 Version 1.0 https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 41/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate Severe aortic plaque Severe aortic plaque (arrow) visualized by gastrointestinal endoscopic ultrasound (EUS) probe. Courtesy of Dr. Zamir Brelvi, Division of Gastroenterology, New Jersey Medical School, Newark, NJ. Graphic 63026 Version 2.0 https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 42/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate Atherosclerotic plaque on CT Atherosclerotic plaque of the descending thoracic and abdominal aorta on CT. Severe atherosclerotic plaque (arrows) visualized by CT in axial (panel A) and sagittal (panel B) projections. CT: computed tomography. Courtesy of Dr. Pierre Maldjian. Graphic 75835 Version 2.0 https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 43/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate Aortic atherosclerosis on MRI Aortic atherosclerosis (arrow) visualized by MRI (T2 weighted images with fat suppression). MRI: magnetic resonance imaging. Courtesy of Dr. Pierre Maldjian. Graphic 55892 Version 2.0 https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 44/45 7/5/23, 11:47 AM Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism) - UpToDate Contributor Disclosures Muhamed Saric, MD, PhD, FACC, FASE Consultant/Advisory Boards: Siemens [Two- and three-dimensional echo imaging]. Speaker's Bureau: Abbott [Structural heart disease]; Boston Scientific [Structural heart disease]; Medtronic [Structural heart disease]; Philips [Two- and three-dimensional echo imaging]. All of the relevant financial relationships listed have been mitigated. Catherine M Otto, MD No relevant financial relationship(s) with ineligible companies to disclose. Jos Biller, MD, FACP, FAAN, FAHA No relevant financial relationship(s) with ineligible companies to disclose. John F Eidt, MD Grant/Research/Clinical Trial Support: Syntactx [Clinical events, data/safety monitoring for medical device trials]. All of the relevant financial relationships listed have been mitigated. Joseph L Mills, Sr, MD No relevant financial relationship(s) with ineligible companies to disclose. Kathryn A Collins, MD, PhD, FACS No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/embolism-from-atherosclerotic-plaque-atheroembolism-cholesterol-crystal-embolism/print 45/45

7/5/23, 11:48 AM Patent foramen ovale - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Patent foramen ovale : Hidehiko Hara, MD : Heidi M Connolly, MD, FACC, FASE : Susan B Yeon, MD, JD, FACC All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Aug 24, 2022. INTRODUCTION Patent foramen ovale (PFO) is a congenital cardiac lesion that frequently persists into adulthood [1-3]. Although most patients with a PFO are asymptomatic, a variety of clinical manifestations may be associated with PFO, most importantly cryptogenic stroke. (See 'Clinical manifestations' below.) Issues related to the prevalence, anatomy, associations with other defects, clinical manifestations, and detection of PFO will be reviewed here. Clinical manifestations of atrial septal defects, including PFO, and the indications for and techniques of closure of a PFO are discussed separately. (See "Clinical manifestations and diagnosis of atrial septal defects in adults" and "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults" and "Stroke associated with patent foramen ovale (PFO): Evaluation" and "Isolated atrial septal defects (ASDs) in children: Classification, clinical features, and diagnosis" and "Isolated atrial septal defects (ASDs) in children: Management and outcome".) PREVALENCE AND PATHOPHYSIOLOGY PFO was found in 25 to 30 percent of individuals in an autopsy study and in a community-based transesophageal echocardiography (TEE) study [4,5]. The following findings were noted in the autopsy study of 965 normal hearts [4]: https://www.uptodate.com/contents/patent-foramen-ovale/print 1/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate Probe-patent PFO was present in 27 percent; the prevalence and size were similar in males and females. The prevalence of PFO declined progressively with age, from 34 percent up to age 30, to 25 percent between ages 30 and 80, to 20 percent over age 80. Among patients who have a PFO, the mean size increased progressively with age, from 3.4 mm up to age 10 to 5.8 mm over age 90. This trend may reflect size selection, as larger defects remain patent while smaller defects close spontaneously. A similar overall prevalence of PFO (26 percent) was noted in a series of 581 subjects 45 years of age who underwent TEE as part of an evaluation of potential stroke risk factors in the community [5]. However, the incidence was stable with increasing age in contrast to the modest decline in the autopsy study [4]. The prevalence of PFO is higher in patients with cryptogenic stroke, particularly those under age 55 years in whom PFO is more likely to play a causal role. Approximately 40 percent of ischemic strokes in adults under 55 are cryptogenic. In the prospective PFO-ASA study of 581 patients with cryptogenic stroke (mean age 42), 37 percent had a PFO alone and another 9 percent had a PFO with an atrial septal aneurysm [6]. A similar prevalence of PFO (39 percent) was noted among 250 older patients (mean age 59) with cryptogenic stroke in the Patent Foramen Ovale in Cryptogenic Stroke Study [7]. In addition, the patients with cryptogenic stroke had a significantly higher rate of a large PFO compared with patients with a stroke of known cause (20 versus 9.7 percent). (See 'Cryptogenic stroke' below.) Although most individuals with PFO are asymptomatic, a PFO can serve as a pathway for venous to arterial transit of emboli (paradoxical emboli) via right-to-left shunting when the pressure in the right atrium exceeds that in the left atrium. A transient right-to-left gradient is sufficient to induce shunting and commonly occurs in patients without net right-to-left shunting (ie, those with no net shunt or a net left-to-right shunt). (See "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults", section on 'Paradoxical emboli'.) A transient right-to-left gradient occurs in normal individuals during early ventricular systole and with Valsalva maneuver (eg, straining to defecate, coughing, lifting or pushing heavy objects). Among 148 patients with a PFO in the community-based series cited above, 57 percent had right-to-left shunting at rest, and 92 percent had right-to-left shunting with straining or coughing [5]. EMBRYOLOGY https://www.uptodate.com/contents/patent-foramen-ovale/print 2/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate During fetal development, a PFO is required for oxygenated blood to flow from the right to the left atrium. Starting at week four of pregnancy, the septum primum and septum secundum form and fuse in the following sequence ( figure 1) [8,9]: The septum primum grows from the primordial atrial roof toward the endocardial cushions. The endocardial cushions grow toward each other and then fuse, dividing the atrioventricular canal into right and left sides. The net effect is creation of the foramen primum. As the septum primum continues to grow toward the endocardial cushions, perforations develop in the septum primum. These perforations then fuse, forming the foramen secundum, which allows oxygenated blood to flow from the right to the left atrium. The foramen primum closes. A second membrane, the septum secundum, grows from the right side of the septum primum. The septum secundum eventually overlaps part of the foramen secundum, forming an incomplete septal partition that becomes the foramen ovale. The remaining septum primum forms a flap-like valve over the foramen ovale. Oxygenated blood from the inferior vena cava crosses the PFO, providing oxygenated blood for the systemic circulation. In contrast, most blood from the superior vena cava flows through the tricuspid valve and enters the right ventricle. At birth, either or both of two factors contribute to flap closure against the septum secundum: Oxygen filling the alveoli causes the pulmonary arterioles to open, resulting in reductions in right heart pressure and pulmonary vascular resistance; and the increasing amount of blood returning from the pulmonary circulation may raise left atrial pressure. Flap fusion is complete by age two in 70 to 75 percent of children, with the remaining 25 to 30 percent having a PFO. Why PFOs fail to close is not known, but familial and genetic factors may be important. This possibility was suggested in a study that compared 62 patients under age 60 with an ischemic stroke and 62 matched controls [10]. The prevalence of a PFO in female siblings of patients with a PFO was 77 percent, compared with 25 percent in female siblings of those without a PFO (odds ratio 9.8); there was no such association in men. ASSOCIATION WITH OTHER DEFECTS PFO is often associated with other cardiac anomalies, including atrial septal aneurysm and Chiari networks. https://www.uptodate.com/contents/patent-foramen-ovale/print 3/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate Atrial septal aneurysm An atrial septal aneurysm (ASA) is defined as redundant and mobile interatrial septal tissue in the region of the fossa ovalis with phasic excursion of at least 10 to 15 mm during the cardiorespiratory cycle. ASAs are frequently associated with PFOs and/or atrial septal defects (ASDs). The prevalence and potential clinical significance of ASAs are discussed separately. (See "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults", section on 'ASA' and "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Atrial septal abnormalities'.) Eustachian valve and Chiari network The Eustachian valve is located at the junction of the inferior vena cava and the right atrium and is prominent in some individuals. A Chiari network is a more fenestrated mobile structure consisting of a network of filamentous structures and fibers in the right atrium that originate from the region of the Eustachian and thebesian valves at the orifice of the inferior vena cava, with attachments to the upper wall of the right atrium or atrial septum [11,12]. A Chiari network is present in 2 to 3 percent of normal hearts [11,13]. (See "Echocardiographic evaluation of the atria and appendages", section on 'Structure'.) These structures are not generally thought to be clinically significant. However, a prominent Eustachian valve or Chiari network may maintain an embryonic right atrial flow pattern into adulthood with blood from the inferior vena cava being preferentially directed toward the interatrial septum. As a result, these structures may favor persistence of a PFO and formation of an ASA or flow through a PFO, indirectly facilitating paradoxical embolism. The association between Chiari network and PFO was illustrated in a review of 1436 consecutive patients referred for transesophageal echocardiography (TEE) [11]: A Chiari network was found in 29 patients (2 percent): 24 (83 percent) had a PFO and seven (24 percent) had an ASA. Transthoracic echocardiography detected only eight of these networks. A PFO with a large right-to-left shunt occurred with greater frequency in patients with Chiari networks (55 versus 12 percent). Chiari networks were more common in patients undergoing TEE for cryptogenic stroke than in those evaluated for other indications (4.6 versus 0.5 percent). Among the 24 patients with cryptogenic stroke and a Chiari network, 15 had a PFO as the only risk factor. In a study of patients undergoing PFO closure, the presence of Eustachian valve or Chiari network was associated with history of recurrent embolic events [14]. Atrial septal defect PFOs are occasionally associated with ASDs. In a review of 103 patients referred for transcatheter closure for a presumed paradoxical embolism, PFO alone was present https://www.uptodate.com/contents/patent-foramen-ovale/print 4/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate in 81, an ASD alone in 12, and both a PFO and ASD in 10 [15]. Ebstein anomaly Defects of the interatrial septum are present in most patients with Ebstein anomaly. In a series of 106 patients, 79 percent had either a persistent or previously closed PFO or ASD [16]. (See "Clinical manifestations and diagnosis of Ebstein anomaly".) CLINICAL MANIFESTATIONS Most patients with a PFO remain asymptomatic. The most important potential manifestation is ischemic stroke due to a paradoxical embolism. The following is a brief summary, since most of these manifestations are discussed in detail separately. Cryptogenic stroke Cryptogenic stroke, which accounts for approximately 20 to 40 percent of ischemic strokes, is defined as a stroke that occurs in the absence of an identified cardioembolic or large vessel source and with a distribution that is not consistent with small vessel disease. Most of these strokes are presumed to be embolic based upon imaging features, as discussed separately (see "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Brain imaging'). There is an increased prevalence of PFO in patients who have had a cryptogenic stroke; thus, paradoxical embolism via PFO is likely one mechanism for stroke in this population. (See "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults", section on 'Prospective studies' and "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Atrial septal abnormalities'.) Of note, patients with an embolic-appearing ischemic stroke in the setting of a PFO with a right- to-left interatrial shunt and no other source of stroke or other risk factors for stroke despite a comprehensive evaluation are recognized as having a PFO-associated stroke. (See "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults", section on 'Risk of embolic stroke' and "Stroke associated with patent foramen ovale (PFO): Evaluation".) Migraine and vascular headache Migraine and vascular headache may be associated with PFO and right-to-left cardiac shunting. As a result, PFO closure has been evaluated as a treatment for migraine headache. Routine screening for PFO in patients with migraine is not recommended. (See "Preventive treatment of episodic migraine in adults", section on 'Other interventions not recommended'.) Decompression sickness and air embolism Decompression sickness in scuba divers can result in air embolism through a PFO. The risk is increased with larger PFOs and in patients who travel by air within 12 to 48 hours after diving. PFOs can also permit paradoxical embolization from other causes of air embolism. (See "Complications of SCUBA diving" and "Air embolism".) https://www.uptodate.com/contents/patent-foramen-ovale/print 5/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate Platypnea-orthodeoxia syndrome The platypnea-orthodeoxia syndrome is a rare disorder characterized by both dyspnea (platypnea) and arterial desaturation (orthodeoxia) in the upright position with improvement in the supine position [17,18]. In addition to PFO and other interatrial defects, this syndrome has also been described with intrapulmonary shunting and with disorders such as pericardial effusion, constrictive pericarditis, emphysema, amiodarone pulmonary toxicity, pneumonectomy, and cirrhosis [18]. Two components are required [19]: An interatrial shunt, such as PFO, atrial septal defect, or fenestrated atrial septal aneurysm (ASA), or intrapulmonary shunting as in the hepatopulmonary syndrome and pulmonary arteriovenous malformations that may occur in patients with cirrhosis. (See "Hepatopulmonary syndrome in adults: Prevalence, causes, clinical manifestations, and diagnosis" and "Pulmonary arteriovenous malformations: Epidemiology, etiology, and pathology in adults".) A functional component that promotes abnormal shunting when the patient rises from a recumbent to an upright position. This could be mediated by a deformity in the atrial septum (that promotes shunt flow) and/or the right atrium that increases streaming of blood from the inferior vena cava through the defect. An elevation in right atrial pressure causing right-to-left shunting is usually required, although blood may flow from right to left even when right atrial pressure is normal, as typically occurs with persistent Eustachian valves [18-20]. Other A variety of less common manifestations have been described in patients with a PFO. These include: Acute myocardial infarction [21,22]. (See "Coronary artery disease and myocardial infarction in young people", section on 'Paradoxical embolism'.) Systemic embolization, such as renal infarction [23]. (See "Renal infarction".) Fat embolism [24]. (See "Fat embolism syndrome".) Right atrial tumors causing increased right atrial pressure can promote paradoxical embolization, including tumor embolism [22]. (See "Cardiac tumors", section on 'Right atrial tumors'.) Left-sided valve disease in carcinoid syndrome [25]. (See "Carcinoid heart disease".) https://www.uptodate.com/contents/patent-foramen-ovale/print 6/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate DIAGNOSIS AND EVALUATION Evaluation for PFO is indicated in patients with cryptogenic stroke or other embolic event as well as in patients with other clinical manifestations of PFO such as platypnea-orthodeoxia syndrome. Ultrasound techniques A variety of ultrasound modalities have been used to diagnose a PFO, including transthoracic echocardiography (TTE), transesophageal echocardiography (TEE) [5,26-30], transcranial Doppler (TCD) [30-38], transmitral Doppler (TMD) [39], and intracardiac echocardiography (ICE) [40]. TTE, TEE, TCD, TMD, and ICE generally in conjunction with injection of agitated saline contrast (a "bubble study") as well as color Doppler imaging (for TTE, TEE, and ICE), can all detect a right-to- left shunt associated with a PFO. PFO is much more common than other lesions causing intracardiac right-to-left shunting [5]. As noted above, transient right to left shunting is sufficient to cause a positive bubble study and occurs in individuals with PFO with normal intracardiac pressures during early ventricular systole or during Valsalva release. PFO detection can be augmented by cough or releasing a sustained Valsalva maneuver. These maneuvers, which are part of standard echocardiographic (TEE and TTE) testing, open the PFO when the right atrium fills with blood from the abdomen, increasing right-to-left shunting [5,41]. In a TEE study that included 148 patients with a PFO, right-to-left shunting was noted in 57 percent at rest compared with 92 percent with straining or coughing [5]. (See 'Prevalence and pathophysiology' above.) TEE, TTE, and ICE Among the ultrasound methods for detection of right-to-left shunts, only TEE and ICE enable visualization of the site of the shunt (eg, PFO, atrial septal defect [ASD], or pulmonary arteriovenous malformation) ( movie 1 and movie 2). Echocardiography (TTE or TEE) can also detect other cardiac abnormalities associated with embolic events such as ASA ( movie 3 and movie 4), intracardiac mass (eg, vegetation, tumor, or thrombus). TEE is generally more sensitive than TTE for identifying potential sources of cardiac embolus including ASA, vegetations, atrial mass, or thrombus and thoracic aortic plaque. (See "Echocardiography in detection of cardiac and aortic sources of systemic embolism".) TEE and ICE enable visualization of the flap of the atrial septum covering the foramen ovale as well as passage of agitated saline contrast through the foramen. Contrast that has passed through a pulmonary arteriovenous malformation may be visualized entering the left atrium via the pulmonary veins. In addition, color Doppler imaging on TEE or ICE (and occasionally on TTE) https://www.uptodate.com/contents/patent-foramen-ovale/print 7/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate may reveal flow through a PFO at rest and/or with maneuvers [42,43]. In a small series, PFO detection by contrast and color Doppler TEE correlated well with autopsy findings [42]. The timing of the appearance of agitated saline contrast (bubbles) in the left heart on echocardiography (TTE, ICE, or TEE) can help distinguish intracardiac shunting (via PFO or ASD) from pulmonary arteriovenous shunting. Early contrast appearance in the left heart (within three beats of contrast appearance in the right heart) suggests intracardiac shunting, while late shunting (after three to five beats) is more consistent with pulmonary arteriovenous shunting. However, the data supporting this timing rule are limited [44-46] and exceptions occur [46,47]. The relative efficacy of TTE and TEE has been evaluated in a number of comparative studies. In general, TEE and ICE have been found to be more sensitive than TTE for PFO detection, although the reported sensitivity of TEE has varied widely (11 to 85 percent of shunts detected by TEE) [28-30,48]. Variation in the sensitivity of TTE is likely related to variation in image quality. Some later studies have reported that TTE with second harmonic imaging (now routinely employed) had greater sensitivity than TEE for shunt detection [49,50]. Potential causes of reduced sensitivity of TEE include ineffective Valsalva maneuver in sedated patients with the TEE probe interfering with glottic closure and reduced right atrial pressures due to fasting and sedation [50]. A limitation of these studies is that a positive TTE or TEE served as the standard for shunt detection, so the rate of false positive results cannot be ascertained. A separate concern is reduction in sensitivity of echocardiography when images are stored digitally rather than on analog videotape. Although digital acquisition and storage of echocardiographic images are generally recommended by the American Society of Echocardiography [51], digital data compression by the approved Joint Photographic Experts Group (JPEG) method may result in loss of some visual information. A study comparing digital TTE and analog TTE results found that digital TTE had poor sensitivity for detection of right to left shunts as compared with analog TTE (50, 63, and 39 percent for rest, Valsalva, and late shunts, respectively) [48]. Longer recorded clip length ( 13 seconds) was associated with only modest improvement in sensitivity (50, 67, and 46 percent, respectively). Other factors that influence the sensitivity of echocardiography for shunt detection are the site of injection of agitated saline contrast (greater sensitivity with femoral rather than brachial venous injection) [52] and the number of bubbles (typically three) required for test positivity. https://www.uptodate.com/contents/patent-foramen-ovale/print 8/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate In summary, TEE with contrast at rest, with cough, and following Valsalva is generally considered the most definitive diagnostic test, although second harmonic TTE in patients with good acoustic windows may offer equal or greater sensitivity. Among those with cryptogenic stroke or other clinical indication to evaluate for PFO, we suggest starting with TTE, with TEE performed if TTE is negative or nondiagnostic. Transcranial Doppler As noted above, TCD is a potential alternative to TEE [30,33-37,39]. TCD has advantages compared with TEE of being noninvasive and easy to perform at the bedside. On the other hand, TCD can only detect a right-to-left shunt, not the location of the shunt. TCD is performed by placing a probe against the side of the skull just above the zygomatic arch (ie, over the middle cerebral artery). A contrast agent (typically agitated saline) is injected and Doppler ultrasonography is performed at baseline and after a Valsalva maneuver [35]. (See "Contrast echocardiography: Contrast agents, safety, and imaging technique".) Although early studies suggested that TCD was highly specific but less sensitive than TEE [30,31], later studies [32,34,35,38] indicated that these studies are comparable for detection of right-to- left shunts, as concluded in a 2004 report from the American Academy of Neurology [37]. However, TEE and ICE are considered a better test because it also provides anatomic information about the site and size of the shunt and possible presence of an atrial septal aneurysm and other possible causes of stroke such as aortic atherosclerosis, intracardiac masses, and infective endocarditis. (See 'Atrial septal aneurysm' above and "Thromboembolism from aortic plaque" and "Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism)" and "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis".) Safety Although intravenous administration of agitated saline contrast for ultrasound detection of shunts has generally been considered safe, case reports suggest that cerebral ischemic events may rarely result from passage of bubbles into the systemic circulation (via an intracardiac shunt or pulmonary arteriovenous malformation) [53,54]. Although data on techniques to enhance safety are lacking, suggestions include thorough agitation to minimize bubble size, vertical position of the injecting syringe to aid withholding of large bubbles and avoidance of additional contrast injections once a large shunt has been identified [53,54]. The safety of TEE is discussed separately. (See "Transesophageal echocardiography: Indications, complications, and normal views", section on 'Safety of TEE examination'.) MDCT and CMR Preliminary reports suggest that PFO may also be detected by multidetector computed tomography (MDCT) [55] or cardiovascular magnetic resonance (CMR) [56-58], https://www.uptodate.com/contents/patent-foramen-ovale/print 9/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate although these methods may be less sensitive than TEE. Assessment of clinical significance Identification of PFO in a patient with an ischemic event does not prove a causal relationship. Since PFO is a common lesion, it may serve as "innocent bystander" in some patients with ischemic events. Evaluation of a patient with PFO with an embolic event should include careful assessment of the likelihood that the PFO is causally related to the event, including identification of other potential causes of thromboembolism and stroke. This assessment is discussed separately. (See "Stroke associated with patent foramen ovale (PFO): Evaluation" and "Stroke associated with patent foramen ovale (PFO): Management", section on 'Patient selection for PFO closure' and "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Evaluation and diagnosis' and "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults", section on 'Risk of embolic stroke'.) Evaluation of sources of venous thromboembolism is also suggested since identification of venous thrombosis provides further support for paradoxical embolism as the mechanism of the embolic event and has treatment implications. (See "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults", section on 'Diagnosis' and "Stroke associated with patent foramen ovale (PFO): Management", section on 'Patient selection for PFO closure'.) MANAGEMENT Management varies depending upon the clinical presentation. An incidentally detected PFO generally requires no follow-up or treatment. Evidence from randomized trials suggests that PFO device closure is more effective than medical therapy alone for select patients aged 60 years with a cryptogenic nonlacunar ischemic stroke who have a PFO with a right-to-left interatrial shunt. The selection of patients with cryptogenic stroke for PFO closure, and the lack of benefit and possible harm from closing incidentally discovered PFOs at the time of cardiac surgery, are discussed separately. (See "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults" and "Stroke associated with patent foramen ovale (PFO): Evaluation" and "Stroke associated with patent foramen ovale (PFO): Management", section on 'Patient selection for PFO closure'.) Definitive treatment for platypnea-orthodeoxia syndrome is closure of the atrial shunt [59,60]. INFORMATION FOR PATIENTS https://www.uptodate.com/contents/patent-foramen-ovale/print 10/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Patent foramen ovale (The Basics)") SUMMARY AND RECOMMENDATIONS Prevalence Patent foramen ovale (PFO) occurs in 25 to 30 percent of the general population. The prevalence of PFO is higher in patients with cryptogenic stroke, particularly those under age 55 years in whom PFO is more likely to play a causal role. (See 'Prevalence and pathophysiology' above.) Clinical manifestations Most individuals with PFO are asymptomatic, although some have clinical manifestations such as cryptogenic stroke, air embolism, or platypnea- orthodeoxia. (See 'Clinical manifestations' above.) When to check for PFO Testing for PFO is indicated in patients with a cerebral ischemic event of uncertain origin or other clinical manifestations of PFO such as platypnea- orthodeoxia. (See 'Diagnosis and evaluation' above.) Diagnosis of PFO Agitated saline contrast with ultrasound techniques (echocardiography or transcranial Doppler) enables shunt identification. On agitated saline contrast echocardiography, appearance of at least three bubbles of contrast in the left heart within three beats after contrast opacification of the right atrium suggests the presence of intracardiac shunt. (See 'Ultrasound techniques' above.) TTE Among those with cryptogenic stroke or other clinical indication for evaluation for PFO, we suggest starting with transthoracic echocardiography (TTE), with transesophageal echocardiography (TEE) performed if TTE is negative or nondiagnostic. https://www.uptodate.com/contents/patent-foramen-ovale/print 11/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate TEE TEE with contrast at rest, with cough, and following Valsalva is generally considered the most definitive diagnostic test for PFO. TEE and transcranial Doppler methods have similar sensitivity and specificity for detection of right-to-left shunts, although echocardiography also permits evaluation of cardiac structure and function. Since digital data compression may reduce the sensitivity of agitated saline contrast study, we suggest analog (videotape) recording and review of TTE and TEE contrast studies. (See 'TEE, TTE, and ICE' above.) Assessing clinical significance of PFO Identification of PFO in a patient with an embolic event does not prove a causal relationship. The evaluation of patients with PFO with an embolic event should include careful assessment of the likelihood that the PFO is causally related to the event, including identification of other potential causes of thromboembolism and stroke and of potential sources of venous thromboembolism. (See 'Assessment of clinical significance' above and "Stroke associated with patent foramen ovale (PFO): Evaluation" and "Stroke associated with patent foramen ovale (PFO): Management", section on 'Patient selection for PFO closure'.) Management An incidentally detected PFO generally requires no follow-up or treatment. Selected patients with cryptogenic stroke are candidates for PFO closure, as discussed separately. (See "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults" and "Stroke associated with patent foramen ovale (PFO): Evaluation" and "Stroke associated with patent foramen ovale (PFO): Management", section on 'Patient selection for PFO closure'.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Robert S Schwartz, MD, FACC, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Hara H, Virmani R, Ladich E, et al. Patent foramen ovale: current pathology, pathophysiology, and clinical status. J Am Coll Cardiol 2005; 46:1768. 2. Wu LA, Malouf JF, Dearani JA, et al. Patent foramen ovale in cryptogenic stroke: current understanding and management options. Arch Intern Med 2004; 164:950. https://www.uptodate.com/contents/patent-foramen-ovale/print 12/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate 3. Kerut EK, Norfleet WT, Plotnick GD, Giles TD. Patent foramen ovale: a review of associated conditions and the impact of physiological size. J Am Coll Cardiol 2001; 38:613. 4. Hagen PT, Scholz DG, Edwards WD. Incidence and size of patent foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clin Proc 1984; 59:17. 5. Meissner I, Whisnant JP, Khandheria BK, et al. Prevalence of potential risk factors for stroke assessed by transesophageal echocardiography and carotid ultrasonography: the SPARC study. Stroke Prevention: Assessment of Risk in a Community. Mayo Clin Proc 1999; 74:862. 6. Lamy C, Giannesini C, Zuber M, et al. Clinical and imaging findings in cryptogenic stroke patients with and without patent foramen ovale: the PFO-ASA Study. Atrial Septal Aneurysm. Stroke 2002; 33:706. 7. Homma S, Sacco RL, Di Tullio MR, et al. Effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in Cryptogenic Stroke Study. Circulation 2002; 105:2625. 8. Konstantinides S, Geibel A, Kasper W, et al. Patent foramen ovale is an important predictor of adverse outcome in patients with major pulmonary embolism. Circulation 1998; 97:1946. 9. Moore KL. The Developing Human: Clinically Oriented Embryology, 6th ed, Saunders, Philad elphia 1998. 10. Arquizan C, Coste J, Touboul PJ, Mas JL. Is patent foramen ovale a family trait? A transcranial Doppler sonographic study. Stroke 2001; 32:1563. 11. Schneider B, Hofmann T, Justen MH, Meinertz T. Chiari's network: normal anatomic variant or risk factor for arterial embolic events? J Am Coll Cardiol 1995; 26:203. 12. Chiari, H . About network development in the right side of the heart. Beitr Pathol Anat 1897; 22:1. 13. Werner JA, Cheitlin MD, Gross BW, et al. Echocardiographic appearance of the Chiari network: differentiation from right-heart pathology. Circulation 1981; 63:1104. 14. Rigatelli G, Dell'avvocata F, Braggion G, et al. Persistent venous valves correlate with increased shunt and multiple preceding cryptogenic embolic events in patients with patent foramen ovale: an intracardiac echocardiographic study. Catheter Cardiovasc Interv 2008; 72:973. 15. Khositseth A, Cabalka AK, Sweeney JP, et al. Transcatheter Amplatzer device closure of atrial septal defect and patent foramen ovale in patients with presumed paradoxical embolism. Mayo Clin Proc 2004; 79:35. 16. Attenhofer Jost CH, Connolly HM, O'Leary PW, et al. Left heart lesions in patients with Ebstein anomaly. Mayo Clin Proc 2005; 80:361. https://www.uptodate.com/contents/patent-foramen-ovale/print 13/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate 17. Seward JB, Hayes DL, Smith HC, et al. Platypnea-orthodeoxia: clinical profile, diagnostic workup, management, and report of seven cases. Mayo Clin Proc 1984; 59:221. 18. Cheng TO. Platypnea-orthodeoxia syndrome: etiology, differential diagnosis, and management. Catheter Cardiovasc Interv 1999; 47:64. 19. Cheng TO. Mechanisms of platypnea-orthodeoxia: what causes water to flow uphill? Circulation 2002; 105:e47. 20. Cheng TO. Reversible orthodeoxia. Ann Intern Med 1992; 116:875. 21. Agostoni P, Gasparini G, Destro G. Acute myocardial infarction probably caused by paradoxical embolus in a pregnant woman. Heart 2004; 90:e12. 22. Diaz Castro O, Bueno H, Nebreda LA. Acute myocardial infarction caused by paradoxical tumorous embolism as a manifestation of hepatocarcinoma. Heart 2004; 90:e29. 23. Iwasaki M, Joki N, Tanaka Y, et al. A suspected case of paradoxical renal embolism through the patent foramen ovale. Clin Exp Nephrol 2011; 15:147. 24. Pell AC, Hughes D, Keating J, et al. Brief report: fulminating fat embolism syndrome caused by paradoxical embolism through a patent foramen ovale. N Engl J Med 1993; 329:926. 25. Pellikka PA, Tajik AJ, Khandheria BK, et al. Carcinoid heart disease. Clinical and echocardiographic spectrum in 74 patients. Circulation 1993; 87:1188. 26. M gge A, Daniel WG, Angermann C, et al. Atrial septal aneurysm in adult patients. A multicenter study using transthoracic and transesophageal echocardiography. Circulation 1995; 91:2785. 27. Pinto FJ. When and how to diagnose patent foramen ovale. Heart 2005; 91:438. 28. Pearson AC, Labovitz AJ, Tatineni S, Gomez CR. Superiority of transesophageal echocardiography in detecting cardiac source of embolism in patients with cerebral ischemia of uncertain etiology. J Am Coll Cardiol 1991; 17:66. 29. Konstantinides S, Kasper W, Geibel A, et al. Detection of left-to-right shunt in atrial septal defect by negative contrast echocardiography: a comparison of transthoracic and transesophageal approach. Am Heart J 1993; 126:909. 30. Di Tullio M, Sacco RL, Venketasubramanian N, et al. Comparison of diagnostic techniques for the detection of a patent foramen ovale in stroke patients. Stroke 1993; 24:1020. 31. Job FP, Ringelstein EB, Grafen Y, et al. Comparison of transcranial contrast Doppler sonography and transesophageal contrast echocardiography for the detection of patent foramen ovale in young stroke patients. Am J Cardiol 1994; 74:381. 32. Nemec JJ, Marwick TH, Lorig RJ, et al. Comparison of transcranial Doppler ultrasound and transesophageal contrast echocardiography in the detection of interatrial right-to-left https://www.uptodate.com/contents/patent-foramen-ovale/print 14/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate shunts. Am J Cardiol 1991; 68:1498. 33. Teague SM, Sharma MK. Detection of paradoxical cerebral echo contrast embolization by transcranial Doppler ultrasound. Stroke 1991; 22:740. 34. Blersch WK, Draganski BM, Holmer SR, et al. Transcranial duplex sonography in the detection of patent foramen ovale. Radiology 2002; 225:693. 35. Droste DW, Lakemeier S, Wichter T, et al. Optimizing the technique of contrast transcranial Doppler ultrasound in the detection of right-to-left shunts. Stroke 2002; 33:2211. 36. Schwarze JJ, Sander D, Kukla C, et al. Methodological parameters influence the detection of right-to-left shunts by contrast transcranial Doppler ultrasonography. Stroke 1999; 30:1234. 37. Sloan MA, Alexandrov AV, Tegeler CH, et al. Assessment: transcranial Doppler ultrasonography: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2004; 62:1468. 38. Droste DW, Schmidt-Rimpler C, Wichter T, et al. Right-to-left-shunts detected by transesophageal echocardiography and transcranial Doppler sonography. Cerebrovasc Dis 2004; 17:191. 39. Kerr AJ, Buck T, Chia K, et al. Transmitral Doppler: a new transthoracic contrast method for patent foramen ovale detection and quantification. J Am Coll Cardiol 2000; 36:1959. 40. Fenster BE, Curran-Everett D, Freeman AM, et al. Saline contrast echocardiography for the detection of patent foramen ovale in hypoxia: a validation study using intracardiac echocardiography. Echocardiography 2014; 31:420. 41. Lynch JJ, Schuchard GH, Gross CM, Wann LS. Prevalence of right-to-left atrial shunting in a healthy population: detection by Valsalva maneuver contrast echocardiography. Am J Cardiol 1984; 53:1478. 42. Schneider B, Zienkiewicz T, Jansen V, et al. Diagnosis of patent foramen ovale by transesophageal echocardiography and correlation with autopsy findings. Am J Cardiol 1996; 77:1202. 43. Schuchlenz HW, Weihs W, Hackl E, Rehak P. A large Eustachian valve is a confounder of contrast but not of color Doppler transesophageal echocardiography in detecting a right-to- left shunt across a patent foramen ovale. Int J Cardiol 2006; 109:375. 44. Woods TD, Patel A. A critical review of patent foramen ovale detection using saline contrast echocardiography: when bubbles lie. J Am Soc Echocardiogr 2006; 19:215. 45. Gazzaniga P, Buscarini E, Leandro G, et al. Contrast echocardiography for pulmonary arteriovenous malformations screening: does any bubble matter? Eur J Echocardiogr 2009; 10:513. https://www.uptodate.com/contents/patent-foramen-ovale/print 15/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate 46. Zukotynski K, Chan RP, Chow CM, et al. Contrast echocardiography grading predicts

first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clin Proc 1984; 59:17. 5. Meissner I, Whisnant JP, Khandheria BK, et al. Prevalence of potential risk factors for stroke assessed by transesophageal echocardiography and carotid ultrasonography: the SPARC study. Stroke Prevention: Assessment of Risk in a Community. Mayo Clin Proc 1999; 74:862. 6. Lamy C, Giannesini C, Zuber M, et al. Clinical and imaging findings in cryptogenic stroke patients with and without patent foramen ovale: the PFO-ASA Study. Atrial Septal Aneurysm. Stroke 2002; 33:706. 7. Homma S, Sacco RL, Di Tullio MR, et al. Effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in Cryptogenic Stroke Study. Circulation 2002; 105:2625. 8. Konstantinides S, Geibel A, Kasper W, et al. Patent foramen ovale is an important predictor of adverse outcome in patients with major pulmonary embolism. Circulation 1998; 97:1946. 9. Moore KL. The Developing Human: Clinically Oriented Embryology, 6th ed, Saunders, Philad elphia 1998. 10. Arquizan C, Coste J, Touboul PJ, Mas JL. Is patent foramen ovale a family trait? A transcranial Doppler sonographic study. Stroke 2001; 32:1563. 11. Schneider B, Hofmann T, Justen MH, Meinertz T. Chiari's network: normal anatomic variant or risk factor for arterial embolic events? J Am Coll Cardiol 1995; 26:203. 12. Chiari, H . About network development in the right side of the heart. Beitr Pathol Anat 1897; 22:1. 13. Werner JA, Cheitlin MD, Gross BW, et al. Echocardiographic appearance of the Chiari network: differentiation from right-heart pathology. Circulation 1981; 63:1104. 14. Rigatelli G, Dell'avvocata F, Braggion G, et al. Persistent venous valves correlate with increased shunt and multiple preceding cryptogenic embolic events in patients with patent foramen ovale: an intracardiac echocardiographic study. Catheter Cardiovasc Interv 2008; 72:973. 15. Khositseth A, Cabalka AK, Sweeney JP, et al. Transcatheter Amplatzer device closure of atrial septal defect and patent foramen ovale in patients with presumed paradoxical embolism. Mayo Clin Proc 2004; 79:35. 16. Attenhofer Jost CH, Connolly HM, O'Leary PW, et al. Left heart lesions in patients with Ebstein anomaly. Mayo Clin Proc 2005; 80:361. https://www.uptodate.com/contents/patent-foramen-ovale/print 13/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate 17. Seward JB, Hayes DL, Smith HC, et al. Platypnea-orthodeoxia: clinical profile, diagnostic workup, management, and report of seven cases. Mayo Clin Proc 1984; 59:221. 18. Cheng TO. Platypnea-orthodeoxia syndrome: etiology, differential diagnosis, and management. Catheter Cardiovasc Interv 1999; 47:64. 19. Cheng TO. Mechanisms of platypnea-orthodeoxia: what causes water to flow uphill? Circulation 2002; 105:e47. 20. Cheng TO. Reversible orthodeoxia. Ann Intern Med 1992; 116:875. 21. Agostoni P, Gasparini G, Destro G. Acute myocardial infarction probably caused by paradoxical embolus in a pregnant woman. Heart 2004; 90:e12. 22. Diaz Castro O, Bueno H, Nebreda LA. Acute myocardial infarction caused by paradoxical tumorous embolism as a manifestation of hepatocarcinoma. Heart 2004; 90:e29. 23. Iwasaki M, Joki N, Tanaka Y, et al. A suspected case of paradoxical renal embolism through the patent foramen ovale. Clin Exp Nephrol 2011; 15:147. 24. Pell AC, Hughes D, Keating J, et al. Brief report: fulminating fat embolism syndrome caused by paradoxical embolism through a patent foramen ovale. N Engl J Med 1993; 329:926. 25. Pellikka PA, Tajik AJ, Khandheria BK, et al. Carcinoid heart disease. Clinical and echocardiographic spectrum in 74 patients. Circulation 1993; 87:1188. 26. M gge A, Daniel WG, Angermann C, et al. Atrial septal aneurysm in adult patients. A multicenter study using transthoracic and transesophageal echocardiography. Circulation 1995; 91:2785. 27. Pinto FJ. When and how to diagnose patent foramen ovale. Heart 2005; 91:438. 28. Pearson AC, Labovitz AJ, Tatineni S, Gomez CR. Superiority of transesophageal echocardiography in detecting cardiac source of embolism in patients with cerebral ischemia of uncertain etiology. J Am Coll Cardiol 1991; 17:66. 29. Konstantinides S, Kasper W, Geibel A, et al. Detection of left-to-right shunt in atrial septal defect by negative contrast echocardiography: a comparison of transthoracic and transesophageal approach. Am Heart J 1993; 126:909. 30. Di Tullio M, Sacco RL, Venketasubramanian N, et al. Comparison of diagnostic techniques for the detection of a patent foramen ovale in stroke patients. Stroke 1993; 24:1020. 31. Job FP, Ringelstein EB, Grafen Y, et al. Comparison of transcranial contrast Doppler sonography and transesophageal contrast echocardiography for the detection of patent foramen ovale in young stroke patients. Am J Cardiol 1994; 74:381. 32. Nemec JJ, Marwick TH, Lorig RJ, et al. Comparison of transcranial Doppler ultrasound and transesophageal contrast echocardiography in the detection of interatrial right-to-left https://www.uptodate.com/contents/patent-foramen-ovale/print 14/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate shunts. Am J Cardiol 1991; 68:1498. 33. Teague SM, Sharma MK. Detection of paradoxical cerebral echo contrast embolization by transcranial Doppler ultrasound. Stroke 1991; 22:740. 34. Blersch WK, Draganski BM, Holmer SR, et al. Transcranial duplex sonography in the detection of patent foramen ovale. Radiology 2002; 225:693. 35. Droste DW, Lakemeier S, Wichter T, et al. Optimizing the technique of contrast transcranial Doppler ultrasound in the detection of right-to-left shunts. Stroke 2002; 33:2211. 36. Schwarze JJ, Sander D, Kukla C, et al. Methodological parameters influence the detection of right-to-left shunts by contrast transcranial Doppler ultrasonography. Stroke 1999; 30:1234. 37. Sloan MA, Alexandrov AV, Tegeler CH, et al. Assessment: transcranial Doppler ultrasonography: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2004; 62:1468. 38. Droste DW, Schmidt-Rimpler C, Wichter T, et al. Right-to-left-shunts detected by transesophageal echocardiography and transcranial Doppler sonography. Cerebrovasc Dis 2004; 17:191. 39. Kerr AJ, Buck T, Chia K, et al. Transmitral Doppler: a new transthoracic contrast method for patent foramen ovale detection and quantification. J Am Coll Cardiol 2000; 36:1959. 40. Fenster BE, Curran-Everett D, Freeman AM, et al. Saline contrast echocardiography for the detection of patent foramen ovale in hypoxia: a validation study using intracardiac echocardiography. Echocardiography 2014; 31:420. 41. Lynch JJ, Schuchard GH, Gross CM, Wann LS. Prevalence of right-to-left atrial shunting in a healthy population: detection by Valsalva maneuver contrast echocardiography. Am J Cardiol 1984; 53:1478. 42. Schneider B, Zienkiewicz T, Jansen V, et al. Diagnosis of patent foramen ovale by transesophageal echocardiography and correlation with autopsy findings. Am J Cardiol 1996; 77:1202. 43. Schuchlenz HW, Weihs W, Hackl E, Rehak P. A large Eustachian valve is a confounder of contrast but not of color Doppler transesophageal echocardiography in detecting a right-to- left shunt across a patent foramen ovale. Int J Cardiol 2006; 109:375. 44. Woods TD, Patel A. A critical review of patent foramen ovale detection using saline contrast echocardiography: when bubbles lie. J Am Soc Echocardiogr 2006; 19:215. 45. Gazzaniga P, Buscarini E, Leandro G, et al. Contrast echocardiography for pulmonary arteriovenous malformations screening: does any bubble matter? Eur J Echocardiogr 2009; 10:513. https://www.uptodate.com/contents/patent-foramen-ovale/print 15/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate 46. Zukotynski K, Chan RP, Chow CM, et al. Contrast echocardiography grading predicts pulmonary arteriovenous malformations on CT. Chest 2007; 132:18. 47. Freeman JA, Woods TD. Use of saline contrast echo timing to distinguish intracardiac and extracardiac shunts: failure of the 3- to 5-beat rule. Echocardiography 2008; 25:1127. 48. Rahmouni HW, Keane MG, Silvestry FE, et al. Failure of digital echocardiography to accurately diagnose intracardiac shunts. Am Heart J 2008; 155:161. 49. Dani ls C, Weytjens C, Cosyns B, et al. Second harmonic transthoracic echocardiography: the new reference screening method for the detection of patent foramen ovale. Eur J Echocardiogr 2004; 5:449. 50. Thanigaraj S, Valika A, Zajarias A, et al. Comparison of transthoracic versus transesophageal echocardiography for detection of right-to-left atrial shunting using agitated saline contrast. Am J Cardiol 2005; 96:1007. 51. Thomas JD, Adams DB, Devries S, et al. Guidelines and recommendations for digital echocardiography. J Am Soc Echocardiogr 2005; 18:287. 52. Gin KG, Huckell VF, Pollick C. Femoral vein delivery of contrast medium enhances transthoracic echocardiographic detection of patent foramen ovale. J Am Coll Cardiol 1993; 22:1994. 53. Christin F, Bouffard Y, Rossi R, Delafosse B. Paradoxical symptomatic air embolism after saline contrast transesophageal echocardiography. Echocardiography 2007; 24:867. 54. Romero JR, Frey JL, Schwamm LH, et al. Cerebral ischemic events associated with 'bubble study' for identification of right to left shunts. Stroke 2009; 40:2343. 55. Kim YJ, Hur J, Shim CY, et al. Patent foramen ovale: diagnosis with multidetector CT comparison with transesophageal echocardiography. Radiology 2009; 250:61. 56. Mohrs OK, Petersen SE, Erkapic D, et al. Diagnosis of patent foramen ovale using contrast- enhanced dynamic MRI: a pilot study. AJR Am J Roentgenol 2005; 184:234. 57. Nusser T, H her M, Merkle N, et al. Cardiac magnetic resonance imaging and transesophageal echocardiography in patients with transcatheter closure of patent foramen ovale. J Am Coll Cardiol 2006; 48:322. 58. Mohrs OK, Petersen SE, Erkapic D, et al. Dynamic contrast-enhanced MRI before and after transcatheter occlusion of patent foramen ovale. AJR Am J Roentgenol 2007; 188:844. 59. Cheng TO. Transcatheter closure of patent foramen ovale: a definitive treatment for platypnea-orthodeoxia. Catheter Cardiovasc Interv 2000; 51:120. 60. Medina A, de Lezo JS, Caballero E, Ortega JR. Platypnea-orthodeoxia due to aortic elongation. Circulation 2001; 104:741. https://www.uptodate.com/contents/patent-foramen-ovale/print 16/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate Topic 1420 Version 23.0 https://www.uptodate.com/contents/patent-foramen-ovale/print 17/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate GRAPHICS Development of the atrial septum Graphic 77749 Version 4.0 https://www.uptodate.com/contents/patent-foramen-ovale/print 18/19 7/5/23, 11:48 AM Patent foramen ovale - UpToDate Contributor Disclosures Hidehiko Hara, MD No relevant financial relationship(s) with ineligible companies to disclose. Heidi M Connolly, MD, FACC, FASE No relevant financial relationship(s) with ineligible companies to disclose. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/patent-foramen-ovale/print 19/19

7/5/23, 11:49 AM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Stroke associated with patent foramen ovale (PFO): Evaluation : Steven R Mess , MD, Stephen JD Brecker, MD, FRCP, FESC, FACC : Scott E Kasner, MD, Heidi M Connolly, MD, FACC, FASE : John F Dashe, MD, PhD, Susan B Yeon, MD, JD, FACC All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 28, 2023. INTRODUCTION When embolic ischemic stroke occurs in an individual with a patent foramen ovale (PFO), the PFO may or may not be causally related to the stroke. This topic will review the approach to the evaluation of patients who have an ischemic stroke in the setting of a PFO. The management of PFO-associated stroke is reviewed elsewhere. (See "Stroke associated with patent foramen ovale (PFO): Management".) Cryptogenic stroke is reviewed in detail separately. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)".) The risk of stroke related to atrial septal abnormalities and indications for treating atrial septal defects in adults are also discussed elsewhere. (See "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults" and "Management of atrial septal defects in adults".) COMPREHENSIVE EVALUATION Goals and approach Determining whether a PFO is incidental or pathogenic in relation to an ischemic stroke is essential to guide decisions about PFO management and secondary stroke prevention. The approach incorporates an evaluation for other possible causes of ischemic stroke, PFO features, and methods (ie, the Risk of Paradoxical Embolism [RoPE] score and PFO- https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 1/20 7/5/23, 11:49 AM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate associated stroke causal likelihood [PASCAL] classification) that estimate the likelihood of paradoxical embolism through a PFO as the mechanism of the stroke. Clues from the history The history should include specific questions that define the circumstances immediately preceding the event. Was the patient doing something that might increase right-to-left shunt flow through a PFO, such as straining, coughing vigorously, or lifting or pushing a heavy object? Was there any risk for deep venous thrombosis (DVT), such as prolonged immobility (eg, postoperative status, sitting in a cramped airline seat with legs dependent and knees flexed), dehydration, or venous hypercoagulability? The presence of the above historical features raise concern for paradoxical embolism. However, absence of these features does not exclude paradoxical embolism. Is the stroke embolic? By definition, PFO-associated stroke is embolic. On evaluation, an embolic mechanism is especially likely when neuroimaging reveals infarcts in multiple vascular territories or a single wedge-shaped infarct involving cortex and the underlying subcortical white matter. With embolic stroke, the neurologic deficit is typically maximal from the onset, with a possibility of rapid improvement if there is spontaneous recanalization. (See "Overview of the evaluation of stroke", section on 'Determining a presumptive diagnosis of stroke subtype'.) Whether or not an embolic stroke is related to PFO or to another mechanism cannot be determined reliably based upon neuroimaging features alone. However, certain findings may be more suggestive of PFO. In an analysis of data from subjects with cryptogenic stroke and PFO (n = 1141) or no PFO (n = 1539) in the RoPE study database, characteristics associated with a significantly higher prevalence of PFO were a large index stroke (odds ratio [OR] 1.36), index stroke seen on imaging (OR 1.53), and superficial (ie, involving the cerebral or cerebellar cortex) stroke location (OR 1.54) [1]. The last of these characteristics is included in the RoPE score. Exclusion of other sources of ischemic stroke Patients with an ischemic stroke and a PFO should undergo a comprehensive evaluation by both a stroke neurologist and a cardiologist to ensure that other causes of ischemic stroke are excluded and that PFO-associated stroke (ie, paradoxical embolism through a PFO) is the most likely mechanism [2]. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Evaluation and diagnosis'.) PFO-associated stroke Patients with an embolic-appearing ischemic stroke who have a medium- or high-risk PFO (see 'PFO assessment' below) and who have no other identified stroke etiology should be recognized as having a PFO-associated stroke [3]. Findings The evaluation of a PFO-associated stroke is characterized by the following findings [4]: https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 2/20 7/5/23, 11:49 AM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate No large vessel stenosis ( 50 percent) or occlusion in the territory of the infarct. Intracranial and extracranial neurovascular imaging should be performed to exclude vascular causes of stroke, including large artery atherosclerosis, dissection, and other vasculopathy. (See "Neuroimaging of acute stroke".) No radiographic acute lacunar infarction (ie, a small [ 1.5 cm] deep perforator infarct) and no clinical lacunar stroke syndrome (ie, hemiparesis/plegia, hemianesthesia without cortical signs) if imaging shows no infarct. (See "Lacunar infarcts", section on 'Clinical features'.) No evidence of occult atrial fibrillation or other high-risk cardioembolic source ( table 1) on cardiac monitoring and echocardiography. Screening for atrial fibrillation should include a 12-lead electrocardiogram (ECG) and 24-hour cardiac monitoring (ambulatory or by telemetry). Adults over age 40 years with cryptogenic ischemic stroke or cryptogenic transient ischemic attack (TIA) with no atrial fibrillation detected on 12-lead ECG and 24-hour monitoring should undergo extended ambulatory monitoring, as discussed elsewhere. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Advanced evaluation'.) Transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) not only enable identification and characterization of PFOs but also enable identification of relevant structural findings including atrial septal aneurysms and other potential embolic sources such as high-risk valve lesions (eg, mitral stenosis), cardiac tumors (eg, myxoma), intracardiac thrombus, fibroelastomas, and other valvular vegetations. Test selection is discussed below and reviewed separately. (See 'PFO assessment' below and "Echocardiography in detection of cardiac and aortic sources of systemic embolism".) No hypercoagulable condition with a high risk for arterial thrombotic events, such as the antiphospholipid syndrome. (See "Clinical manifestations of antiphospholipid syndrome" and "Diagnosis of antiphospholipid syndrome" and "Management of antiphospholipid syndrome".) PFO assessment Methods to detect a right-to-left shunt associated with a PFO include TTE, TEE, and transcranial Doppler (TCD), in conjunction with agitated saline contrast (a "bubble study")Among these methods, TCD cannot confirm intracardiac shunting or relevant structural findings (e.g., atrial septal aneurysm), and generally only TEE enables visualization of the type https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 3/20 7/5/23, 11:49 AM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate (eg, PFO, atrial septal defect [ASD]), site, and size of the shunt. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Cardiac and aortic evaluation'.) While cardiac CT and cardiovascular magnetic resonance (CMR) imaging have been used to identify PFO, they are less sensitive than TEE [5-7]. Identification of PFO The diagnostic evaluation of PFO is reviewed here briefly and discussed in detail separately. (See "Patent foramen ovale", section on 'Diagnosis and evaluation'.) TTE or TEE These tests are performed with intravenous injection of agitated saline contrast at rest, with Valsalva, and with cough; the study is considered positive if microbubbles (typically three or more) appear in the left heart within three cardiac cycles of bubbles filling the right atrium [8]. Multiple agitated saline contrast injections with provocative maneuvers may be required to enhance sensitivity for identification of a shunt via the PFO [9]. In some cases, intermittent flow through the PFO is also visualized by color Doppler. (See "Patent foramen ovale", section on 'Diagnosis and evaluation'.) TTE is often used as the initial study because it is better tolerated than TEE and is more widely available than TEE or TCD. Also, TTE provides a better assessment (with a microbubble ultrasound-enhancing agent) for left ventricular thrombus (particularly apical), which is an important component of the evaluation in patients who may have ischemic heart disease or cardiomyopathy. In addition, some patients are better able to perform the Valsalva maneuver and cough during TTE than during TEE (due to the effects of sedation and/or discomfort during TEE). Thus, in some cases, TTE may be more sensitive than TEE for PFO shunt detection [10]. However, TEE is the reference standard for the detection of PFO [9], is generally more sensitive than TTE [11], and better demonstrates its anatomic features. Therefore, patients who are candidates for PFO closure (ie, those 60 years of age with an embolic-appearing stroke or a TIA who have no evident source of stroke or TIA other than a PFO, despite a comprehensive evaluation) should undergo TEE as either the initial study or as a follow-up study to TTE or TCD, even when a preceding TTE is negative or nondiagnostic for PFO. (See "Stroke associated with patent foramen ovale (PFO): Management", section on 'Patient selection for PFO closure'.) For patients who do not meet selection criteria for PFO closure, a follow-up TEE may still be indicated to identify a stroke etiology but is not required to assess for PFO. Note that all patients who are candidates for PFO closure should have preprocedural imaging with TEE, including those with features suggesting PFO detected by TTE or TCD. (See "Stroke https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 4/20 7/5/23, 11:49 AM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate associated with patent foramen ovale (PFO): Management", section on 'Preprocedural imaging'.) TCD Insonating the middle cerebral artery through the temporal bone window, TCD is performed with intravenous injection of agitated saline contrast at rest, with Valsalva, and with cough; the study is considered positive for a right-to-left shunt if bubbles are detected in the middle cerebral artery. This approach is at least as sensitive as TEE to identify right- to-left shunt [12-15]; TCD also has advantages compared with TEE in being noninvasive and relatively easy to perform at the bedside. However, TCD cannot confirm the location of the shunt (which may be intracardiac or extracardiac), identify an atrial septal aneurysm, or rule out other cardioembolic sources. Thus, when TCD is positive, imaging (generally with TEE) is performed to identify shunt location [11]. PFO shunt size PFO size (small versus large) is a component of the PASCAL approach to risk classification. PFO size is generally inferred from the degree of right-to-left shunting apparent on echocardiography with agitated saline contrast, based on the number of microbubbles appearing in a single frame in the left atrium either spontaneously or after a provocative (Valsalva) maneuver within three cardiac cycles after opacification of the right atrium [16,17]. PFO size is categorized as small or large in the PASCAL classification described below. We use the following categories (based upon thresholds in four of six randomized trials in the meta-analysis discussed below [18]): Large: >20 microbubbles (which was the threshold used in four of the six included randomized trials) Small: 20 microbubbles Some trials have classified shunt size into small, moderate, and large categories [19]. In one small study, PFO measured ante mortem by assessment of jet size on color Doppler TEE and number of microbubbles on contrast TEE correlated well with autopsy finding; patients with a PFO >10 mm at autopsy had large shunts with >25 microbubbles on contrast TEE [20]. Among patients with an embolic stroke topography, a PFO, and no alternative cause, features associated with medium- to high-risk PFO include factors that increase right-to-left shunt flow (eg, large PFO size, chronic right atrial hypertension, or a Valsalva maneuver at onset of stroke) and concomitant pulmonary embolism or deep venous thrombosis preceding the ischemic stroke [3]. Individual patient characteristics (age and vascular risk factors) are also important in the assessment of PFO risk. https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 5/20 7/5/23, 11:49 AM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate Atrial septal aneurysm An atrial septal aneurysm (ASA) is defined as redundant and mobile interatrial septal tissue in the region of the fossa ovalis with phasic oscillation (intrusion) of at least 10 to 15 mm into the left or right atrium during the cardiorespiratory cycle and is most commonly identified on TEE (with lower sensitivity of detection by TTE). Although not a consistent finding across all studies, the risk of stroke is likely increased when a PFO is associated with an ASA. (See "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults", section on 'ASA' and "Patent foramen ovale", section on 'Atrial septal aneurysm'.) Straddling thrombus Thrombus trapped in a PFO is rarely encountered [21-24], but this finding confirms paradoxical embolus in transit via a very high-risk PFO, which may in some cases warrant surgical treatment to remove the clot and repair the PFO [3]. Search for venous thromboembolism We suggest performing a standard evaluation for DVT with D-dimer level and/or ultrasonography of the lower extremities for patients with a PFO- associated embolic infarct and no other evident source of stroke; additional investigations such as CT or MRI venography are generally not warranted. Details of the evaluation are discussed separately. (See "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity".) Identification of DVT or other evidence of venous thromboembolism can help strengthen the clinical inference of paradoxical embolism and also has important implications for therapy (including identifying an indication for anticoagulation, which impacts the timing and need for PFO device closure). Ideally, the evaluation should be done within two to three days of stroke onset, before venous thrombosis develops secondary to stroke-related immobility [3]. Studies using radiograph venography or magnetic resonance venography to examine patients with ischemic cerebral events or other suspected embolic events have found variable rates of proximal leg or pelvic deep venous thrombosis (10 to 22 percent) [25-27]. Among those with documented DVT, most had no symptoms or signs of venous thrombosis. There are several potential explanations for the low rates of proximal DVT in patients with PFO-associated embolic infarct and no other evident source of stroke: Evaluation for DVT was incomplete in these studies since venography evaluated either the lower extremities or pelvic veins, but not both. The emboli consist of platelet fibrin particles that normally circulate in the systemic venous bed and are too small to be seen with conventional testing. These particles are removed by the efficient lytic system of the lungs; however, when shunted across a PFO or ASD, they may travel unlysed into the cerebral circulation [28]. https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 6/20 7/5/23, 11:49 AM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate The clot forms in the heart at the edges or in the tunnel of the PFO, or in an ASA. The embolic source is in the systemic arterial circulation. (See "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults", section on 'Left-sided sources'.) DVTs have resolved (lysed, completely embolized, or recanalized) during the delay between onset of the embolic event and venography. Proximal DVTs may be lysed in some patients treated with intravenous thrombolytic therapy [27]. Hypercoagulable evaluation Hematologic testing to exclude hypercoagulable states (eg, antiphospholipid syndrome and hyperhomocysteinemia) is indicated for patients with stroke being considered for PFO closure. (See "Diagnosis of antiphospholipid syndrome".) LIKELIHOOD OF A PFO-ASSOCIATED STROKE RoPE score The Risk of Paradoxical Embolism (RoPE) score, as shown in the table ( table 2) and calculator (calculator 1), estimates the probability that a PFO is incidental or pathogenic in a patient with a seemingly cryptogenic stroke [29]. The PFO-attributable fraction of stroke derived from the RoPE score ( table 3) varies widely and decreases with age and the presence of vascular risk factors. High RoPE scores, as found in younger patients who lack vascular risk factors and have a cortical infarct on neuroimaging, suggest pathogenic, higher risk PFOs. By contrast, low RoPE scores, as found in older patients with vascular risk factors, suggest incidental, lower-risk PFOs. The RoPE score is a major component of the PFO-associated stroke causal likelihood (PASCAL) classification system, which provides additional discrimination, as described below. PASCAL classification The PASCAL classification system ( table 4) estimates the probability that stroke is associated with a PFO in patients with embolic infarct topography and without other major sources of ischemic stroke [3]. The classification is based upon the RoPE score combined with anatomic and clinical factors (see 'PFO assessment' above) including shunt size, presence or absence of atrial septal aneurysm, and/or venous thromboembolism; PASCAL categorizes the likelihood that the stroke is caused by a PFO as unlikely, possible, probable, highly probable, or definite, as shown in the table ( table 4). Given the high prevalence of PFO in the general population and the low risk of stroke related to PFO, there is always some degree of uncertainty about the causal relationship between PFO and an embolic-appearing ischemic stroke with no other evident stroke mechanism despite a https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 7/20 7/5/23, 11:49 AM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate comprehensive evaluation [30]. The possibility that the PFO is an "innocent bystander" and that another mechanism is responsible for the stroke is particularly applicable to older patients and to those with known risk factors for stroke (eg, hypertension, hypercholesterolemia, smoking) [31-33]. Causality can best be inferred in younger patients with no other apparent etiology for stroke [34], particularly if DVT is present (as a potential source for paradoxical emboli). MANAGEMENT The management of PFO-associated stroke, including selection of appropriate candidates for PFO closure ( algorithm 1), is reviewed separately. (See "Stroke associated with patent foramen ovale (PFO): Management".) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Patent foramen ovale (The Basics)") SUMMARY AND RECOMMENDATIONS https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 8/20 7/5/23, 11:49 AM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate Is the PFO incidental or pathogenic? Determining whether a patent foramen ovale (PFO) is incidental or pathogenic in relation to an ischemic stroke is essential to guide decisions about PFO management and secondary stroke prevention. This determination incorporates an evaluation for other possible causes of ischemic stroke, PFO features, and methods (ie, the Risk of Paradoxical Embolism [RoPE] score and PFO-associated stroke causal likelihood [PASCAL] classification) that estimate the likelihood of paradoxical embolism through a PFO as the mechanism of the stroke. (See 'Goals and approach' above.) Is the stroke embolic? By definition, PFO-associated stroke is embolic. Neuroimaging features that suggest embolism include infarcts in multiple vascular territories or a single wedge-shaped infarct involving cortex and the underlying subcortical white matter. (See 'Is the stroke embolic?' above.) Exclusion of other sources of ischemic stroke A PFO-associated embolic infarct requires that other causes of ischemic stroke are excluded by the following (see 'Exclusion of other sources of ischemic stroke' above): No large vessel stenosis in the territory of the infarct by neurovascular imaging No evidence of atrial fibrillation on telemetry and 30-day ambulatory cardiac monitoring A PFO but no other high-risk source of cardiogenic embolism identified on transthoracic echocardiography (TTE) or transesophageal echocardiography (TEE) No hypercoagulable condition with a high risk for arterial thrombotic events, such as the antiphospholipid syndrome PFO assessment The diagnostic evaluation of PFO should assess for the presence and size of a right-to-left shunting and other features suggestive of high risk for paradoxical embolism (eg, an atrial septal aneurysm or [rarely] a straddling thrombus). (See 'PFO assessment' above.) Evaluation for venous thromboembolism and hypercoagulable state We evaluate for these in all patients with a PFO-associated embolic infarct and no other evident source of stroke. (See 'Search for venous thromboembolism' above and 'Hypercoagulable evaluation' above.) Likelihood of a PFO-associated stroke The RoPE score ( table 2) and the PASCAL classification system ( table 4) are useful to estimate the probability that stroke is associated with a PFO in patients with embolic infarct topography and without other major sources of ischemic stroke ( algorithm 1). (See 'Likelihood of a PFO-associated stroke' above.) https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 9/20 7/5/23, 11:49 AM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Naser M Ammash, MD, and Robert S Schwartz, MD, and Joseph K Perloff, MD who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Thaler DE, Ruthazer R, Di Angelantonio E, et al. Neuroimaging findings in cryptogenic stroke patients with and without patent foramen ovale. Stroke 2013; 44:675. 2. Farb A, Ibrahim NG, Zuckerman BD. Patent Foramen Ovale after Cryptogenic Stroke - Assessing the Evidence for Closure. N Engl J Med 2017; 377:1006. 3. Elgendy AY, Saver JL, Amin Z, et al. Proposal for Updated Nomenclature and Classification of Potential Causative Mechanism in Patent Foramen Ovale-Associated Stroke. JAMA Neurol 2020; 77:878. 4. Hart RG, Diener HC, Coutts SB, et al. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 2014; 13:429. 5. Lou J, Bao Y, Lv T, Yang Y. Computed Tomography for Detecting Patent Foramen Ovale: A Meta-Analysis. Heart Surg Forum 2022; 25:E849. 6. Hamilton-Craig C, Sestito A, Natale L, et al. Contrast transoesophageal echocardiography remains superior to contrast-enhanced cardiac magnetic resonance imaging for the diagnosis of patent foramen ovale. Eur J Echocardiogr 2011; 12:222. 7. Zahuranec DB, Mueller GC, Bach DS, et al. Pilot study of cardiac magnetic resonance imaging for detection of embolic source after ischemic stroke. J Stroke Cerebrovasc Dis 2012; 21:794. 8. Rana BS, Thomas MR, Calvert PA, et al. Echocardiographic evaluation of patent foramen ovale prior to device closure. JACC Cardiovasc Imaging 2010; 3:749. 9. Silvestry FE, Cohen MS, Armsby LB, et al. Guidelines for the Echocardiographic Assessment of Atrial Septal Defect and Patent Foramen Ovale: From the American Society of Echocardiography and Society for Cardiac Angiography and Interventions. J Am Soc Echocardiogr 2015; 28:910. 10. Rodrigues AC, Picard MH, Carbone A, et al. Importance of adequately performed Valsalva maneuver to detect patent foramen ovale during transesophageal echocardiography. J Am Soc Echocardiogr 2013; 26:1337. https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 10/20 7/5/23, 11:49 AM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate 11. Pristipino C, Sievert H, D'Ascenzo F, et al. European position paper on the management of patients with patent foramen ovale. General approach and left circulation thromboembolism. Eur Heart J 2019; 40:3182. 12. Park S, Oh JK, Song JK, et al. Transcranial Doppler as a Screening Tool for High-Risk Patent Foramen Ovale in Cryptogenic Stroke. J Neuroimaging 2021; 31:165. 13. Jauss M, Zanette E. Detection of right-to-left shunt with ultrasound contrast agent and transcranial Doppler sonography. Cerebrovasc Dis 2000; 10:490. 14. Spencer MP, Moehring MA, Jesurum J, et al. Power m-mode transcranial Doppler for diagnosis of patent foramen ovale and assessing transcatheter closure. J Neuroimaging 2004; 14:342. 15. Palazzo P, Ingrand P, Agius P, et al. Transcranial Doppler to detect right-to-left shunt in cryptogenic acute ischemic stroke. Brain Behav 2019; 9:e01091. 16. Webster MW, Chancellor AM, Smith HJ, et al. Patent foramen ovale in young stroke patients. Lancet 1988; 2:11. 17. Kerut EK, Norfleet WT, Plotnick GD, Giles TD. Patent foramen ovale: a review of associated conditions and the impact of physiological size. J Am Coll Cardiol 2001; 38:613. 18. Kent DM, Saver JL, Kasner SE, et al. Heterogeneity of Treatment Effects in an Analysis of Pooled Individual Patient Data From Randomized Trials of Device Closure of Patent Foramen Ovale After Stroke. JAMA 2021; 326:2277. 19. S ndergaard L, Kasner SE, Rhodes JF, et al. Patent Foramen Ovale Closure or Antiplatelet Therapy for Cryptogenic Stroke. N Engl J Med 2017; 377:1033. 20. Schneider B, Zienkiewicz T, Jansen V, et al. Diagnosis of patent foramen ovale by transesophageal echocardiography and correlation with autopsy findings. Am J Cardiol 1996; 77:1202. 21. Acikel S, Ertem AG, Kiziltepe U, et al. Double-edged sword in the heart: trapped deep venous thrombus in a patent foramen ovale. Blood Coagul Fibrinolysis 2012; 23:673. 22. Rajani R, Mirza F, Teoh Y, Gandhi S. Entrapment: thrombus within a patent foramen ovale. J Cardiovasc Med (Hagerstown) 2009; 10:576. 23. Ozdogru I, Kaya MG, Dogan A, et al. Thrombus crossing through a patent foramen ovale. Int J Cardiol 2009; 133:e55. 24. Mirode A, Tribouilloy C, Adam MC, et al. [Echocardiographic diagnosis of a thrombus trapped in a patent foramen ovale. Apropos of a case]. Arch Mal Coeur Vaiss 1993; 86:1065. 25. Lethen H, Flachskampf FA, Schneider R, et al. Frequency of deep vein thrombosis in patients with patent foramen ovale and ischemic stroke or transient ischemic attack. Am J Cardiol https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 11/20 7/5/23, 11:49 AM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate 1997; 80:1066. 26. St llberger C, Slany J, Schuster I, et al. The prevalence of deep venous thrombosis in patients with suspected paradoxical embolism. Ann Intern Med 1993; 119:461. 27. Cramer SC, Rordorf G, Maki JH, et al. Increased pelvic vein thrombi in cryptogenic stroke: results of the Paradoxical Emboli from Large Veins in Ischemic Stroke (PELVIS) study. Stroke 2004; 35:46. 28. Meier B, Lock JE. Contemporary management of patent foramen ovale. Circulation 2003; 107:5. 29. Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology 2013; 81:619. 30. Kasner SE, Lattanzi S, Fonseca AC, Elgendy AY. Uncertainties and Controversies in the Management of Ischemic Stroke and Transient Ischemic Attack Patients With Patent Foramen Ovale. Stroke 2021; 52:e806. 31. Homma S, Di Tullio MR, Sacco RL, et al. Surgical closure of patent foramen ovale in cryptogenic stroke patients. Stroke 1997; 28:2376. 32. Lechat P, Mas JL, Lascault G, et al. Prevalence of patent foramen ovale in patients with stroke. N Engl J Med 1988; 318:1148. 33. Overell JR, Bone I, Lees KR. Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies. Neurology 2000; 55:1172. 34. Holmes DR Jr, Cabalka A. Was your mother right do we always need to close the door? Circulation 2002; 106:1034. Topic 1100 Version 51.0 https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 12/20 7/5/23, 11:49 AM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate GRAPHICS Cardioaortic sources of cerebral embolism Sources with high primary risk for Sources with low or uncertain primary ischemic stroke risk for ischemic stroke Atrial fibrillation Cardiac sources of embolism: Paroxysmal atrial fibrillation Mitral annular calcification Left atrial thrombus Patent foramen ovale Left ventricular thrombus Atrial septal aneurysm Sick sinus syndrome Atrial septal aneurysm and patent foramen ovale Atrial flutter Left ventricular aneurysm without thrombus Recent myocardial infarction (within one month Left atrial spontaneous echo contrast prior to stroke) ("smoke") Mitral stenosis or rheumatic valve disease Congestive heart failure with ejection fraction <30% Mechanical heart valves Bioprosthetic heart valves Chronic myocardial infarction together with low ejection fraction (<28%) Apical akinesia Dilated cardiomyopathy (prior established Wall motion abnormalities (hypokinesia, diagnosis or left ventricular dilatation with an ejection fraction of <40% or fractional shortening of <25%) akinesia, dyskinesia) other than apical akinesia Nonbacterial thrombotic endocarditis Hypertrophic cardiomyopathy Infective endocarditis Left ventricular hypertrophy Papillary fibroelastoma Left ventricular hypertrabeculation/non- compaction Left atrial myxoma Recent aortic valve replacement or coronary artery bypass graft surgery Presence of left ventricular assist device Paroxysmal supraventricular tachycardia Aortic sources of embolism: Complex atheroma in the ascending aorta or proximal arch (protruding with >4 mm thickness, or mobile debris, or plaque ulceration) https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 13/20 7/5/23, 11:49 AM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate The high- and low-risk cardioaortic sources in this table are separated using an arbitrary 2% annual or one-time primary stroke risk threshold. Data from: 1. Ay H, Benner T, Arsava EM, et al. A computerized algorithm for etiologic classi cation of ischemic stroke: the Causative Classi cation of Stroke System. Stroke 2007; 38:2979. 2. Ay H, Furie KL, Singhal A, et al. An evidence-based causative classi cation system for acute ischemic stroke. Ann Neurol 2005; 58:688. 3. Arsava EM, Ballabio E, Benner T, et al. The Causative Classi cation of Stroke system: an international reliability and optimization study. Neurology 2010; 75:1277. 4. Kamel H, Elkind MS, Bhave PD, et al. Paroxysmal supraventricular tachycardia and the risk of ischemic stroke. Stroke 2013; 44:1550. 5. Kirklin JK, Pagani FD, Kormos RL, et al. Eighth annual INTERMACS report: Special focus on framing the impact of adverse events. J Heart Lung Transplant 2017; 36:1080. Reproduced and modi ed with permission from: Ay H, Furie KL, Singhal A, et al. An evidence-based causative classi cation system for acute ischemic stroke. Ann Neurol 2005; 58:688. Copyright 2005 American Neurological Association. Graphic 60843 Version 11.0 https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 14/20 7/5/23, 11:49 AM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate Risk of Paradoxical Embolism (RoPE) score RoPE Characteristic Points score No history of hypertension 1 No history of diabetes 1 No history of stroke or TIA 1 Nonsmoker 1 Cortical infarct on imaging 1 Age, years 18 to 29 5 30 to 39 4 40 to 49 3 50 to 59 2 60 to 69 1 70 0 Total score (sum of individual points) Maximum score (a patient <30 years with no hypertension, no 10 diabetes, no history of stroke or TIA, nonsmoker, and cortical infarct) Minimum score (a patient 70 years with hypertension, diabetes, prior stroke, current smoker, and no cortical infarct) 0 TIA: transient ischemic attack. From: Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology 2013; 81:619. DOI: 10.1212/WNL.0b013e3182a08d59. Reproduced with permission from Lippincott Williams & Wilkins. Copyright 2013 American Academy of Neurology. Unauthorized reproduction of this material is prohibited. Graphic 97895 Version 5.0 https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 15/20 7/5/23, 11:49 AM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate PFO prevalence, attributable fraction, and estimated two-year risk of stroke/TIA CS patients with PFO (n = Cryptogenic stroke (n = 3023) 1324) Estimated two-year stroke/TIA Prevalence of PFO- RoPE patients with a PFO, attributable fraction, Number of CS patients with score Number of patients recurrence rate (Kaplan- percent (95% CI)* percent (95% CI)* PFO* Meier), percent (95% CI) 0 to 3 613 23 (19 to 26) 0 (0 to 4) 108 20 (12 to 28) 4 511 35 (31 to 39) 38 (25 to 48) 148 12 (6 to 18) 5 516 34 (30 to 38) 34 (21 to 45) 186 7 (3 to 11) 6 482 47 (42 to 51) 62 (54 to 68) 236 8 (4 to 12) 7 434 54 (49 to 59) 72 (66 to 76) 263 6 (2 to 10) 8 287 67 (62 to 73) 84 (79 to 87) 233 6 (2 to 10) 9 to 10 180 73 (66 to 79) 88 (83 to 91) 150 2 (0 to 4) CI: confidence interval; CS: cryptogenic stroke; PFO: patent foramen ovale; RoPE: Risk of Paradoxical Embolism; TIA: transient ischemic attack. NOTE: 95% CI for PFO prevalence and attributable fraction based on normal approximation to the binomial distribution. From: Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology 2013; 81:619. DOI: 10.1212/WNL.0b013e3182a08d59. Reproduced with permission from Lippincott Williams & Wilkins. Copyright 2013 American Academy of Neurology. Unauthorized reproduction of this material is prohibited. Graphic 97896 Version 5.0 https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 16/20 7/5/23, 11:49 AM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate Proposed flexible clinical practice approach to classifying patent foramen ovale causal association in patients with embolic infarct topography and without other major stroke sources* RoPE score Risk source Features Low High Very high A PFO and a straddling thrombus Definite Definite High (1) Concomitant pulmonary embolism Probable Highly probable or deep venous thrombosis preceding an index infarct combined with either (2a) a PFO and an atrial septal aneurysm or (2b) a large-shunt PFO Medium Either (1) a PFO and an atrial septal Possible Probable aneurysm or (2) a large-shunt PFO Low A small-shunt PFO without an atrial septal aneurysm Unlikely Possible RoPE: Risk of Paradoxical Embolism; PFO: patent foramen ovale. The algorithm in this table is proposed for use in flexible clinical practice when application of an entire formal classification system is not being conducted. The RoPE score includes points for 5 age categories, cortical infarct, absence of hypertension, diabetes, prior stroke or transient ischemic attack, and smoking. A higher RoPE score ( 7 points) increases probability of causal association. Reproduced with permission from: Elgendy AY, Saver JL, Amin Z, et al. Proposal for updated nomenclature and classi cation of potential causative mechanism in patent foramen ovale-associated Stroke. JAMA Neurol 2020; 77:878. Copyright 2020 American Medical Association. All rights reserved. Graphic 134674 Version 3.0 https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 17/20 7/5/23, 11:49 AM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate Approach to management for a patient with PFO and embolic-appearing ischem without other identified cause This algorithm is intended to provide general guidance to PFO management in patients with a recent emboli ischemic stroke who have a PFO and no other identified cause of stroke. For most patients who are 60 year possible, probable, or definite likelihood by RoPE and PASCAL that the PFO was causally associated with the s percutaneous PFO device closure in addition to antiplatelet therapy. PFO device closure may be temporarily d patients with an indication for short-term anticoagulation. The benefit of PFO device closure is uncertain for of age and for patients with an indication for long-term anticoagulation; in such cases, an individualized app decision-making is appropriate. Patients with ischemic stroke should generally be treated with all available ri

Mechanical heart valves Bioprosthetic heart valves Chronic myocardial infarction together with low ejection fraction (<28%) Apical akinesia Dilated cardiomyopathy (prior established Wall motion abnormalities (hypokinesia, diagnosis or left ventricular dilatation with an ejection fraction of <40% or fractional shortening of <25%) akinesia, dyskinesia) other than apical akinesia Nonbacterial thrombotic endocarditis Hypertrophic cardiomyopathy Infective endocarditis Left ventricular hypertrophy Papillary fibroelastoma Left ventricular hypertrabeculation/non- compaction Left atrial myxoma Recent aortic valve replacement or coronary artery bypass graft surgery Presence of left ventricular assist device Paroxysmal supraventricular tachycardia Aortic sources of embolism: Complex atheroma in the ascending aorta or proximal arch (protruding with >4 mm thickness, or mobile debris, or plaque ulceration) https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 13/20 7/5/23, 11:49 AM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate The high- and low-risk cardioaortic sources in this table are separated using an arbitrary 2% annual or one-time primary stroke risk threshold. Data from: 1. Ay H, Benner T, Arsava EM, et al. A computerized algorithm for etiologic classi cation of ischemic stroke: the Causative Classi cation of Stroke System. Stroke 2007; 38:2979. 2. Ay H, Furie KL, Singhal A, et al. An evidence-based causative classi cation system for acute ischemic stroke. Ann Neurol 2005; 58:688. 3. Arsava EM, Ballabio E, Benner T, et al. The Causative Classi cation of Stroke system: an international reliability and optimization study. Neurology 2010; 75:1277. 4. Kamel H, Elkind MS, Bhave PD, et al. Paroxysmal supraventricular tachycardia and the risk of ischemic stroke. Stroke 2013; 44:1550. 5. Kirklin JK, Pagani FD, Kormos RL, et al. Eighth annual INTERMACS report: Special focus on framing the impact of adverse events. J Heart Lung Transplant 2017; 36:1080. Reproduced and modi ed with permission from: Ay H, Furie KL, Singhal A, et al. An evidence-based causative classi cation system for acute ischemic stroke. Ann Neurol 2005; 58:688. Copyright 2005 American Neurological Association. Graphic 60843 Version 11.0 https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 14/20 7/5/23, 11:49 AM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate Risk of Paradoxical Embolism (RoPE) score RoPE Characteristic Points score No history of hypertension 1 No history of diabetes 1 No history of stroke or TIA 1 Nonsmoker 1 Cortical infarct on imaging 1 Age, years 18 to 29 5 30 to 39 4 40 to 49 3 50 to 59 2 60 to 69 1 70 0 Total score (sum of individual points) Maximum score (a patient <30 years with no hypertension, no 10 diabetes, no history of stroke or TIA, nonsmoker, and cortical infarct) Minimum score (a patient 70 years with hypertension, diabetes, prior stroke, current smoker, and no cortical infarct) 0 TIA: transient ischemic attack. From: Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology 2013; 81:619. DOI: 10.1212/WNL.0b013e3182a08d59. Reproduced with permission from Lippincott Williams & Wilkins. Copyright 2013 American Academy of Neurology. Unauthorized reproduction of this material is prohibited. Graphic 97895 Version 5.0 https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 15/20 7/5/23, 11:49 AM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate PFO prevalence, attributable fraction, and estimated two-year risk of stroke/TIA CS patients with PFO (n = Cryptogenic stroke (n = 3023) 1324) Estimated two-year stroke/TIA Prevalence of PFO- RoPE patients with a PFO, attributable fraction, Number of CS patients with score Number of patients recurrence rate (Kaplan- percent (95% CI)* percent (95% CI)* PFO* Meier), percent (95% CI) 0 to 3 613 23 (19 to 26) 0 (0 to 4) 108 20 (12 to 28) 4 511 35 (31 to 39) 38 (25 to 48) 148 12 (6 to 18) 5 516 34 (30 to 38) 34 (21 to 45) 186 7 (3 to 11) 6 482 47 (42 to 51) 62 (54 to 68) 236 8 (4 to 12) 7 434 54 (49 to 59) 72 (66 to 76) 263 6 (2 to 10) 8 287 67 (62 to 73) 84 (79 to 87) 233 6 (2 to 10) 9 to 10 180 73 (66 to 79) 88 (83 to 91) 150 2 (0 to 4) CI: confidence interval; CS: cryptogenic stroke; PFO: patent foramen ovale; RoPE: Risk of Paradoxical Embolism; TIA: transient ischemic attack. NOTE: 95% CI for PFO prevalence and attributable fraction based on normal approximation to the binomial distribution. From: Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology 2013; 81:619. DOI: 10.1212/WNL.0b013e3182a08d59. Reproduced with permission from Lippincott Williams & Wilkins. Copyright 2013 American Academy of Neurology. Unauthorized reproduction of this material is prohibited. Graphic 97896 Version 5.0 https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 16/20 7/5/23, 11:49 AM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate Proposed flexible clinical practice approach to classifying patent foramen ovale causal association in patients with embolic infarct topography and without other major stroke sources* RoPE score Risk source Features Low High Very high A PFO and a straddling thrombus Definite Definite High (1) Concomitant pulmonary embolism Probable Highly probable or deep venous thrombosis preceding an index infarct combined with either (2a) a PFO and an atrial septal aneurysm or (2b) a large-shunt PFO Medium Either (1) a PFO and an atrial septal Possible Probable aneurysm or (2) a large-shunt PFO Low A small-shunt PFO without an atrial septal aneurysm Unlikely Possible RoPE: Risk of Paradoxical Embolism; PFO: patent foramen ovale. The algorithm in this table is proposed for use in flexible clinical practice when application of an entire formal classification system is not being conducted. The RoPE score includes points for 5 age categories, cortical infarct, absence of hypertension, diabetes, prior stroke or transient ischemic attack, and smoking. A higher RoPE score ( 7 points) increases probability of causal association. Reproduced with permission from: Elgendy AY, Saver JL, Amin Z, et al. Proposal for updated nomenclature and classi cation of potential causative mechanism in patent foramen ovale-associated Stroke. JAMA Neurol 2020; 77:878. Copyright 2020 American Medical Association. All rights reserved. Graphic 134674 Version 3.0 https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 17/20 7/5/23, 11:49 AM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate Approach to management for a patient with PFO and embolic-appearing ischem without other identified cause This algorithm is intended to provide general guidance to PFO management in patients with a recent emboli ischemic stroke who have a PFO and no other identified cause of stroke. For most patients who are 60 year possible, probable, or definite likelihood by RoPE and PASCAL that the PFO was causally associated with the s percutaneous PFO device closure in addition to antiplatelet therapy. PFO device closure may be temporarily d patients with an indication for short-term anticoagulation. The benefit of PFO device closure is uncertain for of age and for patients with an indication for long-term anticoagulation; in such cases, an individualized app decision-making is appropriate. Patients with ischemic stroke should generally be treated with all available ri strategies including antithrombotic therapy, blood pressure control, low-density lipoprotein (LDL)-lowering th lifestyle modification, as appropriate. For details regarding the evaluation required for a comprehensive stroke evaluation, choice of antithromboti other factors that impact decision-making for PFO management, refer to appropriate UpToDate topics. PFO: patent foramen ovale; DVT: deep venous thrombosis; PE: pulmonary embolism; RoPE: Risk of Paradoxic PASCAL: PFO-associated stroke causal likelihood; ASA: atrial septal aneurysm. https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 18/20 7/5/23, 11:49 AM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate For most patients with an indication for anticoagulation >1 year, PFO closure is not performed, as benefit in uncertain. PFO closure may be an option for selected patients, such as those who experience recurrent embo other identified cause while therapeutically anticoagulated and those who are no longer anticoagulated. An approach to decision-making is based upon patient preferences, risk factors, and comorbidities. Patients who undergo PFO closure (percutaneous or surgical) are treated with antiplatelet agents. We treat to 81 mg/day) plus clopidogrel (75 mg/day) for three months, followed by continued aspirin therapy. For the rare patient who has a concurrent indication for surgical valve intervention, surgical (rather than pe closure is appropriate. If percutaneous PFO closure is not feasible and there is no concurrent indication for c suggest against surgical PFO closure. For most patients >60 years old, PFO closure is not performed since such patients were excluded from tria and the benefit of closure in this setting is unproven. PFO closure may be an option for selected patients >60 as younger patients in this age range who have low estimated atherosclerotic cardiovascular disease risk. An approach to decision-making is based upon patient preferences, risk factors, and comorbidities. Refer to UpToDate topic on cryptogenic stroke. Graphic 138535 Version 1.0 https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 19/20 7/5/23, 11:49 AM Stroke associated with patent foramen ovale (PFO): Evaluation - UpToDate Contributor Disclosures Steven R Mess , MD Equity Ownership/Stock Options: Neuralert Technologies [Stroke monitoring]. Grant/Research/Clinical Trial Support: Biogen [Hemispheric ischemic stroke]; Mallinkrodt, Inc [Nitric oxide and cerebral perfusion]; Novartis [Intracerebral hemorrhage]; WL Gore & Associates [PFO closure for secondary stroke prevention, neurologic outcomes from proximal aortic repair]. Consultant/Advisory Boards: Boston Scientific [steering committee for PROTECTED-TAVR trial of embolic protection during TAVR]; EmStop [embolic protection during TAVR]; WL Gore [DSMB for post marketing study of PFO closure for secondary stroke prevention]. Other Financial Interest: Novo Nordisk [ONWARDS trial event adjudication committee]; Terumo [Patient selection committee, Relay Branch trial]. All of the relevant financial relationships listed have been mitigated. Stephen JD Brecker, MD, FRCP, FESC, FACC Grant/Research/Clinical Trial Support: Medtronic [Transcatheter valves]. Consultant/Advisory Boards: Aortic Innovations LLC [Transcatheter valves]; Medtronic [Transcatheter valves]. Speaker's Bureau: Medtronic [Transcatheter valves]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Heidi M Connolly, MD, FACC, FASE No relevant financial relationship(s) with ineligible companies to disclose. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-evaluation/print 20/20

7/5/23, 11:49 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Stroke associated with patent foramen ovale (PFO): Management : Steven R Mess , MD, Stephen JD Brecker, MD, FRCP, FESC, FACC : Scott E Kasner, MD, Heidi M Connolly, MD, FACC, FASE : John F Dashe, MD, PhD, Susan B Yeon, MD, JD, FACC All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 27, 2023. INTRODUCTION This topic will review the approach to management of patients with an embolic-appearing ischemic stroke who have a patent foramen ovale (PFO) and no other apparent cause of stroke. The evaluation of patients with ischemic stroke and a PFO is reviewed elsewhere. (See "Stroke associated with patent foramen ovale (PFO): Evaluation".) The risk of stroke related to atrial septal abnormalities and indications for treating atrial septal defects in adults are discussed elsewhere. (See "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults" and "Management of atrial septal defects in adults".) Despite a possible association of migraine with right-to-left cardiac shunts, PFO closure is not an effective treatment for migraine. This is reviewed elsewhere. (See "Preventive treatment of episodic migraine in adults", section on 'Other interventions not recommended'.) PATIENT SELECTION FOR PFO CLOSURE Role of RoPE and PASCAL in patient selection For patients with an embolic stroke without an evident cause, we use the PFO-associated stroke causal likelihood (PASCAL) classification system ( table 1), which incorporates the Risk of Paradoxical Embolism (RoPE) score ( table 2) (calculator 1), to classify the causal association of PFO with the stroke and to guide decision-making for PFO device closure. In the setting of a patient 60 years of age and no other https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 1/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate evident source of stroke despite a comprehensive evaluation, PFO closure is warranted if the RoPE score is >6 and/or there is a large shunt or atrial septal aneurysm. (See "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'RoPE score' and "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'PASCAL classification' and 'Benefit' below.) Given the high prevalence of PFO in the general population and the low risk of stroke related to PFO, there is always some degree of uncertainty about the causal relationship between PFO and an embolic-appearing ischemic stroke with no other evident stroke mechanism despite a comprehensive evaluation [1]. The possibility that the PFO is an "innocent bystander" and that another mechanism is responsible for the stroke is particularly applicable to older patients and to those with known risk factors for stroke (eg, hypertension, hypercholesterolemia, smoking) [2-4]. Causality can best be inferred in younger patients with no other apparent etiology for stroke [5], particularly if DVT is present (as a potential source for paradoxical emboli). Selection criteria PFO associated stroke Selected patients with PFO with all of the following characteristics are candidates for percutaneous PFO closure ( algorithm 1): Age 60 years Embolic stroke topography (see "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'Is the stroke embolic?') No other evident source of stroke despite a comprehensive evaluation (see "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'Exclusion of other sources of ischemic stroke') A possible, probable, or definite likelihood that the stroke was causally related to the PFO according to the PASCAL classification system ( table 1), which incorporates the RoPE score and high-risk features of the PFO on echocardiogram ( table 2) (calculator 1) No concurrent indication for anticoagulation (see 'Special considerations in anticoagulated patients' below) For most patients without a concurrent indication for anticoagulation who are 60 years of age with a possible, probable, or definite likelihood by PASCAL that the stroke was causally associated with the PFO, we suggest percutaneous PFO device closure in addition to antiplatelet therapy. (See 'Percutaneous PFO closure' below.) https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 2/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate For patients age >60 years with a PASCAL determination of possible, probable, or definite causal association, the safety and benefit of PFO device closure is unknown since these patients were excluded from the vast majority of randomized trials of PFO device closure (see 'Benefit' below). Furthermore, a patient-level meta-analysis demonstrated that risk of atrial fibrillation after PFO closure increases with age [6]. Thus, decisions about PFO closure for such patients should be based upon an individualized assessment of potential risks and benefits and patient preferences. PFO closure is not performed in most patients >60 years old in this setting but may be an option for selected patients such as younger patients in this age range who have low estimated atherosclerotic cardiovascular disease risk. Exceptions Among patients who otherwise meet criteria for percutaneous PFO closure, management may differ in the following clinical settings: Concurrent indication for anticoagulation If otherwise indicated, PFO device closure may be temporarily deferred for patients with a concurrent indication for short- term anticoagulation ( 1 year); the benefit of PFO device closure is uncertain for patients with a concurrent indication for long-term anticoagulation, as discussed below. (See 'Special considerations in anticoagulated patients' below.) Concurrent indication for cardiac surgery For rare patients aged 60 years who meet criteria for PFO device closure but have a concurrent indication for cardiac surgery (eg, for valve surgery), surgical closure of PFO for secondary stroke prevention is appropriate. (See 'Surgical PFO closure' below.) Percutaneous PFO closure not feasible For rare patients who have a PFO that is not amenable to percutaneous closure but meet PASCAL criteria for PFO causal association, the benefit of surgical closure is uncertain. In the absence of a concurrent indication for cardiac surgery, we suggest against surgical closure. PFO unlikely to be associated with stroke For patients who are unlikely to have a PFO- associated stroke by PASCAL classification ( table 1), we suggest against percutaneous PFO device closure. (See 'Benefit' below.) Note that the evidence from a 2021 meta-analysis [6] supporting the use of the PASCAL classification was published after the 2018 European position paper on the management of patients with PFO [7], the 2019 Clinical Commissioning Policy for PFO closure from the National Health Service in England [8], the 2020 American Academy of Neurology practice advisory [9], and the 2021 stroke prevention guideline from the American Heart Association/American Stroke Association [10]. Therefore, recommendations from these guidelines did not incorporate the PASCAL classification. https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 3/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate Special considerations in anticoagulated patients Patients with venous thromboembolism that is provoked by a known event or an identifiable transient risk factor are generally treated with anticoagulation for 3 to 12 months, and anticoagulation is generally the sole antithrombotic therapy required. In such cases, PFO device closure, if otherwise indicated, can be postponed until anticoagulation is stopped. For patients assigned to PFO closure in the RESPECT trial, the incidence of venous thromboembolism more than 30 days postprocedure was higher among those with a history of overt deep vein thrombosis than for those without such a history [11]. For patients with an embolic-appearing stroke who have an indication for chronic (>12 months) anticoagulation (eg, unprovoked or recurrent deep venous thrombosis), the benefit of PFO closure is uncertain. For such patients, we suggest individualized, multidisciplinary, shared decision-making that accounts for the risks of thrombosis, embolism, and intervention in determining whether to proceed with chronic anticoagulation alone or to also perform percutaneous PFO closure. For most patients with a concurrent indication for anticoagulation >1 year, PFO closure is not performed, given its uncertain benefit. PFO closure may be an option for selected patients such as those who experience recurrent embolic stroke without other identified cause while therapeutically anticoagulated and those who are no longer anticoagulated. Excepting venous thromboembolism, most common indications for anticoagulation are also potential higher-risk mechanisms for embolic stroke, such as atrial fibrillation and prosthetic heart valves. For patients with these conditions, cardiogenic embolism is the most likely cause of the stroke, and a PFO likely to be an incidental finding; in these settings, the presence of a PFO does not generally alter management. Informed decision-making Consideration of PFO closure, including benefits, risks, and alternative treatment options, must be discussed with the patient by the neurologist and cardiologist. The patient should understand the immediate and long-term potential benefits and risks of treatment options (including decreased risk of recurrent stroke and increased risk of atrial fibrillation with PFO percutaneous device closure) in order to make an appropriately informed decision that accounts for their own values and preferences. PERCUTANEOUS PFO CLOSURE Indications and exclusions Selection criteria for candidates for percutaneous PFO closure are discussed above. (See 'Patient selection for PFO closure' above.) Exclusions to percutaneous device closure include the presence of an inferior vena cava filter, elevated bleeding risk or coagulopathy, and vascular, cardiac, or PFO anatomy that is unsuitable https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 4/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate for device placement. Benefit The balance of evidence from randomized controlled trials suggests that percutaneous PFO closure is more effective for preventing recurrent ischemic stroke than antiplatelet therapy alone for highly selected patients who have an apparently embolic (seemingly cryptogenic) ischemic stroke and a PFO [11-14]. (See 'Percutaneous PFO closure' above.) Clinical trial evidence suggests that PFO percutaneous device closure is more effective than antiplatelet therapy alone for reducing the risk of recurrent stroke in select patients aged 60 years with an embolic-appearing ischemic stroke who have a PFO with a right-to-left interatrial shunt and who have no other identified stroke cause or mechanism. The risk of recurrent stroke with device closure is reduced by approximately 60 percent compared with medical therapy (eg, from approximately 5 to 2 percent during a three- to six-year period) [15]; the corresponding number needed to treat to prevent one recurrent stroke during this period is approximately 30. The patients most likely to benefit may be those with a large right-to-left interatrial shunt and/or an associated atrial septal aneurysm (ASA), characteristics that suggest an increased risk for paradoxical embolism. Almost all randomized controlled trials of percutaneous PFO closure have reported point estimates suggesting that PFO closure is more effective than medical therapy for reducing recurrent stroke rates. These results were not statistically significant by intention-to-treat analyses in the first three trials (CLOSURE I [16], PC [17], and RESPECT [18]), but were significant in later trials (RESPECT extended follow-up [11], REDUCE [14], and CLOSE [12]). The trials that found clear benefit for PFO device closure were likely positive because of several factors. First, these latter trials enrolled subjects when off-label PFO closure had waned to some extent, and thus it is possible that patients who were more likely to benefit were included in these studies. Furthermore, to varying degrees for the individual studies, they included a requirement for neuroimaging confirmation of stroke prior to enrollment, excluded lacunar infarcts, provided longer follow-up, and selected patients with PFO features (ie, large shunt size or presence of an associated ASA) that may portend an increased risk of paradoxical embolism. Meta-analyses of closure trials consistently show that patients in the PFO closure groups had increased rates of newly detected atrial fibrillation compared with the medical therapy groups [15,19]. (See 'Adverse effects' below.) Meta-analyses In a 2018 meta-analysis that included four trials (PC [17], RESPECT extended follow-up [11], REDUCE [14], and CLOSE [12]) with 2531 subjects and follow-up ranging from 3.2 to 5.9 years, PFO closure reduced the risk of recurrent stroke from 5.1 percent with medical therapy to 1.8 percent (absolute risk reduction [ARR] 3.3 percent, 95% https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 5/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate CI 6.2-0.4 percent) [15,20]. Based on these data, the number needed to treat with PFO device closure to prevent one recurrent stroke was approximately 30. Similarly, a separate 2018 meta-analysis that included the same trials, with follow-up ranging from 2.1 to 5.3 years, found that PFO closure reduced the risk of recurrent stroke from 4.1 percent with medical therapy to 1.2 percent (ARR 3.1 percent, 95% CI 5.1-1.0 percent) [19]. Both meta- analyses excluded the CLOSURE I trial because it used the STARFlex PFO closure device, which was associated with higher complication and lower procedural success rates than the PFO closure devices used in the other trials and is no longer available [15,19]. Other meta-analyses of PFO closure have generally reported similar findings [21-29]. A 2021 meta-analysis of individual patient data (n = 3740) from six randomized controlled trials, with a median follow-up of 57 months, found that PFO closure reduced the annualized incidence of stroke compared with medical therapy alone (0.47 versus 1.09 percent, adjusted hazard ratio [HR] 0.41, 95% CI 0.28-0.60) [6]. Importantly, the risk reduction for recurrent stroke with PFO closure varied among subgroups with different probabilities that the stroke was causally related to the PFO, as determined by the Risk of Paradoxical Embolism (RoPE) score ( table 2) and a modified PFO-associated stroke causal likelihood (PASCAL) classification ( table 1). For the risk of recurrent ischemic stroke with PFO closure compared with medical therapy alone, patients with high RoPE score (ie, higher risk PFO) had an HR of 0.21 (95% CI 0.11-0.42), while those with a low RoPE score (ie, lower risk PFO) had an HR of 0.61 (95% CI 0.37-1.00). However, patients categorized by the PASCAL classification as probable, possible, or unlikely to have a PFO- associated stroke had HRs of 0.10 (95% CI 0.03-0.35), 0.38 (95% CI 0.22-0.65), and 1.14 (95% CI 0.53-2.46), respectively. Thus, the PASCAL score provides greater discrimination of who is likely to benefit from closure and by what degree, compared with the RoPE score alone. (See "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'RoPE score' and "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'PASCAL classification'.) Individual trials The individual trials used the broad term "cryptogenic" rather than "PFO-associated" stroke but aimed to enroll the latter, and reported the following results: In the CLOSURE I trial, 909 adult patients 60 years old with a PFO and cryptogenic stroke or transient ischemic attack (TIA) were randomly assigned either to PFO device closure (n = 447) or to medical therapy (n = 462) [16]. Patients in the device group were treated with the STARFlex PFO closure device and received aspirin plus clopidogrel for six months followed by aspirin alone; those in the medical therapy group were treated with aspirin or warfarin or both. The primary endpoint was a composite of stroke or TIA at two years plus 30-day mortality and neurologic mortality beyond 30 days. At two https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 6/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate years, by intention-to-treat analysis, there was no significant difference between device closure and medical therapy in the rates of the primary endpoint (5.5 versus 6.8 percent, hazard ratio [HR] 0.78, 95% CI 0.45-1.35), stroke (2.9 versus 3.1 percent), or TIA (3.1 versus 4.1 percent). Major vascular complications were significantly more frequent with device closure (3.2 versus 0 percent), as was atrial fibrillation (5.7 versus 0.7 percent), most of which was periprocedural. The PC trial randomly assigned 414 adults (<60 years of age) with PFO and ischemic stroke, TIA, or a peripheral embolic event to treatment with the Amplatzer PFO Occluder or medical therapy [17]. After a mean follow-up of four years, the composite primary endpoint of death, nonfatal stroke, TIA, or peripheral embolism for the intention-to- treat cohort occurred in 7 of 204 patients (3.4 percent) in the device closure group and 11 of 210 patients (5.2 percent) in the medical therapy group; the difference was not statistically significant (HR 0.63, 95% CI 0.24-1.62). Serious adverse events were slightly more frequent in the device closure group (21.1 percent versus 17.6 percent), including a nonsignificantly higher rate of new-onset atrial fibrillation in the device closure group (2.9 versus 1.0 percent). In the RESPECT trial, 980 patients (age 18 to 60 years) with a PFO and cryptogenic ischemic stroke were randomly assigned to receive treatment with the Amplatzer PFO Occluder or medical therapy [18]. The primary endpoint was a composite of recurrent nonfatal ischemic stroke, fatal ischemic stroke, or early death after randomization. The trial results were analyzed after reaching the target of 25 primary endpoint events; all 25 events were nonfatal ischemic strokes. The mean follow-up was approximately 2.6 years, and the primary endpoint for the intention-to-treat cohort occurred in 9 of 499 patients (1.8 percent) in the closure group and 16 of 481 patients (3.3 percent) in the medical therapy group, a difference that was not statistically significant (0.66 versus 1.38 events per 100 patient-years, HR 0.49, 95% CI 0.22-1.11). A later RESPECT publication reported outcomes at a median follow-up of 5.9 years [11]. By intention-to-treat analysis, recurrent ischemic stroke was less frequent in the closure group compared with the medical therapy group (18 versus 28 events, 0.58 versus 1.07 events per 100 patient-years, HR 0.55, 95% CI 0.31-0.99). However, the dropout rate was higher and treatment exposure lower in the medical therapy group, leading to an unequal exposure to the risk of outcome events among the two groups. The REDUCE trial randomly assigned 664 patients 18 to 59 years of age with cryptogenic embolic-appearing ischemic stroke and PFO with a right-to-left shunt demonstrated by means of transesophageal echocardiography [14,30]. Patients were randomly assigned https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 7/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate to PFO closure combined with antiplatelet therapy or treatment with antiplatelet therapy alone in a 2:1 ratio. During a median follow-up of 5 years, clinical ischemic stroke by intention-to-treat analysis occurred in fewer patients in the PFO closure group compared with the antiplatelet-only group (8 of 441 versus 12 of 223 patients, 1.8 versus 5.4 percent, HR 0.31, 95% CI 0.13-0.76). The CLOSE trial enrolled patients 16 to 60 years of age with recent cryptogenic stroke attributed to PFO who had an associated ASA or large interatrial shunt on echocardiography [12]. Patients were randomly assigned in a 1:1:1 ratio to PFO closure plus antiplatelet therapy, antiplatelet therapy alone, or oral anticoagulation, with the exception that patients with contraindications to PFO device closure or to anticoagulation were assigned to alternative noncontraindicated treatment or to antiplatelet therapy. The main arm of the trial (n = 473) compared PFO closure with antiplatelet therapy; at a mean follow-up of 5.3 years, there were no recurrent strokes among 238 patients in the PFO closure group compared with 14 strokes among 233 patients the antiplatelet-only group (HR 0.03, 95% CI 0.0-0.26). In the nonclosure arms of the trial, there was a nonsignificant trend toward fewer recurrent strokes in the anticoagulation group (3 among 187 patients) compared with the antiplatelet group (7 among 174 patients) (HR 0.44, 95% CI 0.11-1.48). Trial limitations There are important limitations of these trials that lower confidence in the results or result in important questions about generalizability. As examples: All of these trials utilized open-label endpoint ascertainment, which increases the risk of bias. However, objective neuroimaging support for the reduction in risk of recurrent stroke with PFO closure comes from the REDUCE trial, which required brain magnetic resonance imaging (MRI) at baseline and after a clinical neurologic event or at two years of follow-up for all subjects [31]. With clinical and imaging data available for approximately 90 percent of patients at two years, the rate of new infarcts (both symptomatic and silent) on MRI was lower for patients who had PFO closure compared with patients who had medical therapy alone (4.7 versus 10.7 percent, relative risk 0.44, 95% CI 0.24-0.81) [31]. The number of primary events was relatively low, with a total of 52 events in the CLOSURE I trial [16], 18 in the PC trial [17], 46 in the RESPECT trial [11], 18 clinical events in the REDUCE trial [14], and 14 events in the treatment groups comparing PFO closure with antiplatelet treatment in the CLOSE trial [12]. https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 8/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate The duration of follow-up in the CLOSURE I trial (two years) and the primary analysis of the RESPECT trial (2.6 years) was not long enough to demonstrate benefit (eg, the trials of endarterectomy for asymptomatic carotid disease would not have demonstrated benefit at only two years). There was slow enrollment in most of these trials and suspicion that patients at high risk of recurrent embolism were disproportionately treated outside of the trials with PFO closure, particularly for the earlier trials. The trials primarily enrolled patients under 60 years of age, and the safety and efficacy of closure remains unclear in patients older than age 60, who are likely to be at increased risk of atrial fibrillation as a complication of PFO closure. An observational study that included 388 patients >60 years undergoing PFO closure found that the incidence of stroke, transient ischemic attack, or peripheral embolism events of 1.6 per 100 patient-years was lower than that expected according to the RoPE score (observed- to-expected ratio 0.31, 95% CI 0.11-0.91), although the event rate in these older patients was higher than in younger patients and postprocedural atrial fibrillation after the procedure was more frequent in older patients [32]. The trials mainly enrolled patients who had recent stroke (eg, within six months); therefore, the benefit of PFO closure for those with a more remote stroke attributed to PFO is less certain. However, given natural history data suggesting a relatively steady 1 to 1.5 percent annual risk of stroke on medical therapy [6], it is likely that the benefit of PFO closure extends beyond six months after stroke in carefully selected patients. Adverse effects New onset atrial fibrillation is the most common adverse effect of PFO device closure. Several meta-analyses have confirmed that PFO closure increases the risk of atrial fibrillation or atrial flutter [6,15,19,21-23,26,33], with a risk difference (ie, absolute risk increase) of 3.4 percent in one of the meta-analyses [19]. Of note, atrial fibrillation is a frequent complication of cardiac surgery, which is relevant for patients undergoing cardiac surgery with concomitant PFO closure. (See "Atrial fibrillation and flutter after cardiac surgery".) One concern about new onset atrial fibrillation is its potential long-term impact on the risk of stroke and other embolic events, but limited information is available on the clinical course of postprocedural atrial fibrillation. The management of new-onset atrial fibrillation after PFO closure (whether by device or surgery) is similar to that after cardiac surgery generally, as reviewed in detail separately. (See "Atrial fibrillation and flutter after cardiac surgery".) Other complications, all rare, include hematoma at the puncture site, device migration, device embolization, device erosion, and device thrombosis with possible and recurrent ischemic https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 9/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate stroke. (See 'Recurrent ischemic stroke' below.) Device erosion is rare (0.2 to 0.3 percent of cases) after device closure of atrial septal defects (ASDs), in most cases occurring during the first six months after implantation [34,35], and may be rarer with device closure of PFOs. Device erosion can lead to cardiac perforation with pericardial effusion, cardiac tamponade, and fistula formation or may rarely create an atrial septal defect [36,37]. Preprocedural imaging Patients with an embolic infarct and no other evident source of stroke who are being considered for PFO closure should undergo transesophageal echocardiography (TEE) to confirm that the intracardiac shunt is caused by a PFO, to define atrial septal anatomy (including thickness of rims around the PFO) and suitability for device closure, and to exclude other causes of embolic stroke (eg, intracardiac thrombus, mass or vegetation) or shunt [38]. The atrial septum is carefully examined to determine whether there are one or more concomitant ASDs and/or an atrial septal aneurysm (defined as a redundant mobile interatrial septal tissue in the region of the fossa ovalis with phasic excursion of at least 10 to 15 mm). The length of the PFO tunnel is also assessed. If a PFO is accompanied by one or more secundum- type ASDs, the location and size of these defects are examined to determine whether all the defects can be closed percutaneously by one or two devices and whether a surgical approach might be preferred. Procedure Percutaneous PFO closure should be performed using an approved PFO closure device. Access to the right atrium is established via the right femoral vein, and the PFO is crossed with a guidewire or catheter under fluoroscopic and echocardiographic (either TEE or intracardiac) guidance [34]. After the left atrium is accessed, an exchange-length stiff guidewire is advanced into a pulmonary vein. Balloon sizing may be used to determine the size of the device (typically twice the size of the balloon-stretched diameter of the defect). After the balloon is withdrawn, the delivery system is advanced into the left atrium over the guidewire. The device and the delivery system are flushed prior to insertion and the catheters aspirated to avoid air embolism. The left-sided occluder is opened in the left atrium and retracted against the interatrial septum before the right-sided occluder is opened. After device position is confirmed by echocardiography, the closure device is released from the delivery system. Echocardiography is performed after device release to assess for residual shunting and presence of any complications. The echocardiographic guidance is achieved by intracardiac echocardiography (ICE) or TEE. ICE, performed via a second venous access to the right atrium, is generally preferred, as it avoids the general anesthesia and intubation required for TEE [39]. When TEE is not used, the percutaneous closure procedure (with ICE) is generally performed with conscious sedation. https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 10/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate Antithrombotic therapy during the procedure Patients undergoing percutaneous device closure routinely receive antithrombotic therapy prior to, during, and following the procedure, though specific regimens vary. As an example, in the CLOSE trial, all patients undergoing percutaneous PFO closure received clopidogrel 300 mg, low molecular weight heparin, or continuation of their prior antiplatelet therapy before the procedure [12]. During the procedure, unfractionated heparin 100 international units/kg (up to 10,000 international units) was administered intravenously. SURGICAL PFO CLOSURE For rare patients aged 60 years with a PFO-associated stroke and no other evident source of stroke despite a comprehensive evaluation who have a concurrent indication for cardiac surgery (eg, an indication for valve surgery rather than a transcatheter procedure), surgical closure of PFO via standard or minimally invasive (including robotic) techniques for secondary stroke prevention after PFO-associated stroke is appropriate. The reported efficacy of surgical closure of a PFO in patients with prior cerebrovascular ischemic events has been variable [2,40-42], and randomized trials comparing surgical PFO closure with percutaneous closure or with medical therapy have not been performed. Rates of recurrent cerebrovascular events following surgical closure have ranged from 7 to 14 percent at one to two years [2,40]. Similar to findings from the randomized controlled trials for device closure of PFO, these events are likely due to mechanisms unrelated to paradoxical embolization, as illustrated by a report of 91 patients (mean age 44 years) with one or more cerebrovascular ischemic events who underwent surgical PFO closure [40]. The overall freedom from an ischemic episode at one and four years was 93 and 83 percent, respectively. The recurrent events were transient ischemic attacks (there were no cerebral infarctions), one of which was attributed to giant cell arteritis. Transesophageal echocardiography showed that the closures were intact in all patients, implying that paradoxical embolization was not the cause of the ischemic events. In patients with high cardiovascular risk and an incidentally discovered PFO, surgical closure may actually increase the risk of postoperative stroke. This conclusion comes from a retrospective study of over 13,000 adults without a prior diagnosis of PFO or atrial septal defect who had cardiothoracic surgery [43]. A PFO was detected intraoperatively in 2277 patients, and closure was performed at the discretion of the surgeon in 28 percent. Using propensity-matched analysis, the risk of perioperative stroke was significantly higher in patients who had surgical PFO closure than in those who did not (2.8 versus 1.2 percent; odds ratio 2.47, 95% CI 1.02-6.0). https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 11/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate There was no difference between the two groups in long-term survival. The uncontrolled retrospective design and small number of events limits confidence in the results of this study. GENERAL MANAGEMENT OF PFO-ASSOCIATED STROKE All patients with PFO and ischemic stroke require antithrombotic therapy, cardiovascular risk reduction measures, and other measures to reduce the risk of recurrent stroke and other adverse cardiovascular events. Antithrombotic therapy Agents Antithrombotic therapy is a key component of secondary prevention for all types of ischemic stroke. Patients without an indication for anticoagulation should be treated with antiplatelet therapy whether or not the PFO is successfully closed. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) After PFO closure For most patients who have undergone percutaneous or surgical PFO closure who have no concurrent indication for anticoagulation, we suggest long-term antiplatelet therapy rather than no treatment or anticoagulation. We treat with aspirin 75 to 81 mg/day plus clopidogrel 75 mg/day for three months, followed by continued aspirin therapy (75 to 81 mg/day). In the CLOSE trial, the antithrombotic regimen after percutaneous PFO closure was aspirin 75 mg/day plus clopidogrel 75 mg/day for three months [12]. From the fourth month, patients were treated with aspirin alone, clopidogrel alone, or the combination product aspirin-extended-release dipyridamole. Without PFO closure For most patients with a PFO-associated embolic infarct and no other evident source of stroke who do not undergo PFO closure, we suggest antithrombotic therapy with antiplatelet agents rather than anticoagulation. However, anticoagulation therapy is used rather than antiplatelet agents for patients with high risk of venous thromboembolism, as discussed below. Although the comparative effectiveness of different types of antithrombotic therapy for secondary stroke prevention among patients with a PFO-associated ischemic stroke or transient ischemic attack (TIA) is uncertain (see 'Comparative studies' below), high-quality data from randomized trials have established that aspirin is effective for ischemic stroke prevention, as discussed elsewhere. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke", section on 'Aspirin'.) Concurrent indication for anticoagulation Anticoagulation is used for patients with a PFO-associated stroke who have a concurrent indication, such as acute deep venous https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 12/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate thrombosis, pulmonary embolism, other venous thromboembolism (VTE), or a hypercoagulable state. Management of these conditions, including the duration of anticoagulation, is discussed separately. (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)" and "Treatment, prognosis, and follow- up of acute pulmonary embolism in adults" and "Placement of vena cava filters and their complications".) Comparative studies The evidence comparing the benefit of antiplatelet therapy with anticoagulation for stroke prevention among patients with a PFO and ischemic stroke comes mainly from nonrandomized studies or randomized trials with important limitations, as illustrated by the following observations: In a 2015 meta-analysis of individual participant data from 12 observational studies involving 2385 medically treated patients with cryptogenic stroke and PFO, there was no significant difference between treatment with oral anticoagulation compared with antiplatelet therapy for the composite outcome of recurrent stroke, TIA, or death (9 versus 10 percent, adjusted hazard ratio [aHR] 0.76, 95% CI 0.52-1.12) and no difference for the outcome of recurrent stroke alone (4 versus 5 percent, aHR 0.75, 95% CI 0.44-1.27) [44]. In an updated meta-analysis of combined data from four trials (PICSS [45], CLOSE [12], NAVIGATE ESUS [46], and RESPECT ESUS [47]) that included patients with PFO and cryptogenic stroke who were randomly assigned to treatment with anticoagulant or antiplatelet therapy, the risk of recurrent ischemic stroke was similar for anticoagulation versus antiplatelet therapy (odds ratio 0.70, 95% CI 0.43-1.14) [47]. However, confidence in this result is limited by imprecision due to the small number of outcome events and wide confidence interval. Other cardiovascular risk reduction Patients with PFO who have an ischemic stroke or TIA should be treated with all appropriate cardiovascular risk reduction strategies (see above) including lifestyle modification (diet and exercise), blood pressure control, and statin therapy (if indicated). (See "Overview of secondary prevention of ischemic stroke" and "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) Additional preventive measures Certain general measures may be beneficial independent of the therapy chosen for the PFO. Since embolic material originates most commonly in lower extremity veins, patients at risk should avoid sitting for extended periods of time with knees flexed and legs dependent or the legs crossed, and should avoid prolonged passive standing. Risk is implicit during long airplane flights. For long-distance travelers with individual risk factors for VTE, we suggest frequent ambulation and calf exercises, avoidance of dehydration or https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 13/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate sedatives, and graduated compression stockings to reduce the risk of travel-associated VTE. These measures are particularly important in patients in whom deep vein thrombosis was identified at the time of the initial cerebrovascular event. Recommendations for prevention of venous thromboembolism are discussed in greater detail separately. (See "Prevention of venous thromboembolism in adult travelers".) RECURRENT ISCHEMIC STROKE As with any stroke, patients with PFO who have a recurrent ischemic stroke (after or without PFO closure) should have a comprehensive re-evaluation to determine the stroke mechanism. For those who have undergone PFO closure, this evaluation should include assessment of the PFO closure site for device thrombosis, residual shunt, and any device defects. Recurrent ischemic stroke may occur in patients with a PFO, regardless of whether the PFO was closed, due to mechanisms unrelated to paradoxical embolism, such as cardiogenic embolism, large artery atherosclerosis, small artery disease, and other determined stroke etiologies. In a minority of patients who have undergone PFO closure, a residual shunt persists, allowing continued potential risk for paradoxical embolism [48-52]. Alternatively, thrombus may

the ischemic events. In patients with high cardiovascular risk and an incidentally discovered PFO, surgical closure may actually increase the risk of postoperative stroke. This conclusion comes from a retrospective study of over 13,000 adults without a prior diagnosis of PFO or atrial septal defect who had cardiothoracic surgery [43]. A PFO was detected intraoperatively in 2277 patients, and closure was performed at the discretion of the surgeon in 28 percent. Using propensity-matched analysis, the risk of perioperative stroke was significantly higher in patients who had surgical PFO closure than in those who did not (2.8 versus 1.2 percent; odds ratio 2.47, 95% CI 1.02-6.0). https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 11/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate There was no difference between the two groups in long-term survival. The uncontrolled retrospective design and small number of events limits confidence in the results of this study. GENERAL MANAGEMENT OF PFO-ASSOCIATED STROKE All patients with PFO and ischemic stroke require antithrombotic therapy, cardiovascular risk reduction measures, and other measures to reduce the risk of recurrent stroke and other adverse cardiovascular events. Antithrombotic therapy Agents Antithrombotic therapy is a key component of secondary prevention for all types of ischemic stroke. Patients without an indication for anticoagulation should be treated with antiplatelet therapy whether or not the PFO is successfully closed. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) After PFO closure For most patients who have undergone percutaneous or surgical PFO closure who have no concurrent indication for anticoagulation, we suggest long-term antiplatelet therapy rather than no treatment or anticoagulation. We treat with aspirin 75 to 81 mg/day plus clopidogrel 75 mg/day for three months, followed by continued aspirin therapy (75 to 81 mg/day). In the CLOSE trial, the antithrombotic regimen after percutaneous PFO closure was aspirin 75 mg/day plus clopidogrel 75 mg/day for three months [12]. From the fourth month, patients were treated with aspirin alone, clopidogrel alone, or the combination product aspirin-extended-release dipyridamole. Without PFO closure For most patients with a PFO-associated embolic infarct and no other evident source of stroke who do not undergo PFO closure, we suggest antithrombotic therapy with antiplatelet agents rather than anticoagulation. However, anticoagulation therapy is used rather than antiplatelet agents for patients with high risk of venous thromboembolism, as discussed below. Although the comparative effectiveness of different types of antithrombotic therapy for secondary stroke prevention among patients with a PFO-associated ischemic stroke or transient ischemic attack (TIA) is uncertain (see 'Comparative studies' below), high-quality data from randomized trials have established that aspirin is effective for ischemic stroke prevention, as discussed elsewhere. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke", section on 'Aspirin'.) Concurrent indication for anticoagulation Anticoagulation is used for patients with a PFO-associated stroke who have a concurrent indication, such as acute deep venous https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 12/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate thrombosis, pulmonary embolism, other venous thromboembolism (VTE), or a hypercoagulable state. Management of these conditions, including the duration of anticoagulation, is discussed separately. (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)" and "Treatment, prognosis, and follow- up of acute pulmonary embolism in adults" and "Placement of vena cava filters and their complications".) Comparative studies The evidence comparing the benefit of antiplatelet therapy with anticoagulation for stroke prevention among patients with a PFO and ischemic stroke comes mainly from nonrandomized studies or randomized trials with important limitations, as illustrated by the following observations: In a 2015 meta-analysis of individual participant data from 12 observational studies involving 2385 medically treated patients with cryptogenic stroke and PFO, there was no significant difference between treatment with oral anticoagulation compared with antiplatelet therapy for the composite outcome of recurrent stroke, TIA, or death (9 versus 10 percent, adjusted hazard ratio [aHR] 0.76, 95% CI 0.52-1.12) and no difference for the outcome of recurrent stroke alone (4 versus 5 percent, aHR 0.75, 95% CI 0.44-1.27) [44]. In an updated meta-analysis of combined data from four trials (PICSS [45], CLOSE [12], NAVIGATE ESUS [46], and RESPECT ESUS [47]) that included patients with PFO and cryptogenic stroke who were randomly assigned to treatment with anticoagulant or antiplatelet therapy, the risk of recurrent ischemic stroke was similar for anticoagulation versus antiplatelet therapy (odds ratio 0.70, 95% CI 0.43-1.14) [47]. However, confidence in this result is limited by imprecision due to the small number of outcome events and wide confidence interval. Other cardiovascular risk reduction Patients with PFO who have an ischemic stroke or TIA should be treated with all appropriate cardiovascular risk reduction strategies (see above) including lifestyle modification (diet and exercise), blood pressure control, and statin therapy (if indicated). (See "Overview of secondary prevention of ischemic stroke" and "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) Additional preventive measures Certain general measures may be beneficial independent of the therapy chosen for the PFO. Since embolic material originates most commonly in lower extremity veins, patients at risk should avoid sitting for extended periods of time with knees flexed and legs dependent or the legs crossed, and should avoid prolonged passive standing. Risk is implicit during long airplane flights. For long-distance travelers with individual risk factors for VTE, we suggest frequent ambulation and calf exercises, avoidance of dehydration or https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 13/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate sedatives, and graduated compression stockings to reduce the risk of travel-associated VTE. These measures are particularly important in patients in whom deep vein thrombosis was identified at the time of the initial cerebrovascular event. Recommendations for prevention of venous thromboembolism are discussed in greater detail separately. (See "Prevention of venous thromboembolism in adult travelers".) RECURRENT ISCHEMIC STROKE As with any stroke, patients with PFO who have a recurrent ischemic stroke (after or without PFO closure) should have a comprehensive re-evaluation to determine the stroke mechanism. For those who have undergone PFO closure, this evaluation should include assessment of the PFO closure site for device thrombosis, residual shunt, and any device defects. Recurrent ischemic stroke may occur in patients with a PFO, regardless of whether the PFO was closed, due to mechanisms unrelated to paradoxical embolism, such as cardiogenic embolism, large artery atherosclerosis, small artery disease, and other determined stroke etiologies. In a minority of patients who have undergone PFO closure, a residual shunt persists, allowing continued potential risk for paradoxical embolism [48-52]. Alternatively, thrombus may spontaneously form on or adjacent to the PFO device or in the left atrium due to stagnant blood flow [53], particularly given the possible increased risk of atrial arrhythmias (mainly atrial fibrillation) in patients with PFO and/or atrial septal aneurysm [54]. This risk may be augmented after PFO closure [16,17], especially in the first few weeks after device implantation. Recurrent stroke should be treated according to the underlying mechanism, if it can be identified: If the recurrence occurs in a patient who has not had their PFO closed, and the PFO still appears to be the most likely cause of stroke, we suggest PFO closure. (See 'Patient selection for PFO closure' above.) For patients on antiplatelet therapy who have a recurrent PFO-associated stroke (regardless of PFO closure status) and no atrial fibrillation on reevaluation with long-term cardiac monitoring, options include continuing the same antiplatelet agent or switching to another antiplatelet regimen. For patients with recurrent embolic stroke of undetermined source (ESUS), switching to empiric anticoagulant therapy is also a reasonable option. These issues are discussed in detail elsewhere. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Embolic stroke of undetermined source'.) https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 14/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate In rare cases, thrombus formation on the PFO closure device should be treated with anticoagulant therapy; recurrent embolism in this setting may require surgical device removal with defect closure [55]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Patent foramen ovale (The Basics)") SUMMARY AND RECOMMENDATIONS Patient selection for PFO closure A causal association between a patent foramen ovale (PFO) and stroke (ie, a PFO-associated stroke) is thought likely in patients with PFO who meet all of the following criteria; patients with PFO who meet all of these criteria are candidates for percutaneous PFO closure: Age 60 years Embolic stroke topography (see "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'Is the stroke embolic?') https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 15/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate No other evident source of stroke despite a comprehensive evaluation (see "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'Exclusion of other sources of ischemic stroke') A possible, probable, or definite likelihood that the stroke was causally related to the PFO according to the PFO-associated stroke causal likelihood (PASCAL) classification system ( table 1), which incorporates the Risk of Paradoxical Embolism (RoPE) score and high-risk features of the PFO on echocardiogram ( table 2) (calculator 1) (see "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'PASCAL classification' and "Stroke associated with patent foramen ovale (PFO): Evaluation", section on 'RoPE score') No concurrent indication for anticoagulation (see 'Special considerations in anticoagulated patients' above) Decision-making for PFO closure Our approach to management of a patient with an embolic appearing stroke, PFO, and no other identified cause is summarized in the algorithm ( algorithm 1). PFO-associated stroke For most patients without a concurrent indication for anticoagulation who are 60 years of age with a possible, probable, or definite likelihood by PASCAL ( table 1) that the PFO was causally associated with the stroke, we suggest percutaneous PFO device closure in addition to antiplatelet therapy (Grade 2B). For patients who are >60 years of age, we use an individualized treatment approach to PFO closure based upon patient preferences and other risk factors and comorbidities. If otherwise indicated, PFO device closure may be temporarily deferred for patients with an indication for short-term anticoagulation. The benefit of PFO device closure is uncertain for patients with an indication for long-term anticoagulation; an individualized approach with shared decision-making is appropriate. (See 'Special considerations in anticoagulated patients' above.) For rare patients who have a concurrent indication for cardiac surgery (eg, valve surgery) and meet PASCAL criteria for PFO causal association, surgical PFO closure is appropriate. For rare patients who have a PFO that is not amenable to percutaneous closure but meet PASCAL criteria for PFO causal association, the benefit of surgical closure is https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 16/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate uncertain. In the absence of a concurrent indication for cardiac surgery, we suggest against surgical closure (Grade 2C). PFO unlikely to be associated with stroke For patients who do not meet criteria for a causal association of PFO with stroke (ie, association unlikely by PASCAL ( table 1)), we suggest against PFO closure (Grade 2C). Benefit of PFO closure PFO device closure is more effective than medical therapy alone for select patients aged 60 years with a PFO-associated stroke (ie, a nonlacunar ischemic stroke in the setting of a PFO with a right-to-left interatrial shunt and no other source of stroke despite a comprehensive evaluation). Compared with medical therapy, PFO device closure reduces risk of recurrent stroke from approximately 5 to 2 percent over a three- to six-year period. (See 'Benefit' above.) For patients age >60 years, the benefit of PFO device closure is unknown, since these patients were generally excluded from randomized trials of PFO device closure. (See 'Benefit' above.) Choice of antithrombotic agent for PFO-associated stroke Following PFO closure For patients in this setting who have no concurrent indication for anticoagulation, we suggest long-term antiplatelet therapy rather than no treatment or anticoagulation (Grade 2C). Patients are treated with antiplatelet therapy whether or not the PFO is successfully closed. (See 'Antithrombotic therapy' above.) Without PFO closure For these patients, treatment with antiplatelet therapy is recommended, which is consistent with the recommendations for cryptogenic stroke. (See 'Antithrombotic therapy' above and "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Secondary prevention'.) Concurrent indication for anticoagulation In this setting (eg, usually venous thromboembolism), standard recommendations for anticoagulation apply, and anticoagulation is generally the sole antithrombotic therapy required. Recommendations are provided in separate topic reviews. (See "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)" and "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation".) Recurrent ischemic stroke Patients with PFO who have a recurrent ischemic stroke (after or without PFO closure) should have a comprehensive re-evaluation to determine the stroke mechanism. For those who have undergone PFO closure, this evaluation should https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 17/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate include assessment of the PFO closure site for device thrombosis, residual shunt, and any device defects. For patients with a previous PFO-associated stroke treated with antiplatelet therapy but not PFO closure who have a recurrent embolic-appearing stroke with no other identified cause, we suggest PFO closure in addition to antithrombotic therapy (Grade 2C). Switching to another antiplatelet agent or to anticoagulant therapy is a reasonable alternative. (See 'Recurrent ischemic stroke' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Kasner SE, Lattanzi S, Fonseca AC, Elgendy AY. Uncertainties and Controversies in the Management of Ischemic Stroke and Transient Ischemic Attack Patients With Patent Foramen Ovale. Stroke 2021; 52:e806. 2. Homma S, Di Tullio MR, Sacco RL, et al. Surgical closure of patent foramen ovale in cryptogenic stroke patients. Stroke 1997; 28:2376. 3. Lechat P, Mas JL, Lascault G, et al. Prevalence of patent foramen ovale in patients with stroke. N Engl J Med 1988; 318:1148. 4. Overell JR, Bone I, Lees KR. Interatrial septal abnormalities and stroke: a meta-analysis of case-control studies. Neurology 2000; 55:1172. 5. Holmes DR Jr, Cabalka A. Was your mother right do we always need to close the door? Circulation 2002; 106:1034. 6. Kent DM, Saver JL, Kasner SE, et al. Heterogeneity of Treatment Effects in an Analysis of Pooled Individual Patient Data From Randomized Trials of Device Closure of Patent Foramen Ovale After Stroke. JAMA 2021; 326:2277. 7. Pristipino C, Sievert H, D'Ascenzo F, et al. European position paper on the management of patients with patent foramen ovale. General approach and left circulation thromboembolism. Eur Heart J 2019; 40:3182. 8. Clinical Commissioning Policy: Percutaneous patent foraman ovale closure for the preventio n of recurrent cerebral embolic stroke in adults (around age 60 years and under). NHS Engla nd July 2019. Available at: https://www.england.nhs.uk/commissioning/wp-content/uploads/ sites/12/2019/07/Clinical-Commissioning-Policy_Percutaneous-patent-foraman-ovale-closur e-for-the-prevention-of-recurrent-cerebr.pdf (Accessed on January 24, 2022). https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 18/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate 9. Mess SR, Gronseth GS, Kent DM, et al. 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Shah R, Nayyar M, Jovin IS, et al. Device Closure Versus Medical Therapy Alone for Patent Foramen Ovale in Patients With Cryptogenic Stroke: A Systematic Review and Meta-analysis. Ann Intern Med 2018; 168:335. 16. Furlan AJ, Reisman M, Massaro J, et al. Closure or medical therapy for cryptogenic stroke with patent foramen ovale. N Engl J Med 2012; 366:991. 17. Meier B, Kalesan B, Mattle HP, et al. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med 2013; 368:1083. 18. Carroll JD, Saver JL, Thaler DE, et al. Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. N Engl J Med 2013; 368:1092. 19. De Rosa S, Sievert H, Sabatino J, et al. Percutaneous Closure Versus Medical Treatment in Stroke Patients With Patent Foramen Ovale: A Systematic Review and Meta-analysis. Ann Intern Med 2018; 168:343. 20. Correction: Device Closure Versus Medical Therapy Alone for Patent Foramen Ovale. Ann Intern Med 2018; 169:428. 21. Tsivgoulis G, Katsanos AH, Mavridis D, et al. Percutaneous patent foramen ovale closure for secondary stroke prevention: Network meta-analysis. Neurology 2018; 91:e8. 22. Saber H, Palla M, Kazemlou S, et al. Network meta-analysis of patent foramen ovale management strategies in cryptogenic stroke. Neurology 2018; 91:e1. 23. Vaduganathan M, Qamar A, Gupta A, et al. Patent Foramen Ovale Closure for Secondary Prevention of Cryptogenic Stroke: Updated Meta-Analysis of Randomized Clinical Trials. Am J Med 2018; 131:575. https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 19/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate 24. Riaz H, Khan MS, Schenone AL, et al. Transcatheter closure of patent foramen ovale following cryptogenic stroke: An updated meta-analysis of randomized controlled trials. Am Heart J 2018; 199:44. 25. Smer A, Salih M, Mahfood Haddad T, et al. Meta-analysis of Randomized Controlled Trials on Patent Foramen Ovale Closure Versus Medical Therapy for Secondary Prevention of Cryptogenic Stroke. Am J Cardiol 2018; 121:1393. 26. Turc G, Calvet D, Gu rin P, et al. Closure, Anticoagulation, or Antiplatelet Therapy for Cryptogenic Stroke With Patent Foramen Ovale: Systematic Review of Randomized Trials, Sequential Meta-Analysis, and New Insights From the CLOSE Study. J Am Heart Assoc 2018; 7. 27. Anantha-Narayanan M, Anugula D, Das G. Patent foramen ovale closure reduces recurrent stroke risk in cryptogenic stroke: A systematic review and meta-analysis of randomized controlled trials. World J Cardiol 2018; 10:41. 28. Pasceri V, Pelliccia F, Bressi E, et al. Net clinical benefit of patent foramen ovale closure in patients with cryptogenic stroke: Meta-analysis and meta-regression of randomized trials. Int J Cardiol 2018; 266:75. 29. Kuijpers T, Spencer FA, Siemieniuk RAC, et al. Patent foramen ovale closure, antiplatelet therapy or anticoagulation therapy alone for management of cryptogenic stroke? A clinical practice guideline. BMJ 2018; 362:k2515. 30. Kasner SE, Rhodes JF, Andersen G, et al. Five-Year Outcomes of PFO Closure or Antiplatelet Therapy for Cryptogenic Stroke. N Engl J Med 2021; 384:970. 31. Mess SR, Erus G, Bilello M, et al. Patent Foramen Ovale Closure Decreases the Incidence but Not the Size of New Brain Infarction on Magnetic Resonance Imaging: An Analysis of the REDUCE Trial. Stroke 2021; 52:3419. 32. Alperi A, Guedeney P, Horlick E, et al. Transcatheter Closure of Patent Foramen Ovale in Older Patients With Cryptogenic Thromboembolic Events. Circ Cardiovasc Interv 2022; 15:e011652. 33. Chen JZ, Thijs VN. Atrial Fibrillation Following Patent Foramen Ovale Closure: Systematic Review and Meta-Analysis of Observational Studies and Clinical Trials. Stroke 2021; 52:1653. 34. Pineda AM, Mihos CG, Singla S, et al. Percutaneous Closure of Intracardiac Defects in Adults: State of the Art. J Invasive Cardiol 2015; 27:561. 35. Moore J, Hegde S, El-Said H, et al. Transcatheter device closure of atrial septal defects: a safety review. JACC Cardiovasc Interv 2013; 6:433. https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 20/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate 36. Divekar A, Gaamangwe T, Shaikh N, et al. Cardiac perforation after device closure of atrial septal defects with the Amplatzer septal occluder. J Am Coll Cardiol 2005; 45:1213. 37. Scacciatella P, Biava LM, Marra S. Iatrogenic erosion of the septum primum resulting in an atrial septal defect with left-to-right shunt: a rare pitfall of patent foramen ovale percutaneous closure. Catheter Cardiovasc Interv 2014; 84:494. 38. Rana BS, Thomas MR, Calvert PA, et al. Echocardiographic evaluation of patent foramen ovale prior to device closure. JACC Cardiovasc Imaging 2010; 3:749. 39. Rigatelli G, Pedon L, Zecchel R, et al. Long-Term Outcomes and Complications of Intracardiac Echocardiography-Assisted Patent Foramen Ovale Closure in 1,000 Consecutive Patients. J Interv Cardiol 2016; 29:530. 40. Dearani JA, Ugurlu BS, Danielson GK, et al. Surgical patent foramen ovale closure for prevention of paradoxical embolism-related cerebrovascular ischemic events. Circulation 1999; 100:II171. 41. Devuyst G, Bogousslavsky J, Ruchat P, et al. Prognosis after stroke followed by surgical closure of patent foramen ovale: a prospective follow-up study with brain MRI and simultaneous transesophageal and transcranial Doppler ultrasound. Neurology 1996; 47:1162. 42. Ruchat P, Bogousslavsky J, Hurni M, et al. Systematic surgical closure of patent foramen ovale in selected patients with cerebrovascular events due to paradoxical embolism. Early results of a preliminary study. Eur J Cardiothorac Surg 1997; 11:824. 43. Krasuski RA, Hart SA, Allen D, et al. Prevalence and repair of intraoperatively diagnosed patent foramen ovale and association with perioperative outcomes and long-term survival. JAMA 2009; 302:290. 44. Kent DM, Dahabreh IJ, Ruthazer R, et al. Anticoagulant vs. antiplatelet therapy in patients with cryptogenic stroke and patent foramen ovale: an individual participant data meta- analysis. Eur Heart J 2015; 36:2381. 45. Homma S, Sacco RL, Di Tullio MR, et al. Effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in Cryptogenic Stroke Study. Circulation 2002; 105:2625. 46. Kasner SE, Swaminathan B, Lavados P, et al. Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial. Lancet Neurol 2018; 17:1053. 47. Diener HC, Chutinet A, Easton JD, et al. Dabigatran or Aspirin After Embolic Stroke of Undetermined Source in Patients With Patent Foramen Ovale: Results From RE-SPECT ESUS. Stroke 2021; 52:1065. https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 21/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate 48. Windecker S, Wahl A, Chatterjee T, et al. Percutaneous closure of patent foramen ovale in patients with paradoxical embolism: long-term risk of recurrent thromboembolic events. Circulation 2000; 101:893. 49. Mart n F, S nchez PL, Doherty E, et al. Percutaneous transcatheter closure of patent foramen ovale in patients with paradoxical embolism. Circulation 2002; 106:1121. 50. Wahl A, Krumsdorf U, Meier B, et al. Transcatheter treatment of atrial septal aneurysm associated with patent foramen ovale for prevention of recurrent paradoxical embolism in high-risk patients. J Am Coll Cardiol 2005; 45:377. 51. Anzola GP, Morandi E, Casilli F, Onorato E. Does transcatheter closure of patent foramen ovale really "shut the door?" A prospective study with transcranial Doppler. Stroke 2004; 35:2140. 52. Deng W, Yin S, McMullin D, et al. Residual Shunt After Patent Foramen Ovale Closure and Long-Term Stroke Recurrence: A Prospective Cohort Study. Ann Intern Med 2020; 172:717. 53. Cabanes L, Mas JL, Cohen A, et al. Atrial septal aneurysm and patent foramen ovale as risk factors for cryptogenic stroke in patients less than 55 years of age. A study using transesophageal echocardiography. Stroke 1993; 24:1865. 54. Berthet K, Lavergne T, Cohen A, et al. Significant association of atrial vulnerability with atrial septal abnormalities in young patients with ischemic stroke of unknown cause. Stroke 2000; 31:398. 55. Ciurus T, Piestrzeniewicz K, Maciejewski M, et al. Thrombus formation on the Amplatzer device: a need for critical attitude in percutaneous patent ovale closure decision-making. Eur Heart J 2015; 36:1195. Topic 138296 Version 4.0 https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 22/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate GRAPHICS Proposed flexible clinical practice approach to classifying patent foramen ovale causal association in patients with embolic infarct topography and without other major stroke sources* RoPE score Risk source Features Low High Very high A PFO and a straddling thrombus Definite Definite High (1) Concomitant pulmonary embolism or deep venous thrombosis preceding Probable Highly probable an index infarct combined with either (2a) a PFO and an atrial septal aneurysm or (2b) a large-shunt PFO Medium Either (1) a PFO and an atrial septal aneurysm or (2) a large-shunt PFO Possible Probable Low A small-shunt PFO without an atrial septal aneurysm Unlikely Possible RoPE: Risk of Paradoxical Embolism; PFO: patent foramen ovale. The algorithm in this table is proposed for use in flexible clinical practice when application of an entire formal classification system is not being conducted. The RoPE score includes points for 5 age categories, cortical infarct, absence of hypertension, diabetes, prior stroke or transient ischemic attack, and smoking. A higher RoPE score ( 7 points) increases probability of causal association. Reproduced with permission from: Elgendy AY, Saver JL, Amin Z, et al. Proposal for updated nomenclature and classi cation of potential causative mechanism in patent foramen ovale-associated Stroke. JAMA Neurol 2020; 77:878. Copyright 2020 American Medical Association. All rights reserved. Graphic 134674 Version 3.0 https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 23/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate Risk of Paradoxical Embolism (RoPE) score RoPE Characteristic Points score No history of hypertension 1 No history of diabetes 1 No history of stroke or TIA 1 Nonsmoker 1 Cortical infarct on imaging 1 Age, years 18 to 29 5 30 to 39 4 40 to 49 3 50 to 59 2 60 to 69 1 70 0 Total score (sum of individual points) Maximum score (a patient <30 years with no hypertension, no 10 diabetes, no history of stroke or TIA, nonsmoker, and cortical infarct) Minimum score (a patient 70 years with hypertension, diabetes, prior stroke, current smoker, and no cortical infarct) 0 TIA: transient ischemic attack. From: Kent DM, Ruthazer R, Weimar C, et al. An index to identify stroke-related vs incidental patent foramen ovale in cryptogenic stroke. Neurology 2013; 81:619. DOI: 10.1212/WNL.0b013e3182a08d59. Reproduced with permission from Lippincott Williams & Wilkins. Copyright 2013 American Academy of Neurology. Unauthorized reproduction of this material is prohibited. Graphic 97895 Version 5.0 https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 24/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate Approach to management for a patient with PFO and embolic-appearing ischem without other identified cause This algorithm is intended to provide general guidance to PFO management in patients with a recent emboli ischemic stroke who have a PFO and no other identified cause of stroke. For most patients who are 60 year possible, probable, or definite likelihood by RoPE and PASCAL that the PFO was causally associated with the s percutaneous PFO device closure in addition to antiplatelet therapy. PFO device closure may be temporarily d patients with an indication for short-term anticoagulation. The benefit of PFO device closure is uncertain for of age and for patients with an indication for long-term anticoagulation; in such cases, an individualized app decision-making is appropriate. Patients with ischemic stroke should generally be treated with all available ri strategies including antithrombotic therapy, blood pressure control, low-density lipoprotein (LDL)-lowering th lifestyle modification, as appropriate. For details regarding the evaluation required for a comprehensive stroke evaluation, choice of antithromboti other factors that impact decision-making for PFO management, refer to appropriate UpToDate topics. PFO: patent foramen ovale; DVT: deep venous thrombosis; PE: pulmonary embolism; RoPE: Risk of Paradoxic PASCAL: PFO-associated stroke causal likelihood; ASA: atrial septal aneurysm. https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 25/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate For most patients with an indication for anticoagulation >1 year, PFO closure is not performed, as benefit in uncertain. PFO closure may be an option for selected patients, such as those who experience recurrent embo other identified cause while therapeutically anticoagulated and those who are no longer anticoagulated. An approach to decision-making is based upon patient preferences, risk factors, and comorbidities. Patients who undergo PFO closure (percutaneous or surgical) are treated with antiplatelet agents. We treat to 81 mg/day) plus clopidogrel (75 mg/day) for three months, followed by continued aspirin therapy. For the rare patient who has a concurrent indication for surgical valve intervention, surgical (rather than pe closure is appropriate. If percutaneous PFO closure is not feasible and there is no concurrent indication for c suggest against surgical PFO closure. For most patients >60 years old, PFO closure is not performed since such patients were excluded from tria and the benefit of closure in this setting is unproven. PFO closure may be an option for selected patients >60 as younger patients in this age range who have low estimated atherosclerotic cardiovascular disease risk. An approach to decision-making is based upon patient preferences, risk factors, and comorbidities. Refer to UpToDate topic on cryptogenic stroke. Graphic 138535 Version 1.0 https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 26/27 7/5/23, 11:50 AM Stroke associated with patent foramen ovale (PFO): Management - UpToDate Contributor Disclosures Steven R Mess , MD Equity Ownership/Stock Options: Neuralert Technologies [Stroke monitoring]. Grant/Research/Clinical Trial Support: Biogen [Hemispheric ischemic stroke]; Mallinkrodt, Inc [Nitric oxide and cerebral perfusion]; Novartis [Intracerebral hemorrhage]; WL Gore & Associates [PFO closure for secondary stroke prevention, neurologic outcomes from proximal aortic repair]. Consultant/Advisory Boards: Boston Scientific [steering committee for PROTECTED-TAVR trial of embolic protection during TAVR]; EmStop [embolic protection during TAVR]; WL Gore [DSMB for post marketing study of PFO closure for secondary stroke prevention]. Other Financial Interest: Novo Nordisk [ONWARDS trial event adjudication committee]; Terumo [Patient selection committee, Relay Branch trial]. All of the relevant financial relationships listed have been mitigated. Stephen JD Brecker, MD, FRCP, FESC, FACC Grant/Research/Clinical Trial Support: Medtronic [Transcatheter valves]. Consultant/Advisory Boards: Aortic Innovations LLC [Transcatheter valves]; Medtronic [Transcatheter valves]. Speaker's Bureau: Medtronic [Transcatheter valves]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Heidi M Connolly, MD, FACC, FASE No relevant financial relationship(s) with ineligible companies to disclose. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Susan B Yeon, MD, JD, FACC No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/stroke-associated-with-patent-foramen-ovale-pfo-management/print 27/27

7/5/23, 11:50 AM Thromboembolism from aortic plaque - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Thromboembolism from aortic plaque : Benjamin J Pearce, MD, FACS : Jos Biller, MD, FACP, FAAN, FAHA, Joseph L Mills, Sr, MD, John F Eidt, MD, Warren J Manning, MD : Kathryn A Collins, MD, PhD, FACS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Aug 11, 2022. INTRODUCTION Aortic atherosclerotic plaques are a manifestation of systemic atherosclerosis ( image 1 and movie 1). They are associated with risk factors for atherosclerotic disease and are more common in patients with coronary artery disease and in older individuals [1-5]. In addition, aortic atherosclerotic plaques are an important cause of systemic embolization [6-9]. Embolic events in the setting of aortic atherosclerosis can occur spontaneously or they can be induced by mechanical interventions including guidewire/catheter manipulation during cardiac catheterization, intraaortic balloon pulsations, and vessel clamping/manipulations during cardiac and vascular surgery [10,11]. The risk of embolism in patients with aortic atherosclerosis is markedly increased for plaques that are mobile and/or protruding, particularly if >4 mm in thickness. The risk factors, clinical manifestations, detection, and preventive treatment of thromboembolism from aortic plaques are reviewed here. Atheroembolism is discussed separately. (See "Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism)".) THROMBOEMBOLISM VERSUS ATHEROEMBOLISM Thromboembolism from aortic plaques is common, whereas cholesterol crystal embolization is fairly rare. Although there is some overlap, these disorders have characteristic distinguishing features: https://www.uptodate.com/contents/thromboembolism-from-aortic-plaque/print 1/23 7/5/23, 11:50 AM Thromboembolism from aortic plaque - UpToDate Thromboembolism may occur when an atherosclerotic plaque from large or medium arteries becomes unstable, and superimposed thrombi embolize. The thromboemboli tend to be single and tend to lodge in small or medium arteries, resulting most often in stroke or transient ischemic attack [6-9,12], limb ischemia (upper or lower extremity), renal infarction, intestinal ischemia, or ischemia of other organs [9,13]. The term atheroembolism is used synonymously with cholesterol crystal embolism, cholesterol embolism, or micro-atheroembolism. These terms refer to arterio-arterial embolism of fragments of atheromatous material originating from an atherosclerotic plaque of the aorta or occasionally other arteries. The result of such embolization is tissue and organ damage produced by multiple small artery occlusions (eg, "blue toe" syndrome, retinal ischemia, renal failure, livedo reticularis, intestinal infarction). (See "Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism)".) PATHOLOGY The material protruding from the aortic wall is typically atheromatous plaque, with the characteristic composition consisting of a lipid pool, a fibrous cap, smooth muscle cell and mononuclear cell infiltration, and varying degrees of calcification [7,14]. Thrombi may be more characteristic of plaques with a high proportion of lipid and with a preponderance of monocytes or macrophages [14]. The mobile component, as seen on transesophageal echocardiography (TEE), is usually thrombus superimposed on the plaque, which has presumably ruptured ( movie 2). In contrast, highly calcified plaques may be more stable (ie, less vulnerable and less likely to develop thrombus and embolize) [15]. (See 'Plaque ulceration and mobility' below.) COMPLEX AORTIC PLAQUE Atherosclerosis of the aorta is a diffuse process, and many of the individual plaques are complex, which is defined as thickness >4 mm, ulceration, or mobility of a component of the plaque. In one series of patients with complex thoracic aortic plaque, mobile thrombi were seen on transesophageal echocardiography (TEE) in 24 percent [16]. Discovery of complex aortic plaque may occur when TEE is performed as part of the evaluation for an acute stroke or peripheral embolism, or for some unrelated reason. Association with embolization Evidence for a cause and effect relationship between complex aortic plaque and embolism comes from the following observations: https://www.uptodate.com/contents/thromboembolism-from-aortic-plaque/print 2/23 7/5/23, 11:50 AM Thromboembolism from aortic plaque - UpToDate Complex aortic plaque is seen in 2 to 14 percent of patients with a history of stroke or peripheral embolization [3,8,17]. The true prevalence may be underestimated since the plaque that has "caused" the event may have migrated with only the remaining or "residual" plaque present. Complex thoracic aortic plaque is seen much more frequently in stroke patients compared with controls without stroke in both TEE and autopsy studies (21 to 27 percent versus 5 to 9 percent) [7,8,12,17]. Complex thoracic aortic plaques are associated with a high frequency of embolization [9,13,16]. A cohort study compared 42 patients with complex thoracic aortic plaque identified on TEE (and no other detected source of emboli) with matched controls without aortic plaque on TEE [13]. Vascular events (stroke, peripheral embolization) occurred in 33 percent of those with aortic plaque, compared with 7 percent in patients without plaque during a mean follow-up of 14 months. Aortic plaques are strongly associated with embolic stroke even in patients with atrial fibrillation. This was illustrated in a subset analysis of the Stroke Prevention in Atrial Fibrillation III (SPAF-III) trial in which 134 of 382 patients (35 percent) with atrial fibrillation were identified as having a complex aortic plaque (>4 mm in thickness or mobile) on TEE [18]. The stroke rate at one year was significantly higher for patients with complex aortic plaque (15.8 versus 8.0 and 1.2 percent with simple or no plaque, respectively). Complex aortic plaque was independently associated with a higher risk of embolization [19]. (See "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack", section on 'Aortic atherosclerosis' and "Atrial fibrillation in adults: Use of oral anticoagulants".) Risk factors for embolization The likelihood of embolization from aortic plaques and the organs that are affected are related to plaque morphology and location as identified on TEE or computed tomographic (CT) angiography, including plaque thickness, ulceration, mobility, as well as a history of aortic instrumentation. Plaque thickness Thicker plaques are more likely to be lipid laden and to have overlying thrombi and embolize [8,9,15,20]. The potential importance of plaque thickness is illustrated by the following two studies [8,9]. In a case control study, 250 patients with ischemic stroke were compared with 250 controls undergoing TEE for cardiac evaluation. Among patients with stroke, 14.4 percent had plaques >4 mm in thickness in the ascending aorta or aortic arch compared with only 2 https://www.uptodate.com/contents/thromboembolism-from-aortic-plaque/print 3/23 7/5/23, 11:50 AM Thromboembolism from aortic plaque - UpToDate percent of controls [8]. Compared with plaque thickness <1 mm, the adjusted odds ratio was 4.2 and 9.1 for plaques 1 to 3.9 mm and >4 mm, respectively. A subsequent prospective study from the French Study of Aortic Plaques in Stroke Group included 331 patients with an initial ischemic stroke who underwent TEE [9]. At two to four years of follow-up: The incidence of recurrent stroke was 2.8, 3.5, and 11.9 percent per year for patients with plaque thickness <1, 1 to 3.9, and >4 mm, respectively. The incidence of all vascular events was 5.9, 9.1 and 26 percent per year for patients with plaque thickness <1, 1 to 3.9 and >4 mm, respectively. After adjustment for carotid artery stenosis, atrial fibrillation, peripheral artery disease, and other risk factors, aortic plaques >4 mm were independent predictors of recurrent ischemic stroke (relative risk 3.8; 95% CI 1.8-7.8). Similarly, a "shaggy" aorta, defined as greater than 75 percent involvement of thoracic aorta with a plaque thickness of >4 mm, increases overall mortality of both open and endovascular abdominal aortic aneurysm repair compared with controls, likely related to visceral and peripheral embolization [21]. A different conclusion was reached in an analysis from the Stroke Prevention: Assessment of Risk in a Community (SPARC) study, which found that complex aortic plaque (>4 mm or mobile) was not associated with a significant increase in risk of cerebrovascular events after adjusting for age, sex, and other clinical risk factors [22]. The reason for this apparent disparity may be related to patient selection bias. Plaque ulceration and mobility In an autopsy study of 500 consecutive patients with cerebrovascular and other neurologic diseases, ulcerated aortic arch plaques were much more common in those with cerebrovascular disease (16.9 versus 5.1 percent in those with other neurologic diseases), particularly in the 28 patients with no other known cause for stroke such as atrial fibrillation (58 percent) [7]. Protruding or pedunculated plaques, compared to flat or layered plaques, are associated with a higher risk of embolic events [13,17,23,24]. This was illustrated in a study of 36 patients with aortic plaque on TEE [23]. The plaque was pedunculated and mobile in 11 patients (31 percent), and layered and immobile in 25 (69 percent). Embolic events occurred more frequently in those with pedunculated plaques (8 of 11 versus 3 of 25 [73 versus 12 percent]). These mobile thrombi can occasionally be very large ( movie 2). https://www.uptodate.com/contents/thromboembolism-from-aortic-plaque/print 4/23 7/5/23, 11:50 AM Thromboembolism from aortic plaque - UpToDate Rupture of "soft" plaque at focal areas of the aorta results in pedunculated thrombi formation ( movie 3). Thrombus in these plaques can easily embolize to visceral organs. The mobile component has been shown to be primarily thrombus either by direct examination during aortic or cardiac surgery [25,26] or by pathologic examination of tissue obtained during surgery or at autopsy [27,28]. Resolution of mobile aortic masses with anticoagulation and fibrinolytic therapy lends further support to the role of thrombus [29-31]. (See 'Treatment' below.) Conversely, the "shaggy" aorta is defined by diffuse, ulcerated plaque arising in the descending thoracic aorta and extending through the visceral segment. The lumen of the aorta is irregular as seen on CT angiography ( image 2), and the contents of the plaque are a mix of atheromatous debris with thrombus coating [32]. Plaque location Although embolization can be a complication of lesions at any site in the aorta, stroke will occur much more commonly with lesions of the ascending aorta and aortic arch. In a review of 250 patients admitted with ischemic stroke who were compared with consecutive controls, the odds ratio for stroke was 13.8 for patients with plaques >4 mm in the aortic arch compared to 1.5 with such lesions in the descending aorta ( figure 1) [8]. (See "Stroke: Etiology, classification, and epidemiology", section on 'Embolism'.) Conversely, complex aortic plaque arising distal to the left subclavian artery may preferentially manifest as visceral, pelvic, or peripheral embolization syndromes [33]. These patients will present with signs of bowel ischemia, flank pain from renal infarction, livido reticularis of the buttocks and thighs, or acute limb ischemia [32]. (See "Acute mesenteric arterial occlusion" and "Embolism to the lower extremities".) Cardiovascular procedures Thromboembolism may occur as a complication of invasive cardiovascular procedures (eg, diagnostic catheterization, percutaneous coronary intervention, intraaortic balloon pump, cardiac surgery, endovascular aortic repair) due to dislodging of debris from the aortic wall when a catheter or wire is advanced in a retrograde fashion from the femoral artery [10,11,21,34-38]. Manipulation of the aorta during open cardiac or aortic surgery is also thought to predispose to embolization due to mechanical disruption of the atheroma. In a review of 70 patients with aortic plaque 5 mm on TEE, the rate of embolic events was 17 percent after cardiac catheterization via the femoral artery [10]. In comparison, there were no embolic events in those (11 patients) catheterized via the brachial route. In addition, embolic events occurred in 5 of 10 patients with complex aortic plaque treated with an intraaortic balloon pump, compared to no events in 12 patients without complex aortic plaque. https://www.uptodate.com/contents/thromboembolism-from-aortic-plaque/print 5/23 7/5/23, 11:50 AM Thromboembolism from aortic plaque - UpToDate In a review of 130 patients 65 years of age undergoing coronary artery bypass grafting, protruding aortic arch plaques were identified in 23 patients (18 percent), 12 of whom had mobile plaques [11]. The risk of stroke was much higher in those with mobile plaques (3 of 12 versus 2 of 118). In a series of 3404 patients undergoing cardiac surgery with cardiopulmonary bypass, intraoperative TEE revealed complex aortic arch plaque ( 5 mm thick and/or mobile) in 268 (8 percent) [37]. Stroke occurred in 12 percent of these patients, sixfold higher than the overall intraoperative stroke risk at that institution. Patients who underwent aortic arch atherectomy in an effort to reduce the stroke risk actually had a higher rate of stroke (35 percent). (See 'Surgery' below and "Neurologic complications of cardiac surgery", section on 'Cerebrovascular disease' and "Neurologic complications of cardiac surgery", section on 'Risk factors'.) Endovascular aneurysm repair is also associated with an increased risk of embolization and decrease in overall survival in patients with aortic plaque compared with patients without diffuse aortic atheroma. Appropriate consideration for the medical risk of open versus endovascular repair should be undertaken for appropriate planning. (See "Complications of endovascular abdominal aortic repair", section on 'Ischemic complications'.) CLINICAL MANIFESTATIONS Clinical manifestations depend upon the arterial segment affected by thromboembolism. In the retrospective cohort study of 519 patients with complex thoracic aortic plaque cited above, the most common manifestations were stroke (50 percent), transient ischemic attack (35 percent), and signs and symptoms of peripheral embolization (14 percent) [16]. The discussion of the differential diagnosis of stroke is found elsewhere. (See "Clinical diagnosis of stroke subtypes" and "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)".) Complex plaques more commonly involve the mid or distal aortic arch or descending aorta and are relatively uncommon in the ascending aorta. This results in a higher likelihood of embolic events involving the left cerebral hemisphere or the peripheral circulation ( image 3), rather than embolic events in the innominate artery distribution (eg, right brain) [17]. (See "Clinical features and diagnosis of acute lower extremity ischemia" and "Overview of intestinal ischemia in adults".) With thromboembolic events, multiple sites may be simultaneously involved (eg, ischemic colitis, acute renal injury, lower extremity ischemia, visual loss), but concurrent embolization is less common compared with cholesterol embolization, which is typically characterized by showers of https://www.uptodate.com/contents/thromboembolism-from-aortic-plaque/print 6/23 7/5/23, 11:50 AM Thromboembolism from aortic plaque - UpToDate small emboli. (See "Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism)".) Mortality Mortality associated with complex aortic plaque may be as high as 20 percent within three years [16]. Almost 20 percent of the deaths are attributed to stroke, and an additional 7 percent to other embolic events (eg, intestinal ischemia). The presence of aortic plaque also worsens outcomes following cardiovascular procedures: In-hospital mortality following cardiac surgery was 15 percent overall and as high as 39 percent with intraoperative stroke during cardiopulmonary bypass in one series [37]. Complex fenestrated endovascular aortic repair (FEVAR) with evidence of increased aortic thrombus volume on preoperative CT angiography significantly increased incidence of mesenteric ischemia [38]. Among patients developing embolic mesenteric ischemia during FEVAR, 80 percent died as a result of the disease. The presence of complex aortic plaque predicts a decreased overall survival after abdominal aortic aneurysm (AAA) repair regardless of technique [21]. This effect is likely secondary to both acute morbidity and mortality from intraoperative embolization of organs as well as being a marker for worse overall atherosclerotic burden. DETECTION Imaging techniques that have been used to detect aortic plaques include transesophageal echocardiography (TEE), computed tomographic (CT) angiography, magnetic resonance angiography and transthoracic echocardiography (TTE). (See 'Complex aortic plaque' above.) TEE is the procedure of choice for the detection and measurement of thoracic aortic plaques, particularly when present in the ascending or proximal descending thoracic aorta, and for cardiac sources of embolization ( movie 1 and movie 2). It is moderately invasive, usually requiring conscious sedation, but has a very low complication rate. The discovery of a complex aortic plaque (>4 mm thick, or mobile, ulcerated, or pedunculated) may occur when TEE is performed as part of the evaluation for an acute stroke, peripheral embolism, or for some unrelated reason. If concern for complex aortic plaque is raised during TEE/TTE, follow-up evaluation with CT or MR angiography is warranted prior to any aortic procedure to aid in planning. (See "Echocardiography in detection of cardiac and aortic sources of systemic embolism".) https://www.uptodate.com/contents/thromboembolism-from-aortic-plaque/print 7/23 7/5/23, 11:50 AM Thromboembolism from aortic plaque - UpToDate The accuracy of TEE in detecting and characterizing aortic plaque was illustrated in a study in which TEE was performed during surgery in 31 patients undergoing repair of an aortic aneurysm or dissection; tissue samples were examined pathologically [27]. TEE and pathologic evaluation were in agreement in distinguishing minimal intimal thickening from more severe plaques in 93 percent of the 62 aortic segments examined. TEE also had a high sensitivity and specificity for the detection of thrombus (91 and 90 percent, respectively). In some patients with thromboembolism from aortic plaque, transthoracic echocardiography may demonstrate the plaques [39]. However, its sensitivity is limited since resolution is insufficient for measuring the prognostically important plaque thickness. CT angiography is the modality of choice for surgical planning in cases of known or suspected atheromatous aorta. MR angiography may be an alternative for those in whom intravenous contrast is contraindicated. CT angiography provides information about the quality of the aortic wall and allows for qualification of the embolic potential of the plaque by appearance, as well as quantification using scales of luminal irregularity and calculation of thrombus volume [38]. Based on location, placement of clamps or guidewires can be planned preoperatively and techniques used to protect branch vessels during repair to limit embolization. TREATMENT Noncoronary atherosclerotic disease is a coronary heart disease risk equivalent, and, as such, all patients with established atherosclerotic aortic plaque, including those who are asymptomatic, should be aggressively treated to prevent future cardiovascular events. These therapies include antithrombotic therapy (aspirin, clopidogrel), lipid-lowering therapy (eg, statins), blood pressure control, smoking cessation, and in patients with diabetes, glycemic control. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".) A separate issue is whether specific therapy might prevent a first or recurrent embolization from atherosclerotic plaques in the aorta. Both medical and surgical approaches have been evaluated. Whether specific medical therapy might prevent a first or recurrent embolization from atherosclerotic plaques in the aorta remains controversial. The mainstays of medical treatment are antiplatelet therapy and HMG-CoA reductase (statin) administration. The role of anticoagulation is reserved for plaques with a majority of thrombotic component as opposed to complex atheromatous plaques. https://www.uptodate.com/contents/thromboembolism-from-aortic-plaque/print 8/23 7/5/23, 11:50 AM Thromboembolism from aortic plaque - UpToDate Antithrombotic therapy In addition to appropriate lifestyle modification consistent with overall cardiovascular care, we suggest the following medical regimen, which is generally consistent with guideline recommendations [40-42]: Discrete recommendations for antiplatelet or anticoagulation therapies are generally lacking. This is likely due to the variable composition of the layers of aortic plaques. Classic "shaggy" aortas with diffuse plaque consisting of mostly cholesterol and calcific debris with a lining of thrombus along the flow channel are best treated as overall cardiac risk. In addition to high- intensity statin therapy, aspirin and a secondary platelet aggregation inhibitor are warranted. Some have speculated that anticoagulation in these patients may destabilize the thrombus along the flow channel and predispose to increased embolic events [32,43]. The Aortic Arch Related Cerebral Hazzard (ARCH) trial was a prospective randomized trial of adults with nondisabling ischemic stroke, transient ischemic attack, peripheral embolism, and at least 4 mm atherosclerotic plaque in the thoracic aorta on transesophageal echocardiography [44]. Subjects were randomly assigned to aspirin (75 to 150 mg daily) plus clopidogrel 75 mg daily or warfarin (international normalized ratio 2.0 to 3.0). The trial was stopped prematurely after enrollment of 349 patients due to poor recruitment and lack of ongoing funding. For the warfarin group, the time in the therapeutic range was 67 percent. After a median follow-up of 3.4 years, the primary endpoint (composite of ischemic stroke, myocardial infarction, peripheral embolism, vascular death, or hemorrhagic stroke) occurred significantly less frequently for patients receiving aspirin plus clopidogrel compared with those receiving warfarin (7.6 versus 11.3 percent). Vascular deaths occurred in no patients in the aspirin plus clopidogrel arm and 3.4 percent in the warfarin arm. Major hemorrhage occurred in 2.3 percent of the aspirin plus clopidogrel and 3.4 percent in the warfarin arm. These differences were not statistically significant. With regards to stroke from more focal ascending aortic plaques, a beneficial effect of anticoagulation with warfarin was suggested by several uncontrolled studies of primary and secondary atherosclerosis prevention [18,29,45,46]. These studies demonstrated a significant risk of stroke in patients with aortic plaque who were not treated with adequate warfarin therapy. The SPAF-III trial compared adjusted-dose warfarin (to maintain an international normalized ratio [INR] of 2 to 3) to low-dose warfarin (INR 1.2 to 1.5) plus aspirin for the prevention of stroke in 1044 patients with atrial fibrillation with at least one thromboembolic risk factor (heart failure or left ventricular fractional shortening 25 percent, previous thromboembolism, systolic blood pressure >160 mmHg, or female >75 years of age) [45]. A subset patients (n = 382) underwent observational TEE; in each treatment group, 35 percent of patients had complex aortic plaque (>4 mm, mobile, ulcerated or pedunculated), of which approximately one half were in the ascending or transverse aorta [18]. At a mean follow-up of https://www.uptodate.com/contents/thromboembolism-from-aortic-plaque/print 9/23 7/5/23, 11:50 AM Thromboembolism from aortic plaque - UpToDate 1.1 years, the incidence of stroke in patients with complex aortic plaque was 4 percent in those treated with adjusted-dose warfarin (median INR 2.3) compared with 16 percent for those on fixed low-dose warfarin plus aspirin. The risk reduction (75 percent) was the same as in the entire study population, but the absolute benefit was greater (12 versus 6 percent) because patients with complex plaque were at higher risk [45]. No data have been reported regarding the role of direct oral anticoagulants (eg, dabigatran, rivaroxaban, apixaban, edoxaban) in the management of aortic atheroma, and these agents are not recommended for this purpose. Statin therapy Statins are reasonable in all patients with complex aortic plaque, as well as patients with simple plaque and a history of otherwise unexplained stroke or peripheral embolism, since such plaques represent systemic atherosclerosis. Statins have a variety of potentially beneficial mechanisms, including anti-inflammatory properties that may be beneficial for those with aortic plaques. For patients with no contraindications (ie, low risk of major bleeding) with stroke and complex aortic plaque ( 4 mm thick and/or atheroma with a mobile component), or without stroke but atheroma with a mobile component, high-intensity statin therapy plus dual antiplatelet therapy is warranted. The optimal approach for patients without stroke and simple plaque (<4 mm without a mobile component) or diffuse atheromatous plaques ("shaggy" aorta) is controversial because the data are limited. High-intensity statin plus aspirin or clopidogrel 75 mg daily (monotherapy) is likely adequate. We suggest using the same targets recommended for the secondary prevention of coronary artery disease. (See "Overview of secondary prevention of ischemic stroke" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".) The efficacy of statin therapy in reducing the risk of embolic events in patients with thoracic aortic atherosclerosis has been evaluated in observational studies and small trials. In the previously cited retrospective analysis of 519 patients (64 percent of whom had a history of coronary heart disease), statin therapy was associated with a significant 17 percent absolute reduction in thromboembolic events (12 versus 29 percent in patients not treated with a statin) [16]. This apparent clinical benefit probably reflects, at least in part, stabilization or even regression of aortic plaque, which some have attempted to evaluate using imaging studies [47- 56]. In one trial, thickness of thoracic and abdominal aortic plaque was measured using magnetic resonance imaging following 12 months of statin therapy [47]. Patients were randomly https://www.uptodate.com/contents/thromboembolism-from-aortic-plaque/print 10/23 7/5/23, 11:50 AM Thromboembolism from aortic plaque - UpToDate assigned to receive 20 mg atorvastatin daily, 400 mg etidronate daily, or both drugs daily. Maximal wall thickness of the thoracic aorta was reduced by 13.8 percent with combination therapy and 12.3 percent in the atorvastatin groups, compared with only 2.2 percent in the etidronate group. Maximal vessel wall thickness of the abdominal aorta was significantly reduced in the combination therapy group compared with the atorvastatin group, or etidronate (11.4 versus 0.9 and 5.5 percent, respectively). Although these results are interesting, there was no correlation between observed changes in aortic wall thickness and clinically significant embolic events [48]. Thus, the impact of these wall thickness changes on potential future clinical or even subclinical events is unknown. Surgery The role of surgical therapy to prevent embolization in patients with aortic plaque is not clearly defined. Randomized trials and large observational studies suggest that, among patients with atherosclerosis who undergo coronary artery bypass graft surgery (CABG), the rate of stroke is reduced with minimally invasive off-pump CABG. The use of intraoperative ultrasound (epicardial or transesophageal echocardiography) to direct the sites of aortic manipulation also may be beneficial. (See "Intraoperative transesophageal echocardiography for noncardiac surgery".) Among patients undergoing cardiac surgery, prophylactic replacement of the aortic arch and aortic arch atherectomy are other procedures that have been evaluated. Aortic arch replacement may be beneficial [57], but prophylactic atherectomy may result in worse outcomes. In one report, aortic arch atherectomy was performed during surgery in 268 patients with >4 mm aortic plaque to reduce the stroke risk [37]. However, these patients had a higher rate of stroke than those in whom atherectomy was not performed (35 versus 12 percent). Aortic arch atherectomy has been performed with good results in the rare younger patient who is a good operative candidate [25,26]. However, this should be considered an experimental approach. We have had mixed results with this approach and only consider atherectomy when the plaque is highly mobile and very large or there has been further growth despite medical therapy. Endovascular stenting Endovascular stent-grafting to manage atheroembolic disease has been reported primarily for descending thoracic and abdominal aortic sources [58-63]. The stent-graft is positioned overlying the atheromatous plaque to exclude it from the circulation, thus preventing subsequent embolization. A case report describes the successful deployment of a thoracic stent-graft to manage a thoracic aortic atheromatous lesion that was the source for massive distal embolization [64]. The endovascular approach is an attractive option for patients who are poor candidates for surgery; however, potential disadvantages include the potential for https://www.uptodate.com/contents/thromboembolism-from-aortic-plaque/print 11/23 7/5/23, 11:50 AM Thromboembolism from aortic plaque - UpToDate iatrogenic embolization due to manipulation of catheters in the region of the lesion, and complications related to intravenous contrast. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute extremity ischemia".) SUMMARY AND RECOMMENDATIONS Thoracic aortic atherosclerotic plaques are an important potential source of systemic emboli (thromboembolus, atheroembolus), leading to stroke, transient ischemic attack, and embolization to visceral and peripheral arterial circulation. The clinical manifestations of thromboembolism depend upon the location of the plaque. (See 'Introduction' above and 'Complex aortic plaque' above and 'Clinical manifestations' above.) The risk of thromboembolism in patients with aortic atherosclerosis is markedly increased when there is complex plaque, which is defined as thickness >4 mm or ulceration or mobility of a component of the plaque. (See 'Complex aortic plaque' above.) All patients with aortic atherosclerosis with or without a history of otherwise unexplained stroke or peripheral embolism should be treated for secondary prevention of cardiovascular disease. These therapies include antiplatelet therapy (eg, aspirin or clopidogrel), lipid-lowering therapy (eg, statin), blood pressure control, smoking cessation, and, in patients with diabetes, glycemic control. The benefit of antithrombotic therapy for aortic arch plaque with or without stroke is uncertain. (See 'Treatment' above and "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".) For patients with stroke and complex aortic plaque ( 4 mm thick and/or atheroma with a mobile component), or patients without stroke but atheroma with a mobile component, dual antiplatelet therapy plus high-intensity statin therapy is warranted. The optimal approach for patients without stroke and simple plaque (<4 mm without a mobile component) or diffuse atheromatous plaques ("shaggy" aorta) is controversial because the data are limited. Aspirin or clopidogrel (monotherapy) plus high-intensity statin is likely adequate. https://www.uptodate.com/contents/thromboembolism-from-aortic-plaque/print 12/23 7/5/23, 11:50 AM Thromboembolism from aortic plaque - UpToDate Although the optimal low density lipoprotein cholesterol target or statin dose intensity is unknown for this population, we believe that using targets similar to those recommended for the secondary prevention of coronary artery disease is appropriate. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".) Prophylactic surgery for the management of atherosclerotic plaque has been performed, but there is no evidence of benefit. Among patients undergoing cardiac surgery or aortic surgery at risk for aortic atherosclerosis, intraoperative ultrasound may be beneficial to help to guide sites of aortic manipulation or clamping. For secondary prevention, endovascular stent-grafting may be feasible in patients who have had an embolic event. (See 'Surgery' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Emile R Mohler, III, MD (deceased), who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Fazio GP, Redberg RF, Winslow T, Schiller NB. Transesophageal echocardiographically detected atherosclerotic aortic plaque is a marker for coronary artery disease. J Am Coll Cardiol 1993; 21:144. 2. Matsuzaki M, Ono S, Tomochika Y, et al. Advances in transesophageal echocardiography for the evaluation of atherosclerotic lesions in thoracic aorta the effects of hypertension, hypercholesterolemia, and aging on atherosclerotic lesions. Jpn Circ J 1992; 56:592. 3. Agmon Y, Khandheria BK, Meissner I, et al. Independent association of high blood pressure and aortic atherosclerosis: A population-based study. Circulation 2000; 102:2087. 4. Jaffer FA, O'Donnell CJ, Larson MG, et al. Age and sex distribution of subclinical aortic atherosclerosis: a magnetic resonance imaging examination of the Framingham Heart Study. Arterioscler Thromb Vasc Biol 2002; 22:849. 5. Agmon Y, Khandheria BK, Meissner I, et al. C-reactive protein and atherosclerosis of the thoracic aorta: a population-based transesophageal echocardiographic study. Arch Intern Med 2004; 164:1781. https://www.uptodate.com/contents/thromboembolism-from-aortic-plaque/print 13/23 7/5/23, 11:50 AM Thromboembolism from aortic plaque - UpToDate 6. Tunick PA, Kronzon I. Atheromas of the thoracic aorta: clinical and therapeutic update. J Am Coll Cardiol 2000; 35:545. 7. Amarenco P, Duyckaerts C, Tzourio C, et al. The prevalence of ulcerated plaques in the aortic arch in patients with stroke. N Engl J Med 1992; 326:221. 8. Amarenco P, Cohen A, Tzourio C, et al. Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. N Engl J Med 1994; 331:1474. 9. French Study of Aortic Plaques in Stroke Group, Amarenco P, Cohen A, et al. Atherosclerotic disease of the aortic arch as a risk factor for recurrent ischemic stroke. N Engl J Med 1996; 334:1216. 10. Karalis DG, Quinn V, Victor MF, et al. Risk of catheter-related emboli in patients with atherosclerotic debris in the thoracic aorta. Am Heart J 1996; 131:1149. 11. Katz ES, Tunick PA, Rusinek H, et al. Protruding aortic atheromas predict stroke in elderly patients undergoing cardiopulmonary bypass: experience with intraoperative transesophageal echocardiography. J Am Coll Cardiol 1992; 20:70. 12. Jones EF, Kalman JM, Calafiore P, et al. Proximal aortic atheroma. An independent risk factor for cerebral ischemia. Stroke 1995; 26:218. 13. Tunick PA, Rosenzweig BP, Katz ES, et al. High risk for vascular events in patients with protruding aortic atheromas: a prospective study. J Am Coll Cardiol 1994; 23:1085. 14. Davies MJ, Richardson PD, Woolf N, et al. Risk of thrombosis in human atherosclerotic plaques: role of extracellular lipid, macrophage, and smooth muscle cell content. Br Heart J 1993; 69:377. 15. Cohen A, Tzourio C, Bertrand B, et al. Aortic plaque morphology and vascular events: a follow-up study in patients with ischemic stroke. FAPS Investigators. French Study of Aortic Plaques in Stroke. Circulation 1997; 96:3838. 16. Tunick PA, Nayar AC, Goodkin GM, et al. Effect of treatment on the incidence of stroke and other emboli in 519 patients with severe thoracic aortic plaque. Am J Cardiol 2002; 90:1320. 17. Tunick PA, Perez JL, Kronzon I. Protruding atheromas in the thoracic aorta and systemic embolization. Ann Intern Med 1991; 115:423. 18. Transesophageal echocardiographic correlates of thromboembolism in high-risk patients with nonvalvular atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators Committee on Echocardiography. Ann Intern Med 1998; 128:639. 19. Zabalgoitia M, Halperin JL, Pearce LA, et al. Transesophageal echocardiographic correlates of clinical risk of thromboembolism in nonvalvular atrial fibrillation. Stroke Prevention in Atrial Fibrillation III Investigators. J Am Coll Cardiol 1998; 31:1622. https://www.uptodate.com/contents/thromboembolism-from-aortic-plaque/print 14/23 7/5/23, 11:50 AM Thromboembolism from aortic plaque - UpToDate 20. Mitusch R, Doherty C, Wucherpfennig H, et al. Vascular events during follow-up in patients with aortic arch atherosclerosis. Stroke 1997; 28:36. 21. Kwon H, Han Y, Noh M, et al. Impact of Shaggy Aorta in Patients with Abdominal Aortic Aneurysm Following Open or Endovascular Aneurysm Repair. Eur J Vasc Endovasc Surg 2016; 52:613. 22. Meissner I, Khandheria BK, Sheps SG, et al. Atherosclerosis of the aorta: risk factor, risk marker, or innocent bystander? A prospective population-based transesophageal echocardiography study. J Am Coll Cardiol 2004; 44:1018. 23. Karalis DG, Chandrasekaran K, Victor MF, et al. Recognition and embolic potential of intraaortic atherosclerotic debris. J Am Coll Cardiol 1991; 17:73. 24. Laperche T, Laurian C, Roudaut R, Steg PG. Mobile thromboses of the aortic arch without aortic debris. A transesophageal echocardiographic finding associated with unexplained arterial embolism. The Filiale Echocardiographie de la Soci t Fran aise de Cardiologie. Circulation 1997; 96:288. 25. Tunick PA, Culliford AT, Lamparello PJ, Kronzon I. Atheromatosis of the aortic arch as an occult source of multiple systemic emboli. Ann Intern Med 1991; 114:391. 26. Tunick PA, Lackner H, Katz ES, et al. Multiple emboli from a large aortic arch thrombus in a patient with thrombotic diathesis. 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mobility of a component of the plaque. (See 'Complex aortic plaque' above.) All patients with aortic atherosclerosis with or without a history of otherwise unexplained stroke or peripheral embolism should be treated for secondary prevention of cardiovascular disease. These therapies include antiplatelet therapy (eg, aspirin or clopidogrel), lipid-lowering therapy (eg, statin), blood pressure control, smoking cessation, and, in patients with diabetes, glycemic control. The benefit of antithrombotic therapy for aortic arch plaque with or without stroke is uncertain. (See 'Treatment' above and "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".) For patients with stroke and complex aortic plaque ( 4 mm thick and/or atheroma with a mobile component), or patients without stroke but atheroma with a mobile component, dual antiplatelet therapy plus high-intensity statin therapy is warranted. The optimal approach for patients without stroke and simple plaque (<4 mm without a mobile component) or diffuse atheromatous plaques ("shaggy" aorta) is controversial because the data are limited. Aspirin or clopidogrel (monotherapy) plus high-intensity statin is likely adequate. https://www.uptodate.com/contents/thromboembolism-from-aortic-plaque/print 12/23 7/5/23, 11:50 AM Thromboembolism from aortic plaque - UpToDate Although the optimal low density lipoprotein cholesterol target or statin dose intensity is unknown for this population, we believe that using targets similar to those recommended for the secondary prevention of coronary artery disease is appropriate. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".) Prophylactic surgery for the management of atherosclerotic plaque has been performed, but there is no evidence of benefit. Among patients undergoing cardiac surgery or aortic surgery at risk for aortic atherosclerosis, intraoperative ultrasound may be beneficial to help to guide sites of aortic manipulation or clamping. For secondary prevention, endovascular stent-grafting may be feasible in patients who have had an embolic event. (See 'Surgery' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Emile R Mohler, III, MD (deceased), who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Fazio GP, Redberg RF, Winslow T, Schiller NB. Transesophageal echocardiographically detected atherosclerotic aortic plaque is a marker for coronary artery disease. J Am Coll Cardiol 1993; 21:144. 2. Matsuzaki M, Ono S, Tomochika Y, et al. 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Disappearance of a large intraaortic mass in a patient with prior systemic embolization. Am Heart J 1993; 125:1445. 32. Hollier LH, Kazmier FJ, Ochsner J, et al. "Shaggy" aorta syndrome with atheromatous embolization to visceral vessels. Ann Vasc Surg 1991; 5:439. 33. Katsanos AH, Giannopoulos S, Kosmidou M, et al. Complex atheromatous plaques in the descending aorta and the risk of stroke: a systematic review and meta-analysis. Stroke 2014; https://www.uptodate.com/contents/thromboembolism-from-aortic-plaque/print 15/23 7/5/23, 11:50 AM Thromboembolism from aortic plaque - UpToDate 45:1764. 34. Keeley EC, Grines CL. Scraping of aortic debris by coronary guiding catheters: a prospective evaluation of 1,000 cases. J Am Coll Cardiol 1998; 32:1861. 35. Baim DS, Wahr D, George B, et al. Randomized trial of a distal embolic protection device during percutaneous intervention of saphenous vein aorto-coronary bypass grafts. Circulation 2002; 105:1285. 36. Henriques JP, Zijlstra F, Ottervanger JP, et al. Incidence and clinical significance of distal embolization during primary angioplasty for acute myocardial infarction. Eur Heart J 2002; 23:1112. 37. Stern A, Tunick PA, Culliford AT, et al. Protruding aortic arch atheromas: risk of stroke during heart surgery with and without aortic arch endarterectomy. Am Heart J 1999; 138:746. 38. Patel SD, Constantinou J, Hamilton H, et al. Editor's choice - A shaggy aorta is associated with mesenteric embolisation in patients undergoing fenestrated endografts to treat paravisceral aortic aneurysms. Eur J Vasc Endovasc Surg 2014; 47:374. 39. Weinberger J, Azhar S, Danisi F, et al. A new noninvasive technique for imaging atherosclerotic plaque in the aortic arch of stroke patients by transcutaneous real-time B- mode ultrasonography: an initial report. Stroke 1998; 29:673. 40. Lansberg MG, O'Donnell MJ, Khatri P, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e601S. 41. Alonso-Coello P, Bellmunt S, McGorrian C, et al. Antithrombotic therapy in peripheral artery disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e669S. 42. Whitlock RP, Sun JC, Fremes SE, et al. Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e576S. 43. Hyman BT, Landas SK, Ashman RF, et al. Warfarin-related purple toes syndrome and cholesterol microembolization. Am J Med 1987; 82:1233. 44. Amarenco P, Davis S, Jones EF, et al. Clopidogrel plus aspirin versus warfarin in patients with stroke and aortic arch plaques. Stroke 2014; 45:1248. 45. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet 1996; 348:633. https://www.uptodate.com/contents/thromboembolism-from-aortic-plaque/print 16/23 7/5/23, 11:50 AM Thromboembolism from aortic plaque - UpToDate 46. Ferrari E, Vidal R, Chevallier T, Baudouy M. Atherosclerosis of the thoracic aorta and aortic debris as a marker of poor prognosis: benefit of oral anticoagulants. J Am Coll Cardiol 1999; 33:1317. 47. Kawahara T, Nishikawa M, Kawahara C, et al. Atorvastatin, etidronate, or both in patients at high risk for atherosclerotic aortic plaques: a randomized, controlled trial. Circulation 2013; 127:2327. 48. Corti R, Fayad ZA, Fuster V, et al. Effects of lipid-lowering by simvastatin on human atherosclerotic lesions: a longitudinal study by high-resolution, noninvasive magnetic resonance imaging. Circulation 2001; 104:249. 49. Kaneko K, Saito H, Takahashi T, et al. Rosuvastatin improves plaque morphology in cerebral embolism patients with normal low-density lipoprotein and severe aortic arch plaque. J Stroke Cerebrovasc Dis 2014; 23:1682. 50. Ueno Y, Yamashiro K, Tanaka Y, et al. Rosuvastatin may stabilize atherosclerotic aortic plaque: transesophageal echocardiographic study in the EPISTEME trial. Atherosclerosis 2015; 239:476. 51. Nishiga M, Izumi C, Matsutani H, et al. Effects of medical treatment on the prognosis and risk of embolic events in patients with severe aortic plaque. J Atheroscler Thromb 2013; 20:821. 52. Lima JA, Desai MY, Steen H, et al. Statin-induced cholesterol lowering and plaque regression after 6 months of magnetic resonance imaging-monitored therapy. Circulation 2004; 110:2336. 53. 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Arterioscler Thromb 1994; 14:1723. https://www.uptodate.com/contents/thromboembolism-from-aortic-plaque/print 17/23 7/5/23, 11:50 AM Thromboembolism from aortic plaque - UpToDate 57. Wareing TH, Davila-Roman VG, Daily BB, et al. Strategy for the reduction of stroke incidence in cardiac surgical patients. Ann Thorac Surg 1993; 55:1400. 58. Scott DJ, White JM, Arthurs ZM. Endovascular management of a mobile thoracic aortic thrombus following recurrent distal thromboembolism: a case report and literature review. Vasc Endovascular Surg 2014; 48:246. 59. Jeyabalan G, Wallace JR, Chaer RA, et al. Endovascular strategies for treatment of embolizing thoracoabdominal aortic lesions. J Vasc Surg 2014; 59:1256. 60. Dougherty MJ, Calligaro KD. Endovascular treatment of embolization of aortic plaque with covered stents. J Vasc Surg 2002; 36:727. 61. Carroccio A, Olin JW, Ellozy SH, et al. The role of aortic stent grafting in the treatment of atheromatous embolization syndrome: results after a mean of 15 months follow-up. J Vasc Surg 2004; 40:424. 62. Donas KP, Sch nefeld T, Schwindt A, et al. Successful percutaneous endovascular treatment of symptomatic infrarenal aortic stenosis caused by soft-plaque with the Endurant stent- graft. J Cardiovasc Surg (Torino) 2011; 52:89. 63. Tsuji Y, Tanaka Y, Kitagawa A, et al. Endovascular stent-graft repair for penetrating atherosclerotic ulcer in the infrarenal abdominal aorta. J Vasc Surg 2003; 38:383. 64. Wolf PS, Burman HE, Starnes BW. Endovascular treatment of massive thoracic aortic thrombus and associated ruptured atheroma. Ann Vasc Surg 2010; 24:416.e9. Topic 8197 Version 28.0 https://www.uptodate.com/contents/thromboembolism-from-aortic-plaque/print 18/23 7/5/23, 11:50 AM Thromboembolism from aortic plaque - UpToDate GRAPHICS Thoracic aortic plaque Three transesophageal echocardiograms of the thoracic aorta: left: normal; middle: moderate (3 mm) plaque; and right: severe (7 mm) plaque. Reproduced with permission from: Tunick, PA, Kronzon, I. Atheroembolism. In: Vascular Medicine. A Companion to Braunwald's Heart Disease, 1st edition, Dzau, VJ, Creager, M, Loscalzo, J, et al (Eds), WB Saunders 2005. Copyright 2005 Elsevier. Graphic 72777 Version 2.0 https://www.uptodate.com/contents/thromboembolism-from-aortic-plaque/print 19/23 7/5/23, 11:50 AM Thromboembolism from aortic plaque - UpToDate Aortic source for distal embolism The patient presented with embolic occlusion of the right common femoral artery presumably from the aorta. In the CT image, the aorta is ectatic with irregular intraluminal thrombus. The selected bone windows help to differentiate the contrast bolus from the calcium in the aortic wall. While the aorta in this segment measures 3.4 cm, the more proximal infrarenal aorta was normal in size at 2.8 cm. CT: computed tomography. Graphic 118891 Version 1.0 https://www.uptodate.com/contents/thromboembolism-from-aortic-plaque/print 20/23 7/5/23, 11:50 AM Thromboembolism from aortic plaque - UpToDate Increasing risk of stroke with aortic plaque thickness Relation between stroke and plaque thickness and location. There is a rising likelihood of stroke with increasing plaque thickness in the ascending aorta (AA) or aortic arch. Plaque in the descending aorta is generally not associated with stroke in the absence of severe aortic regurgitation . Data from Amarenco, P, Cohen, A, Tzourio, C, et al, N Engl J Med 1994; 331:1474. Graphic 61664 Version 1.0 https://www.uptodate.com/contents/thromboembolism-from-aortic-plaque/print 21/23 7/5/23, 11:50 AM Thromboembolism from aortic plaque - UpToDate Femoral artery emboli on CT scan A transverse CT scan through the pelvis (A) shows nonocclusive thrombus in the left superficial femoral and deep femoral arteries (circle). (B) is a magnified view of (A) and shows nonocclusive thrombus in the SFA (arrowhead) and in the DFA (arrow). (C) is a magnified sagittal reformat of the CT scan and shows the thrombus straddling the bifurcation (dashed arrow) and extending into the SFA (arrowhead) and DFA (arrow). CT: computed tomography; SFA: superficial femoral artery; DFA: deep femoral artery. Graphic 98593 Version 2.0 https://www.uptodate.com/contents/thromboembolism-from-aortic-plaque/print 22/23 7/5/23, 11:50 AM Thromboembolism from aortic plaque - UpToDate Contributor Disclosures Benjamin J Pearce, MD, FACS No relevant financial relationship(s) with ineligible companies to disclose. Jos Biller, MD, FACP, FAAN, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Joseph L Mills, Sr, MD No relevant financial relationship(s) with ineligible companies to disclose. John F Eidt, MD Grant/Research/Clinical Trial Support: Syntactx [Clinical events, data/safety monitoring for medical device trials]. All of the relevant financial relationships listed have been mitigated. Warren J Manning, MD Equity Ownership/Stock Options: Pfizer [Anticoagulants]. All of the relevant financial relationships listed have been mitigated. Kathryn A Collins, MD, PhD, FACS No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/thromboembolism-from-aortic-plaque/print 23/23

7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Clinical diagnosis of stroke subtypes : Louis R Caplan, MD : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 28, 2022. INTRODUCTION The two broad categories of stroke, hemorrhage and ischemia, are diametrically opposite conditions: hemorrhage is characterized by too much blood within the closed cranial cavity, while ischemia is characterized by too little blood to supply an adequate amount of oxygen and nutrients to a part of the brain [1]. Each of these categories can be divided into subtypes that have somewhat different causes, clinical pictures, clinical courses, outcomes, and treatment strategies. As an example, intracranial hemorrhage can be caused by intracerebral hemorrhage (ICH), also called parenchymal hemorrhage, which involves bleeding directly into brain tissue, and subarachnoid hemorrhage (SAH), which involves bleeding into the cerebrospinal fluid that surrounds the brain and spinal cord [1]. This topic will review the categories of stroke and their clinical diagnosis. An overview of the evaluation of stroke and the clinical manifestations of transient cerebral ischemia are discussed separately. (See "Overview of the evaluation of stroke" and "Definition, etiology, and clinical manifestations of transient ischemic attack".) The classification of stroke is reviewed here briefly and discussed in detail separately. (See "Stroke: Etiology, classification, and epidemiology".) CLASSIFICATION Stroke is classified into the following subtypes: intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH), and brain ischemia due to thrombosis, embolism, or systemic https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 1/29 7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate hypoperfusion. Brain ischemia The three main subtypes of brain ischemia are thrombosis, embolism, and hypoperfusion. Thrombosis generally refers to local in situ obstruction of an artery. The obstruction may be due to disease of the arterial wall, such as arteriosclerosis, dissection, or fibromuscular dysplasia; there may or may not be superimposed thrombosis. Thrombotic strokes can be divided into either large or small vessel disease ( table 1). These two subtypes of thrombosis are worth distinguishing since the causes, outcomes, and treatments are different. Atherosclerosis is by far the most common cause of in situ local disease within the large extracranial and intracranial arteries that supply the brain. In patients with thrombosis, the neurologic symptoms often fluctuate, remit, or progress in a stuttering fashion ( figure 1). (See 'Clinical course of symptoms and signs' below and "Definition, etiology, and clinical manifestations of transient ischemic attack".) Embolism refers to particles of debris originating elsewhere that block arterial access to a particular brain region. Embolic strokes may arise from a source in the heart, aorta, or large vessels ( table 1). The embolus suddenly blocks the recipient site so that the onset of symptoms is abrupt and usually maximal at the start ( figure 2). Unlike thrombosis, multiple sites within different vascular territories may be affected when the source is the heart (eg, left atrial appendage or left ventricular thrombus) or aorta. Systemic hypoperfusion is a more general circulatory problem, manifesting itself in the brain and perhaps other organs. Reduced cerebral blood flow is more global in patients with systemic hypoperfusion and does not affect isolated regions. Symptoms of brain dysfunction typically are diffuse and nonfocal in contrast to the other two categories of ischemia. The neurologic signs are typically bilateral, although they may be asymmetric when there is preexisting asymmetrical craniocerebral vascular occlusive disease. Intracerebral hemorrhage Bleeding in ICH is usually derived from arterioles or small arteries. The bleeding is directly into the brain, forming a localized hematoma that spreads along white matter pathways. Accumulation of blood occurs over minutes or hours and the neurologic symptoms usually increase gradually over minutes or a few hours. In contrast to brain embolism and SAH, the neurologic symptoms do not begin abruptly and are not maximal at onset ( figure 3). Subarachnoid hemorrhage Rupture of an aneurysm releases blood directly into the cerebrospinal fluid (CSF) under arterial pressure. The blood spreads quickly within the CSF, https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 2/29 7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate rapidly increasing intracranial pressure. Death or deep coma ensues if the bleeding continues. The bleeding usually lasts only a few seconds but rebleeding is very common. With causes of SAH other than aneurysm rupture, the bleeding is less abrupt and may continue over a longer period of time. Symptoms of SAH begin abruptly in contrast to the more gradual onset of ICH. The sudden increase in pressure causes a cessation of activity (eg, loss of memory or focus or knees buckling). Headache is an invariable symptom and is typically instantly severe and widespread. There are usually no important focal neurologic signs unless bleeding occurs into the brain and CSF at the same time (meningocerebral hemorrhage). Onset headache is more common in SAH than in ICH, whereas the combination of onset headache and vomiting is infrequent in ischemic stroke ( figure 4). DISTINGUISHING STROKE SUBTYPES Many findings of the history and physical examination suggest certain stroke subtypes ( table 2). This presumptive clinical diagnosis requires confirmation by brain and vascular imaging. (See "Overview of the evaluation of stroke".) Clinical course of symptoms and signs The most important historical item for differentiating stroke subtypes is the pace and course of the symptoms and signs and their clearing [1]. Each subtype has a characteristic course [2]. Embolic strokes most often occur suddenly ( figure 2). The deficits indicate focal loss of brain function that is usually maximal at onset. Rapid recovery also favors embolism. Thrombosis-related symptoms often fluctuate, varying between normal and abnormal or progressing in a stepwise or stuttering fashion with some periods of improvement ( figure 1). Penetrating artery occlusions usually cause symptoms that develop during a short period of time, hours or at most a few days ( figure 5), compared with large artery-related brain ischemia, which can evolve over a longer period. Intracerebral hemorrhage (ICH) does not improve during the early period; it progresses gradually during minutes or a few hours ( figure 3). Aneurysmal subarachnoid hemorrhage (SAH) develops in an instant. Focal brain dysfunction is less common. https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 3/29 7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate Patients often do not give a specific history regarding the course of neurologic symptoms. It is useful to ask if the patient could walk, talk, use the phone, use the hand, etc, as the events developed after the first symptoms occurred [1]. Neurologic worsening after acute ischemic stroke is not uncommon. In a large prospective study, neurologic deterioration during the acute phase (48 to 72 hours from onset) of cerebral ischemia occurred in 256 (13 percent) of 1964 patients [3]. Deterioration was related mainly to progressive infarction, increased intracranial pressure, recurrent cerebral ischemia, and secondary parenchymal hemorrhage. Independent predictors of neurologic deterioration included the following: Internal carotid artery occlusion Brainstem infarction Middle cerebral artery M1 segment occlusion Territorial infarction Diabetes mellitus Silent brain infarcts Silent brain infarcts (ie, silent strokes) are infarcts identified only by neuroimaging. There is no accompanying clinical history of stroke or TIA. However, this relationship is somewhat clouded because a more detailed history may elicit symptoms to suggest that a lesion is not truly silent [4]. In addition, these lesions seem to be associated with cognitive deficits [5,6]. Therefore, it is more appropriate to refer to these clinically unrecognized lesions as covert brain infarcts. Patients with TIA and minor stroke appear to have a high risk of covert infarcts as well as clinically symptomatic infarcts. This point is illustrated by a study of 143 hospital patients with TIA or minor stroke [7]. On follow-up at 30 days, the risk of new ischemic lesions on magnetic resonance imaging (MRI) diffusion-weighted imaging or fluid-attenuated inversion recovery (FLAIR) sequences was approximately 10 percent, and nearly half of these new lesions were asymptomatic [7]. Covert brain infarction may be more common than symptomatic stroke [8]. In a population- based cross-sectional survey of 267 older adult community residents in Germany, the prevalence of silent stroke was 12.7 percent [9]; the presence of silent stroke was associated with diminished cognitive performance in the domain of procedural speed. Patients with severe atherosclerotic disease may have silent infarcts at younger ages than those without such disease burden [10]. In the Cardiovascular Health Study, 1433 participants with no brain infarcts on a baseline head MRI scan had a repeat head MRI at five years [5]. One or more infarcts were detected in 18 https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 4/29 7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate percent of subjects, and these MRI defined infarcts were typically: Single infarcts (76 percent) Small (3 to 20 mm in 87 percent) Subcortical (80 percent) Without acute symptoms recognized as a TIA or stroke (89 percent) Furthermore, these covert infarcts were associated with subtle cognitive change. Subjects with MRI defined infarcts had a significantly greater decline on the Modified Mini-Mental State Examination and Digit Symbol Substitution test than those without infarcts at follow-up. The severity of white matter changes on initial MRI was the strongest predictor of new infarcts. Covert infarcts may have important prognostic implications for stroke risk and cognitive decline. In the Rotterdam Scan Study, patients with silent brain infarcts were at significantly increased risk for subsequent stroke (adjusted hazard ratio 3.9) [11]. Patients with more than one silent infarct were at higher risk than those with one silent infarct, and patients with more white matter lesions were also at increased risk for subsequent stroke. In another report from the Rotterdam Scan Study, the presence of silent brain infarcts significantly increased the risk of dementia (hazard ratio 2.26) [6]. The presence of silent brain infarcts on the baseline MRI was associated with decreased performance on neuropsychological tests and a steeper decline in global cognitive function. Ecology and risk factors Ecology refers to known demographic and historical features that provide probabilities of the patient having one or more of the stroke subtypes. The presence of these risk factors increase the odds that a stroke is due to a particular mechanism, but the clinician cannot make a firm diagnosis simply on the basis of probability. As examples: some conditions such as hypertension predispose to more than one subtype (thrombosis, ICH); the presence of a prior myocardial infarction increases the likelihood of cardiac origin embolism, but also increases the likelihood of carotid and vertebral artery neck occlusive disease (thrombosis); and an older patient with severe atherosclerosis may also harbor an unexpected cerebral aneurysm. Age, sex, and race Age, sex, and race are important demographic variables known to the clinician before taking the history [2]. Most thrombotic and embolic strokes related to atherosclerosis occur in older patients. Individuals under age 40 rarely have severe atherosclerosis unless they also have important risk factors such as diabetes, hypertension, hyperlipidemia, smoking, or a strong family history. In contrast, hemorrhages (both ICH and SAH) are common in adolescents https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 5/29 7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate and young adults [12]. Cardiac-origin embolism is also common in young people who are known to have heart disease. Hypertensive ICH is more common among Black and Asian individuals than among White individuals. Premenopausal women have a lower frequency of atherosclerosis than men of similar age unless they have major stroke risk factors. While data are limited, stroke prevalence may be increasing in women aged 45 to 54 years [13]. Black and Asian populations, and adult females have a lower incidence of occlusive disease of the extracranial carotid and vertebral arteries than adult White males [14-16]. Small vessel strokes, strokes of undetermined origin and large vessel strokes are more common among Black people compared with White people. (See "Stroke: Etiology, classification, and epidemiology", section on 'Epidemiology'.) Heart disease Heart disease, including atrial fibrillation, valvular disease, recent myocardial infarction, and endocarditis, increases the probability of a stroke due to embolism ( table 3) [17]. Of these, atrial fibrillation is the most prominent, causing nearly half of all cardioembolic strokes. The risk of stroke appears to be greatly increased after myocardial infarction (MI), particularly in the first 30 days [18,19]. A number of minor cardiac sources of emboli are known but have an uncertain association with stroke. (See "Stroke: Etiology, classification, and epidemiology", section on 'Embolism'.) Hypertension Hypertension is the most common and most important stroke risk factor [20,21], including isolated systolic hypertension [22,23]. Epidemiologic studies show that there is a gradually increasing incidence of both coronary disease and stroke as the blood pressure rises above 110/75 mmHg ( figure 6) [20,24]. Both prior blood pressure and current blood pressure are important risk factors [25]. However, these observations do not prove a causal relationship, since increasing blood pressure could be a marker for other risk factors such as increasing body weight, which is associated with dyslipidemia, glucose intolerance, and the metabolic syndrome. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)".) The best evidence for a causal role of increasing blood pressure in cardiovascular complications is an improvement in outcome with antihypertensive therapy. An overview of 14 hypertension treatment trials concluded that a long-term (mean five years) 5 to 6 mmHg decrease in the usual diastolic blood pressure was associated with a 35 to 40 percent reduction in stroke [21]. https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 6/29 7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate Severe uncontrolled hypertension is a strong risk factor for ICH. A young person who enters the hospital with the acute onset of a focal neurologic deficit and a blood pressure greater than 220/120 mmHg has a high likelihood of having an ICH. In a Korean cohort study, for each 20 mmHg increase in systolic blood pressure, the increased relative risk for hemorrhagic stroke was greater than that for ischemic stroke (3.18 versus 2.23) [26]. For blood pressures great than 180/110 mmHg, the difference in relative risk was even more pronounced between hemorrhagic and ischemic stroke subtypes (28.83 versus 9.56). Chronic hypertension is a risk factor for both thrombotic extracranial and intracranial large artery disease and penetrating artery disease. Conversely, the absence of a history of hypertension or of present hypertension reduces the likelihood of ICH and penetrating artery disease. Smoking Smoking increases the likelihood of extracranial occlusive vascular disease, nearly doubling the risk of stroke [27,28]. The risk of ischemic stroke decreases over time after smoking cessation. In one series of middle-aged women, for example, the excess risk among former smokers largely disappeared two to four years after cessation [29]. Other risk factors Other risk factors for stroke include the following: Diabetes increases the likelihood of large and small artery occlusive disease and ischemic stroke but has not been shown to predispose to hemorrhagic stroke [30]. However, data from the Nurses' Health Study suggest that type 1 diabetes might also be a risk factor for hemorrhagic stroke [31]. Elevated total cholesterol and decreased high-density lipoprotein cholesterol have been associated with increased risk of ischemic stroke and large artery stroke in some, but not all, studies. This topic is discussed separately. (See "Overview of secondary prevention of ischemic stroke", section on 'Dyslipidemia'.) Elevated serum lipoprotein(a) has been associated with intracranial [32], extracranial [33], and aortic [34] large artery occlusive disease. The use of amphetamines increases the likelihood of both ICH and SAH but not brain ischemia. Many younger individuals who suffer an ICH following amphetamine use have an underlying vascular lesion such as an aneurysm or arteriovenous malformation [35]. Cocaine-related strokes are often hemorrhagic (ICH and SAH), due to hypertensive surges and aneurysms [36]. Cocaine is also associated with brain ischemia, especially involving the posterior circulation intracranial arteries; this is probably due to vasoconstriction [37]. (See https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 7/29 7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate "Clinical manifestations, diagnosis, and management of the cardiovascular complications of cocaine abuse", section on 'Stroke'.) Stroke during the puerperium has an increased likelihood of being related to venous or arterial thrombosis. The presence of a known bleeding disorder or prescription of oral anticoagulants predisposes to hemorrhage, into either the brain or the cerebrospinal fluid. Phenylpropanolamine in appetite suppressants appears to be an independent risk factor for hemorrhagic stroke (including ICH and SAH) in women, especially in those who take a higher than recommended amount [38]. The link between stroke and oral contraceptive use has been a controversial issue. Initial studies suggesting this association were performed with oral contraceptives containing higher doses of estrogen [39]; the risk may not be as great with current low dose oral contraceptives. (See "Combined estrogen-progestin contraception: Side effects and health concerns".) Other historical features Previous transient ischemic attack A history of transient ischemic attack (TIA), especially more than one, in the same territory as the stroke strongly favors the presence of a local vascular lesion (thrombosis). Attacks in more than one vascular territory suggest brain embolism from the heart or aorta. TIAs are not a feature of brain hemorrhage. Patients often will not volunteer a prior history of symptoms consistent with a TIA. Many patients, for example, do not relate prior hand or eye problems to subsequent leg problems. Thus, the physician must ask directly about specific symptoms. "Did your arm, hand, or leg ever transiently go numb?" "Did you ever having difficulty speaking?" "Did you ever lose vision? If so, in what part of your vision? Was it in one eye and, if so, which one?" Activity at the onset or just before the stroke Hemorrhages (ICH and SAH) can be precipitated by sex or other physical activity, while thrombotic strokes are unusual under these circumstances. Trauma before the stroke suggests traumatic dissection or occlusion of arteries or traumatic brain hemorrhage. Sudden coughing and sneezing sometimes precipitates brain embolism. Similarly, getting up during the night to urinate seems to promote brain embolism (a matutinal embolus). There is a trend toward clustering of ischemic stroke in the morning hours, but insufficient specificity to predict with any reasonable likelihood the stroke subtype according to the circadian pattern of symptom onset [40]. https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 8/29 7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate Associated symptoms The presence of fever, headache, vomiting, seizures, and hypotension are suggestive of specific stroke subtypes. Fever raises the suspicion of endocarditis and resulting embolic stroke. Infections activate acute phase blood reactants, thereby predisposing to thrombosis. Severe headache at the onset of neurologic symptoms favors SAH, while headache that develops after symptom onset that is accompanied by gradually increasing neurologic signs, decreased consciousness, and vomiting is most often indicative of ICH ( figure 4). Some patients have headaches in the prodromal period before thrombotic strokes. A prior history of intermittent severe headaches that are instantaneous in onset, persist for days, and prevent daily activities often reflects the presence of an aneurysm. Vomiting is common in patients with ICH, SAH, and posterior circulation large artery ischemia ( figure 4). Seizures in the acute phase of stroke are most often seen in patients with lobar ICH or brain embolism; they are less common in patients with acute thrombosis [41]. In a population-based study, the incidence of seizures within the first 24 hours of stroke onset for SAH, ICH, and ischemic stroke was 10, 8, and 3 percent, respectively [42]. Reduced alertness favors the presence of hemorrhage. Accompanying neurologic signs are suggestive of ICH, while the absence of focal signs suggests SAH. Reduced consciousness may also occur with thrombotic and embolic strokes that are large or involve the posterior circulation large arteries. In particular, ischemia involving the tegmentum of the pons can cause loss of consciousness. Large hemispheric infarcts are typically followed by edema that can progress to coma. CLINICAL EVALUATION General physical examination Important clues in the general physical examination include the following: Absent pulses (inferior extremity, radial, or carotid) favors a diagnosis of atherosclerosis with thrombosis, although the sudden onset of a cold, blue limb favors embolism. The internal carotid arteries in the neck cannot be reliably palpated but, in some patients, occlusion of the common carotid artery in the neck can be diagnosed by the absence of a carotid pulse. https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 9/29 7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate The presence of a neck bruit suggests the presence of occlusive extracranial disease, especially if the bruit is long, focal, and high pitched. Palpating the facial pulses is helpful in diagnosing common carotid and internal carotid artery occlusions and temporal arteritis. The facial pulses on the side of the occlusion are often lost with common carotid artery occlusions. In contrast, some patients with internal carotid artery occlusion will have increased facial pulses on the side of the occlusion because collateral channels develop between the external carotid artery facial branches and the carotid arteries intracranially. Cardiac findings, especially atrial fibrillation, murmurs and cardiac enlargement, favor cardiac-origin embolism. (See "Auscultation of cardiac murmurs in adults".) Careful examination of the optic fundus may reveal a cholesterol crystal, white platelet- fibrin, or red clot emboli. Subhyaloid hemorrhages in the eye suggest a suddenly developing brain or SAH. When the carotid artery is occluded, the iris may appear speckled and the ipsilateral pupil can become dilated and poorly reactive. The retina in that circumstance may also show evidence of chronic ischemia (venous stasis retinopathy). Neurologic examination The patient's account of his or her neurologic symptoms and the neurologic signs found on examination tell more about the location of the process in the brain than the particular stroke subtype. Nevertheless, the presence of some constellations of symptoms and signs occasionally suggests a specific process. As examples: Weakness of the face, arm, and leg on one side of the body unaccompanied by sensory, visual, or cognitive abnormalities (pure motor stroke) favors the presence of a thrombotic stroke involving penetrating arteries or a small ICH. Large focal neurologic deficits that begin abruptly or progress quickly are characteristic of embolism or ICH. Abnormalities of language suggest anterior circulation disease, as does the presence of motor and sensory signs on the same side of the body ( figure 7). Vertigo, staggering, diplopia, deafness, crossed symptoms (one side of the face and other side of the body), bilateral motor and/or sensory signs, and hemianopsia suggest involvement of the posterior circulation. (See "Posterior circulation cerebrovascular syndromes".) The sudden onset of impaired consciousness in the absence of focal neurologic signs is characteristic of SAH. (See 'Clinical course of symptoms and signs' above.) https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 10/29 7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate Neuroimaging In the evaluation of acute stroke, imaging studies are necessary to identify hemorrhage as a cause of the deficit, and they are useful to assess the degree of brain injury and to identify the vascular lesion responsible for the ischemic deficit. Advanced CT and MRI technologies are able to distinguish between brain tissue that is irreversibly infarcted and that which is potentially salvageable, thereby allowing better selection of patients who are likely to benefit from therapy. (See "Neuroimaging of acute stroke".) Biomarkers Numerous biomarkers and panels of biomarkers have been studied to improve the early diagnosis of stroke. Two blood biomarkers, NT-proBNP and D-dimer, may have the strongest data to support clinical use in differentiating stroke mechanism, but none have sufficient sensitivity or specificity for routine clinical use. They must be interpreted in the context of the clinical and other laboratory findings. These issues are discussed in greater detail elsewhere. (See "Blood biomarkers for stroke".) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Stroke (The Basics)") Beyond the Basics topics (see "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)") https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 11/29 7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate SUMMARY Classification Stroke is classified into three main subtypes: intracerebral hemorrhage (ICH), subarachnoid hemorrhage (SAH), and ischemic stroke. The classification of stroke is discussed in detail separately. (See "Stroke: Etiology, classification, and epidemiology".) Distinguishing stroke subtypes Patient demographic variables, the presence of stroke risk factors, and findings from the history and physical examination may suggest certain stroke subtypes ( table 2). This presumptive clinical diagnosis requires confirmation by brain and vascular imaging. (See 'Distinguishing stroke subtypes' above.) Clinical course The most important historical item for differentiating stroke subtypes is the pace and course of the symptoms and signs and their clearing. Embolic strokes most often occur suddenly ( figure 2). Thrombosis-related symptoms often fluctuate ( figure 1). Penetrating artery occlusions usually cause symptoms that develop during a short period of time, hours or at most a few days ( figure 5), whereas large artery-related brain ischemia can evolve over a longer period. Intracerebral hemorrhage (ICH) does not improve during the early period; it progresses gradually during minutes or a few hours ( figure 3). Aneurysmal subarachnoid hemorrhage (SAH) develops in an instant. Focal brain dysfunction is less common. (See 'Clinical course of symptoms and signs' above.) Ecology and risk factors Ecology refers to known demographic and historical features that provide probabilities of the patient having one or more of the stroke subtypes. The presence of these risk factors increases the odds that a stroke is due to a particular mechanism, but the clinician cannot make a firm diagnosis simply on the basis of probability. Age, sex, and race (see 'Age, sex, and race' above) Heart disease and atrial fibrillation (see 'Heart disease' above) Hypertension (see 'Hypertension' above) Smoking (see 'Smoking' above) Hyperlipidemia and diabetes (see 'Other risk factors' above) Other historical features A history of transient ischemic attack (TIA), activity just before or at the time of stroke onset, and associated symptoms (eg, fever, severe headache, vomiting, seizure, reduced alertness) are additional features that may favor particular stroke subtypes. (See 'Other historical features' above.) https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 12/29 7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate Clinical evaluation The general physical examination may provide clues suggesting a particular stroke subtype. As an example, the presence of atrial fibrillation favors embolism from the heart. The symptoms and signs found on neurologic examination tell more about the stroke localization than the particular stroke subtype. However, some constellations of symptoms and signs occasionally suggest a specific process; as an example, unilateral weakness unaccompanied by sensory, visual, or cognitive abnormalities (pure motor stroke) favors the presence of a thrombotic stroke involving penetrating arteries or a small ICH. (See 'Clinical evaluation' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Caplan LR. Basic pathology, anatomy, and pathopysiology of stroke. In: Caplan's Stroke: A Cli nical Approach, 4th edition, Saunders Elsevier, Philadelphia 2009. p.22. 2. Caplan LR, Gorelick PB, Hier DB. Race, sex and occlusive cerebrovascular disease: a review. Stroke 1986; 17:648. 3. Weimar C, Mieck T, Buchthal J, et al. Neurologic worsening during the acute phase of ischemic stroke. Arch Neurol 2005; 62:393. 4. Saini M, Ikram K, Hilal S, et al. Silent stroke: not listened to rather than silent. Stroke 2012; 43:3102. 5. Longstreth WT Jr, Dulberg C, Manolio TA, et al. Incidence, manifestations, and predictors of brain infarcts defined by serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study. Stroke 2002; 33:2376. 6. Vermeer SE, Prins ND, den Heijer T, et al. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 2003; 348:1215. 7. Coutts SB, Hill MD, Simon JE, et al. Silent ischemia in minor stroke and TIA patients identified on MR imaging. Neurology 2005; 65:513. 8. Leary MC, Saver JL. Annual incidence of first silent stroke in the United States: a preliminary estimate. Cerebrovasc Dis 2003; 16:280. 9. Schmidt WP, Roesler A, Kretzschmar K, et al. Functional and cognitive consequences of silent stroke discovered using brain magnetic resonance imaging in an elderly population. J Am Geriatr Soc 2004; 52:1045. 10. Giele JL, Witkamp TD, Mali WP, et al. Silent brain infarcts in patients with manifest vascular disease. Stroke 2004; 35:742. https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 13/29 7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate 11. Vermeer SE, Hollander M, van Dijk EJ, et al. Silent brain infarcts and white matter lesions increase stroke risk in the general population: the Rotterdam Scan Study. Stroke 2003; 34:1126. 12. Marini C, Totaro R, De Santis F, et al. Stroke in young adults in the community-based L'Aquila registry: incidence and prognosis. Stroke 2001; 32:52. 13. Towfighi A, Saver JL, Engelhardt R, Ovbiagele B. A midlife stroke surge among women in the United States. Neurology 2007; 69:1898. 14. Wang MY, Mimran R, Mohit A, et al. Carotid stenosis in a multiethnic population. J Stroke Cerebrovasc Dis 2000; 9:64. 15. Wolma J, Nederkoorn PJ, Goossens A, et al. Ethnicity a risk factor? The relation between ethnicity and large- and small-vessel disease in White people, Black people, and Asians within a hospital-based population. Eur J Neurol 2009; 16:522. 16. Rockman CB, Hoang H, Guo Y, et al. The prevalence of carotid artery stenosis varies significantly by race. J Vasc Surg 2013; 57:327. 17. Arboix A, Alio J. Acute cardioembolic cerebral infarction: answers to clinical questions. Curr Cardiol Rev 2012; 8:54. 18. Witt BJ, Brown RD Jr, Jacobsen SJ, et al. A community-based study of stroke incidence after myocardial infarction. Ann Intern Med 2005; 143:785. 19. Yaghi S, Pilot M, Song C, et al. Ischemic Stroke Risk After Acute Coronary Syndrome. J Am Heart Assoc 2016; 5. 20. MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke, and coronary heart disease. Part 1, Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990; 335:765. 21. Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke, and coronary heart disease. Part 2, Short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet 1990; 335:827. 22. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. JAMA 1991; 265:3255. 23. Staessen JA, Fagard R, Thijs L, et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet 1997; 350:757. 24. Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 14/29 7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate studies. Lancet 2002; 360:1903. 25. Seshadri S, Wolf PA, Beiser A, et al. Elevated midlife blood pressure increases stroke risk in elderly persons: the Framingham Study. Arch Intern Med 2001; 161:2343. 26. Song YM, Sung J, Lawlor DA, et al. Blood pressure, haemorrhagic stroke, and ischaemic stroke: the Korean national prospective occupational cohort study. BMJ 2004; 328:324. 27. Markidan J, Cole JW, Cronin CA, et al. Smoking and Risk of Ischemic Stroke in Young Men. Stroke 2018; 49:1276. 28. Boehme AK, Esenwa C, Elkind MS. Stroke Risk Factors, Genetics, and Prevention. Circ Res 2017; 120:472. 29. Kawachi I, Colditz GA, Stampfer MJ, et al. Smoking cessation and decreased risk of stroke in women. JAMA 1993; 269:232. 30. Karapanayiotides T, Piechowski-Jozwiak B, van Melle G, et al. Stroke patterns, etiology, and prognosis in patients with diabetes mellitus. Neurology 2004; 62:1558. 31. Janghorbani M, Hu FB, Willett WC, et al. Prospective study of type 1 and type 2 diabetes and risk of stroke subtypes: the Nurses' Health Study. Diabetes Care 2007; 30:1730. 32. Arenillas JF, Molina CA, Chac n P, et al. High lipoprotein (a), diabetes, and the extent of symptomatic intracranial atherosclerosis. Neurology 2004; 63:27. 33. Baldassarre D, Tremoli E, Franceschini G, et al. Plasma lipoprotein(a) is an independent factor associated with carotid wall thickening in severely but not moderately hypercholesterolemic patients. Stroke 1996; 27:1044. 34. Peltier M, Iannetta Peltier MC, Sarano ME, et al. Elevated serum lipoprotein(a) level is an independent marker of severity of thoracic aortic atherosclerosis. Chest 2002; 121:1589. 35. McEvoy AW, Kitchen ND, Thomas DG. Lesson of the week: intracerebral haemorrhage in young adults: the emerging importance of drug misuse. BMJ 2000; 320:1322. 36. Toossi S, Hess CP, Hills NK, Josephson SA. Neurovascular complications of cocaine use at a tertiary stroke center. J Stroke Cerebrovasc Dis 2010; 19:273. 37. Bhattacharya P, Taraman S, Shankar L, et al. Clinical profiles, complications, and disability in cocaine-related ischemic stroke. J Stroke Cerebrovasc Dis 2011; 20:443. 38. Kernan WN, Viscoli CM, Brass LM, et al. Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med 2000; 343:1826. 39. Oral contraceptives and stroke in young women. Associated risk factors. JAMA 1975; 231:718. 40. Chaturvedi S, Adams HP Jr, Woolson RF. Circadian variation in ischemic stroke subtypes. Stroke 1999; 30:1792. https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 15/29 7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate 41. Bladin CF, Alexandrov AV, Bellavance A, et al. Seizures after stroke: a prospective multicenter study. Arch Neurol 2000; 57:1617. 42. Szaflarski JP, Rackley AY, Kleindorfer DO, et al. Incidence of seizures in the acute phase of stroke: a population-based study. Epilepsia 2008; 49:974. Topic 1134 Version 24.0 https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 16/29 7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate GRAPHICS Pathophysiologic ischemic stroke classification Large vessel atherothrombotic stroke More common Bifurcation of the common carotid artery Siphon portion of the common carotid artery Middle cerebral artery stem Intracranial vertebral arteries proximal to middle basilar artery Origin of the vertebral arteries Less common Origin of the common carotid artery

Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Caplan LR. Basic pathology, anatomy, and pathopysiology of stroke. In: Caplan's Stroke: A Cli nical Approach, 4th edition, Saunders Elsevier, Philadelphia 2009. p.22. 2. Caplan LR, Gorelick PB, Hier DB. Race, sex and occlusive cerebrovascular disease: a review. Stroke 1986; 17:648. 3. Weimar C, Mieck T, Buchthal J, et al. Neurologic worsening during the acute phase of ischemic stroke. Arch Neurol 2005; 62:393. 4. Saini M, Ikram K, Hilal S, et al. Silent stroke: not listened to rather than silent. Stroke 2012; 43:3102. 5. Longstreth WT Jr, Dulberg C, Manolio TA, et al. Incidence, manifestations, and predictors of brain infarcts defined by serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study. Stroke 2002; 33:2376. 6. Vermeer SE, Prins ND, den Heijer T, et al. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 2003; 348:1215. 7. Coutts SB, Hill MD, Simon JE, et al. Silent ischemia in minor stroke and TIA patients identified on MR imaging. Neurology 2005; 65:513. 8. Leary MC, Saver JL. Annual incidence of first silent stroke in the United States: a preliminary estimate. Cerebrovasc Dis 2003; 16:280. 9. Schmidt WP, Roesler A, Kretzschmar K, et al. Functional and cognitive consequences of silent stroke discovered using brain magnetic resonance imaging in an elderly population. J Am Geriatr Soc 2004; 52:1045. 10. Giele JL, Witkamp TD, Mali WP, et al. Silent brain infarcts in patients with manifest vascular disease. Stroke 2004; 35:742. https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 13/29 7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate 11. Vermeer SE, Hollander M, van Dijk EJ, et al. Silent brain infarcts and white matter lesions increase stroke risk in the general population: the Rotterdam Scan Study. Stroke 2003; 34:1126. 12. Marini C, Totaro R, De Santis F, et al. Stroke in young adults in the community-based L'Aquila registry: incidence and prognosis. Stroke 2001; 32:52. 13. Towfighi A, Saver JL, Engelhardt R, Ovbiagele B. A midlife stroke surge among women in the United States. Neurology 2007; 69:1898. 14. Wang MY, Mimran R, Mohit A, et al. Carotid stenosis in a multiethnic population. J Stroke Cerebrovasc Dis 2000; 9:64. 15. Wolma J, Nederkoorn PJ, Goossens A, et al. Ethnicity a risk factor? The relation between ethnicity and large- and small-vessel disease in White people, Black people, and Asians within a hospital-based population. Eur J Neurol 2009; 16:522. 16. Rockman CB, Hoang H, Guo Y, et al. The prevalence of carotid artery stenosis varies significantly by race. J Vasc Surg 2013; 57:327. 17. Arboix A, Alio J. Acute cardioembolic cerebral infarction: answers to clinical questions. Curr Cardiol Rev 2012; 8:54. 18. Witt BJ, Brown RD Jr, Jacobsen SJ, et al. A community-based study of stroke incidence after myocardial infarction. Ann Intern Med 2005; 143:785. 19. Yaghi S, Pilot M, Song C, et al. Ischemic Stroke Risk After Acute Coronary Syndrome. J Am Heart Assoc 2016; 5. 20. MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke, and coronary heart disease. Part 1, Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990; 335:765. 21. Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke, and coronary heart disease. Part 2, Short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet 1990; 335:827. 22. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. JAMA 1991; 265:3255. 23. Staessen JA, Fagard R, Thijs L, et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet 1997; 350:757. 24. Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 14/29 7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate studies. Lancet 2002; 360:1903. 25. Seshadri S, Wolf PA, Beiser A, et al. Elevated midlife blood pressure increases stroke risk in elderly persons: the Framingham Study. Arch Intern Med 2001; 161:2343. 26. Song YM, Sung J, Lawlor DA, et al. Blood pressure, haemorrhagic stroke, and ischaemic stroke: the Korean national prospective occupational cohort study. BMJ 2004; 328:324. 27. Markidan J, Cole JW, Cronin CA, et al. Smoking and Risk of Ischemic Stroke in Young Men. Stroke 2018; 49:1276. 28. Boehme AK, Esenwa C, Elkind MS. Stroke Risk Factors, Genetics, and Prevention. Circ Res 2017; 120:472. 29. Kawachi I, Colditz GA, Stampfer MJ, et al. Smoking cessation and decreased risk of stroke in women. JAMA 1993; 269:232. 30. Karapanayiotides T, Piechowski-Jozwiak B, van Melle G, et al. Stroke patterns, etiology, and prognosis in patients with diabetes mellitus. Neurology 2004; 62:1558. 31. Janghorbani M, Hu FB, Willett WC, et al. Prospective study of type 1 and type 2 diabetes and risk of stroke subtypes: the Nurses' Health Study. Diabetes Care 2007; 30:1730. 32. Arenillas JF, Molina CA, Chac n P, et al. High lipoprotein (a), diabetes, and the extent of symptomatic intracranial atherosclerosis. Neurology 2004; 63:27. 33. Baldassarre D, Tremoli E, Franceschini G, et al. Plasma lipoprotein(a) is an independent factor associated with carotid wall thickening in severely but not moderately hypercholesterolemic patients. Stroke 1996; 27:1044. 34. Peltier M, Iannetta Peltier MC, Sarano ME, et al. Elevated serum lipoprotein(a) level is an independent marker of severity of thoracic aortic atherosclerosis. Chest 2002; 121:1589. 35. McEvoy AW, Kitchen ND, Thomas DG. Lesson of the week: intracerebral haemorrhage in young adults: the emerging importance of drug misuse. BMJ 2000; 320:1322. 36. Toossi S, Hess CP, Hills NK, Josephson SA. Neurovascular complications of cocaine use at a tertiary stroke center. J Stroke Cerebrovasc Dis 2010; 19:273. 37. Bhattacharya P, Taraman S, Shankar L, et al. Clinical profiles, complications, and disability in cocaine-related ischemic stroke. J Stroke Cerebrovasc Dis 2011; 20:443. 38. Kernan WN, Viscoli CM, Brass LM, et al. Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med 2000; 343:1826. 39. Oral contraceptives and stroke in young women. Associated risk factors. JAMA 1975; 231:718. 40. Chaturvedi S, Adams HP Jr, Woolson RF. Circadian variation in ischemic stroke subtypes. Stroke 1999; 30:1792. https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 15/29 7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate 41. Bladin CF, Alexandrov AV, Bellavance A, et al. Seizures after stroke: a prospective multicenter study. Arch Neurol 2000; 57:1617. 42. Szaflarski JP, Rackley AY, Kleindorfer DO, et al. Incidence of seizures in the acute phase of stroke: a population-based study. Epilepsia 2008; 49:974. Topic 1134 Version 24.0 https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 16/29 7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate GRAPHICS Pathophysiologic ischemic stroke classification Large vessel atherothrombotic stroke More common Bifurcation of the common carotid artery Siphon portion of the common carotid artery Middle cerebral artery stem Intracranial vertebral arteries proximal to middle basilar artery Origin of the vertebral arteries Less common Origin of the common carotid artery Posterior cerebral artery stem Origin of the major branches of the basilar-vertebral arteries Origin of the branches of the anterior, middle, and posterior cerebral arteries Small vessel (lacunar) stroke Mechanism Lipohyalinotic occlusion Less frequently proximal atherothrombotic occlusion Least likely embolic occlusion Most common locations Penetrating branches of the anterior, middle, and posterior cerebral and basilar arteries Cardioaortic embolic stroke Cardiac sources definite - antithrombotic therapy generally used Left atrial thrombus Left ventricular thrombus Atrial fibrillation and paroxysmal atrial fibrillation Sustained atrial flutter Recent myocardial infarction (within one month) Rheumatic mitral or aortic valve disease Bioprosthetic and mechanical heart valve https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 17/29 7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate Chronic myocardial infarction with ejection fraction <28 percent Symptomatic heart failure with ejection fraction <30 percent Dilated cardiomyopathy Cardiac sources definite - anticoagulation hazardous Bacterial endocarditis (exception nonbacterial) Atrial myxoma Cardiac sources possible Mitral annular calcification Patent foramen ovale Atrial septal aneurysm Atrial septal aneurysm with patent foramen ovale Left ventricular aneurysm without thrombus Isolated left atrial spontaneous echo contrast ("smoke") without mitral stenosis or atrial fibrillation Mitral valve strands Ascending aortic atheromatous disease (>4 mm) True unknown source embolic stroke Other Dissection Moyamoya Binswanger's disease Primary thrombosis Cerebral mass Graphic 55099 Version 4.0 https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 18/29 7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate Stuttering time course of thrombotic stroke The course of weakness of the right limb in a patient with a thrombotic stroke reveals fluctuating symptoms, varying between normal and abnormal, progressing in a stepwise or stuttering fashion with some periods of improvement. Graphic 64107 Version 2.0 https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 19/29 7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate Time course of embolic stroke Embolic stroke occurs suddenly, with symptoms maximal at onset. This patient had multiple embolic events with different clinical symptoms (initially weakness, followed by paresthesias). Graphic 73261 Version 1.0 https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 20/29 7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate Time course of neurologic changes in intracerebral hemorrhage Schematic representation of rapid downhill course in terms of unusual behavior (solid line), hemimotor function (dotted line), and consciousness (dash-dotted line) in a patient with intracerebral (intraparenchymal) hemorrhage. Graphic 61491 Version 3.0 https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 21/29 7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate Headache and vomiting in stroke subtypes The frequency of sentinel headache, onset headache, and vomiting in three subtypes of stroke: subarachnoid hemorrhage, intraparenchymal (intracerebral) hemorrhage, and ischemic stroke. Onset headache was present in virtually all patients with SAH and about one-half of those with IPH; all of these symptoms were infrequent in patients with IS. SAH: subarachnoid hemorrhage; IPH: intraparenchymal (intracerebral) hemorrhage; IS: ischemic stroke. Data from: Gorelick PB, Hier DB, Caplan LR, Langenberg P. Headache in acute cerebrovascular disease. Neurology 1986; 36:1445. Graphic 60831 Version 4.0 https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 22/29 7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate Characteristics of stroke subtypes Stroke type Clinical course Risk factors Other clues Intracerebral hemorrhage Gradual onset and progression during minutes or hours in most patients, but may present abruptly with Hypertension, trauma, bleeding diatheses, illicit drugs (eg, amphetamines, cocaine), vascular malformations. More common in Black people and Asian people than May be precipitated by sex or other physical activity. Patient may have maximal deficit at onset. in White people. reduced alertness. Subarachnoid hemorrhage Abrupt onset of sudden, severe headache. Focal brain dysfunction less common than with other Smoking, hypertension, moderate to heavy alcohol use, genetic susceptibility (eg, polycystic kidney disease, family history of May be precipitated by sex or other physical activity. types. subarachnoid hemorrhage) and Patient may have sympathomimetic drugs (eg, cocaine) reduced alertness. Ischemic Stuttering progression Atherosclerotic risk factors (age, May have neck (thrombotic) with periods of improvement. Lacunes smoking, diabetes mellitus, etc). Males affected more commonly than bruit. develop over hours or at females. May have history of TIA. most a few days; large artery ischemia may evolve over longer periods. Ischemic Sudden onset with Atherosclerotic risk factors as listed Can be (embolic) deficit maximal at onset. Clinical findings may above. Males affected more commonly than females. History of precipitated by getting up at improve quickly. heart disease (valvular, atrial night to urinate fibrillation, endocarditis). or sudden coughing or sneezing. Graphic 69907 Version 5.0 https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 23/29 7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate Time course of lacunar infarction Penetrating artery occlusions usually cause symptoms that develop over a short period of time, hours or at most a few days, compared to large artery-related brain ischemia which can evolve over a longer period. A stuttering course may ensue, as with large artery thrombosis. This patient had a pure motor hemiparesis. Graphic 52246 Version 1.0 https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 24/29 7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate Cardioaortic sources of cerebral embolism Sources with high primary risk for Sources with low or uncertain primary ischemic stroke risk for ischemic stroke Atrial fibrillation Cardiac sources of embolism: Paroxysmal atrial fibrillation Mitral annular calcification Left atrial thrombus Patent foramen ovale Left ventricular thrombus Atrial septal aneurysm Sick sinus syndrome Atrial septal aneurysm and patent foramen ovale Atrial flutter Left ventricular aneurysm without thrombus Recent myocardial infarction (within one month prior to stroke) Left atrial spontaneous echo contrast ("smoke") Mitral stenosis or rheumatic valve disease Congestive heart failure with ejection fraction <30% Mechanical heart valves Bioprosthetic heart valves Chronic myocardial infarction together with low ejection fraction (<28%) Apical akinesia Dilated cardiomyopathy (prior established Wall motion abnormalities (hypokinesia, diagnosis or left ventricular dilatation with an ejection fraction of <40% or fractional shortening akinesia, dyskinesia) other than apical akinesia of <25%) Nonbacterial thrombotic endocarditis Hypertrophic cardiomyopathy Infective endocarditis Left ventricular hypertrophy Papillary fibroelastoma Left ventricular hypertrabeculation/non- compaction Left atrial myxoma Recent aortic valve replacement or coronary artery bypass graft surgery Presence of left ventricular assist device Paroxysmal supraventricular tachycardia Aortic sources of embolism: Complex atheroma in the ascending aorta or proximal arch (protruding with >4 mm thickness, or mobile debris, or plaque ulceration) The high- and low-risk cardioaortic sources in this table are separated using an arbitrary 2% annual https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 25/29 7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate or one-time primary stroke risk threshold. Data from: 1. Ay H, Benner T, Arsava EM, et al. A computerized algorithm for etiologic classi cation of ischemic stroke: the Causative Classi cation of Stroke System. Stroke 2007; 38:2979. 2. Ay H, Furie KL, Singhal A, et al. An evidence-based causative classi cation system for acute ischemic stroke. Ann Neurol 2005; 58:688. 3. Arsava EM, Ballabio E, Benner T, et al. The Causative Classi cation of Stroke system: an international reliability and optimization study. Neurology 2010; 75:1277. 4. Kamel H, Elkind MS, Bhave PD, et al. Paroxysmal supraventricular tachycardia and the risk of ischemic stroke. Stroke 2013; 44:1550. 5. Kirklin JK, Pagani FD, Kormos RL, et al. Eighth annual INTERMACS report: Special focus on framing the impact of adverse events. J Heart Lung Transplant 2017; 36:1080. Reproduced and modi ed with permission from: Ay H, Furie KL, Singhal A, et al. An evidence-based causative classi cation system for acute ischemic stroke. Ann Neurol 2005; 58:688. Copyright 2005 American Neurological Association. Graphic 60843 Version 11.0 https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 26/29 7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate Stroke mortality related to blood pressure and age Stroke mortality rate, pictured on a log scale with 95% CI, in each decade of age in relation to the estimated usual systolic and diastolic blood pressure at the start of that decade. Stroke mortality increases with both higher pressures and older ages. For diastolic pressure, each age-specific regression line ignores the left-hand point (ie, at slightly less than 75 mmHg) for which the risk lies significantly above the fitted regression line (as indicated by the broken line below 75 mmHg). CI: confidence interval. Data from Prospective Studies Collaboration, Lancet 2002; 360:1903. Graphic 66793 Version 5.0 https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 27/29 7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate Occlusion of middle and anterior cerebral arteries Reproduced with permission from: Netter, FH, Caplan, LR. Cerebrovascular Disease, Section III, Plate 8. In: The Netter Collection of Medical Illustrations, Vol 1, Nervous System, Part II, Neurologic and Neuromuscular Disorders, Netter, FH, Jones, HR, Dingle, RV (Eds), MediMedia USA, Inc 1986. Copyright 1986 Elsevier. Graphic 69630 Version 1.0 https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 28/29 7/5/23, 11:52 AM Clinical diagnosis of stroke subtypes - UpToDate Contributor Disclosures Louis R Caplan, MD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/clinical-diagnosis-of-stroke-subtypes/print 29/29

7/5/23, 11:53 AM Intracranial epidural hematoma in adults - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Intracranial epidural hematoma in adults : William McBride, MD : Jos Biller, MD, FACP, FAAN, FAHA, Alejandro A Rabinstein, MD : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 03, 2022. INTRODUCTION Subdural hematoma (SDH) and epidural hematoma (EDH) are characterized by bleeding into the spaces surrounding the brain or spinal cord. SDHs form between the dura and the arachnoid membranes. EDHs arise in the potential space between the dura and the skull. Clinical issues related to intracranial EDH in adults will be reviewed here. A rapid overview summarizes the clinical features, evaluation, and management of EDH in adults ( table 1). EDH in children and SDH are discussed separately: (See "Intracranial epidural hematoma in children: Epidemiology, anatomy, and pathophysiology".) (See "Intracranial epidural hematoma in children: Clinical features, diagnosis, and management".) (See "Subdural hematoma in adults: Etiology, clinical features, and diagnosis".) EPIDEMIOLOGY AND ETIOLOGY EDH is an uncommon but serious complication of head injury. While the exact incidence is unknown, it is found in 1 to 4 percent of traumatic head injury cases and 5 to 15 percent of https://www.uptodate.com/contents/intracranial-epidural-hematoma-in-adults/print 1/25 7/5/23, 11:53 AM Intracranial epidural hematoma in adults - UpToDate autopsy series [1,2]. The incidence of EDH is highest among adolescents and young adults. In observational studies, the mean age of patients with EDH is between 20 and 30 years of age [2]. EDH is rare in patients older than 50 to 60 years of age. Most cases of EDH are due to head trauma caused by traffic accidents, falls, and assaults. Skull fractures are present in 75 to 95 percent of patients [3]. In the setting of closed head injury, the linear translation of acceleration along the diameter of the skull in the lateral direction can produce injury to veins, arteries, or brain parenchyma, resulting in subdural hematoma (SDH), EDH, or coup-countercoup contusions [4]. In addition, thalamic lesions and secondary brainstem injury may develop as a consequence of the mass effect produced by a large EDH or SDH. Key differences between SDH and EDH are readily demonstrable by unenhanced computed tomography (CT) of the head. EDH does not cross sutural margins but does cross dural attachments because it is located in the potential space between dura and skull. As a result, EDH characteristically has a lens-shaped appearance. In comparison, SDH can cross sutural margins but is limited by dural attachments and therefore appears as a crescent-shaped extra-axial lesion. EDH in adults is most commonly (approximately 85 percent of cases) due to arterial injury [1,2,5]. The major cause of arterial injury is trauma to the skull base with associated tearing of the middle meningeal artery as it courses through the foramen spinosum, resulting in hemorrhage over the cerebral convexity in the middle cranial fossa. In addition, EDH is occasionally found in the anterior cranial fossa, owing to rupture of the anterior meningeal artery, and rarely due to a dural arteriovenous fistula at the vertex [6]. In approximately 15 percent of cases, injury to one of the dural sinuses or the confluence of sinuses in the posterior cranial fossa proves to be the source of hemorrhage [1]. Nontraumatic acute EDH is rare. Potential etiologies include: Infection, coagulopathy, congenital anomalies, vascular malformations of the dura, and hemorrhagic tumors [7,8] Complication of neurosurgical procedures Epidural abscess, leading to pressure necrosis of meningeal vessels [9] https://www.uptodate.com/contents/intracranial-epidural-hematoma-in-adults/print 2/25 7/5/23, 11:53 AM Intracranial epidural hematoma in adults - UpToDate Pregnancy, sickle cell disease, systemic lupus erythematosus, open heart surgery, Paget disease of the skull, and hemodialysis [8,10-14] Postulated mechanisms of EDH during hemodialysis include fluctuations of intracranial pressure, heparin administration, hypertension in the presence of anticoagulation, and uremic platelet dysfunction [11,15]. CLINICAL MANIFESTATIONS As with subdural hematoma (SDH), the initial presentation of EDH has a spectrum of manifestations. Severe head trauma may result in EDH with coma, while a lesser injury may produce EDH with only momentary loss of consciousness. In some patients with acute EDH and transient loss of consciousness, there is a so-called "lucid interval" with recovery of consciousness, followed by deterioration over a period of hours due to continued arterial bleeding and hematoma expansion [16]. This deterioration is typically associated with symptoms such as headache, vomiting, drowsiness, confusion, aphasia, seizures, and hemiparesis [2,17]. In a systematic review, a lucid interval followed by deterioration was observed in 456 of 963 patients (47 percent) who had surgery for EDH [2]. A similar sequence can be seen with EDH due to venous bleeding, with the exception that the neurologic decline is typically slower, occurring over days to weeks [17]. In any of the above settings, unchecked hematoma expansion leads to elevated intracranial pressure and clinical signs, such as an ipsilateral dilated pupil (due to uncal herniation with compression of the oculomotor nerve) or the Cushing reflex (ie, hypertension, bradycardia, and respiratory depression/irregularity). Such events will culminate in brain herniation and death unless immediate decompression is undertaken. Approximately 7 to 14 percent of traumatic intracranial EDHs occur in the posterior fossa [18]. Such patients may present with elevated intracranial pressure due to venous sinus obstruction [19]. In some instances, cortical blindness is observed secondary to bioccipital dysfunction [20]. DIAGNOSTIC EVALUATION In the setting of acute head trauma, imaging serves a key role in both diagnosis and appropriate initial treatment [21,22]. In addition to EDH, head trauma is a major cause of a variety of other central nervous system lesions including subdural hematoma (SDH), subarachnoid hemorrhage, https://www.uptodate.com/contents/intracranial-epidural-hematoma-in-adults/print 3/25 7/5/23, 11:53 AM Intracranial epidural hematoma in adults - UpToDate cerebral contusion, diffuse brain swelling, and laceration [2,17]. Any of these injuries may coexist in a given patient following trauma, and their clinical manifestations can be difficult to distinguish. However, it is important to identify the specific nature of the lesion during initial evaluation, since potentially life-saving treatment will differ with the lesion. Lumbar puncture is contraindicated in cases where a space-occupying lesion such as EDH is suspected, due to the risk of herniation. Head CT Computed tomography of the head is the most widely used imaging study for acute head trauma owing to its speed, relative simplicity, and widespread availability [21]. Most EDHs are identifiable on CT. Findings Epidural blood produces a lens-shaped or biconvex pattern on head CT because its collection is limited by firm dural attachments at the cranial sutures ( image 1) [1,22]. Occasionally, heterogeneous foci of lower attenuation appear within an acute EDH. This finding of a mixed-density blood clot (or swirl sign) indicates active extravasation of blood and represents an indication for immediate surgical evaluation [4]. Of note, acute EDH may not be apparent on initial head CT in up to 8 percent of cases [23]. Several issues may be associated with a nondiagnostic head CT, including: Severe anemia, which lowers the density of the hemorrhage Severe hypotension, which reduces the rate of arterial extravasation Early scanning after trauma, before enough blood has accumulated to be visible on imaging Venous bleeding with slow accumulation of blood Hematoma volume estimation Hematoma volume influences management decisions in adult patients with acute EDH because it correlates with outcome. The hematoma volume can be estimated quickly from the head CT scan by using the formula ABC/2, which approximates the volume of an ellipsoid. This formula was originally used to estimate intracerebral hemorrhage volume but can be applied to EDH as well [2]. The formula is calculated using the centimeter scale on the CT images as follows [24]: A is the greatest hemorrhage diameter on the CT slice with the largest area of hemorrhage B is the largest diameter 90 degrees to A on the same CT slice C is the approximate number of CT slices with hemorrhage multiplied by the slice thickness in centimeters https://www.uptodate.com/contents/intracranial-epidural-hematoma-in-adults/print 4/25 7/5/23, 11:53 AM Intracranial epidural hematoma in adults - UpToDate To calculate C, each CT slice with hemorrhage is visually compared with the CT slice with the largest hemorrhage [24]. An individual hemorrhage slice is counted as one full slice for determining C if the hemorrhage area is >75 percent of the area on the slice with the largest hemorrhage. A slice is counted as one-half if the hemorrhage area is approximately 25 to 75 percent of the area on the largest hemorrhage slice. The slice is not counted if the area is <25 percent of the largest hemorrhage slice. Brain MRI Although head CT is more widely used, brain magnetic resonance imaging is more sensitive than head CT for the detection of intracranial bleeding ( image 2) [25]. MRI is especially useful in the diagnosis EDH at the vertex [26]. In most centers, MRI is typically used an adjunct to CT in the evaluation of acute head trauma when there is a strong suspicion for EDH or SDH (ie, suppressed level of consciousness or focal neurologic deficit in the setting of trauma) despite no clear evidence of hematoma by CT. The MRI signal appearance of EDH can evolve over time in a manner similar to that observed in parenchymal hematoma [17]. However, the timing of MRI signal progression in EDH is more variable and less well studied than with intracerebral hemorrhage. In the hyperacute phase (within hours of onset), the clot may be isointense or hyperintense on T2-weighted images. Signal heterogeneity within the clot may reflect active bleeding. The acute clot may be hypointense on T2-weighted images due to the presence of deoxyhemoglobin. On T2*-weighted (gradient recall echo or susceptibility-weighted) images, blood is typically hypointense. Over subsequent weeks, deoxyhemoglobin degrades to methemoglobin, which appears hyperintense on both T1- and T2-weighted images. At several months, only hemosiderin remains, and the clot again becomes hypointense on the T1-weighted images. Angiography Under unusual conditions, cerebral angiography is indicated for the evaluation of EDH. As an example, EDH located at the vertex can originate from a dural arteriovenous fistula of the middle meningeal artery. In this setting, angiography is necessary to fully evaluate the possibility of an underlying vascular lesion [6,27]. MANAGEMENT Acute symptomatic EDH is a neurologic emergency that often requires surgical treatment to prevent irreversible brain injury and death caused by hematoma expansion, elevated intracranial https://www.uptodate.com/contents/intracranial-epidural-hematoma-in-adults/print 5/25 7/5/23, 11:53 AM Intracranial epidural hematoma in adults - UpToDate pressure, and brain herniation. Select patients who present in good clinical condition with small- volume EDH can be managed nonoperatively as long as they remain stable. Close observation and serial brain imaging is an important aspect of nonoperative management, since hematoma enlargement and neurologic deterioration requiring surgery may occur in such patients. Glucocorticoid therapy is not indicated following head injury including EDH as it has been associated with increased acute mortality. This issue is discussed separately. (See "Evaluation and management of elevated intracranial pressure in adults", section on 'Glucocorticoids'.) Reversing anticoagulation Coexistent anticoagulation in patients with either traumatic or spontaneous EDH is not uncommon and must be reversed before surgical intervention. In addition, we reverse anticoagulation for most patients who are managed nonoperatively. However, the potential benefit of reversing anticoagulation (a reduced risk of hematoma enlargement) must be weighed against the risk related to the underlying need for anticoagulation in this group (eg, atrial fibrillation, mechanical heart valve, etc). Effective reversal of the effects of anticoagulation therapy varies by agent. Our preferred strategy for patients with EDH is similar to that recommended for patients with other forms of intracranial hemorrhage. (See "Reversal of anticoagulation in intracranial hemorrhage".) Warfarin We use 4-factor prothrombin complex concentrate (PCC) along with vitamin K 10 mg by slow intravenous infusion ( table 2). We use fresh frozen plasma (FFP) if PCC is not available. The goal of therapy should be an INR in the normal range (ie, <1.2 in most laboratories). (See "Reversal of anticoagulation in intracranial hemorrhage", section on 'Warfarin'.) Dabigatran We use idarucizumab or a 4-factor PCC if idarucizumab is unavailable ( table 3). (See "Reversal of anticoagulation in intracranial hemorrhage", section on 'Dabigatran'.) Direct factor Xa inhibitors (eg, apixaban, edoxaban, rivaroxaban) We use either andexanet alfa or a 4-factor PCC ( table 3). (See "Reversal of anticoagulation in intracranial hemorrhage", section on 'Apixaban, edoxaban, and rivaroxaban'.) Heparin and low molecular weight heparins Protamine sulfate reverses the effects of heparins. The dose varies by the type of heparin used and the time elapsed since the last dose. Andexanet alfa may be used for patients taking low molecular weight heparin. (See "Reversal of anticoagulation in intracranial hemorrhage", section on 'Unfractionated heparin' and "Reversal of anticoagulation in intracranial hemorrhage", section on 'LMW heparin'.) https://www.uptodate.com/contents/intracranial-epidural-hematoma-in-adults/print 6/25 7/5/23, 11:53 AM Intracranial epidural hematoma in adults - UpToDate Deciding who needs surgery Most patients with large or symptomatic EDH require emergent surgical hematoma evacuation to prevent irreversible brain injury or death caused by hematoma expansion, elevated intracranial pressure, and brain herniation. Criteria for surgery established by an expert panel in 2006 include patients with EDH and any of the following features [2]: Focal signs or symptoms attributable to the acute EDH Coma (Glasgow Coma Scale [GCS] score <9) and pupillary abnormalities due to acute EDH 3 Large hematoma volume (>30 cm [>30 mL]) Hematoma growth causing elevated intracranial pressure or neurologic deterioration For patients with acute EDH who are awake and have no focal neurologic deficits, we suggest management based upon the size of the hematoma and the degree of midline shift, in 3 agreement with guidelines [2]. Patients with a small hematoma (hematoma volume <30 cm and clot thickness <15 mm and midline shift <5 mm on brain imaging) are managed nonoperatively with close observation. Those not meeting these criteria are managed surgically. Surgical techniques Craniotomy with hematoma evacuation is the mainstay of surgical treatment of symptomatic acute EDH. When indicated, identification and ligation of the bleeding vessel must be undertaken. However, there are few data comparing different surgical techniques. Burr hole evacuation (trephination) has been used for acute EDH and may be lifesaving if access to neurosurgical expertise is limited or likely to be delayed [28]. Open craniotomy affords a more complete evacuation of the hematoma [2]. Craniectomy may be performed in selected cases when the EDH is associated with significant underlying cerebral edema or midline shift. An endovascular approach with middle meningeal artery embolization has been used to stabilize bleeding and avoid open surgery for some patients with small EDH [29]. Timing of surgery The available evidence, though limited, suggests that surgery should be performed within one to two hours after head trauma or the onset of neurologic deterioration for comatose patients with acute EDH and signs of brain herniation. One series of patients with acute EDH compared surgery within two hours after onset of coma (n = 18) with later surgery (n = 16). Patients who had early evacuation had a significantly lower mortality rate (17 versus 56 percent) and higher rate of good recovery (67 versus 13 percent) [30]. Another series of adults with acute EDH and admission GCS score <8 included 10 patients who developed new anisocoria after admission [31]. Five patients had craniotomy more than 90 minutes after onset of anisocoria, and all of these patients died. Another five patients had craniotomy within 70 minutes after anisocoria onset, and all survived with either good recovery or moderate disability. https://www.uptodate.com/contents/intracranial-epidural-hematoma-in-adults/print 7/25 7/5/23, 11:53 AM Intracranial epidural hematoma in adults - UpToDate Nonoperative management We recommend close observation to monitor for neurologic deterioration or hematoma enlargement for all patients with small or mildly symptomatic EDH who are managed nonoperatively. (See 'Deciding who needs surgery' above.) Serial clinical examinations We monitor patients with EDH in an inpatient setting with neurosurgical expertise [2]. Neurologic assessments including the GCS score ( table 4) should be performed every one to two hours for at least the first 24 hours after presentation. The frequency of examinations may be subsequently reduced for patients with stable imaging and clinical findings. Repeat head CT We obtain surveillance repeat head CT scan no later than six to eight hours after initial imaging, in agreement with guidelines [2]. In addition, urgent repeat head CT is warranted for all patients with neurologic deterioration. EDH expansion is likeliest in the first 36 hours after injury and may precede neurologic deterioration when expansion is mild or when severe initial impairment on neurologic examination limits the ability to assess for clinical deterioration. In a retrospective study of 160 adult patients with EDH who were managed nonoperatively, hematoma expansion on follow-up head CT was observed in 23 percent [32]. The mean time to enlargement after injury was eight hours, and enlargement occurred within 36 hours after injury in all cases where it was observed. Another retrospective study evaluated patients who had two head CT scans in the first 24 hours after traumatic brain injury, with a mean time to follow-up scan of seven hours [33]. Early hemorrhage expansion was seen in 22 percent of patients with EDH. Progressive hematoma enlargement of small EDHs over several weeks has also been reported in patients followed by serial CT [17]. Calcification and ossification of persistent EDH has been reported and would suggest a need for surgical evacuation of EDHs that do not spontaneously absorb over the course of serial follow-up examinations, even if the patient's clinical condition is good [34]. No randomized trials have compared surgery with conservative management for patients with EDH, but retrospective data suggest that stable patients with EDH who have small hematomas and mild symptoms can be managed nonoperatively [35-37]. In one case series, 80 patients with acute EDH were selected for nonoperative management on the basis of a GCS score >8, an EDH 3 volume <30 mL (<30 cm ), and clot thickness <20 mm [37]. Subsequent surgical evacuation for neurologic deterioration and hematoma enlargement occurred in five patients, one of whom died and four had a good outcome. In another series of 74 patients with traumatic EDH and good initial clinical status (GCS score >12) who were managed nonoperatively, neurologic https://www.uptodate.com/contents/intracranial-epidural-hematoma-in-adults/print 8/25 7/5/23, 11:53 AM Intracranial epidural hematoma in adults - UpToDate deterioration occurred in 14 patients (19 percent), prompting delayed surgery [38]. Patients requiring surgery were more likely to have EDH volume >30 mL, clot thickness >15 mm, and midline shift >5 mm than those who did not have surgery. All patients in this series achieved a good outcome. Intracranial pressure Patients with EDH may develop elevated intracranial pressure requiring urgent intervention. Definitive therapy is usually hematoma evacuation; medical resuscitation techniques include head elevation, hyperventilation, and osmotic diuresis with intravenous mannitol or hypertonic saline. The management of elevated intracranial pressure is reviewed elsewhere. (See "Evaluation and management of elevated intracranial pressure in adults".) PROGNOSIS Data regarding outcome after EDH are mainly from observational studies. In surgical series, mortality after EDH in adults and children is approximately 10 and 5 percent, respectively [2]. The full range of outcomes is illustrated by the following studies: In a study that prospectively collected data for 107 consecutive patients with EDH, the overall mortality was 5 percent, and there were no deaths among patients with a Glasgow Coma Scale (GCS) score 8 who underwent hematoma evacuation [39]. At six months after injury, a good recovery was observed in 89 percent of the cohort. In a retrospective review of 139 adult patients with EDH admitted to an intensive care unit, 46 percent had a good recovery, 31 percent were moderately disabled, 10 percent were severely disabled, 4 percent were persistently vegetative, and 9 percent died [40]. Prognostic indicators In observational studies, the following variables have been associated with unfavorable outcome from EDH [2]: Low GCS score on admission or before surgery [39,41-44]. The GCS grades coma severity according to three categories of responsiveness: best eye opening, best verbal, and best motor response. The GCS is scored between 3 and 15, with higher scores indicating better performance ( table 4). Presence of pupillary abnormalities, particularly contralateral or bilateral unreactive pupils [31,42,43,45,46]. Older age [43]. https://www.uptodate.com/contents/intracranial-epidural-hematoma-in-adults/print 9/25 7/5/23, 11:53 AM Intracranial epidural hematoma in adults - UpToDate Coagulopathy or leukocytosis at admission [44]. Longer time interval between neurologic deterioration and surgery [30,31]. Postoperative elevated intracranial pressure [40,46]. In addition, several studies have identified head CT findings that correlate with poor outcome: 3 Hematoma volume >30 to 150 cm [42,45] Presence of midline shift >10 to 12 mm [42] Mixed-density blood clot, indicating acute bleeding [45] Presence of associated intracranial lesions such as contusions, intracerebral hemorrhage, subarachnoid hemorrhage, and diffuse brain swelling [30,42,43,45] SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) SUMMARY AND RECOMMENDATIONS Rapid overview A rapid overview summarizes the clinical features, evaluation, and management of EDH in adults ( table 1). Definition and etiology Epidural hematoma (EDH) is caused by bleeding in the potential space between the dura and the skull, usually as a consequence of traumatic injury. Nontraumatic acute EDH is rare. The source of blood in EDH is most often arterial, but 15 percent of cases are due to venous bleeding. (See 'Epidemiology and etiology' above.) Clinical features Clinical manifestations of EDH are highly variable and include altered consciousness, headache, vomiting, drowsiness, confusion, aphasia, seizures, and hemiparesis. Some patients with acute EDH and transient loss of consciousness have a "lucid interval" with recovery of consciousness, followed by deterioration due to hematoma enlargement. (See 'Clinical manifestations' above.) Imaging diagnosis Head CT is a fast and accurate method for the detection of acute intracranial hemorrhage ( image 1). Epidural blood produces a lens-shaped pattern on https://www.uptodate.com/contents/intracranial-epidural-hematoma-in-adults/print 10/25 7/5/23, 11:53 AM Intracranial epidural hematoma in adults - UpToDate head CT. Brain MRI has a higher sensitivity than CT and can be useful when diagnostic uncertainty exists. (See 'Diagnostic evaluation' above.) Management Reverse anticoagulation Coexistent anticoagulation must be reversed before surgical intervention for patients with either traumatic or spontaneous EDH. In addition, we reverse anticoagulation for most patients who are managed nonoperatively ( table 2 and table 3). However, the potential benefit of reversing anticoagulation to prevent EDH expansion must be weighed against the risk related to the underlying need for anticoagulation in this group. (See 'Reversing anticoagulation' above.) Surgery for most patients Urgent surgical hematoma evacuation is required for patients with EDH that is large (ie, >30 mL) or causing focal or progressive neurologic deficits to prevent irreversible brain injury or death caused by hematoma expansion, elevated intracranial pressure, and brain herniation. In addition, we recommend surgical evacuation for patients with coma or early signs of brain herniation on imaging, given the potential for recovery (Grade 1C). Other patients with smaller EDH and milder symptoms may be managed nonoperatively with close observation. (See 'Management' above and 'Deciding who needs surgery' above.) Nonoperative surveillance We recommend close observation to monitor for neurologic deterioration or hematoma enlargement for all patients with small or mildly symptomatic EDH who are managed nonoperatively. (See 'Nonoperative management' above.) We monitor patients with EDH in an inpatient setting with neurosurgical expertise. Neurologic assessments including the Glasgow Coma Scale (GCS) score ( table 4) should be performed every one to two hours for at least the first 24 hours after presentation. The frequency of examinations may be subsequently reduced for patients with stable imaging and clinical findings. We obtain surveillance repeat head CT scan no later than six to eight hours after initial imaging. In addition, urgent repeat head CT is warranted for all patients with neurologic deterioration. Prognosis The majority of patients have a good recovery with appropriate management of EDH, but mortality in adults and children is approximately 10 and 5 percent, respectively. Factors associated with poor prognosis include the severe neurologic deficits, the presence https://www.uptodate.com/contents/intracranial-epidural-hematoma-in-adults/print 11/25 7/5/23, 11:53 AM Intracranial epidural hematoma in adults - UpToDate of pupillary abnormalities, larger hematoma volume or degree of midline brain shift, and coexisting trauma or coagulation disorders. (See 'Prognosis' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges David Brock, MD, CIP, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Mayer S, Rowland L. Head injury. In: Merritt's Neurology, Rowland L (Ed), Lippincott Williams & Wilkins, Philadelphia 2000. p.401. 2. Bullock MR, Chesnut R, Ghajar J, et al. Surgical management of acute epidural hematomas. Neurosurgery 2006; 58:S7. 3. Talbott JF, Gean A, Yuh EL, Stiver SI. Calvarial fracture patterns on CT imaging predict risk of a delayed epidural hematoma following decompressive craniectomy for traumatic brain injury. AJNR Am J Neuroradiol 2014; 35:1930. 4. Besenski N. Traumatic injuries: imaging of head injuries. Eur Radiol 2002; 12:1237. 5. Charcos IB, Wong TW, Larsen BR, et al. Location of Traumatic Cranial Epidural Hematoma Correlates with the Source of Hemorrhage: A 12-Year Surgical Review. World Neurosurg 2021; 152:e138. 6. Matsumoto K, Akagi K, Abekura M, Tasaki O. Vertex epidural hematoma associated with traumatic arteriovenous fistula of the middle meningeal artery: a case report. Surg Neurol 2001; 55:302. 7. McIver JI, Scheithauer BW, Rydberg CH, Atkinson JL. Metastatic hepatocellular carcinoma presenting as epidural hematoma: case report. Neurosurgery 2001; 49:447. 8. Ng WH, Yeo TT, Seow WT. Non-traumatic spontaneous acute epidural haematoma report of two cases and review of the literature. J Clin Neurosci 2004; 11:791. 9. Moonis G, Granados A, Simon SL. Epidural hematoma as a complication of sphenoid sinusitis and epidural abscess: a case report and literature review. Clin Imaging 2002; 26:382. 10. Takahashi K, Koiwa F, Tayama H, et al. A case of acute spontaneous epidural haematoma in a chronic renal failure patient undergoing haemodialysis: successful outcome with surgical https://www.uptodate.com/contents/intracranial-epidural-hematoma-in-adults/print 12/25 7/5/23, 11:53 AM Intracranial epidural hematoma in adults - UpToDate management. Nephrol Dial Transplant 1999; 14:2499. 11. Shimokawa S, Hayashi T, Anegawa S, et al. [Spontaneous epidural hematoma in a patient undergoing hemodialysis: a case report]. No To Shinkei 2003; 55:163. 12. Naran AD, Fontana L. Sickle cell disease with orbital infarction and epidural hematoma. Pediatr Radiol 2001; 31:257. 13. Mart nez-Lage JF, Saez V, Requena L, et al. Cranial epidural hematoma in Paget's disease of the bone. Intensive Care Med 2000; 26:1582. 14. Komarla R, Soares BP, Chern JJ, Milla SS. Spontaneous epidural hematoma secondary to bone infarction in sickle cell anemia: case report. J Neurosurg Pediatr 2018; 22:18. 15. Shahlaie K, Fox A, Butani L, Boggan JE. Spontaneous epidural hemorrhage in chronic renal failure. A case report and review. Pediatr Nephrol 2004; 19:1168. 16. Ganz JC. The lucid interval associated with epidural bleeding: evolving understanding. J Neurosurg 2013; 118:739. 17. Victor M, Ropper A. Craniocerebral trauma. In: Adams and Victor's Principles of Neurology, 7 th ed, Victor M, Ropper A (Eds), McGraw-Hill, New York 2001. p.925. 18. Radulovi D, Tasi G, Jokovic M. [Epidural hematomas of the posterior fossa]. Vojnosanit Pregl 2004; 61:133. 19. Owler BK, Besser M. Extradural hematoma causing venous sinus obstruction and pseudotumor cerebri syndrome. Childs Nerv Syst 2005; 21:262. 20. Yilmazlar S, Taskapilioglu O, Aksoy K. Transient Anton's syndrome: a presenting feature of acute epidural hematoma at the confluens sinuum. Pediatr Neurosurg 2003; 38:156. 21. Grossman RI. Head Trauma. In: Neuroradiology: The Requisites, 2nd ed, Mosby, Philadelphi a 2003. p.243. 22. Heit JJ, Iv M, Wintermark M. Imaging of Intracranial Hemorrhage. J Stroke 2017; 19:11. 23. Epidural hematoma. In: Color atlas of emergency trauma, Cambridge University Press, New York 2003. p.11. 24. Kothari RU, Brott T, Broderick JP, et al. The ABCs of measuring intracerebral hemorrhage volumes. Stroke 1996; 27:1304. 25. Gentry LR, Godersky JC, Thompson B, Dunn VD. Prospective comparative study of intermediate-field MR and CT in the evaluation of closed head trauma. AJR Am J Roentgenol 1988; 150:673. 26. Miller DJ, Steinmetz M, McCutcheon IE. Vertex epidural hematoma: surgical versus conservative management: two case reports and review of the literature. Neurosurgery 1999; 45:621. https://www.uptodate.com/contents/intracranial-epidural-hematoma-in-adults/print 13/25 7/5/23, 11:53 AM Intracranial epidural hematoma in adults - UpToDate 27. Hori E, Ogiichi T, Hayashi N, et al. Case report: acute subdural hematoma due to angiographically unvisualized ruptured aneurysm. Surg Neurol 2005; 64:144. 28. Nelson JA. Local skull trephination before transfer is associated with favorable outcomes in cerebral herniation from epidural hematoma. Acad Emerg Med 2011; 18:78. 29. Peres CMA, Caldas JGMP, Puglia P, et al. Endovascular management of acute epidural hematomas: clinical experience with 80 cases. J Neurosurg 2018; 128:1044. 30. Haselsberger K, Pucher R, Auer LM. Prognosis after acute subdural or epidural haemorrhage. Acta Neurochir (Wien) 1988; 90:111. 31. Cohen JE, Montero A, Israel ZH. Prognosis and clinical relevance of anisocoria-craniotomy latency for epidural hematoma in comatose patients. J Trauma 1996; 41:120. 32. Sullivan TP, Jarvik JG, Cohen WA. Follow-up of conservatively managed epidural hematomas: implications for timing of repeat CT. AJNR Am J Neuroradiol 1999; 20:107. 33. Oertel M, Kelly DF, McArthur D, et al. Progressive hemorrhage after head trauma: predictors and consequences of the evolving injury. J Neurosurg 2002; 96:109. 34. Chang JH, Choi JY, Chang JW, et al. Chronic epidural hematoma with rapid ossification. Childs Nerv Syst 2002; 18:712. 35. Bullock R, Smith RM, van Dellen JR. Nonoperative management of extradural hematoma. Neurosurgery 1985; 16:602. 36. Cucciniello B, Martellotta N, Nigro D, Citro E. Conservative management of extradural haematomas. Acta Neurochir (Wien) 1993; 120:47. 37. Bezircio lu H, Er ahin Y, Demir ivi F, et al. Nonoperative treatment of acute extradural hematomas: analysis of 80 cases. J Trauma 1996; 41:696. 38. Chen TY, Wong CW, Chang CN, et al. The expectant treatment of "asymptomatic" supratentorial epidural hematomas. Neurosurgery 1993; 32:176. 39. Bricolo AP, Pasut LM. Extradural hematoma: toward zero mortality. A prospective study. Neurosurgery 1984; 14:8. 40. Heinzelmann M, Platz A, Imhof HG. Outcome after acute extradural haematoma, influence of additional injuries and neurological complications in the ICU. Injury 1996; 27:345. 41. Gennarelli TA, Spielman GM, Langfitt TW, et al. Influence of the type of intracranial lesion on outcome from severe head injury. J Neurosurg 1982; 56:26. 42. Lee EJ, Hung YC, Wang LC, et al. Factors influencing the functional outcome of patients with acute epidural hematomas: analysis of 200 patients undergoing surgery. J Trauma 1998; 45:946. https://www.uptodate.com/contents/intracranial-epidural-hematoma-in-adults/print 14/25 7/5/23, 11:53 AM Intracranial epidural hematoma in adults - UpToDate 43. van den Brink WA, Zwienenberg M, Zandee SM, et al. The prognostic importance of the volume of traumatic epidural and subdural haematomas revisited. Acta Neurochir (Wien) 1999; 141:509. 44. Kim NY, Lim J, Lee S, et al. Hematological factors predicting mortality in patients with traumatic epidural or subdural hematoma undergoing emergency surgical evacuation: A retrospective cohort study. Medicine (Baltimore) 2020; 99:e22074. 45. Rivas JJ, Lobato RD, Sarabia R, et al. Extradural hematoma: analysis of factors influencing the courses of 161 patients. Neurosurgery 1988; 23:44. 46. Lobato RD, Rivas JJ, Cordobes F, et al. Acute epidural hematoma: an analysis of factors influencing the outcome of patients undergoing surgery in coma. J Neurosurg 1988; 68:48. Topic 1107 Version 23.0 https://www.uptodate.com/contents/intracranial-epidural-hematoma-in-adults/print 15/25 7/5/23, 11:53 AM Intracranial epidural hematoma in adults - UpToDate GRAPHICS Epidural hematoma in adults: Rapid overview of emergency management Clinical manifestations When to suspect: Head trauma (eg, motor vehicle accident, fall, assault) Unexplained acute progressive neurologic symptoms (confusion, weakness, speech impairment) Transient loss of consciousness followed by lucid interval, then neurologic deterioration Neurologic signs and symptoms: Headache Nausea and/or vomiting Confusion or drowsiness Hemiparesis Signs of elevated intracranial pressure: Dilated pupil(s) with reduced/absent reactivity to light Progressive drowsiness Cushing triad (bradycardia, respiratory depression, hypertension) Evaluation Assess airway, breathing, circulation, and disability to initiate supportive care Determine GCS and neurologic deficits (eg, hemiparesis, speech impairment) Identify exposure to anticoagulant medications (eg, warfarin, DOACs, heparins) Obtain emergency imaging (eg, head CT or fast MRI) Laboratory evaluation: complete blood count, PT, PTT, INR; basic electrolytes; pregnancy test in female of childbearing age Serial monitoring for nonoperative patients: Neurologic examination (hourly) for signs of deterioration Repeat head CT 6 to 8 hours after initial study and for any clinical signs of deterioration https://www.uptodate.com/contents/intracranial-epidural-hematoma-in-adults/print 16/25 7/5/23, 11:53 AM Intracranial epidural hematoma in adults - UpToDate Treatment Manage trauma patients according to principles of advanced trauma life support* Perform tracheal intubation for any patient unable to protect their airway, with rapidly deteriorating mental status, or with GCS 8 Obtain immediate neurosurgical consultation Reverse anticoagulation (agent specific): Warfarin reverse with 4-factor PCC and IV vitamin K Dabigatran reverse with idarucizumab Factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) reverse with 4-factor PCC or andexanet alfa Heparin (unfractionated) reverse with protamine sulfate Low molecular weight heparin reverse with andexanet alfa; protamine sulfate is an alternative Medical management of intracranial pressure: Prevent HYPOtension to maintain SBP >100 mmHg: fluid resuscitation with isotonic IV fluids; phenylephrine for refractory symptoms initial dose 0.5 to 2 mcg/kg per minute IV; maintenance dose 0.25 to 5 mcg/kg per minute Treat HYPERtension: Initial treatment to rapidly reduce SBP to <220 mmHg: nicardipine 5 mg/hour IV, titrate by 2.5 mg/hour every 5 to 15 minutes (maximum dose 15 mg/hour); alternate: labetalol 20 mg IV bolus, may repeat every 10 minutes Subsequent treatment to reduce SBP to <160 mmHg while monitoring for stability of neurologic status Elevate head of bed >30 degrees Give antipyretics for temperature >38 degrees Celsius (eg, acetaminophen [paracetamol] 325 to 650 mg orally or PR every 4 to 6 hours or 650 mg IV every 4 hours) Osmotic therapy (mannitol or hypertonic saline) or hyperventilation is temporary treatment for patients with signs of elevated intracranial pressure GCS: Glasgow Coma Scale; DOAC: direct oral anticoagulant; CT: computed tomography; MRI: magnetic resonance imaging; PT: prothrombin time; PTT: partial thromboplastin time; INR: international normalized ratio; PCC: prothrombin complex concentrate; IV: intravenous; SBP: systolic blood pressure; PR: per rectum. Refer to the UpToDate topics on trauma management in adults. https://www.uptodate.com/contents/intracranial-epidural-hematoma-in-adults/print 17/25 7/5/23, 11:53 AM Intracranial epidural hematoma in adults - UpToDate Refer to the UpToDate topics on management of elevated intracranial pressure in adults. Graphic 138469 Version 2.0 https://www.uptodate.com/contents/intracranial-epidural-hematoma-in-adults/print 18/25 7/5/23, 11:53 AM Intracranial epidural hematoma in adults - UpToDate Non contrast head CT demonstrates an acute traumatic epidural hematoma over the left parietal region

1988; 150:673. 26. Miller DJ, Steinmetz M, McCutcheon IE. Vertex epidural hematoma: surgical versus conservative management: two case reports and review of the literature. Neurosurgery 1999; 45:621. https://www.uptodate.com/contents/intracranial-epidural-hematoma-in-adults/print 13/25 7/5/23, 11:53 AM Intracranial epidural hematoma in adults - UpToDate 27. Hori E, Ogiichi T, Hayashi N, et al. Case report: acute subdural hematoma due to angiographically unvisualized ruptured aneurysm. Surg Neurol 2005; 64:144. 28. Nelson JA. Local skull trephination before transfer is associated with favorable outcomes in cerebral herniation from epidural hematoma. Acad Emerg Med 2011; 18:78. 29. Peres CMA, Caldas JGMP, Puglia P, et al. Endovascular management of acute epidural hematomas: clinical experience with 80 cases. J Neurosurg 2018; 128:1044. 30. Haselsberger K, Pucher R, Auer LM. Prognosis after acute subdural or epidural haemorrhage. Acta Neurochir (Wien) 1988; 90:111. 31. Cohen JE, Montero A, Israel ZH. Prognosis and clinical relevance of anisocoria-craniotomy latency for epidural hematoma in comatose patients. J Trauma 1996; 41:120. 32. Sullivan TP, Jarvik JG, Cohen WA. Follow-up of conservatively managed epidural hematomas: implications for timing of repeat CT. AJNR Am J Neuroradiol 1999; 20:107. 33. Oertel M, Kelly DF, McArthur D, et al. Progressive hemorrhage after head trauma: predictors and consequences of the evolving injury. J Neurosurg 2002; 96:109. 34. Chang JH, Choi JY, Chang JW, et al. Chronic epidural hematoma with rapid ossification. Childs Nerv Syst 2002; 18:712. 35. Bullock R, Smith RM, van Dellen JR. Nonoperative management of extradural hematoma. Neurosurgery 1985; 16:602. 36. Cucciniello B, Martellotta N, Nigro D, Citro E. Conservative management of extradural haematomas. Acta Neurochir (Wien) 1993; 120:47. 37. Bezircio lu H, Er ahin Y, Demir ivi F, et al. Nonoperative treatment of acute extradural hematomas: analysis of 80 cases. J Trauma 1996; 41:696. 38. Chen TY, Wong CW, Chang CN, et al. The expectant treatment of "asymptomatic" supratentorial epidural hematomas. Neurosurgery 1993; 32:176. 39. Bricolo AP, Pasut LM. Extradural hematoma: toward zero mortality. A prospective study. Neurosurgery 1984; 14:8. 40. Heinzelmann M, Platz A, Imhof HG. Outcome after acute extradural haematoma, influence of additional injuries and neurological complications in the ICU. Injury 1996; 27:345. 41. Gennarelli TA, Spielman GM, Langfitt TW, et al. Influence of the type of intracranial lesion on outcome from severe head injury. J Neurosurg 1982; 56:26. 42. Lee EJ, Hung YC, Wang LC, et al. Factors influencing the functional outcome of patients with acute epidural hematomas: analysis of 200 patients undergoing surgery. J Trauma 1998; 45:946. https://www.uptodate.com/contents/intracranial-epidural-hematoma-in-adults/print 14/25 7/5/23, 11:53 AM Intracranial epidural hematoma in adults - UpToDate 43. van den Brink WA, Zwienenberg M, Zandee SM, et al. The prognostic importance of the volume of traumatic epidural and subdural haematomas revisited. Acta Neurochir (Wien) 1999; 141:509. 44. Kim NY, Lim J, Lee S, et al. Hematological factors predicting mortality in patients with traumatic epidural or subdural hematoma undergoing emergency surgical evacuation: A retrospective cohort study. Medicine (Baltimore) 2020; 99:e22074. 45. Rivas JJ, Lobato RD, Sarabia R, et al. Extradural hematoma: analysis of factors influencing the courses of 161 patients. Neurosurgery 1988; 23:44. 46. Lobato RD, Rivas JJ, Cordobes F, et al. Acute epidural hematoma: an analysis of factors influencing the outcome of patients undergoing surgery in coma. J Neurosurg 1988; 68:48. Topic 1107 Version 23.0 https://www.uptodate.com/contents/intracranial-epidural-hematoma-in-adults/print 15/25 7/5/23, 11:53 AM Intracranial epidural hematoma in adults - UpToDate GRAPHICS Epidural hematoma in adults: Rapid overview of emergency management Clinical manifestations When to suspect: Head trauma (eg, motor vehicle accident, fall, assault) Unexplained acute progressive neurologic symptoms (confusion, weakness, speech impairment) Transient loss of consciousness followed by lucid interval, then neurologic deterioration Neurologic signs and symptoms: Headache Nausea and/or vomiting Confusion or drowsiness Hemiparesis Signs of elevated intracranial pressure: Dilated pupil(s) with reduced/absent reactivity to light Progressive drowsiness Cushing triad (bradycardia, respiratory depression, hypertension) Evaluation Assess airway, breathing, circulation, and disability to initiate supportive care Determine GCS and neurologic deficits (eg, hemiparesis, speech impairment) Identify exposure to anticoagulant medications (eg, warfarin, DOACs, heparins) Obtain emergency imaging (eg, head CT or fast MRI) Laboratory evaluation: complete blood count, PT, PTT, INR; basic electrolytes; pregnancy test in female of childbearing age Serial monitoring for nonoperative patients: Neurologic examination (hourly) for signs of deterioration Repeat head CT 6 to 8 hours after initial study and for any clinical signs of deterioration https://www.uptodate.com/contents/intracranial-epidural-hematoma-in-adults/print 16/25 7/5/23, 11:53 AM Intracranial epidural hematoma in adults - UpToDate Treatment Manage trauma patients according to principles of advanced trauma life support* Perform tracheal intubation for any patient unable to protect their airway, with rapidly deteriorating mental status, or with GCS 8 Obtain immediate neurosurgical consultation Reverse anticoagulation (agent specific): Warfarin reverse with 4-factor PCC and IV vitamin K Dabigatran reverse with idarucizumab Factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) reverse with 4-factor PCC or andexanet alfa Heparin (unfractionated) reverse with protamine sulfate Low molecular weight heparin reverse with andexanet alfa; protamine sulfate is an alternative Medical management of intracranial pressure: Prevent HYPOtension to maintain SBP >100 mmHg: fluid resuscitation with isotonic IV fluids; phenylephrine for refractory symptoms initial dose 0.5 to 2 mcg/kg per minute IV; maintenance dose 0.25 to 5 mcg/kg per minute Treat HYPERtension: Initial treatment to rapidly reduce SBP to <220 mmHg: nicardipine 5 mg/hour IV, titrate by 2.5 mg/hour every 5 to 15 minutes (maximum dose 15 mg/hour); alternate: labetalol 20 mg IV bolus, may repeat every 10 minutes Subsequent treatment to reduce SBP to <160 mmHg while monitoring for stability of neurologic status Elevate head of bed >30 degrees Give antipyretics for temperature >38 degrees Celsius (eg, acetaminophen [paracetamol] 325 to 650 mg orally or PR every 4 to 6 hours or 650 mg IV every 4 hours) Osmotic therapy (mannitol or hypertonic saline) or hyperventilation is temporary treatment for patients with signs of elevated intracranial pressure GCS: Glasgow Coma Scale; DOAC: direct oral anticoagulant; CT: computed tomography; MRI: magnetic resonance imaging; PT: prothrombin time; PTT: partial thromboplastin time; INR: international normalized ratio; PCC: prothrombin complex concentrate; IV: intravenous; SBP: systolic blood pressure; PR: per rectum. Refer to the UpToDate topics on trauma management in adults. https://www.uptodate.com/contents/intracranial-epidural-hematoma-in-adults/print 17/25 7/5/23, 11:53 AM Intracranial epidural hematoma in adults - UpToDate Refer to the UpToDate topics on management of elevated intracranial pressure in adults. Graphic 138469 Version 2.0 https://www.uptodate.com/contents/intracranial-epidural-hematoma-in-adults/print 18/25 7/5/23, 11:53 AM Intracranial epidural hematoma in adults - UpToDate Non contrast head CT demonstrates an acute traumatic epidural hematoma over the left parietal region Courtesy of Neuroradiology Department, Thomas Je erson University, Philadelphia, PA. Graphic 60726 Version 4.0 https://www.uptodate.com/contents/intracranial-epidural-hematoma-in-adults/print 19/25 7/5/23, 11:53 AM Intracranial epidural hematoma in adults - UpToDate MRI of the brain demonstrates a traumatic epidural hematoma in the left parieto-occipital region MRI: magnetic resonance imaging. Courtesy of Neuroradiology Department, Thomas Je erson University, Philadelphia, PA. Graphic 77358 Version 3.0 https://www.uptodate.com/contents/intracranial-epidural-hematoma-in-adults/print 20/25 7/5/23, 11:53 AM Intracranial epidural hematoma in adults - UpToDate Emergency reversal of anticoagulation from warfarin for life-threatening hemorrhage in adults: Suggested approaches based upon available resources A. If 4-factor prothrombin complex concentrate (4F PCC) is available (preferred approach): 1. Give 4F PCC* 1500 to 2000 units IV over 10 minutes. Check INR 15 minutes after completion of the infusion. If INR is not 1.5, give additional 4F PCC (refer to topic or drug reference for details). 2. Give vitamin K 10 mg IV over 10 to 20 minutes. B. If 3-factor prothrombin complex concentrate (3F PCC) is available but 4F PCC is not available: 1. Give 3F PCC* 1500 to 2000 units IV over 10 minutes. Check INR 15 minutes after completion of the infusion. If INR is not 1.5, give additional 3F PCC (refer to topic or drug reference for details). 2. Give Factor VIIa 20 mcg/kg IV OR give FFP 2 units IV by rapid infusion. Factor VIIa may be preferred if volume overload is a concern. 3. Give vitamin K 10 mg IV over 10 to 20 minutes. C. If neither 3F PCC nor 4F PCC is available: 1. Give FFP 2 units IV by rapid infusion. Check INR 15 minutes after completion of infusion. If INR 1.5, administer 2 additional units of FFP IV rapid infusion. Repeat process until INR 1.5. May wish to administer loop diuretic between FFP infusions if volume overload is a concern. 2. Give vitamin K 10 mg IV over 10 to 20 minutes. These products and doses are for use in life-threatening bleeding only. Evidence of life-threatening bleeding and over-anticoagulation with a vitamin K antagonist (eg, warfarin) are required. Anaphylaxis and transfusion reactions can occur. It may be reasonable to thaw 4 units of FFP while awaiting the PT/INR. The transfusion service may substitute other plasma products for FFP (eg, Plasma Frozen Within 24 Hours After Phlebotomy [PF24]); these products are considered clinically interchangeable. PCC will reverse anticoagulation within minutes of administration; FFP administration can take hours due to the volume required; vitamin K effect takes 12 to 24 hours, but administration of vitamin K is needed to counteract the long half-life of warfarin. Subsequent monitoring of the PT/INR is needed to guide further therapy. Refer to topics on warfarin reversal in individual situations for further management. PCC: unactivated prothrombin complex concentrate; 4F PCC: PCC containing coagulation factors II, VII, IX, X, protein S and protein C; 3F PCC: PCC containing factors II, IX, and X and only trace factor VII; FFP: fresh frozen plasma; PT: prothrombin time; INR: international normalized ratio; FEIBA: factor eight inhibitor bypassing agent. Before use, check product label to confirm factor types (3 versus 4 factor) and concentration. Activated complexes and single-factor IX products (ie, FEIBA, AlphaNine, Mononine, Immunine, BeneFix) are NOT used for warfarin reversal. https://www.uptodate.com/contents/intracranial-epidural-hematoma-in-adults/print 21/25 7/5/23, 11:53 AM Intracranial epidural hematoma in adults - UpToDate PCC doses shown are those suggested for initial treatment of emergency conditions. Subsequent treatment is based on INR and patient weight if available. Refer to topic and Lexicomp drug reference included with UpToDate for INR-based dosing. Graphic 89478 Version 10.0 https://www.uptodate.com/contents/intracranial-epidural-hematoma-in-adults/print 22/25 7/5/23, 11:53 AM Intracranial epidural hematoma in adults - UpToDate Direct oral anticoagulant reversal agents for life-threatening bleeding (imminent risk of death from bleeding) Reversal agent (all are given Anticoagulant intravenously) Dabigatran (Pradaxa; oral thrombin inhibitor) Idarucizumab (Praxbind). Dose: 5 grams* Oral factor Xa inhibitors: Andexanet alfa (AndexXa). Dosing for the initial bolus and subsequent infusion depend on the dose level of the factor Xa inhibitor and the interval since it was last taken. Apixaban (Eliquis) Edoxaban (Lixiana, Savaysa) Rivaroxaban (Xarelto) OR- 4-factor PCC (Kcentra, Beriplex P/N, Octaplex). Dosing can be done with a fixed dose of 2000 units OR a weight-based dose of 25 to 50 units per kg. Reversal agents carry a risk of life-threatening thrombosis and should only be used under the direction of a specialist with expertise in their use and/or in a patient at imminent risk of death from bleeding. In general, a single dose is given; dosing may be repeated in rare situations in which the oral anticoagulant persists for longer in the circulation, such as severe kidney dysfunction. Andexanet dosing is as follows: If the patient took rivaroxaban >10 mg, apixaban >5 mg, or dose unknown within the previous 8 hours: Andexanet 800 mg bolus at 30 mg/minute followed by 960 mg infusion at 8 mg/minute for up to 120 minutes. OR- If the patient took rivaroxaban 10 mg or apixaban 5 mg, or if 8 hours have elapsed since the last dose of a factor Xa inhibitor: Andexanet 400 mg bolus at 30 mg/minute followed by 480 mg infusion at 4 mg/minute for up to 120 minutes. Refer to UpToDate topics on treatment of bleeding in patients receiving a DOAC or perioperative management of patients receiving a DOAC for additional information on administration, risks, and alternative therapies. DOAC: direct oral anticoagulant; PCC: prothrombin complex concentrate; FEIBA: factor eight inhibitor bypassing activity. If idarucizumab is unavailable, an activated PCC (FEIBA, 50 to 80 units per kg intravenously) may be a reasonable alternative. Graphic 112299 Version 9.0 https://www.uptodate.com/contents/intracranial-epidural-hematoma-in-adults/print 23/25 7/5/23, 11:53 AM Intracranial epidural hematoma in adults - UpToDate Glasgow Coma Scale (GCS) Score Eye opening Spontaneous 4 Response to verbal command 3 Response to pain 2 No eye opening 1 Best verbal response Oriented 5 Confused 4 Inappropriate words 3 Incomprehensible sounds 2 No verbal response 1 Best motor response Obeys commands 6 Localizing response to pain 5 Withdrawal response to pain 4 Flexion to pain 3 Extension to pain 2 No motor response 1 Total The GCS is scored between 3 and 15, 3 being the worst and 15 the best. It is composed of three parameters: best eye response (E), best verbal response (V), and best motor response (M). The components of the GCS should be recorded individually; for example, E2V3M4 results in a GCS score of 9. A score of 13 or higher correlates with mild brain injury, a score of 9 to 12 correlates with moderate injury, and a score of 8 or less represents severe brain injury. Graphic 81854 Version 9.0 https://www.uptodate.com/contents/intracranial-epidural-hematoma-in-adults/print 24/25 7/5/23, 11:53 AM Intracranial epidural hematoma in adults - UpToDate Contributor Disclosures William McBride, MD No relevant financial relationship(s) with ineligible companies to disclose. Jos Biller, MD, FACP, FAAN, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Alejandro A Rabinstein, MD Grant/Research/Clinical Trial Support: Chiesi [Small investigator- initiated project]. Consultant/Advisory Boards: AstraZeneca [Secondary stroke prevention]; Brainomix [AI for stroke diagnostics]; Novo Nordisk [Stroke risk]; Shionogi [Stroke neuroprotection]. Other Financial Interest: Boston Scientific [Adverse event adjudication committee member for stroke risk reduction device in patients with atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/intracranial-epidural-hematoma-in-adults/print 25/25

7/5/23, 11:53 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis : As'ad Ehtisham, MD, MBBS, FAHA, Tanya N Turan, MD, MSCR : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 27, 2023. INTRODUCTION Atherosclerotic stenosis of the major intracranial arteries, also known as intracranial atherosclerosis (ICAS) or cerebral atherosclerosis, is an important cause of ischemic stroke. This topic focuses on the epidemiology, clinical manifestations, and diagnosis of ICAS. The treatment and prognosis of ICAS is reviewed separately. (See "Intracranial large artery atherosclerosis: Treatment and prognosis".) Other ischemic stroke subtypes are discussed elsewhere. (See "Stroke: Etiology, classification, and epidemiology" and "Clinical diagnosis of stroke subtypes" and "Lacunar infarcts" and "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)".) PATHOPHYSIOLOGY Atherosclerosis is a pathologic process that causes disease of the aorta, coronary, cerebral, and peripheral arteries. Multiple factors contribute to the pathogenesis of atherosclerosis, including endothelial dysfunction, inflammatory and immunologic factors, plaque rupture, and the traditional risk factors of hypertension, diabetes, dyslipidemia, and smoking. The first stage of atherosclerosis begins in childhood with the development of fatty streaks, followed by progression involving the development of fibrous plaques, fibrous caps, and advanced atheromatous lesions. (See "Pathogenesis of atherosclerosis".) https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 1/24 7/5/23, 11:53 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Atherosclerosis is the most common cause of in situ local disease within the large extracranial and intracranial arteries that supply the brain ( picture 1 and image 1). An intracranial artery stenosis is considered symptomatic when the degree of stenosis is at least 50 percent and the stroke or transient ischemic attack (TIA) symptoms are localized to the region of the brain supplied by the artery. ICAS can lead to ischemic stroke or TIA by a variety of mechanisms ( image 2), which include [1-5]: In situ thromboembolism leading most often to artery-to-artery embolism, and less often to hemodynamic insufficiency or to a combination of embolism and hemodynamic insufficiency Progression of luminal stenosis resulting in hemodynamic insufficiency Atheroma encroaching on the orifice of small penetrating vessels ("branch atheromatous disease") causing small vessel occlusion Subtypes and mechanisms of ischemic stroke are discussed in greater detail elsewhere. (See "Pathophysiology of ischemic stroke" and "Stroke: Etiology, classification, and epidemiology" and "Clinical diagnosis of stroke subtypes".) EPIDEMIOLOGY Frequency of stroke due to intracranial atherosclerosis ICAS is an important cause of ischemic stroke, particularly among Asian and Black populations worldwide, and among Hispanic populations originating in Latin America [1,6-9]. In the United States, ICAS accounts for approximately 8 to 10 percent of ischemic stroke, and may account for 30 to 50 percent of ischemic stroke in Asian populations [10-12]. Racial and ethnic differences Several studies have found that ICAS is more prevalent in Asian, Black, and Hispanic populations compared with White populations [1,13-16]. As an example, one population-based study found that the adjusted annual incidence of intracranial atherosclerotic stroke among Black, Hispanic, and White patients was 15, 13, and 3 per 100,000, respectively [15]. The explanation for the variance in the distribution of ICAS in different races is uncertain. One hypothesis is that Black, Hispanic, and Asian populations have a genetic susceptibility to intracranial large artery disease [17,18]. An alternative hypothesis is that racial and ethnic differences in lifestyle and risk factor profiles (eg, higher rates of diabetes and hypercholesterolemia in some populations) play a more important role in determining the distribution of atherosclerosis [11,19,20]. Based on the ethnic make-up of the world population, ICAS may be the most common cause of stroke worldwide [21]. https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 2/24 7/5/23, 11:53 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Risk factors Risk factors associated with symptomatic ICAS include the following [1,2,7,22,23]: Age Hypertension Hyperlipidemia/dyslipidemia Smoking Diabetes A post hoc analysis of data from the WASID study of patients with TIA or stroke due to 50 to 99 percent intracranial large artery atherosclerosis showed that risk factors were more prevalent than reported for other stroke subtypes and that a history of a lipid disorder was independently associated with severe (70 to 99 percent) intracranial stenosis (odds ratio 1.62, 95% CI 1.09-2.42) [24]. Risk factors also differed by location of stenosis, with basilar artery stenoses associated with older age and hyperlipidemia, middle cerebral artery stenoses more common in women and Black individuals, and intracranial carotid artery stenoses associated with diabetes. Similar associations between risk factors and location of stenosis were reported in a post hoc analysis of data from the SAMMPRIS trial, which included patients with 70 to 99 percent intracranial stenosis [25]. CLINICAL MANIFESTATIONS The manifestations of ischemia due to intracranial large artery atherosclerosis are not specific, as the same stroke syndromes may arise from other sources of ischemia, including cardiac embolism, artery-to-artery embolism from extracranial large artery stenosis, and small vessel disease. Anterior circulation In the anterior circulation, ICAS most often involves the middle cerebral artery (MCA); the intracranial internal carotid artery (ICA) is also commonly affected. In situ thrombotic occlusion of the MCA or artery-to-artery embolism of an ICA or MCA thrombus can lead to a cortical infarction with symptoms that may include aphasia, neglect, and/or contralateral hemiparesis. MCA atherosclerosis may also cause subcortical infarction via branch atheromatous disease, resulting in a clinical presentation similar to lacunar infarction with motor, sensory, or sensorimotor symptoms affecting the contralateral hemibody. Less commonly, low flow or hypoperfusion through a stenotic ICA or MCA can be the result of hypotension or positional changes. Such symptoms may be transient and improve with increased intravascular volume, or may result in watershed (borderzone) or hypoperfusion https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 3/24 7/5/23, 11:53 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate infarcts. Limb-shaking transient ischemic attack (TIA) is a rare, but classic, hypoperfusion syndrome of repetitive jerking movements of the arm or leg due to a contralateral ICA stenosis or occlusion [26]. Posterior circulation In the posterior circulation, ischemic symptoms and signs may include dizziness, nausea or vomiting, unilateral limb weakness or ataxia, gait ataxia, dysarthria, diplopia, nystagmus, altered level of consciousness, and visual field loss. This section provides a brief overview; a more complete discussion is found separately. (See "Posterior circulation cerebrovascular syndromes".) ICAS of the distal vertebral arteries presents in a variety of ways. Infarction may involve the medulla (eg, lateral medullary infarction) or cerebellum in the territory of the posterior inferior cerebellar artery via branch atheromatous occlusion. Artery-to-artery embolization of a vertebral artery thrombus may cause TIA or infarction in the territory of the basilar artery or its branches. Basilar artery atherosclerosis most often presents as ischemia in the pons due to branch atheromatous occlusion; the predominant symptoms and signs are motor and oculomotor. Although less common, ischemic infarction of the ventral pons due to basilar artery embolism or thrombosis can cause locked-in syndrome; infarction of the bilateral medial pontine tegmentum can cause a reduced level of consciousness or coma. Occlusion of the rostral portion of the basilar artery (the "top of the basilar") can cause ischemia of the midbrain, thalami, and temporal and occipital lobe hemispheral territories supplied by the posterior cerebral artery branches of the basilar artery. The major abnormalities associated with rostral brainstem infarction involve alertness, behavior, memory, and oculomotor and pupillary functions. Most infarcts in the territory of the posterior cerebral artery (PCA) are due to embolism from a more proximal source, such as the vertebral or basilar arteries. The most frequent neurologic deficit with PCA territory infarction involving the occipital lobe is visual loss (eg, a hemianopia or quadrantanopia), sometimes accompanied by visual neglect. Infarction due to in situ atherosclerosis of the PCAs is less common but can cause thalamic or midbrain infarction through branch occlusion. Lateral thalamic infarction typically leads to somatosensory symptoms and signs. DIAGNOSTIC EVALUATION The standard evaluation of patients with acute ischemic stroke or transient ischemic stroke (TIA) includes a history and physical examination, brain imaging to determine the location and https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 4/24 7/5/23, 11:53 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate topography of the ischemic lesion, and vessel imaging and a cardiac evaluation to help determine the most likely cause. Laboratory testing typically includes a complete blood count, cardiac enzymes and troponin, prothrombin time, international normalized ratio (INR), and activated partial thromboplastin time. (See "Initial assessment and management of acute stroke" and "Initial evaluation and management of transient ischemic attack and minor ischemic stroke".) Brain and vascular imaging All patients with acute ischemic stroke or TIA should have brain and neurovascular imaging. The brain imaging study can be done with either computed tomography (CT) or magnetic resonance imaging (MRI), while large vessel imaging can be obtained with either computed tomography angiography (CTA) or magnetic resonance angiography (MRA); additional methods include duplex ultrasound (DUS) and transcranial Doppler ultrasound (TCD), which assess the patency of the extracranial and intracranial large arteries, respectively. The brain and neurovascular imaging studies should not be considered in isolation, but rather as one part of the acute stroke evaluation. However, the approach to imaging may differ according to individual patient characteristics (eg, time from stroke onset, potential candidate for reperfusion therapies) and local availability of stroke expertise and imaging capabilities. (See "Neuroimaging of acute stroke".) Choice of vascular imaging We use CTA or MRA to evaluate the extracranial arteries (internal carotid and vertebral) and intracranial arteries (internal carotid, middle cerebral, anterior cerebral, vertebral, basilar, posterior cerebral) that supply blood to the brain. Noninvasive methods (MRA, CTA, or TCD) are preferred because they are more easily obtained, less invasive, safer, and less expensive compared with gold-standard conventional contrast angiography (eg, digital subtraction angiography [DSA]). (See 'Accuracy of noninvasive vascular imaging' below.) Conventional contrast angiography is usually reserved for situations in which noninvasive studies are inconclusive. (See 'Role of catheter angiography' below.) Need for urgent imaging Patients with acute ischemic stroke who are potential candidates for reperfusion therapies should be rapidly screened for treatment with intravenous thrombolysis ( table 1) and/or mechanical thrombectomy ( algorithm 1). Diagnostic neuroimaging is essential before considering these interventions. Reperfusion therapy for patients with acute ischemic stroke is reviewed in detail elsewhere. (See "Approach to reperfusion therapy for acute ischemic stroke" and "Intravenous thrombolytic https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 5/24 7/5/23, 11:53 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate therapy for acute ischemic stroke: Therapeutic use" and "Mechanical thrombectomy for acute ischemic stroke".) Accuracy of noninvasive vascular imaging Noninvasive imaging methods (mainly MRA and CTA) are useful for excluding moderate to severe (50 to 99 percent) stenosis of large proximal intracranial arteries and are usually sufficient to identify intracranial arteries with moderate to severe stenosis. However, MRA and CTA have certain limitations related to accuracy and sensitivity when compared with the gold standard of catheter angiography. As examples, noninvasive methods may not be sufficiently accurate to differentiate an occlusion from pseudo- occlusion with critical stenosis or to confirm the severity of a clinically significant stenosis. In addition, they tend to overestimate the severity of stenosis. In the prospective multicenter SONIA trial of patients with TIA or ischemic stroke who were suspected of having intracranial large artery stenosis, both TCD ultrasonography and MRA had high negative predictive values (86 and 91 percent) and low positive predictive values (36 and 59 percent) for the detection of intracranial stenosis in the MCA, intracranial ICA, vertebral, and basilar arteries compared with catheter angiography [27]. Similarly, a subsequent report from SONIA found that CTA had a good negative predictive value (73 percent) and a low positive predictive value (47 percent) [28]. Nevertheless, intensive medical therapy is indicated for patients with a first event related to symptomatic intracranial large artery stenosis detected by noninvasive imaging (see "Intracranial large artery atherosclerosis: Treatment and prognosis"); more precise characterization of the stenosis with catheter angiography would not affect the initial management in most cases. Role of catheter angiography Catheter angiography is unnecessary for the vast majority of cases with suspected intracranial large artery atherosclerosis since it will seldom alter clinical management. Angiography enables an accurate measurement of the degree of stenosis of the diseased artery [29], differentiation of arterial occlusion from a very severe stenosis, assessment of collateral flow patterns, and evaluation of other intracranial and extracranial arteries. Thus, conventional angiography may be needed in some cases to confirm the presence of intracranial stenosis when noninvasive imaging is inconclusive or to investigate an alternative etiology such as moyamoya disease, intracranial dissection, and vasculitis. The major drawback of angiography is the risk of stroke [30,31], which was as high as 1.2 percent in the Asymptomatic Carotid Atherosclerosis Study (ACAS) [30]. Among patients with ICAS in the WASID study, the risk of neurological events was 2 percent, but all of these events were transient. Identifying other causes of intracranial stenosis Neurovascular imaging plays a key role in identifying intracranial stenosis caused by other types of vasculopathy such as arterial https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 6/24 7/5/23, 11:53 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate dissection, fibromuscular dysplasia, cerebral vasoconstriction, primary or secondary vasculitis, moyamoya disease, and other vasculopathies. These conditions are less common than atherosclerotic disease among adult populations with vascular risk factors; clinical or radiologic features can help to distinguish them from atherosclerosis: Dissection Dissection is suspected when vascular imaging demonstrates an arterial string sign, a tapered stenosis or occlusion, a flame-shaped occlusion, an intimal flap, a dissecting aneurysm, or a distal pouch. Fat-saturated MRI sequences may show an intramural hematoma. (See "Cerebral and cervical artery dissection: Clinical features and diagnosis", section on 'Choice of neuroimaging study'.) Dissection of intracranial arteries is far less frequent than dissection of extracranial cervical arteries. (See "Cerebral and cervical artery dissection: Clinical features and diagnosis", section on 'Epidemiology'.) Conditions characterized by segmental arterial narrowing The angiographic demonstration of alternating focal concentric narrowing resembling a "string of beads" in one or more intracranial vessels is a nonspecific finding that may be present due to atherosclerosis, infection, vasospasm or vasoconstriction, and fibromuscular dysplasia. The clinical setting is crucial to determining the most likely cause. Primary angiitis of the central nervous system Primary angiitis of the central nervous system is a rare disorder associated with headache, cognitive impairment, and TIA or stroke, with multiple infarcts in different vascular territories. The onset is typically subacute and insidious. The angiographic appearance of a "string of beads" predominantly involves the smaller distal intracranial vessels, not the proximal larger arteries, which are affected by atherosclerosis. (See "Primary angiitis of the central nervous system in adults", section on 'Neuroimaging' and "Primary angiitis of the central nervous system in adults", section on 'Alternative diagnoses'.) Reversible cerebral vasoconstriction syndrome Reversible cerebral vasoconstriction syndrome (RCVS) represents a group of conditions that show reversible multifocal narrowing of the cerebral arteries with clinical manifestations that typically include thunderclap headache and sometimes include neurologic deficits related to brain edema, stroke, or seizure. (See "Reversible cerebral vasoconstriction syndrome".) Fibromuscular dysplasia With fibromuscular dysplasia, the most frequently involved arteries are the renal and internal carotid and vertebral arteries. Less commonly, there is involvement of the external carotid artery and the larger intracranial arteries (the middle cerebral, anterior cerebral, basilar, and anterior communicating arteries). The https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 7/24 7/5/23, 11:53 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate most common manifestations are hypertension, headache, dizziness, tinnitus, TIA, and stroke, but other manifestations may occur, depending upon the arterial segment involved and the severity of disease. (See "Clinical manifestations and diagnosis of fibromuscular dysplasia".) Moyamoya disease Moyamoya disease is diagnosed based upon the characteristic angiographic appearance of bilateral stenoses affecting the distal internal carotid arteries and proximal circle of Willis vessels, along with the presence of prominent basal collateral moyamoya vessels. (See "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis".) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults" and "Society guideline links: Occlusive carotid, aortic, renal, mesenteric, and peripheral atherosclerotic disease".) SUMMARY AND RECOMMENDATIONS Atherosclerotic stenosis of the major intracranial arteries (intracranial carotid artery, middle cerebral artery, vertebral artery, and basilar artery) is an important cause of ischemic stroke, especially in Asian, Black, and Hispanic populations. (See 'Epidemiology' above.) The symptoms of ischemic stroke or TIA attributed to large artery intracranial atherosclerosis (ICAS) depend upon the mechanism (eg, in situ thromboembolism, branch atheroma) and the size and location of the brain region affected by ischemia ( table 2). (See 'Clinical manifestations' above.) All patients with acute ischemic stroke or TIA should have brain and neurovascular imaging. Patients with acute ischemic stroke who are potential candidates for reperfusion therapies should be rapidly screened for treatment with intravenous thrombolysis ( table 1) and/or mechanical thrombectomy ( algorithm 1). Noninvasive imaging methods (mainly magnetic resonance angiography [MRA] and computed tomographic angiography [CTA]) are useful for excluding moderate to severe (50 to 99 percent) stenosis of large proximal intracranial arteries and are usually sufficient to identify intracranial vessels with moderate to severe stenosis. MRA and CTA have certain limitations related to https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 8/24 7/5/23, 11:53 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate accuracy and sensitivity when compared with the gold standard of catheter angiography, but catheter angiography is unnecessary for the vast majority of cases with suspected intracranial large artery atherosclerosis since it will seldom alter clinical management. (See 'Diagnostic evaluation' above.) Neurovascular imaging plays a key role in identifying intracranial stenosis caused by other types of vasculopathy such as arterial dissection, fibromuscular dysplasia, cerebral vasoconstriction, primary or secondary vasculitis, moyamoya disease, and others. These conditions are less common than atherosclerotic disease among adult populations with vascular risk factors, and clinical or radiologic features can help to distinguish them from atherosclerosis. (See 'Identifying other causes of intracranial stenosis' above.) The treatment and prognosis of TIA and stroke attributed to intracranial large artery atherosclerosis is reviewed in detail separately. (See "Intracranial large artery atherosclerosis: Treatment and prognosis".) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Qureshi AI, Caplan LR. Intracranial atherosclerosis. Lancet 2014; 383:984. 2. Holmstedt CA, Turan TN, Chimowitz MI. Atherosclerotic intracranial arterial stenosis: risk factors, diagnosis, and treatment. Lancet Neurol 2013; 12:1106. 3. Bang OY. Intracranial atherosclerosis: current understanding and perspectives. J Stroke 2014; 16:27. 4. Caplan LR, Hennerici M. 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Intracranial Large and Medium Artery https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 9/24 7/5/23, 11:53 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Atherosclerotic Disease and Stroke. J Stroke Cerebrovasc Dis 2018; 27:1723. 10. Mattioni A, Cenciarelli S, Biessels G, et al. Prevalence of intracranial large artery stenosis and occlusion in patients with acute ischaemic stroke or TIA. Neurol Sci 2014; 35:349. 11. Sacco RL, Kargman DE, Gu Q, Zamanillo MC. Race-ethnicity and determinants of intracranial atherosclerotic cerebral infarction. The Northern Manhattan Stroke Study. Stroke 1995; 26:14. 12. Wong LK. Global burden of intracranial atherosclerosis. Int J Stroke 2006; 1:158. 13. Wong KS, Li H. Long-term mortality and recurrent stroke risk among Chinese stroke patients with predominant intracranial atherosclerosis. 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Cerebral atherosclerosis a comparative autopsy study between Nigerian Negroes and American Negroes and Caucasians. Neurology 1969; 19:205. 20. Arenillas JF, Molina CA, Chac n P, et al. High lipoprotein (a), diabetes, and the extent of symptomatic intracranial atherosclerosis. Neurology 2004; 63:27. 21. Gorelick PB, Wong KS, Bae HJ, Pandey DK. Large artery intracranial occlusive disease: a large worldwide burden but a relatively neglected frontier. Stroke 2008; 39:2396. 22. Rincon F, Sacco RL, Kranwinkel G, et al. Incidence and risk factors of intracranial atherosclerotic stroke: the Northern Manhattan Stroke Study. Cerebrovasc Dis 2009; 28:65. 23. Sirimarco G, Deplanque D, Lavall e PC, et al. Atherogenic dyslipidemia in patients with transient ischemic attack. Stroke 2011; 42:2131. 24. Turan TN, Makki AA, Tsappidi S, et al. Risk factors associated with severity and location of intracranial arterial stenosis. Stroke 2010; 41:1636. https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 10/24 7/5/23, 11:53 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate 25. Almallouhi E, Al Kasab S, Yamada L, et al. Relationship Between Vascular Risk Factors and Location of Intracranial Atherosclerosis in the SAMMPRIS Trial. J Stroke Cerebrovasc Dis 2020; 29:104713. 26. Persoon S, Kappelle LJ, Klijn CJ. Limb-shaking transient ischaemic attacks in patients with internal carotid artery occlusion: a case-control study. Brain 2010; 133:915. 27. Feldmann E, Wilterdink JL, Kosinski A, et al. The Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) trial. Neurology 2007; 68:2099. 28. Liebeskind DS, Kosinski AS, Saver JL, et al. Computed Tomography Angiography in the Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) Study. Interv Neurol 2014; 2:153. 29. Samuels OB, Joseph GJ, Lynn MJ, et al. A standardized method for measuring intracranial arterial stenosis. AJNR Am J Neuroradiol 2000; 21:643. 30. Endarterectomy for asymptomatic carotid artery stenosis. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. JAMA 1995; 273:1421. 31. Dion JE, Gates PC, Fox AJ, et al. Clinical events following neuroangiography: a prospective study. Stroke 1987; 18:997. Topic 131456 Version 6.0 https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 11/24 7/5/23, 11:53 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate GRAPHICS Atherosclerotic lesions in the Circle of Willis of a 90-year-old patient Circle of Willis of a 90-year-old patient. Macroscopically, atherosclerotic lesions can be identified by the white whereas nondiseased arteries appear largely transparent. This case shows prominent atherosclerosis mainly internal carotid artery, vertebral artery, basilar artery, left middle cerebral artery, and posterior cerebral arter https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 12/24 7/5/23, 11:53 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate From: Ritz K, Denswil NP, Stam OC, et al. Cause and mechanisms of intracranial atherosclerosis. Circulation 2014; 130:1407. DOI: 10.1161/CIRCULATIONAHA.114.011147. Copyright 2014 American Heart Association. Reproduced with permission from Wolters Kluw Unauthorized reproduction of this material is prohibited. Graphic 105011 Version 8.0 https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 13/24 7/5/23, 11:53 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Intracranial plaque and arterial wall imaging by high-resolution MRI Intracranial plaque and arterial wall imaging by high-resolution MRI. An intracranial atherosclerosis lesion located at proximal basilar artery with severe luminal stenosis was identified on time-of-flight magnetic resonance angiography (arrow, A). High-resolution MRI revealed an eccentric atherosclerotic plaque along the anterolateral and posterolateral walls of basilar artery (arrowhead, B through D). From: Leng X, Wong KS, Liebeskind DS. Evaluating intracranial atherosclerosis rather than intracranial stenosis. Stroke 2014; 45:645. DOI: 10.1161/STROKEAHA.113.002491. Copyright 2014 American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 14/24 7/5/23, 11:53 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Graphic 105006 Version 5.0 https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 15/24 7/5/23, 11:53 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Mechanisms of stroke in patients with intracranial atherosclerotic disease Mechanisms of stroke in patients with ICAD. (A) Thrombotic occlusion is a rare phenotype of ICAD. MRA shows in situ thrombotic occlusion at the site of st plaque. DWI shows territorial infarcts by severe hemodynamic compromise and embolic infarcts on the corte High-resolution MRI can show vulnerable plaque on intracranial vessels. (B) Artery-to-artery embolism is one of common phenotypes of ICAD. Artery-to-artery embolism is usually associated with a severe degree of intracranial stenosis, and transcranial Doppler ultrasonography can detec symptomatic or asymptomatic embolism during microembolic signal monitoring. DWI shows small, scattered cortical embolic infarcts. (C) Hemodynamic impairment is another phenotype of ICAD. This phenotype is usually associated with a seve stenosis and a marked hemodynamic compromise, as seen on a PWI. DWI typically shows borderzone-type in and infarct growth is common with clinical deterioration. (D) Branch occlusive disease is a common phenotype of ICAD. This phenotype is often misclassified as small a disease due to a mild degree of stenosis on MRA, small deep infarcts on DWI, and relatively small perfusion d High-resolution MRI can reveal plaque without stenosis near the orifices of penetrating arteries. https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 16/24 7/5/23, 11:53 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate ICAD: intracranial atherosclerotic disease; DWI: diffusion-weighted imaging; PWI: perfusion-weighted imagin MRA: time-of-flight magnetic resonance angiography. Reproduced with permission from: Bang OY. Intracranial atherosclerosis: current understanding and perspectives. J Stroke 2014; 16:27 Copyright 2014 Korean Stroke Academy. Graphic 105007 Version 1.0 https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 17/24 7/5/23, 11:53 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Eligibility criteria for the treatment of acute ischemic stroke with intravenous thrombolysis (recombinant tissue plasminogen activator or tPA) Inclusion criteria Clinical diagnosis of ischemic stroke causing measurable neurologic deficit Onset of symptoms <4.5 hours before beginning treatment; if the exact time of stroke onset is not known, it is defined as the last time the patient was known to be normal or at neurologic baseline Age 18 years Exclusion criteria Patient history Ischemic stroke or severe head trauma in the previous three months Previous intracranial hemorrhage Intra-axial intracranial neoplasm Gastrointestinal malignancy Gastrointestinal hemorrhage in the previous 21 days Intracranial or intraspinal surgery within the prior three months Clinical Symptoms suggestive of subarachnoid hemorrhage Persistent blood pressure elevation (systolic 185 mmHg or diastolic 110 mmHg) Active internal bleeding Presentation consistent with infective endocarditis Stroke known or suspected to be associated with aortic arch dissection Acute bleeding diathesis, including but not limited to conditions defined under 'Hematologic' Hematologic 3 Platelet count <100,000/mm * Current anticoagulant use with an INR >1.7 or PT >15 seconds or aPTT >40 seconds* Therapeutic doses of low molecular weight heparin received within 24 hours (eg, to treat VTE and ACS); this exclusion does not apply to prophylactic doses (eg, to prevent VTE) Current use (ie, last dose within 48 hours in a patient with normal renal function) of a direct thrombin inhibitor or direct factor Xa inhibitor with evidence of anticoagulant effect by laboratory tests such as aPTT, INR, ECT, TT, or appropriate factor Xa activity assays Head CT Evidence of hemorrhage https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 18/24 7/5/23, 11:53 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Extensive regions of obvious hypodensity consistent with irreversible injury Warnings Only minor and isolated neurologic signs or rapidly improving symptoms Serum glucose <50 mg/dL (<2.8 mmol/L) Serious trauma in the previous 14 days Major surgery in the previous 14 days History of gastrointestinal bleeding (remote) or genitourinary bleeding Seizure at the onset of stroke with postictal neurologic impairments Pregnancy** Arterial puncture at a noncompressible site in the previous seven days Large ( 10 mm), untreated, unruptured intracranial aneurysm Untreated intracranial vascular malformation Additional warnings for treatment from 3 to 4.5 hours from symptom onset Age >80 years Oral anticoagulant use regardless of INR Severe stroke (NIHSS score >25) Combination of both previous ischemic stroke and diabetes mellitus ACS: acute coronary syndrome; aPTT: activated partial thromboplastin time; ECT: ecarin clotting time; INR: international normalized ratio; PT: prothrombin time; NIHSS: National Institutes of Health Stroke Scale; tPA: intravenous alteplase; TT: thrombin time; VTE: venous thromboembolism. Although it is desirable to know the results of these tests, thrombolytic therapy should not be delayed while results are pending unless (1) there is clinical suspicion of a bleeding abnormality or thrombocytopenia, (2) the patient is currently on or has recently received anticoagulants (eg, heparin, warfarin, a direct thrombin inhibitor, or a direct factor Xa inhibitor), or (3) use of anticoagulants is not known. Otherwise, treatment with intravenous tPA can be started before availability of coagulation test results but should be discontinued if the INR, PT, or aPTT exceed the limits stated in the table, or 3 if platelet count is <100,000 mm . With careful consideration and weighting of risk-to-benefit, patients may receive intravenous alteplase despite one or more warnings. Patients who have a persistent neurologic deficit that is potentially disabling, despite improvement of any degree, should be treated with tPA in the absence of other contraindications. Any of the following should be considered disabling deficits: Complete hemianopia: 2 on NIHSS question 3, or Severe aphasia: 2 on NIHSS question 9, or Visual or sensory extinction: 1 on NIHSS question 11, or Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6, or Any deficits that lead to a total NIHSS >5, or https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 19/24 7/5/23, 11:53 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Any remaining deficit considered potentially disabling in the view of the patient and the treating practitioner using clinical judgment Patients may be treated with intravenous alteplase if glucose level is subsequently normalized. The potential risks of bleeding with alteplase from injuries related to the trauma should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. The increased risk of surgical site bleeding with alteplase should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. There is a low increased risk of new bleeding with alteplase in the setting of past gastrointestinal or genitourinary bleeding. However, alteplase administration within 21 days of gastrointestinal bleeding is not recommended.

15/24 7/5/23, 11:53 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Mechanisms of stroke in patients with intracranial atherosclerotic disease Mechanisms of stroke in patients with ICAD. (A) Thrombotic occlusion is a rare phenotype of ICAD. MRA shows in situ thrombotic occlusion at the site of st plaque. DWI shows territorial infarcts by severe hemodynamic compromise and embolic infarcts on the corte High-resolution MRI can show vulnerable plaque on intracranial vessels. (B) Artery-to-artery embolism is one of common phenotypes of ICAD. Artery-to-artery embolism is usually associated with a severe degree of intracranial stenosis, and transcranial Doppler ultrasonography can detec symptomatic or asymptomatic embolism during microembolic signal monitoring. DWI shows small, scattered cortical embolic infarcts. (C) Hemodynamic impairment is another phenotype of ICAD. This phenotype is usually associated with a seve stenosis and a marked hemodynamic compromise, as seen on a PWI. DWI typically shows borderzone-type in and infarct growth is common with clinical deterioration. (D) Branch occlusive disease is a common phenotype of ICAD. This phenotype is often misclassified as small a disease due to a mild degree of stenosis on MRA, small deep infarcts on DWI, and relatively small perfusion d High-resolution MRI can reveal plaque without stenosis near the orifices of penetrating arteries. https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 16/24 7/5/23, 11:53 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate ICAD: intracranial atherosclerotic disease; DWI: diffusion-weighted imaging; PWI: perfusion-weighted imagin MRA: time-of-flight magnetic resonance angiography. Reproduced with permission from: Bang OY. Intracranial atherosclerosis: current understanding and perspectives. J Stroke 2014; 16:27 Copyright 2014 Korean Stroke Academy. Graphic 105007 Version 1.0 https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 17/24 7/5/23, 11:53 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Eligibility criteria for the treatment of acute ischemic stroke with intravenous thrombolysis (recombinant tissue plasminogen activator or tPA) Inclusion criteria Clinical diagnosis of ischemic stroke causing measurable neurologic deficit Onset of symptoms <4.5 hours before beginning treatment; if the exact time of stroke onset is not known, it is defined as the last time the patient was known to be normal or at neurologic baseline Age 18 years Exclusion criteria Patient history Ischemic stroke or severe head trauma in the previous three months Previous intracranial hemorrhage Intra-axial intracranial neoplasm Gastrointestinal malignancy Gastrointestinal hemorrhage in the previous 21 days Intracranial or intraspinal surgery within the prior three months Clinical Symptoms suggestive of subarachnoid hemorrhage Persistent blood pressure elevation (systolic 185 mmHg or diastolic 110 mmHg) Active internal bleeding Presentation consistent with infective endocarditis Stroke known or suspected to be associated with aortic arch dissection Acute bleeding diathesis, including but not limited to conditions defined under 'Hematologic' Hematologic 3 Platelet count <100,000/mm * Current anticoagulant use with an INR >1.7 or PT >15 seconds or aPTT >40 seconds* Therapeutic doses of low molecular weight heparin received within 24 hours (eg, to treat VTE and ACS); this exclusion does not apply to prophylactic doses (eg, to prevent VTE) Current use (ie, last dose within 48 hours in a patient with normal renal function) of a direct thrombin inhibitor or direct factor Xa inhibitor with evidence of anticoagulant effect by laboratory tests such as aPTT, INR, ECT, TT, or appropriate factor Xa activity assays Head CT Evidence of hemorrhage https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 18/24 7/5/23, 11:53 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Extensive regions of obvious hypodensity consistent with irreversible injury Warnings Only minor and isolated neurologic signs or rapidly improving symptoms Serum glucose <50 mg/dL (<2.8 mmol/L) Serious trauma in the previous 14 days Major surgery in the previous 14 days History of gastrointestinal bleeding (remote) or genitourinary bleeding Seizure at the onset of stroke with postictal neurologic impairments Pregnancy** Arterial puncture at a noncompressible site in the previous seven days Large ( 10 mm), untreated, unruptured intracranial aneurysm Untreated intracranial vascular malformation Additional warnings for treatment from 3 to 4.5 hours from symptom onset Age >80 years Oral anticoagulant use regardless of INR Severe stroke (NIHSS score >25) Combination of both previous ischemic stroke and diabetes mellitus ACS: acute coronary syndrome; aPTT: activated partial thromboplastin time; ECT: ecarin clotting time; INR: international normalized ratio; PT: prothrombin time; NIHSS: National Institutes of Health Stroke Scale; tPA: intravenous alteplase; TT: thrombin time; VTE: venous thromboembolism. Although it is desirable to know the results of these tests, thrombolytic therapy should not be delayed while results are pending unless (1) there is clinical suspicion of a bleeding abnormality or thrombocytopenia, (2) the patient is currently on or has recently received anticoagulants (eg, heparin, warfarin, a direct thrombin inhibitor, or a direct factor Xa inhibitor), or (3) use of anticoagulants is not known. Otherwise, treatment with intravenous tPA can be started before availability of coagulation test results but should be discontinued if the INR, PT, or aPTT exceed the limits stated in the table, or 3 if platelet count is <100,000 mm . With careful consideration and weighting of risk-to-benefit, patients may receive intravenous alteplase despite one or more warnings. Patients who have a persistent neurologic deficit that is potentially disabling, despite improvement of any degree, should be treated with tPA in the absence of other contraindications. Any of the following should be considered disabling deficits: Complete hemianopia: 2 on NIHSS question 3, or Severe aphasia: 2 on NIHSS question 9, or Visual or sensory extinction: 1 on NIHSS question 11, or Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6, or Any deficits that lead to a total NIHSS >5, or https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 19/24 7/5/23, 11:53 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Any remaining deficit considered potentially disabling in the view of the patient and the treating practitioner using clinical judgment Patients may be treated with intravenous alteplase if glucose level is subsequently normalized. The potential risks of bleeding with alteplase from injuries related to the trauma should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. The increased risk of surgical site bleeding with alteplase should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. There is a low increased risk of new bleeding with alteplase in the setting of past gastrointestinal or genitourinary bleeding. However, alteplase administration within 21 days of gastrointestinal bleeding is not recommended. Alteplase is reasonable in patients with a seizure at stroke onset if evidence suggests that residual impairments are secondary to acute ischemic stroke and not to a postictal phenomenon. * Alteplase can be given in pregnancy when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding. The safety and efficacy of administering alteplase is uncertain for these relative exclusions. Although these were exclusions in the trial showing benefit in the 3 to 4.5 hour window, intravenous alteplase appears to be safe and may be beneficial for patients with these criteria, including patients taking oral anticoagulants with an INR <1.7. Adapted from: 1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359:1317. 2. Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke Association. Stroke 2009; 40:2945. 3. Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force:, Levine SR, Khatri P, et al. Review, historical context, and clari cations of the NINDS rt-PA stroke trials exclusion criteria: Part 1: rapidly improving stroke symptoms. Stroke 2013; 44:2500. 4. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scienti c rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2016; 47:581. 5. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. Graphic 71462 Version 26.0 https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 20/24 7/5/23, 11:53 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Indications for mechanical thrombectomy to treat patients with acute ischemic IV: intravenous; tPA: tissue plasminogen activator (alteplase or tenecteplase); CTA: computed tomography an artery occlusion; MT: mechanical thrombectomy; ASPECTS: Alberta Stroke Program Early CT Score; NIHSS: Na tomography; MRI: magnetic resonance imaging; mRS: modified Rankin Scale; MCA: middle cerebral artery; IC recovery. Patients are not ordinarily eligible for IV tPA unless the time last known to be well is <4.5 hours. However, im that is diffusion positive and FLAIR negative) is an option at expert stroke centers to select patients with wake associated UpToDate topics for details. Usually assessed with MRA or CTA, less often with digital subtraction angiography. There is intracranial arterial occlusion of the distal ICA, middle cerebral (M1/M2), or anterior cerebral (A1/A2 MT may be a treatment option for patients with acute ischemic stroke caused by occlusion of the basilar ar stroke centers, but benefit is uncertain. [1] Based upon data from the Aurora study . Reference: https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 21/24 7/5/23, 11:53 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate 1. Albers GW, Lansberg MG, Brown S, et al. Assessment of Optimal Patient Selection for Endovascular Thrombectomy Beyond 6 Hou Neurol 2021; 78:1064. Graphic 117086 Version 3.0 https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 22/24 7/5/23, 11:53 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Acute ischemic stroke syndromes according to vascular territory Artery involved Syndrome Anterior cerebral artery Motor and/or sensory deficit (leg > face, arm) Grasp, sucking reflexes Abulia, paratonic rigidity, gait apraxia Middle cerebral artery Dominant hemisphere: aphasia, motor and sensory deficit (face, arm > leg > foot), may be complete hemiplegia if internal capsule involved, homonymous hemianopia Non-dominant hemisphere: neglect, anosognosia, motor and sensory deficit (face, arm > leg > foot), homonymous hemianopia Posterior cerebral artery Homonymous hemianopia; alexia without agraphia (dominant hemisphere); visual hallucinations, visual perseverations (calcarine cortex); sensory loss, choreoathetosis, spontaneous pain (thalamus); III nerve palsy, paresis of vertical eye movement, motor deficit (cerebral peduncle, midbrain) Penetrating vessels Pure motor hemiparesis (classic lacunar syndromes) Pure sensory deficit Pure sensory-motor deficit Hemiparesis, homolateral ataxia Dysarthria/clumsy hand Vertebrobasilar Cranial nerve palsies Crossed sensory deficits Diplopia, dizziness, nausea, vomiting, dysarthria, dysphagia, hiccup Limb and gait ataxia Motor deficit Coma Bilateral signs suggest basilar artery disease Internal carotid artery Progressive or stuttering onset of MCA syndrome, occasionally ACA syndrome as well if insufficient collateral flow Graphic 75487 Version 7.0 https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 23/24 7/5/23, 11:53 AM Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis - UpToDate Contributor Disclosures As'ad Ehtisham, MD, MBBS, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Tanya N Turan, MD, MSCR No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-epidemiology-clinical-manifestations-and-diagnosis/print 24/24

7/5/23, 11:53 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Intracranial large artery atherosclerosis: Treatment and prognosis : Tanya N Turan, MD, MSCR, Jose Gutierrez, MD, MPH : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Oct 06, 2022. INTRODUCTION Atherosclerotic stenosis of the major intracranial arteries, also known as intracranial atherosclerosis (ICAS) or cerebral atherosclerosis, is an important cause of ischemic stroke. This topic focuses on the treatment and prognosis of ICAS. The epidemiology, clinical manifestations, and diagnosis of ICAS are reviewed separately. (See "Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis".) Other ischemic stroke subtypes are discussed elsewhere. (See "Stroke: Etiology, classification, and epidemiology" and "Clinical diagnosis of stroke subtypes" and "Lacunar infarcts" and "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)".) TREATMENT OF ACUTE STROKE OR TIA The initial treatment of acute stroke or transient ischemic attack (TIA) due to ICAS is similar to the treatment of acute ischemic stroke or TIA attributed to other mechanisms, as reviewed in detail separately. (See "Initial assessment and management of acute stroke".) Of utmost importance, timely restoration of blood flow using reperfusion therapies (intravenous thrombolysis and/or mechanical thrombectomy) is the most effective way to salvage ischemic brain tissue that is not already infarcted. There is a relatively narrow time window during which this can be accomplished, since the benefit of these interventions decreases over time. Thus, an https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 1/25 7/5/23, 11:54 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate important aspect of the hyperacute phase of acute ischemic stroke management is the rapid determination of patients who are eligible for intravenous thrombolysis and mechanical thrombectomy. (See "Approach to reperfusion therapy for acute ischemic stroke" and "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use" and "Mechanical thrombectomy for acute ischemic stroke".) Antiplatelet therapy has an important role in the both the acute and chronic phase of ischemic stroke management, as discussed below. (See 'Antiplatelet therapy' below.) SECONDARY PREVENTION Our approach For patients with transient ischemic attack (TIA) or ischemic stroke attributed to ICAS, we employ intensive medical therapy that includes antiplatelet therapy and strict control of vascular risk factors including the use of antihypertensive agents; low density lipoprotein cholesterol (LDL-C) lowering therapy; and physical activity and other lifestyle modification (eg, smoking cessation, weight control, salt restriction, and a healthy diet) [1]. (See 'Antiplatelet therapy' below and 'Risk factor management' below.) Intensive medical therapy is superior to intracranial arterial stenting for patients with recent stroke or TIA attributed to severe ICAS. (See 'Stenting' below.) Antiplatelet therapy Aspirin and other antithrombotic agents should not be given for the first 24 hours following treatment with intravenous thrombolysis. Otherwise, antiplatelet therapy should be started for most patients without an indication for anticoagulation as soon as possible after the diagnosis of TIA or ischemic stroke is confirmed, even before the evaluation for ischemic mechanism is complete. This issue is reviewed in detail elsewhere. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Treatment on presentation'.) For patients without serious bleeding complications who are not on anticoagulation or antiplatelet therapy at baseline, we start antiplatelet therapy as soon as possible while evaluating the ischemic stroke mechanism, as follows: For patients with a recent (within 30 days) stroke or TIA attributed to atherosclerotic intracranial large artery stenosis of 70 to 99 percent, we suggest short-term (up to 90 days) dual antiplatelet therapy (DAPT) with aspirin (325 mg daily) plus clopidogrel (300 to 600 mg loading dose, followed by 75 mg daily), rather than aspirin monotherapy, followed by long-term aspirin monotherapy [1-3]. https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 2/25 7/5/23, 11:54 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate For patients with a recent minor stroke (NIHSS score 5) or TIA attributed to atherosclerotic intracranial large artery stenosis of 50 to 69 percent, options for initial treatment include aspirin monotherapy or short-term (21-day) DAPT. For patients with brain ischemia attributed to atherosclerotic intracranial large artery stenosis of 50 to 69 percent who have 2 a low-risk TIA, defined by an ABCD score <4, or a moderate to major ischemic stroke, defined by a National Institutes of Health Stroke Scale (NIHSS) score >5, we start treatment 2 with aspirin (325 mg daily) alone. For patients with a high-risk TIA, defined by an ABCD score 4, or minor ischemic stroke, defined by a NIHSS score 5, we begin with dual antiplatelet therapy (DAPT) for 21 days using aspirin (160 to 325 mg loading dose, followed by 50 to 100 mg daily) plus clopidogrel (300 to 600 mg loading dose, followed by 75 mg daily) rather than aspirin alone. For long-term stroke prevention (beyond the 21- or 90-day duration of DAPT), we recommend treatment with aspirin. Clopidogrel monotherapy or the combination drug aspirin-extended- release dipyridamole are reasonable alternatives to aspirin but have not been specifically studied in ICAS. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) Exceptions may include patients with an indication for anticoagulation, as discussed separately. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Cardioembolic source' and "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Treatment on presentation'.) Evidence supporting short-term DAPT Accumulating data suggest that short-term (up to 90 days) DAPT may be beneficial for patients with acute stroke or TIA attributed to high- grade ICAS. Short-term DAPT with aspirin and clopidogrel The multicenter SAMMPRIS trial enrolled patients with 70 to 99 percent stenosis of a major intracranial artery who had a TIA or ischemic stroke within 30 days prior to study entry; in the aggressive medical treatment arm of the trial, the short-term use of DAPT with aspirin and clopidogrel for the first 90 days after enrollment may have contributed to the relatively low rate of combined stroke and death at one year of 12.2 percent [4,5]. This contrasts with findings from a post hoc analysis of the WASID trial, which enrolled patients with a stroke or TIA attributed to a 50 to 99 percent intracranial stenosis; the subgroup of patients in WASID who would have met the SAMMPRIS trial entry criteria (ie, 70 to 99 percent intracranial large artery stenosis and TIA or stroke within 30 days prior to study entry) and who were treated with aspirin or warfarin had a combined stroke and death rate at one year of 23 percent [6]. Additional support for DAPT comes from a subgroup https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 3/25 7/5/23, 11:54 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate analysis of patients with ICAS in the CHANCE trial, which reported that those treated with DAPT had a lower rate of early recurrent stroke than those on monotherapy, although the difference was not statistically significant [7]. Similarly, the CLAIR study showed that patients with middle cerebral artery (MCA) stenosis on DAPT had significantly lower rates of microemboli distal to the stenosis when compared with those on aspirin alone and a lower (nonsignificant) rate of recurrent stroke [8]. In summary, the lower rates of recurrent stroke in SAMMPRIS patients on DAPT compared with similar patients from WASID, combined with the supportive CHANCE and CLAIR data, make a compelling argument to continue DAPT up to 90 days in patients with severe ICAS. Most importantly, the high risk of recurrent stroke from ICAS that persists beyond the first month distinguishes these patients from other stroke subtypes and argues for longer DAPT treatment. Short-term DAPT with aspirin and ticagrelor The THALES trial compared ticagrelor (90 mg twice daily after 180 mg loading dose) plus aspirin (75 to 100 mg once daily after 300 to 325 mg loading dose) among patients with recent non-cardioembolic stroke with NIHSS 5 or high-risk TIA or symptomatic >30 percent intracranial or extracranial stenosis. A subgroup analysis of THALES patients with ICAS 30 percent ipsilateral to the qualifying ischemic event found lower rates of ischemic stroke in those on combination ticagrelor plus aspirin compared with those on aspirin alone at 30 days (9.5 versus 15.2 percent, hazard ratio [HR] 0.66, 95% CI 0.47 0.93) [9]. Unlike other ICAS trials wherein the stenosis was determined by the investigator to be symptomatic for study qualification, the stenosis in this THALES analysis may have been incidental (eg, a 40 percent cavernous carotid stenosis ipsilateral to a lenticulostriate stroke). Additionally, the treatment duration was limited to 30 days, as were the reported outcomes. Given that ICAS stroke risk remains high beyond 30 days and the bleeding risk with ticagrelor and aspirin reported in THALES, additional long-term and comparative data are needed to better understand the role of this combination compared with other DAPT options. Additional support for the use of short-term DAPT in the setting of acute minor ischemic stroke or high-risk TIA comes from several randomized trials and meta-analysis, as reviewed in detail separately. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Efficacy of DAPT'.) Evidence supporting long-term antiplatelet therapy Aspirin, clopidogrel, and the combination aspirin-extended-release dipyridamole have been established as effective for prevention of recurrent ischemic stroke in the patients with a history of noncardioembolic ischemic stroke or TIA of atherothrombotic, lacunar (small vessel occlusive), or cryptogenic type. Since antiplatelet drugs are effective in this larger group of patients with different https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 4/25 7/5/23, 11:54 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate types of noncardioembolic ischemic stroke, they are likely to be effective in patients with ICAS, a subgroup that appears to be at particularly high risk of recurrent ischemic stroke. However, antiplatelet drugs have not been compared with placebo or with each other in randomized controlled trials specifically for patients with stroke or TIA attributed to ICAS. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) Cilostazol is a phosphodiesterase 3 inhibitor and antiplatelet agent with vasodilating and possible antiatherogenic effects [10]. Early randomized trials conducted in East Asia failed to show a benefit of cilostazol plus aspirin compared with aspirin alone or clopidogrel plus aspirin for reducing stroke risk due to ICAS [11,12]. Later randomized trials from East Asia of cilostazol in combination with aspirin or clopidogrel showed a benefit for stroke prevention in patients with ICAS, but the findings may not be generalizable to all populations [13,14]. The CATHARSIS trial compared cilostazol plus aspirin with aspirin alone in patients with symptomatic 50 to 99 percent ICAS [13]. At two years, rates of vascular events and silent brain infarcts were lower in those on dual therapy (10.7 versus 25 percent, HR 0.37, 95% CI 0.14-0.97) without an increased bleeding risk. Similarly, among ICAS patients in the CSPS.com trial, with 0.5- to 3.5-year follow-up, those randomly assigned to cilostazol plus aspirin or clopidogrel had a lower rate of ischemic stroke compared with patients randomly assigned to placebo plus aspirin or clopidogrel (4.5 versus 9.9 percent, HR 0.48, 95% CI 0.21-1.11) and no increased bleeding risk [14]. In addition, other randomized trials support the safety and efficacy of cilostazol for secondary ischemic stroke prevention in East Asian populations, as described elsewhere. (See "Long- term antithrombotic therapy for the secondary prevention of ischemic stroke", section on 'Cilostazol'.) Other antiplatelet agents such as prasugrel and vorapaxar are not well studied in this population. No role for oral anticoagulation There is randomized trial evidence that oral anticoagulation with warfarin is harmful for patients with TIA or stroke due to ICAS. The WASID trial enrolled patients with TIA or nondisabling stroke caused by an angiographically verified 50 to 99 percent stenosis of a major intracranial artery; patients were randomly assigned to treatment with either warfarin (target international normalized ratio [INR] 2.0 to 3.0) or aspirin (1300 mg/day) [15]. The study was stopped prematurely because of safety concerns for patients in the warfarin arm after enrolling 569 patients with an average follow-up of 1.8 years. Aspirin treatment was associated with a significantly lower rate of death than warfarin (4.3 versus 9.7 percent, HR 0.46, 95% CI 0.23-0.90). The composite rate of ischemic stroke, brain hemorrhage, or death from vascular cause other than stroke was similar between aspirin and warfarin treatment (22.1 versus 21.8 percent, hazard ratio [HR] https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 5/25 7/5/23, 11:54 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate 1.04, 95% CI 0.73-1.48). The rate of ischemic stroke recurrence in the territory of the stenotic intracranial artery was high for both aspirin and warfarin treatment (15.0 versus 12.1 percent, HR 1.26, 95% CI 0.81-1.97) and primarily occurred within the first year from the qualifying event, suggesting that neither aspirin alone nor warfarin was particularly effective for preventing early recurrent stroke. Of note, the WASID trial was performed before the era of intensive risk factor management that included statin therapy for aggressive LDL-lowering. The efficacy of direct (non-vitamin K) oral anticoagulants (DOACs) for prevention of stroke due to ICAS has not been systematically studied, but planning is underway for a trial that will randomize patients to aspirin plus either clopidogrel, ticagrelor or low-dose rivaroxaban. Risk factor management Management of risk factors including hypertension, hyperlipidemia, physical inactivity, obesity, diabetes, and smoking is a critical component of the treatment of patients with atherosclerotic cardiovascular disease, including those with ischemic stroke. Post hoc analyses from the WASID trial showed that patients with ICAS and poorly controlled blood pressure or elevated cholesterol during follow-up had a significantly higher rate of stroke, myocardial infarction, or vascular death compared with patients with good control of these risk factors [16,17]. In addition, post hoc analyses of patients in the aggressive medical management only arm of the SAMMPRIS trial (see 'Stenting' below) found that intensive treatment of blood pressure and LDL-C was important to prevent recurrent vascular events and that physical inactivity was the most important independent predictor of vascular events and stroke [18]. Given that risk factor control reduces the risk of vascular events and recurrent stroke in patients with heterogeneous causes of stroke (see "Overview of secondary prevention of ischemic stroke"), combined with the post hoc analyses described above [16-18], it is likely that patients with stroke due to ICAS have better outcomes with intensive risk factor control that includes antihypertensive therapy, LDL-C lowering therapy, and lifestyle modification. (See "Overview of secondary prevention of ischemic stroke".) Antihypertensive therapy We treat all patients with hypertension using nonpharmacologic therapy (ie, salt restriction, adequate potassium intake, weight control, healthy diet, limited alcohol intake, and exercise) and pharmacologic therapy. For patients with hypertension, we suggest targeting a systolic blood pressure (SBP) of <140 mmHg [1- 3]. In the absence of definitive data supporting lower SBP targets in patients with ICAS, we advise caution when pursuing lower targets of SBP (eg, SBP <130 or <120), especially in patients with ICAS and fluctuating neurological symptoms, a recent stroke, or documented https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 6/25 7/5/23, 11:54 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate low flow on quantitative magnetic resonance angiography. More research is needed to establish an alternative blood pressure target for such patients. The optimal target blood pressure to reduce the risk of recurrent ischemic stroke in patients with stroke due to ICAS is informed largely by post hoc analyses and data from a randomized controlled trial. The WASID and SAMMPRIS clinical trials demonstrated that in the vast majority of stable patients with stroke due to ICAS, lowering SBP to <140 mmHg was safe and was associated with a reduced risk of recurrent stroke [16-19]. However, targets below 140 mmHg were not studied in those analyses, and emerging data suggests caution should be advised with lower targets. As an example, a randomized controlled trial from Korea of 132 patients with recent subacute stroke due to ICAS found the group assigned to aggressive blood pressure control (mean SBP 124.6 mmHg) had a tendency toward larger infarct volume and more fluid-attenuated inversion recovery lesions on magnetic resonance imaging (MRI) at follow-up compared with the group assigned to standard blood pressure control (mean SBP 132 mmHg) [20]. In the MYRIAD observational study of patients with symptomatic ICAS, a change in systolic blood pressure from baseline to six- to eight-week follow-up was an independent predictor of early recurrent stroke [21]. Another study found that patients with ICAS who had a low translesional pressure gradient (measured using computational fluid dynamics from computed tomographic angiography) and a mean SBP <130 mmHg during follow-up had an increased risk of recurrent stroke in the territory compared with patients who had a SBP of 130 to 150 mmHg during follow-up [22]. Similarly, a post hoc analysis of the VERiTAS study of patients with posterior circulation stenosis reported that patients with both low flow on quantitative MRI and a mean SBP <140 mmHg had a higher risk of stroke compared with patients lacking one or both of these factors [19]. Specific aspects of the pharmacologic and nonpharmacologic evaluation and management of hypertension are discussed in greater detail separately. (See "Overview of hypertension in adults" and "Salt intake, salt restriction, and primary (essential) hypertension" and "Potassium and hypertension" and "Diet in the treatment and prevention of hypertension" and "Overweight, obesity, and weight reduction in hypertension" and "Exercise in the treatment and prevention of hypertension".) LDL-C lowering therapy For patients with a history of ischemic stroke or TIA, independent of the baseline LDL-C level, we recommend lifelong high-intensity statin therapy (atorvastatin 40 to 80 mg or rosuvastatin 20 to 40 mg); we prefer the highest approved dose in most cases. For patients who do not tolerate these doses, the maximally tolerated dose of a statin should be used. For patients whose LDL-C is 70 mg/dL (1.8 mmol/L) on high-intensity statin therapy, we recommend adding ezetimibe or a PCSK9 https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 7/25 7/5/23, 11:54 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate inhibitor to statin therapy. In most cases, this second drug will be ezetimibe for reasons of cost and convenience. For patients who do not tolerate any statin regimen, we start ezetimibe. For those patients whose LDL-C remains above 70 mg/dL (1.8 mmol/L), we consider adding a PCSK9 inhibitor. This approach is similar to that presented in many societal guidelines, including the 2022 American Academy of Neurology guidelines [1] and the 2019 multisociety American guidelines [23]; recommendations from the 2019 European Society of Cardiology are somewhat more aggressive for the highest-risk patients [24]. There is overwhelming evidence from randomized trials that LDL-C lowering reduces the risk of cardiovascular events including ischemic stroke. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease", section on 'Benefits of LDL-C lowering'.) Data specific to patients with ICAS has also emerged for the use of high-intensity statins and targeting LDL <70 mg/dL (1.8 mmol/L). A single-center randomized controlled trial of 120 patients from China with symptomatic MCA or basilar stenosis found a lower rate of recurrent cerebrovascular events during follow-up in those treated with high-intensity statins compared with low- and standard-intensity statins [25]. A post hoc analysis from the SAMMPRIS trial showed a lower risk of recurrent stroke and vascular events with lower LDL- C when analyzed as a continuous variable, but achieving the target LDL-C <70 mg/dL was associated with only a trend toward benefit [18]. However, the TST trial of over 2800 patients with recent ischemic stroke or TIA and atherosclerosis (including ICAS) found lower rates of recurrent vascular events, particularly stroke, in those assigned to the LDL target of <70 mg/dL compared with those assigned to a target range of 90 to 110 mg/dL [26]. (See "Overview of secondary prevention of ischemic stroke", section on 'LDL-C lowering therapy'.) Lifestyle modification A number of behavioral and lifestyle modifications may be beneficial for reducing the risk of ischemic stroke and cardiovascular disease [1]. These include smoking cessation, regular aerobic physical activity, limited alcohol consumption, weight control, salt restriction, and a Mediterranean diet. Physical activity, in particular, is strongly recommended for patients with ICAS since it was independently associated with lower rates of recurrent stroke, myocardial infarction, and vascular death in the medically treated patients in the SAMMPRIS trial (odds ratio [OR] 0.6, 95% CI 0.4 0.8), with higher rates of activity increasing the protective effect [18]. (See "Overview of secondary prevention of ischemic stroke", section on 'Lifestyle modification'.) https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 8/25 7/5/23, 11:54 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate Glycemic control Tight glucose control reduces microvascular complications. Diet, exercise, oral hypoglycemic drugs, and insulin are proven methods to achieve glycemic control. A reasonable goal of therapy for most patients with diabetes is a hemoglobin A1C value of 7 percent. However, the available evidence has not demonstrated a consistent beneficial effect of intensive glucose-lowering therapy or lifestyle modification for reducing macrovascular outcomes (eg, stroke and death) in patients with type 2 diabetes. (See "Overview of primary prevention of cardiovascular disease", section on 'Management of type 2 diabetes' and "Overview of secondary prevention of ischemic stroke", section on 'Glycemic control'.) Failure of medical therapy Although unproven, therapies of last resort for patients who have recurrent ischemic stroke due to ICAS despite maximal medical therapy include endovascular stenting (see 'Stenting' below) or submaximal angioplasty (see 'Submaximal angioplasty' below) as reviewed in the sections below. However, there are no comparative data from randomized trials demonstrating benefit of these treatments over medical therapy that can be used to guide management for patients with recurrent stroke in this setting. Intracranial arterial stenting and other interventional procedures are not recommended for patients with a first stroke or TIA attributable to severe intracranial artery stenosis [1-3], since results from the SAMMPRIS and VISSIT trials showed that medical management was superior to intracranial stenting (see 'Stenting' below). In the United States, the policy of the Centers for Medicare and Medicaid Services is not to reimburse for intracranial angioplasty with or without stenting outside the context of a clinical trial [27]. Other interventions are not routinely used because of lack of evidence or evidence of harm: Intracranial angioplasty without stenting has been studied only in small observational studies [28]. There are numerous drawbacks to intracranial angioplasty, including immediate elastic recoil of the artery, intimal damage, dissection, acute vessel closure, residual stenosis >50 percent following the procedure, and high restenosis rates [29-31]. A 2019 systematic review and meta-analysis of balloon angioplasty for ICAS including 25 studies and 674 patients showed a 30-day stroke and death rate of 16.3 percent in patients with severe stenosis [32]. Therefore, angioplasty alone has largely been replaced with submaximal angioplasty to minimize periprocedural complications. Extracranial-intracranial bypass, or direct bypass, was mostly abandoned for the treatment of ICAS after the extracranial-intracranial (EC-IC) bypass trial results were reported in 1985 [33]. In that study, 1377 patients with symptomatic extracranial carotid occlusion, distal carotid occlusive disease, or MCA stenosis were randomly assigned to either medical https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 9/25 7/5/23, 11:54 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate therapy alone (usually aspirin) or to extracranial-intracranial anastomosis surgery (joining the superficial temporal artery and the middle cerebral artery) combined with medical therapy. The mean follow-up was 56 months. The results demonstrated that EC-IC bypass was ineffective for preventing stroke in these patients [33]. Subgroup analyses showed that EC-IC bypass was ineffective in patients with distal carotid stenosis, and was actually hazardous in patients with MCA stenosis [33,34]. In 109 patients with 70 percent MCA stenosis, stroke frequency was significantly higher for patients who had EC-IC compared with medically treated patients (44 versus 24 percent). Indirect bypass, also known as encephaloduroarteriosynangiosis (EDAS), is an investigational surgical procedure that showed some early promising results for stroke prevention in ICAS in a two-center prospective uncontrolled study [35]. However, evidence of efficacy from randomized trials is needed before the procedure is widely adopted to treat medically refractory ICAS. Stenting Several multicenter randomized trials, described below, found that patients with symptomatic ICAS treated with angioplasty and stenting had worse outcomes than those who received medical therapy or showed no benefit of stenting [4,36,37]. In addition, a systematic review that identified three randomized controlled trials (including SAMMPRIS [4,5], VISSIT [36], and a trial from China [38]) with 632 patients who had symptomatic intracranial atherosclerotic stenosis found that, compared with medical treatment alone, endovascular therapy plus medical treatment led to higher rate of death or stroke at 30 days (16 versus 5 percent, absolute risk increase 11 percent, risk ratio [RR] 3.07, 95% CI 1.80-5.24) and at one year (24 versus 14 percent, absolute risk increase 10 percent, RR 1.69, 95% CI 1.21-2.36) [39]. Given these data, we recommend against intracranial stenting for patients with recent stroke or TIA attributed to ICAS [1-3]. All patients should be treated with intensive medical therapy that includes antiplatelet therapy and strict control of vascular risk factors, as described above. (See 'Secondary prevention' above.) SAMMPRIS trial The multicenter SAMMPRIS trial enrolled patients with 70 to 99 percent stenosis of a major intracranial artery who had a TIA or ischemic stroke within 30 days prior to study entry [4,5]. Patients were randomly assigned to treatment with intracranial angioplasty and stenting using the Wingspan system plus aggressive medical management, or to treatment with aggressive medical management alone. Aggressive medical therapy consisted of aspirin 325 mg daily for the duration of follow-up, clopidogrel 75 mg daily for 90 days after enrollment, and intensive risk factor management with a target blood pressure of <140/90 mmHg (or <130/80 mmHg if diabetic) and an LDL-C target of <70 mg/dL (<1.81 mmol/L). https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 10/25 7/5/23, 11:54 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate Trial enrollment in SAMMPRIS was halted prematurely after recruitment of 451 of the planned 764 patients because the 30-day rate of stroke or death was higher for patients treated with angioplasty and stenting compared with those treated with medical therapy alone (14.7 versus 5.8 percent) [4]. The periprocedural rate of stroke was higher than expected for the stenting group, and the early stroke rate was lower than estimated for the medical management group. Of the 33 early symptomatic stroke events in the stenting group, 25 occurred within one day of the procedure, and the remaining 8 occurred within six days of the procedure [40]. Of the early strokes, symptomatic intracranial, subarachnoid, or intraventricular hemorrhage occurred in 10 patients (4.5 percent), resulting in death in 4 patients (1.8 percent). By contrast, there were 12 early strokes in the medical management group, and none were hemorrhagic. In the stenting group, the main cause of the early ischemic strokes was occlusion of perforating vessels. Of the early hemorrhagic strokes, approximately one-half involved predominantly subarachnoid bleeding that was evident immediately after the procedure, while the rest were intraparenchymal hemorrhages that were attributed to reperfusion. At study end, with a median follow-up of 32 months, the rate of stroke or death remained significantly higher for the angioplasty and stenting group compared with the medical management group (19.7 versus 12.6 percent at one year, and 23.9 versus 14.9 percent at three years) [5]. These long-term differences were driven largely by the 30-day outcomes, since the rates of stroke and death beyond 30 days were similar for the two groups, demonstrating no long-term benefit from stenting. VISSIT trial The VISSIT trial randomly assigned 112 patients with symptomatic ICAS to treatment with a balloon-expandable stent plus medical therapy or to medical therapy alone. It was terminated early by the sponsor due to the low likelihood of detecting superiority of stenting over medical therapy [36]. At 30 days, the rate of the primary safety outcome, a composite of any stroke, death, or intracranial hemorrhage, was significantly higher in the stent group compared with the medical group (24 versus 9 percent). At 12 months, the rate of the primary outcome measure, a composite of stroke and TIA in the same territory, was significantly higher in the stent group (36 versus 15 percent). CASSISS trial The CASSISS trial, conducted at eight sites in China, was an open-label, randomized trial of 358 patients with symptomatic ICAS enrolled at least three weeks after the index stroke that compared angioplasty and stenting with the Wingspan stenting system with medical therapy [37,41]. In contrast to SAMMPRIS and VISSIT, CASSISS excluded patients with perforator ischemic events in the basal ganglia, thalamus, and https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 11/25 7/5/23, 11:54 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate brainstem and patients with MRI evidence of recent stroke by diffusion-weighted imaging (DWI) at the time of randomization in order to reduce the risk of periprocedural complications and symptomatic intracranial hemorrhage that was seen in earlier trials [41]. CASSISS reported a lower primary endpoint rate (a composite of any stroke or death within 30 days or stroke in territory within one year) than prior trials in both the stenting and medical groups (8 versus 7.2 percent, respectively), likely because of the lower-risk population enrolled and differences in event ascertainment during follow-up [37]. Nevertheless, the CASSISS trial found no benefit over medical therapy from angioplasty and stenting with the Wingspan stenting system for any of the primary or secondary outcome measures. Periprocedural brain hemorrhage affected four patients in the stenting group (two of which were fatal) versus none in the medical group. There was a trend toward higher three-year mortality in the stenting arm (4.4 versus 1.3 percent, 95% CI 0.77- 18.13). Although stenting for stroke prevention in patients with ICAS has been shown to be harmful in these randomized trials [39], some physicians treat with stenting as a last resort for patients with high-grade intracranial large artery stenosis who have multiple symptomatic ischemic events. Results from the WEAVE study, an open-label, single-arm postmarket surveillance study of the WINGSPAN stent, suggested that stenting appeared safe with a relatively low risk of recurrent stroke in highly-selected patients with symptomatic ICAS who are at least seven days from their most recent ischemic event and have had two or more recurrent ischemic events in the vascular territory of the stenotic intracranial large artery despite optimal medical management [42]. However, patients were only required to be followed for 72 hours or until discharge, and in some cases, assessments were done by phone if the patient was already discharged. Additionally, the stroke and death rate in WEAVE for patients with ICAS who did not meet strict US Food and Drug Administration criteria (eg, did not fail medical therapy, were less than seven days since last stroke, or more than two strokes) was approximately 24 percent [43,44]. Along those lines, another ICAS registry of patients treated with stenting or angioplasty who failed medical therapy or had with progressive stroke symptoms reported a 90-day ischemic stroke rate of 6.7 percent and 90-day mortality of 11.2 percent [45]. Given the high complication rates and low-quality evidence supporting safety in these uncontrolled studies, randomized controlled trials are needed before stenting is adopted as a rescue therapy even in those who have failed medical therapy. Analyses of the SAMMPRIS trial found no benefit for stenting for any subgroup of patients, including those patients with a prior ischemic stroke in the territory of the symptomatic intracranial artery and those who had their qualifying ischemic event on antithrombotic therapy [5,46,47]. https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 12/25 7/5/23, 11:54 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate Submaximal angioplasty Submaximal angioplasty involves angioplasty alone with slow expansion of a balloon undersized to 50 to 70 percent of nominal vessel diameter to limit periprocedural complications. A 2020 meta-analysis identified nine studies (eight retrospective) with 395 patients who had 408 procedures with submaximal angioplasty [48]. The pooled periprocedural complication rate for stroke or death was approximately 5 percent, while the pooled rate beyond 30 days was approximately 4 percent. Technical success reported in six studies was achieved in approximately 96 percent of procedures. These results compare favorably with periprocedural event rates observed in the stenting and medical treatment arms of the SAMMPRIS and VISSIT trials described above. (See 'Stenting' above.) These limited data suggest that submaximal angioplasty may be a promising strategy for safe revascularization in the future, but more research is needed before it is widely used in practice. Recommendations of others The 2021 American Heart Association/American Stroke Association recommendations for intracranial stenosis are as follows [2]: For patients with a stroke or TIA attributable to a 50 to 99 percent stenosis of a major intracranial artery, aspirin 325 mg daily is recommended in preference to warfarin. For patients with recent stroke or TIA (within 30 days) attributable to severe stenosis (70 to 99 percent) of a major intracranial artery, the addition of clopidogrel 75 mg daily to aspirin for up to 90 days is reasonable. For patients with a stroke or TIA attributable to severe stenosis (70 to 99 percent) of a major intracranial artery, the addition of cilostazol 200 mg daily to aspirin or clopidogrel might be considered. For patients with recent (within 24 hours) minor stroke or high-risk TIA and concomitant ipsilateral >30 percent stenosis of a major intracranial artery, the addition of ticagrelor 90 mg twice daily to aspirin for up to 30 days might be considered. For patients with a stroke or TIA attributable to a 50 to 99 percent stenosis of a major intracranial artery, maintenance of SBP below 140 mm Hg, high-intensity statin therapy, and at least moderate physical activity are recommended. For patients with stroke or TIA attributable to severe stenosis (70 to 99 percent) of a major intracranial artery, angioplasty or stenting should not be performed as initial treatment, even for patients who were taking an antithrombotic agent at the time of the stroke or TIA. In patients with severe stenosis (70 to 99 percent) of a major intracranial artery and actively progressing symptoms or recurrent TIA or stroke after institution of aspirin and clopidogrel https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 13/25 7/5/23, 11:54 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate therapy, achievement of SBP <140 mmHg, and high-intensity statin therapy (so-called medical failures), the usefulness of angioplasty alone or stent placement to prevent

three years) [5]. These long-term differences were driven largely by the 30-day outcomes, since the rates of stroke and death beyond 30 days were similar for the two groups, demonstrating no long-term benefit from stenting. VISSIT trial The VISSIT trial randomly assigned 112 patients with symptomatic ICAS to treatment with a balloon-expandable stent plus medical therapy or to medical therapy alone. It was terminated early by the sponsor due to the low likelihood of detecting superiority of stenting over medical therapy [36]. At 30 days, the rate of the primary safety outcome, a composite of any stroke, death, or intracranial hemorrhage, was significantly higher in the stent group compared with the medical group (24 versus 9 percent). At 12 months, the rate of the primary outcome measure, a composite of stroke and TIA in the same territory, was significantly higher in the stent group (36 versus 15 percent). CASSISS trial The CASSISS trial, conducted at eight sites in China, was an open-label, randomized trial of 358 patients with symptomatic ICAS enrolled at least three weeks after the index stroke that compared angioplasty and stenting with the Wingspan stenting system with medical therapy [37,41]. In contrast to SAMMPRIS and VISSIT, CASSISS excluded patients with perforator ischemic events in the basal ganglia, thalamus, and https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 11/25 7/5/23, 11:54 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate brainstem and patients with MRI evidence of recent stroke by diffusion-weighted imaging (DWI) at the time of randomization in order to reduce the risk of periprocedural complications and symptomatic intracranial hemorrhage that was seen in earlier trials [41]. CASSISS reported a lower primary endpoint rate (a composite of any stroke or death within 30 days or stroke in territory within one year) than prior trials in both the stenting and medical groups (8 versus 7.2 percent, respectively), likely because of the lower-risk population enrolled and differences in event ascertainment during follow-up [37]. Nevertheless, the CASSISS trial found no benefit over medical therapy from angioplasty and stenting with the Wingspan stenting system for any of the primary or secondary outcome measures. Periprocedural brain hemorrhage affected four patients in the stenting group (two of which were fatal) versus none in the medical group. There was a trend toward higher three-year mortality in the stenting arm (4.4 versus 1.3 percent, 95% CI 0.77- 18.13). Although stenting for stroke prevention in patients with ICAS has been shown to be harmful in these randomized trials [39], some physicians treat with stenting as a last resort for patients with high-grade intracranial large artery stenosis who have multiple symptomatic ischemic events. Results from the WEAVE study, an open-label, single-arm postmarket surveillance study of the WINGSPAN stent, suggested that stenting appeared safe with a relatively low risk of recurrent stroke in highly-selected patients with symptomatic ICAS who are at least seven days from their most recent ischemic event and have had two or more recurrent ischemic events in the vascular territory of the stenotic intracranial large artery despite optimal medical management [42]. However, patients were only required to be followed for 72 hours or until discharge, and in some cases, assessments were done by phone if the patient was already discharged. Additionally, the stroke and death rate in WEAVE for patients with ICAS who did not meet strict US Food and Drug Administration criteria (eg, did not fail medical therapy, were less than seven days since last stroke, or more than two strokes) was approximately 24 percent [43,44]. Along those lines, another ICAS registry of patients treated with stenting or angioplasty who failed medical therapy or had with progressive stroke symptoms reported a 90-day ischemic stroke rate of 6.7 percent and 90-day mortality of 11.2 percent [45]. Given the high complication rates and low-quality evidence supporting safety in these uncontrolled studies, randomized controlled trials are needed before stenting is adopted as a rescue therapy even in those who have failed medical therapy. Analyses of the SAMMPRIS trial found no benefit for stenting for any subgroup of patients, including those patients with a prior ischemic stroke in the territory of the symptomatic intracranial artery and those who had their qualifying ischemic event on antithrombotic therapy [5,46,47]. https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 12/25 7/5/23, 11:54 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate Submaximal angioplasty Submaximal angioplasty involves angioplasty alone with slow expansion of a balloon undersized to 50 to 70 percent of nominal vessel diameter to limit periprocedural complications. A 2020 meta-analysis identified nine studies (eight retrospective) with 395 patients who had 408 procedures with submaximal angioplasty [48]. The pooled periprocedural complication rate for stroke or death was approximately 5 percent, while the pooled rate beyond 30 days was approximately 4 percent. Technical success reported in six studies was achieved in approximately 96 percent of procedures. These results compare favorably with periprocedural event rates observed in the stenting and medical treatment arms of the SAMMPRIS and VISSIT trials described above. (See 'Stenting' above.) These limited data suggest that submaximal angioplasty may be a promising strategy for safe revascularization in the future, but more research is needed before it is widely used in practice. Recommendations of others The 2021 American Heart Association/American Stroke Association recommendations for intracranial stenosis are as follows [2]: For patients with a stroke or TIA attributable to a 50 to 99 percent stenosis of a major intracranial artery, aspirin 325 mg daily is recommended in preference to warfarin. For patients with recent stroke or TIA (within 30 days) attributable to severe stenosis (70 to 99 percent) of a major intracranial artery, the addition of clopidogrel 75 mg daily to aspirin for up to 90 days is reasonable. For patients with a stroke or TIA attributable to severe stenosis (70 to 99 percent) of a major intracranial artery, the addition of cilostazol 200 mg daily to aspirin or clopidogrel might be considered. For patients with recent (within 24 hours) minor stroke or high-risk TIA and concomitant ipsilateral >30 percent stenosis of a major intracranial artery, the addition of ticagrelor 90 mg twice daily to aspirin for up to 30 days might be considered. For patients with a stroke or TIA attributable to a 50 to 99 percent stenosis of a major intracranial artery, maintenance of SBP below 140 mm Hg, high-intensity statin therapy, and at least moderate physical activity are recommended. For patients with stroke or TIA attributable to severe stenosis (70 to 99 percent) of a major intracranial artery, angioplasty or stenting should not be performed as initial treatment, even for patients who were taking an antithrombotic agent at the time of the stroke or TIA. In patients with severe stenosis (70 to 99 percent) of a major intracranial artery and actively progressing symptoms or recurrent TIA or stroke after institution of aspirin and clopidogrel https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 13/25 7/5/23, 11:54 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate therapy, achievement of SBP <140 mmHg, and high-intensity statin therapy (so-called medical failures), the usefulness of angioplasty alone or stent placement to prevent ischemic stroke in the territory of the stenotic artery is unknown. For patients with a stroke or TIA attributable to moderate stenosis (50 to 69 percent) of a major intracranial artery, angioplasty or stenting is associated with excess morbidity and mortality compared with medical management alone. Recommendations from the 2017 update to the Canadian stroke best practice recommendations for ICAS are as follows [49]: Intracranial stenting is not recommended for the treatment of recently symptomatic intracranial 70 to 99 percent stenosis. As in the medical management arm of the SAMMPRIS trial, dual antiplatelet therapy with aspirin and clopidogrel started within 30 days of stroke or TIA and treatment for up to 90 days should be considered for patients on an individual basis, along with aggressive management of all vascular risk factors including blood pressure, lipids, diabetes mellitus, and other at-risk lifestyle patterns. In patients managed with maximal medical therapy in the presence of intracranial stenosis who experience a recurrent stroke, there is lack of clear evidence to guide further management decisions; intracranial angioplasty (with or without stenting) may be reasonable in carefully selected patients. Recommendations from the UK National Institute for Health and Care Excellence (NICE) state that endovascular stent insertion for intracranial atherosclerotic disease should only be used in the context of research, noting that evidence shows a significant risk of periprocedural stroke and death [50]. PROGNOSIS Risk and location of recurrent stroke ICAS is associated with a high risk of recurrent stroke. As an example, a randomized controlled trial (WASID) published in 2005 that compared warfarin with aspirin in 569 patients with symptomatic stenosis (50 to 99 percent) of a major intracranial found that the ischemic stroke rate in the territory of the stenotic artery at one year was 11 to 12 percent in both treatment groups [15]. The risk of recurrent stroke is likely lower in the modern era with the advent of intensive medical therapy (ie, dual antiplatelet therapy for three months followed by long-term antiplatelet therapy, antihypertensive, and high-intensity LDL-C lowering https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 14/25 7/5/23, 11:54 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate treatment), as suggested by stroke rates among medically treated patients in the SAMMPRIS and VISSIT trials. Patients in the medical arm of SAMMPRIS treated with dual-antiplatelet therapy and intensive risk factor control had a lower primary endpoint rate at six months compared with similar patients from WASID with severe stenosis treated with aspirin alone (approximately 9 versus 18 percent, respectively) [17]. (See 'Stenting' above.) Populations at high risk of recurrent stroke Available evidence suggests there may be subgroups of patients with ICAS who are at particularly high risk of stroke: Patients with severe intracranial large artery stenosis [51]. In the prospective WASID trial, severe stenosis ( 70 percent) was associated with a significantly higher risk of stroke in the same territory compared with stenosis <70 percent (hazard ratio [HR] 2.03, 95% CI 1.29- 3.22) ( figure 1) [52]. Patients with recent ischemic symptoms [51]. WASID also demonstrated that patients with symptoms within the prior 17 days were at significantly higher risk of stroke in the same territory compared with patients whose symptoms were more remote (HR 1.67, 95% CI 1.1- 2.9) [52]. Patients with borderzone infarcts and impaired collateral flow. In a post hoc analysis of a subgroup of SAMMPRIS patients with middle cerebral artery stenosis, patients with borderzone pattern of infarcts and those who had impaired collateral flow had the highest risk of recurrent stroke (37 percent) compared with those without impaired collaterals or other infarct patterns [53]. Patients with clinically significant hemodynamic intracranial stenosis, described below. (See 'Implications of hemodynamic stenosis' below.) Women. The WASID trial found that the frequency of the combined end point of stroke or vascular death in patients with symptomatic intracranial arterial stenosis was greater in women than in men (28.4 versus 16.6 percent, respectively; HR 1.58, 95% CI 1.01-2.48) [54]. In addition, women had a higher risk of recurrent ischemic stroke than men (HR 1.85, 95% CI 1.14-3.01). In the medical treatment arm of the SAMMPRIS trial, which enrolled patients with ischemic stroke or transient ischemic attack (TIA) attributed to severe (70 to 99 percent) stenosis of a major intracranial artery, high-risk features for recurrent stroke were the presence of an old infarct in the territory of the stenosis, presentation with stroke, and absence of statin use at trial entry [55]. https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 15/25 7/5/23, 11:54 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate Implications of hemodynamic stenosis Intracranial stenosis considered "hemodynamically significant" purely on clinical grounds emerged as another potential risk factor for recurrent ischemic stroke in the GESICA study, a prospective observational report that enrolled 102 patients with 50 percent symptomatic intracranial large artery atherosclerotic stenosis [56]. Intracranial stenosis was classified as hemodynamic in GESICA if symptoms related to the stenosis occurred during a change in body position from supine to prone, during effort/exertion, or with the introduction or increase of antihypertensive medication. Patients with a hemodynamic stenosis had a higher frequency of recurrent ischemic stroke or TIA in the territory of the stenotic artery than those without a hemodynamic stenosis (61 versus 32 percent). By contrast, among patients in the SAMMPRIS trial with a 70 to 99 percent stenosis who had qualifying symptoms suggestive of hypoperfusion (same definition as above) and were assigned to the aggressive medical management group (n = 31), the two-year probability of an outcome event (ie, 30-day stroke and death and later strokes in the territory of the qualifying artery) was only 7 percent (95% CI 1.8-25.3) [47]. The observational VERITAS study analyzed hemodynamics for 72 patients with recent posterior circulation TIA or stroke and >50 percent atherosclerotic stenosis or occlusion of the vertebral and/or basilar arteries [57]. Low blood flow in these arteries, as determined by quantitative magnetic resonance angiography (QMRA), was associated with an increased risk for subsequent vertebrobasilar stroke (adjusted HR 11.55, 95% CI 1.88-71.00). By contrast, the MyRIAD observational cohort of 105 patients with 50 to 99 percent intracranial stenosis in either the anterior or posterior circulation did not show an association between low flow (as measured by QMRA and perfusion MRI) and recurrent infarcts [58]. Given that measures of hemodynamic stability (eg, clinical symptoms, perfusion or flow imaging) inconsistently predict ischemic risk, further research is needed to identify a more accurate biomarker that may be used to select patients at high risk due to hypoperfusion. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults" and "Society guideline links: Occlusive carotid, aortic, renal, mesenteric, and peripheral atherosclerotic disease".) SUMMARY AND RECOMMENDATIONS https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 16/25 7/5/23, 11:54 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate The initial treatment of acute stroke or transient ischemic attack (TIA) due to intracranial large artery atherosclerosis (ICAS) is similar to the treatment of acute ischemic stroke or TIA attributed to other mechanisms. An important aspect of the hyperacute phase of acute ischemic stroke management is the rapid determination of patients who are eligible for intravenous thrombolysis and mechanical thrombectomy. (See "Initial assessment and management of acute stroke" and "Approach to reperfusion therapy for acute ischemic stroke".) For patients with recent (within 30 days) stroke or TIA attributed to intracranial large artery stenosis of 70 to 99 percent, we recommend against intracranial stenting because there is evidence of harm with higher rates of stroke or death compared with medical therapy alone (Grade 1B). All patients with recent ischemic stroke or TIA attributed to an intracranial large artery stenosis should receive intensive medical therapy with antiplatelet therapy and strict control of vascular risk factors, including the use of antihypertensive agents, low density lipoprotein cholesterol (LDL-C) lowering therapy, physical activity, and other lifestyle modification (eg, smoking cessation, weight control, salt restriction, and a healthy diet). (See 'Our approach' above.) For patients with a recent (within 30 days) TIA or stroke attributed to atherosclerotic intracranial large artery stenosis of 70 to 99 percent, we suggest dual antiplatelet therapy (DAPT) with aspirin plus clopidogrel (rather than aspirin monotherapy) for up to 90 days (Grade 2C). For patients with brain ischemia attributed to atherosclerotic intracranial large artery stenosis of 50 to 69 percent who have a low-risk TIA, defined by 2 an ABCD score <4, or a moderate to major ischemic stroke, defined by a National Institutes of Health Stroke Scale (NIHSS) score >5, we start treatment with aspirin alone. 2 For patients with a high-risk TIA, defined by an ABCD score 4, or minor ischemic stroke, defined by a NIHSS score 5, we begin with dual antiplatelet therapy (DAPT) for 21 days using aspirin plus clopidogrel rather than aspirin alone. For long-term stroke prevention (beyond the 21- or 90-day duration of DAPT), we treat with aspirin monotherapy. Clopidogrel monotherapy or the combination drug aspirin-extended- release dipyridamole are reasonable alternatives to aspirin but have not been specifically studied in ICAS. (See 'Antiplatelet therapy' above.) We treat all patients with hypertension with nonpharmacologic therapy (ie, salt restriction, adequate potassium intake, weight control, healthy diet, limited alcohol intake) and pharmacologic therapy. For patients with hypertension who have a stroke or TIA attributed to intracranial large artery stenosis of 50 to 99 percent, we suggest targeting a systolic blood pressure (SBP) of <140 mmHg rather than a lower target SBP (Grade 2C). (See 'Risk factor management' above.) https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 17/25 7/5/23, 11:54 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate For patients with TIA or ischemic stroke of atherosclerotic origin, including those with symptomatic ICAS, we use high-intensity statin therapy with atorvastatin 40 to 80 mg daily or rosuvastatin 20 to 40 mg daily; we prefer the highest approved dose in most cases. We also target treatment to achieve a low-density lipoprotein cholesterol (LDL-C) level <70 mg/dL. (See 'Risk factor management' above and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".) Although unproven, therapies of last resort for patients who have recurrent ischemic stroke due to ICAS despite maximal medical therapy include indirect bypass, endovascular stenting, or submaximal angioplasty. However, there are no comparative data from randomized trials to suggest these treatments provide benefit over medical therapy. (See 'Failure of medical therapy' above.) ICAS is associated with a high risk of recurrent stroke. Subgroups that may be at particularly high risk of stroke in the territory of the affected vessel include patients with clinically significant hemodynamic intracranial stenosis, patients with borderzone infarct pattern and impaired collateral flow, patients with severe ( 70 percent) intracranial stenosis, patients with recent ischemic symptoms, and women. (See 'Prognosis' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Marc I Chimowitz, MD, and Cathy A Sila, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Turan TN, Zaidat OO, Gronseth GS, et al. 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Topic 1101 Version 41.0 https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 23/25 7/5/23, 11:54 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate GRAPHICS Stroke probability by stenosis Product-limit estimate of the cumulative probability of an ischemic stroke in the territory of the stenotic artery versus years after randomization, according to percent stenosis ( 70 percent stenosis shown as red solid line, <70 percent stenosis as blue dashed line); log- rank test P 0.0010. Reproduced with permission from Kasner, SE, Chimowitz, MI, Lynn, MJ, et al. Predictors of ischemic stroke in the territory of a symptomatic intracranial arterial stenosis. Circulation 2006; 113:555. Copyright 2006 Lippincott Williams & Wilkins. Graphic 73498 Version 1.0 https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 24/25 7/5/23, 11:54 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate Contributor Disclosures Tanya N Turan, MD, MSCR No relevant financial relationship(s) with ineligible companies to disclose. Jose Gutierrez, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 25/25

7/5/23, 11:57 AM Intraventricular hemorrhage - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Intraventricular hemorrhage : Brett L Cucchiara, MD : Scott E Kasner, MD, Alejandro A Rabinstein, MD : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Oct 04, 2022. INTRODUCTION Intraventricular hemorrhage (IVH) confined to the ventricular system within the brain is uncommon, accounting for only about 3 percent of all spontaneous intracranial hemorrhage [1]. IVH more commonly occurs in the setting of intracerebral hemorrhage or subarachnoid hemorrhage. The assessment of the patient with IVH focuses on identifying the underlying cause of the hemorrhage, which may have significant treatment implications. Common to patients with IVH, regardless of etiology, is a risk for sudden and potentially fatal obstructive hydrocephalus, requiring acute clinical decision-making regarding the use of external ventricular drainage and other interventions. This topic discusses the causes, clinical presentation, diagnosis, and treatment of IVH. Intracerebral, subarachnoid, subdural, and epidural hemorrhage are discussed separately: (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis".) (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis".) (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".) (See "Subdural hematoma in adults: Etiology, clinical features, and diagnosis".) (See "Subdural hematoma in adults: Management and prognosis".) (See "Intracranial epidural hematoma in adults".) https://www.uptodate.com/contents/intraventricular-hemorrhage/print 1/26 7/5/23, 11:57 AM Intraventricular hemorrhage - UpToDate IVH in the newborn is also discussed separately. (See "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Risk factors, clinical features, screening, and diagnosis" and "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Management and outcome".) EPIDEMIOLOGY AND DEFINITIONS Primary IVH refers to bleeding confined to the ventricular system within the brain. Primary IVH is uncommon, accounting for only about 3 percent of all spontaneous intracerebral hemorrhage [1]. The following demographic characteristics were reported in a 2008 review of published cases series of primary IVH [2]: The median age is 55 years (range 9 to 91 years). Males and females are equally represented. Half of patients have a history of hypertension. Secondary IVH refers to the more common occurrence of IVH in the setting of intracerebral hemorrhage or subarachnoid hemorrhage. The epidemiology of intracerebral hemorrhage and subarachnoid hemorrhage is discussed separately. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis" and "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) ETIOLOGY IVH most commonly occurs as a secondary phenomenon when parenchymal or intracerebral hemorrhage (ICH) ruptures into the ventricular space or when subarachnoid hemorrhage (SAH) extends into the ventricles. IVH is estimated to complicate 40 to 60 percent of ICH and 10 percent of SAH cases [3-5]. In one retrospective review, warfarin therapy was associated with IVH risk, volume at presentation, and subsequent expansion in patients with deep or lobar ICH [6]. The underlying causes of ICH and SAH are discussed separately. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis" and "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis" and "Nonaneurysmal subarachnoid hemorrhage".) IVH can also complicate closed head injury. Usually, this is in the setting of other traumatic brain injury, including contusion and traumatic SAH; isolated IVH is a relatively rare complication of head trauma [7-9]. https://www.uptodate.com/contents/intraventricular-hemorrhage/print 2/26 7/5/23, 11:57 AM Intraventricular hemorrhage - UpToDate Primary IVH is uncommon; in consequence, studies estimating the frequency of various etiologies have been limited. Retrospective case series derived from tertiary referral centers are subject to ascertainment bias. Further, definitions of primary IVH have varied among different authors and studies. While most limit their use of the term to hemorrhages entirely localized within the ventricle, others have included hemorrhages that originate within 15 mm of the ependymal surface [10]. The latter criteria invariably classify thalamic, caudate, and medial putaminal bleeds (usually secondary to chronic hypertension) associated with IVH as primary IVH. Among series that more strictly limit the definition of IVH, vascular malformations are the most frequently identified cause of primary IVH. In small case series, vascular malformations have been identified in 14 to 58 percent of patients with primary IVH [2,10-15]. Reported causes of primary IVH include: Vascular malformations (usually arteriovenous malformations or arteriovenous fistulas) [1,2,10-19]. (See "Brain arteriovenous malformations".) Intraventricular tumors (papilloma, neurocytoma, meningioma, metastases, astrocytoma, ependymoma) [11,20-26]. (See "Overview of the clinical features and diagnosis of brain tumors in adults".) Intraventricular aneurysms developing within the distal lenticulostriate or choroidal arteries (occasionally reported in association with Moyamoya disease) [10,16,22,27]. Occasionally aneurysms of the anterior communicating artery, posterior inferior cerebellar artery, or basilar tip rupture into the ventricles without other overt subarachnoid blood [2,10,14]. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) Moyamoya disease [1,2,16,22,28-31]. (See "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis".) Coagulopathies, acquired or inherited [2,10,12,29,32-34]. (See "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis".) Pituitary apoplexy [35]. (See "Causes, presentation, and evaluation of sellar masses", section on 'Causes'.) Vasculitis [36]. (See "Primary angiitis of the central nervous system in adults".) Fibromuscular dysplasia [10]. (See "Clinical manifestations and diagnosis of fibromuscular dysplasia".) https://www.uptodate.com/contents/intraventricular-hemorrhage/print 3/26 7/5/23, 11:57 AM Intraventricular hemorrhage - UpToDate Sympathomimetic agents [37,38]. (See "Clinical manifestations, diagnosis, and management of the cardiovascular complications of cocaine abuse" and "Acute amphetamine and synthetic cathinone ("bath salt") intoxication", section on 'Central and peripheral nervous system'.) In approximately 20 to 50 percent of cases (depending in part on the intensity of the investigation), no cause is identified [11,12,16,33]. About half of these patients have chronic hypertension; this is believed, but not known, to cause primary IVH in the same way it is understood to cause ICH. It is speculated that some patients with IVH may have had a small hypertensive intraparenchymal hemorrhage, too small to see on computed tomography (CT) or magnetic resonance imaging (MRI), which arises in proximity to the ventricular system and produces IVH as its primary manifestation. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Pathogenesis and etiologies'.) CLINICAL FEATURES Clinical presentation Patients with secondary IVH present with clinical features typical of intracerebral hemorrhage or subarachnoid hemorrhage. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis" and "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) Patients with primary IVH typically present with abrupt headache, often associated with nausea, vomiting, and impaired consciousness (confusion, disorientation) [2,11,33,39]. A minority of patients have frank loss of consciousness at the onset [12]. Symptoms are usually sudden in onset; however, nearly a quarter of patients are reported to have progressive or fluctuating symptoms [11,12]. The degree of neurologic impairment, often measured as the Glasgow Coma Scale ( table 1) is an important prognostic indicator. (See 'Prognosis' below.) Focal neurologic findings are relatively uncommon with primary IVH and most typically involve cranial nerve abnormalities [10]. Such cranial nerve palsies are generally of the "false localizing" type due to stretching across the basilar skull surface and include dysfunction of the sixth and third nerves. Seizures are not common but can occur [1,10,11,17]. Most patients are hypertensive on presentation, and some will have an elevated body temperature or suffer cardiac arrhythmias [12]. Nuchal rigidity is inconsistently present. The clinical symptoms and signs of IVH reflect a sudden increase in intracranial pressure that results from sudden introduction of blood volume into the intracranial space [40]. In addition to pressure effects, it is speculated that blood products in the cerebrospinal fluid space may affect brain function. https://www.uptodate.com/contents/intraventricular-hemorrhage/print 4/26 7/5/23, 11:57 AM Intraventricular hemorrhage - UpToDate Complications Patients with primary or secondary IVH are at risk for sudden neurologic deterioration, which may result from obstructive hydrocephalus, recurrent hemorrhage, or other complications [12]: Hydrocephalus Acute obstructive hydrocephalus can result when cerebrospinal fluid circulation is obstructed by blood clots. Patients with blood in the third or fourth ventricle are at most risk of this complication [12]. One-half to two-thirds of patients with IVH have some degree of hydrocephalus on the initial computed tomography (CT) scan of the head [2,11,12,15,41]. This can be rapidly fatal and usually requires urgent intervention with insertion of an external ventricular drain [8,40]. (See 'External ventricular drain' below.) Patients may also develop communicating hydrocephalus as a delayed complication of IVH; this usually presents more gradually. (See 'Prognosis' below.) Hemorrhage extension Recurrent hemorrhage or hemorrhage extension occurs in 10 to 20 percent of patients with IVH [12,40]. The highest risk of this is in those with an underlying etiology of vascular malformation or aneurysm or in the setting of a coagulopathy. The presence of a coexisting intraparenchymal hemorrhage is also associated with an elevated risk of IVH expansion, especially those that have expanded on follow-up imaging or are located in the thalamus [42]. Cerebral vasospasm Cerebral ischemia due to arterial vasospasm is unusual in cases of primary IVH, but this complication has been described in isolated cases [19,43-45]. In contrast, vasospasm is a common complication of aneurysmal subarachnoid hemorrhage. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) Other medical complications Neurologic deterioration due to medical complications is common in the setting of IVH. These include pulmonary embolism, pneumonia and other infections, and electrolyte imbalance. Other medical complications of IVH include cardiovascular instability, deep venous thrombosis, and gastrointestinal bleeding. DIFFERENTIAL DIAGNOSIS The presentation of primary IVH overlaps with those of aneurysmal subarachnoid hemorrhage and other forms of stroke. Urgent diagnostic evaluation, including head CT, is required to identify these alternative conditions to reduce risk of morbidity and initiate time-sensitive therapeutic interventions. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis" and "Approach to reperfusion therapy for acute ischemic stroke" and https://www.uptodate.com/contents/intraventricular-hemorrhage/print 5/26 7/5/23, 11:57 AM Intraventricular hemorrhage - UpToDate "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis" and "Cerebral venous thrombosis: Treatment and prognosis".) Other conditions that may present with a headache with sudden onset also include reversible cerebral vasoconstriction syndrome, cervical artery dissection, and posterior reversible leukoencephalopathy syndrome, among others ( table 2). A noncontrast head CT can distinguish IVH from these other entities. (See "Overview of thunderclap headache", section on 'Diagnostic evaluation'.) DIAGNOSTIC EVALUATION Imaging diagnosis Noncontrast head CT is the test of choice to diagnose IVH. CT rapidly and reliably identifies blood within the ventricular system, helps to identify parenchymal intracerebral hemorrhage (ICH) or subarachnoid hemorrhage (SAH) associated with the IVH, and also identifies concurrent hydrocephalus. IVH may be identified infrequently by brain MRI or other neuroimaging studies, typically when these studies are performed to evaluate other conditions. Evaluation for underlying causes and monitoring Neuroimaging studies are typically required to define the etiology of a primary IVH. In the absence of an obvious precipitant such as trauma or coagulopathy, we recommend patients with primary IVH undergo neuroimaging to assess for underlying causes. Computed tomography Close examination of the initial head CT should be performed to identify secondary IVH due to ICH or aneurysmal SAH. Hemorrhagic findings in the brain regions surrounding the ventricles (caudate and thalamus, in particular) may identify ICH ( image 1). Similarly, the presence of subarachnoid blood in the basal cisterns or cortical sulci should raise concern for aneurysmal SAH with secondary IVH. If ICH or SAH is present, diagnostic evaluation should be pursued. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Evaluation and diagnosis' and "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Identifying the source of bleeding'.) The extent of IVH can be graded by head CT. The Graeb score and other scoring systems have been proposed [46-48], but none are widely implemented in clinical practice. The CT scan should be repeated emergently for any neurologic deterioration to identify recurrent hemorrhage or obstructive hydrocephalus. CT scans are also used to monitor https://www.uptodate.com/contents/intraventricular-hemorrhage/print 6/26 7/5/23, 11:57 AM Intraventricular hemorrhage - UpToDate hydrocephalus, particularly during attempts to clamp or remove a drain. Transcranial ultrasonography has been suggested as a possible alternative to serial CT to monitor ventricular size, but the reliability and reproducibility of this technique has yet to be independently validated [49]. Other neuroimaging studies For most patients with IVH, we typically start with MRI and magnetic resonance angiography (MRA) or CT angiography to investigate for underlying causes ( image 2). If the MRI/MRA or CT angiography is unrevealing, we recommend digital subtraction angiography, in agreement with guidelines from the American Heart Association/American Stroke Association [50]. In a prospective observational study of patients with IVH who underwent catheter angiography, vascular lesions were found in 11 of 17 (65 percent), including 10 patients with arteriovenous malformations, and one with aneurysm [14]. A retrospective review of published case series similarly estimated the yield of angiography at 56 percent, additionally identifying cases of Moyamoya and dural arteriovenous fistula [2]. If the cause of the IVH remains undetermined, it is reasonable in some cases to consider repeat contrast MRI and possibly catheter angiography one to two months following the initial studies after reabsorption of blood products has occurred. Other tests Other tests that are important to include are blood clotting studies (prothrombin time, partial thromboplastin time, and platelet count). A toxicology screen should also be considered. Because electrolyte imbalances can complicate IVH, these should be measured at baseline and followed regularly. MANAGEMENT General measures The treatment of IVH focuses on cessation of bleeding, relieving hydrocephalus, and controlling intracranial pressure (ICP). Specific therapy aimed at treating the underlying cause should be undertaken (aneurysm or arteriovenous malformation obliteration). (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis" and "Vascular malformations of the central nervous system".) Patients who have a moderate to severe IVH (impaired alertness and/or extensive intraventricular blood on imaging) should be followed in an intensive care setting. Medical complications are common (eg, pneumonia, deep venous thrombosis, gastrointestinal bleeding, https://www.uptodate.com/contents/intraventricular-hemorrhage/print 7/26 7/5/23, 11:57 AM Intraventricular hemorrhage - UpToDate cardiovascular instability, supraventricular tachycardia, hypo- and hypernatremia) and require appropriate monitoring and treatment [1,11]. The head of the bed should be placed at 30 degrees or greater to decrease ICP and reduce the risk of aspiration. Euvolemia should be maintained using isotonic crystalloid solutions, and any elevations in body temperature should be treated aggressively. For prevention of deep venous thrombosis, mechanical thromboprophylaxis using intermittent pneumatic compression stockings is recommended until a bleeding source has been identified and secured. At that time, antithrombotic therapy can be used. (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".) Because seizures are an infrequent complication of IVH, prophylactic antiseizure medications are not generally used but should be initiated immediately should seizures occur. Management of antithrombotic medications Reversing anticoagulation For most patients with IVH, we discontinue anticoagulant medications and give agents to reverse their effects. However, for some patients with small acute IVH and no signs of hydrocephalus who are receiving anticoagulation for a compelling indication such as a mechanical heart valve, the risk-benefit calculation may favor continued anticoagulation with close observation of neurologic status. In such circumstances, we generally use intravenous heparin during the acute period given the ability to rapidly reverse its anticoagulant effect. (See "Anticoagulation for prosthetic heart valves: Management of bleeding and invasive procedures", section on 'Management of bleeding'.) If reversal of anticoagulation is indicated, the appropriate intervention depends upon the anticoagulant the patient is taking, the time since last dose, and the urgency with which reversal is needed. Some patients prescribed anticoagulant medications may not require reversal agents if laboratory testing or the time interval since last dose indicates they are effectively not anticoagulated. The strategies used to reverse anticoagulation in patients with IVH are the same as those used for patients with intracerebral hemorrhage. These strategies are discussed separately. (See "Reversal of anticoagulation in intracranial hemorrhage", section on 'Reversal strategy for specific anticoagulants'.) Patients on antiplatelets Antiplatelet medications are typically stopped at the time of diagnosis for most patients with acute IVH. However, we balance the thrombotic risks of discontinuation with the hemorrhagic risks of continuing antiplatelets at an individual level. We may continue antiplatelet medications during acute monitoring for selected patients at high risk https://www.uptodate.com/contents/intraventricular-hemorrhage/print 8/26 7/5/23, 11:57 AM Intraventricular hemorrhage - UpToDate of thrombosis such as those with established atherosclerotic disease or who have undergone intravascular stent placement and who have small IVH. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk" and "Antithrombotic therapy for elective percutaneous coronary intervention: General use" and "Overview of carotid artery stenting" and "Endovascular techniques for lower extremity revascularization", section on 'Antiplatelet therapy'.) We reserve platelet transfusions for those with specific indications, including those with a thrombocytopenia (<100,000/microL) or a known platelet defect. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Platelet function disorders'.) Blood pressure management The optimal blood pressure management in patients with IVH remains undefined. Aggressive blood pressure lowering may minimize the risk of further hemorrhage but must be weighed against the risk of decreased cerebral perfusion in patients with increased ICP. It seems reasonable to gradually lower elevated blood pressure in patients with normal ICP. Intravenous antihypertensives such as labetalol or nicardipine are typically used, although other agents are acceptable [51]. In the absence of better data specific to IVH, the guidelines outlined for blood pressure management in the setting of ICH seem reasonable [50]. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Blood pressure management'.) External ventricular drain An external ventricular drain (EVD) is a small catheter inserted through the skull usually into the lateral ventricle, which is typically connected to a closed collecting device to allow for drainage of cerebrospinal fluid ( figure 1). The EVD can also be connected to a transducer that records ICP. We recommend an EVD for patients with IVH with hydrocephalus and neurologic decline [50]. Rarely, bilateral EVDs may be needed if hemorrhage obstructs the foramen of Monro [52]. The major complications associated with EVD are catheter occlusion due to clotted blood at the intraventricular orifice and infection. The former may be relieved by irrigation or catheter replacement. Symptoms suggestive of infection should prompt cerebrospinal fluid analysis for cell count and culture along with antibiotic therapy as appropriate. Staphylococci are the most common pathogens. Higher rates of bacterial ventriculitis/meningitis occur with longer duration of EVD placement [53]. Prophylactic catheter change does not reduce the risk of infection. The management and prevention of infections in patients with an EVD are discussed in greater detail separately. (See "Infections of cerebrospinal fluid shunts and other devices".) https://www.uptodate.com/contents/intraventricular-hemorrhage/print 9/26 7/5/23, 11:57 AM Intraventricular hemorrhage - UpToDate Additional management options In addition to EVD placement, adjunctive approaches have also been used for selected patients with IVH for the prevention and treatment of hydrocephalus. Intraventricular thrombolysis The utility of intraventricular thrombolysis (IVT) for patients with IVH and an EVD is uncertain. IVT use involves shared decision-making and includes discussing individual risks and benefits. Instillation of thrombolytic agents into the ventricles may improve mortality by hastening clot resolution, thereby avoiding the morbidity associated with EVD occlusion and shortening the duration of EVD use. It is also possible, although unproven, that more rapid resolution of IVH may decrease the long-term incidence of communicating hydrocephalus. However, IVT use may increase the risk of bleeding and severe disability. Evidence supporting the use of IVT for EVD has been reported in case series, observational studies, and pooled analyses. These studies have suggested a benefit for IVT, showing increased clot resolution and, in some cases, decreased mortality [3,39,54-65]. The results of randomized clinical trials, on the other hand, have not shown clear benefit: The Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR III) trial included 500 patients with IVH and compared treatment with 1 mg alteplase (tPA) or placebo injected through an EVD every eight hours until clot reduction or a clinical endpoint occurred, or 12 doses were given [66]. At 180 days, the primary efficacy outcome of a modified Rankin scale (mRS) score of 3 or less was similar in each group (48 versus 45 percent comparing alteplase to placebo; risk ratio [RR] 1.06, 95% CI 0.88-1.28). Patients who received IVT had a lower mortality (18 versus 29 percent; RR 0.60, 95% CI 0.41-0.86), but a higher rate of severe disability indicated by an mRS score of 5 (17 versus 9 percent; RR 1.99, 95% CI 1.22-3.26). Bleeding complication rates were similar (2 percent) in both groups. One criticism of the CLEAR-III trial is that only a minority of patients experienced substantial IVT removal, suggesting the possibility of benefit with more effective methods for clot removal. The Intraventricular Hemorrhage Thrombolysis Trial, a multicenter randomized controlled study, enrolled 48 patients and compared IVT (3 mg tPA) to control (normal saline); each treatment was injected through an EVD every 12 hours until clot reduction or a clinical endpoint occurred (median duration of dosing was 7.5 days for IVT) [67]. The rate of clot resolution was faster for IVT than placebo (18 versus 8 percent per day). Rates of death and ventriculitis were lower than expected and did not differ significantly between treatment groups. Symptomatic bleeding complications were more frequent in the tPA group (23 versus 5 percent), but this did not reach statistical significance. The dose used in this study was higher than that used in the CLEAR III trial. https://www.uptodate.com/contents/intraventricular-hemorrhage/print 10/26 7/5/23, 11:57 AM Intraventricular hemorrhage - UpToDate Bleeding complications are a concern with IVT; recurrent IVH and/or ICH expansion is reported in 8 to 20 percent of patients after IVT [16,40,56,57,67,68]. Typically, patients with known aneurysm or vascular malformation were excluded from early studies of IVT. However, IVT has been used without complication in a few reported cases after the vascular malformation or aneurysm was surgically treated [16,69-71], and even before surgery, in few patients with these lesions [17,72]. Systemic bleeding complications are unlikely to be significantly increased with IVT; in CLEAR IVH, systemic coagulation parameters were similar after administration of tPA and placebo [73]. It is also possible that the risk of bacterial meningitis/ventriculitis may be increased with IVT therapy, but this has not been demonstrated so far [40,56,66,67]. IVT has not been associated with systemic complications [74]. IVT is reserved for selected patients with acute IVH and an EVD at centers experienced with this approach. Lumbar drainage The use of lumbar drainage combined with IVT was studied in an open- label trial that was stopped early after 30 patients were enrolled; patients with severe IVH with tamponade of the third and fourth ventricles requiring EVD were treated with IVT (control group) or IVT combined with lumbar drainage [75]. The primary endpoint (need for permanent shunt placement of prolonged requirement for cerebrospinal fluid drainage) occurred more frequently in the control versus combined treatment groups (7 out of 16 versus 0 out of 14). In a meta- analysis that included patients in this study as well as an additional 67 patients treated outside of the clinical trial, the combined intervention was associated with a significant reduction (OR 0.24; 95% CI 0.01-0.36) for shunt dependency. This analysis found no significant differences in functional outcomes or cerebrospinal fluid infection rates at 90 days; bleeding complications were less frequent in the combined treatment group (odds ratio 0.4, 95% CI 0.30-0.53). PROGNOSIS The reported in-hospital mortality of IVH varies from 20 to 50 percent [1,2,4,10-12,33,56]. Secondary IVH carries a higher risk of death than primary IVH [15,33,74]. Advanced age, underlying coagulopathy, Glasgow Coma Scale score of 8 or less, and hydrocephalus at presentation are also associated with a higher risk of death [2,12,33,41,74]. While some studies have found that the extent of IVH correlates with prognosis [2,12,41,47], others have not [10,11,15]. The results of one study found that the volume of blood in the third ventricle was a strong and independent predictor of poor outcomes, while the volume of blood in the lateral ventricles, fourth ventricle, or entire ventricular system did not correlate significantly with https://www.uptodate.com/contents/intraventricular-hemorrhage/print 11/26 7/5/23, 11:57 AM Intraventricular hemorrhage - UpToDate prognosis [76]. The authors speculated that blood in the third ventricle may affect critical contiguous structures in the midbrain. Other long-term complications of IVH include: Neurocognitive sequelae Patients with significant IVH are often confused, agitated, and disoriented [1]. These symptoms are often slow to recover and a significant proportion (about half of survivors) are left with disabling cognitive deficits [1,11,16]. Noncommunicating hydrocephalus IVH along with a secondary inflammatory/fibrotic response may lead to impaired absorption of cerebrospinal fluid at the arachnoid granulations. This may be manifest by a more subacute decline in cognition, gait, and urinary continence that can occur weeks or later after the initial IVH or as a failure to wean off EVD. Such patients may require permanent ventriculoperitoneal shunt [40]. Approximately 30 to 50 percent of patients with IVH require a shunt placement [16,56,63,70,77-80]. (See "Normal pressure hydrocephalus".) Late recurrence of intracerebral hemorrhage or IVH Recurrent hemorrhage is uncommonly reported after IVH. In one series, 2 of 14 survivors had a subsequent intracerebral hemorrhage [12], while in another series there was no recurrent bleeding in a group of 13 patients after 67 months [11]. The risk of this complication is likely highest in those with an unrecognized and/or unsecured vascular lesion (eg, Moyamoya) [27,81]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) SUMMARY AND RECOMMENDATIONS Terminology and etiologies Intraventricular hemorrhage (IVH) can complicate intracerebral hemorrhage or subarachnoid hemorrhage (secondary IVH). Less commonly, IVH occurs in isolation (primary IVH). The most commonly identified cause of primary IVH is a vascular malformation. Up to half of patients with primary IVH do not have a cause (other than hypertension) identified. (See 'Epidemiology and definitions' above and 'Etiology' above.) Clinical features Patients with IVH usually present with sudden headache, nausea and vomiting, and impaired alertness. (See 'Clinical features' above.) https://www.uptodate.com/contents/intraventricular-hemorrhage/print 12/26 7/5/23, 11:57 AM Intraventricular hemorrhage - UpToDate Diagnostic evaluation Patients with a clinical presentation of IVH should undergo immediate noncontrast head computed tomography (CT). The primary purpose is to exclude subarachnoid hemorrhage and to identify the IVH and evaluate its severity and potential for obstructive hydrocephalus. (See 'Computed tomography' above.) Individuals with primary IVH should have magnetic resonance imaging with magnetic resonance angiography and/or conventional angiography to identify the underlying etiology, particularly a vascular malformation or aneurysm that may require surgical intervention. (See 'Other neuroimaging studies' above.) Management Monitoring Because acute obstructive hydrocephalus often complicates IVH that involves the third and fourth ventricles, such patients should be closely monitored. When neurologic deterioration occurs, emergent CT scan should be done to exclude the development of obstructive hydrocephalus or recurrent hemorrhage. (See 'General measures' above and 'Computed tomography' above.) Blood pressure The optimal blood pressure management in patients with IVH is uncertain. For patients with IVH and elevated blood pressure, intravenous antihypertensives such as labetalol or nicardipine may be used to lower blood pressure gradually while maintaining adequate cerebral perfusion. Aggressive blood pressure lowering may minimize the risk of further hemorrhage but must be weighed against the risk of decreased cerebral perfusion in patients with increased ICP. (See 'Blood pressure management' above.) External ventricular drain We recommend external ventricular drainage (EVD) for patients with neurologic deterioration that occurs with ventricular enlargement over conservative management (Grade 1B). An EVD can reduce clot burden, treat hydrocephalus, and facilitate ICP monitoring. (See 'External ventricular drain' above.) Additional management options The use of intraventricular thrombolysis involves shared decision-making and after assessing individual risks and benefits and is reserved for patients at experienced centers with established protocols. (See 'Intraventricular thrombolysis' above and 'Lumbar drainage' above.) ACKNOWLEDGMENT https://www.uptodate.com/contents/intraventricular-hemorrhage/print 13/26 7/5/23, 11:57 AM Intraventricular hemorrhage - UpToDate The UpToDate editorial staff acknowledges James Pacelli Jr, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Darby DG, Donnan GA, Saling MA, et al. Primary intraventricular hemorrhage: clinical and neuropsychological findings in a prospective stroke series. Neurology 1988; 38:68. 2. Flint AC, Roebken A, Singh V. 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Stroke 1997; 28:1406. https://www.uptodate.com/contents/intraventricular-hemorrhage/print 14/26 7/5/23, 11:57 AM Intraventricular hemorrhage - UpToDate 15. Roos YB, Hasan D, Vermeulen M. Outcome in patients with large intraventricular haemorrhages: a volumetric study. J Neurol Neurosurg Psychiatry 1995; 58:622. 16. Goh KY, Poon WS. Recombinant tissue plasminogen activator for the treatment of spontaneous adult intraventricular hemorrhage. Surg Neurol 1998; 50:526. 17. Kumar K, Demeria DD, Verma A. Recombinant tissue plasminogen activator in the treatment of intraventricular hemorrhage secondary to periventricular arteriovenous malformation before surgery: case report. Neurosurgery 2003; 52:964. 18. Irie F, Fujimoto S, Uda K, et al. Primary intraventricular hemorrhage from dural arteriovenous fistula. J Neurol Sci 2003; 215:115. 19. Gerard E, Frontera JA, Wright CB. Vasospasm and cerebral infarction following isolated intraventricular hemorrhage. Neurocrit Care 2007; 7:257. 20. Okamura A, Goto S, Sato K, Ushio Y. Central neurocytoma with hemorrhagic onset. Surg Neurol 1995; 43:252. 21. Lee EJ, Choi KH, Kang SW, Lee IW. Intraventricular hemorrhage caused by lateral ventricular meningioma: a case report. Korean J Radiol 2001; 2:105. 22. Vates GE, Arthur KA, Ojemann SG, et al. A neurocytoma and an associated lenticulostriate artery aneurysm presenting with intraventricular hemorrhage: case report. Neurosurgery 2001; 49:721. 23. Lindboe CF, Stolt-Nielsen A, Dale LG. Hemorrhage in a highly vascularized subependymoma of the septum pellucidum: case report. Neurosurgery 1992; 31:741. 24. Smets K, Salgado R, Simons PJ, et al. Central neurocytoma presenting with intraventricular hemorrhage: case report and review of literature. Acta Neurol Belg 2005; 105:218. 25. Zuccaro G, Sosa F, Cuccia V, et al. Lateral ventricle tumors in children: a series of 54 cases. Childs Nerv Syst 1999; 15:774. 26. Akamatsu Y, Utsunomiya A, Suzuki S, et al. Subependymoma in the lateral ventricle manifesting as intraventricular hemorrhage. Neurol Med Chir (Tokyo) 2010; 50:1020. 27. Hamada J, Hashimoto N, Tsukahara T. Moyamoya disease with repeated intraventricular hemorrhage due to aneurysm rupture. Report of two cases. J Neurosurg 1994; 80:328. 28. Khan M, Novakovic RL, Rosengart AJ. Intraventricular hemorrhage disclosing neurofibromatosis 1 and moyamoya phenomena. Arch Neurol 2006; 63:1653. 29. Jabbour R, Taher A, Shamseddine A, Atweh SF. Moyamoya syndrome with intraventricular hemorrhage in an adult with factor V Leiden mutation. Arch Neurol 2005; 62:1144. 30. Nah HW, Kwon SU, Kang DW, et al. Moyamoya disease-related versus primary intracerebral hemorrhage: [corrected] location and outcomes are different. Stroke 2012; 43:1947. https://www.uptodate.com/contents/intraventricular-hemorrhage/print 15/26 7/5/23, 11:57 AM Intraventricular hemorrhage - UpToDate 31. Yu Z, Guo R, Zheng J, et al. Comparison of Acute Moyamoya Disease-Related and Idiopathic Primary Intraventricular Hemorrhage in Adult Patients. World Neurosurg 2019; 125:e313. 32. Ionita CC, Ferrara J, McDonagh DL, et al. Systemic hemostasis with recombinant-activated factor VII followed by local thrombolysis with recombinant tissue plasminogen activator in intraventricular hemorrhage. Neurocrit Care 2005; 3:246. 33. Kiymaz N, Demir O, Cirak B. Is external ventricular drainage useful in primary intraventricular hemorrhages? Adv Ther 2005; 22:447.

exclude subarachnoid hemorrhage and to identify the IVH and evaluate its severity and potential for obstructive hydrocephalus. (See 'Computed tomography' above.) Individuals with primary IVH should have magnetic resonance imaging with magnetic resonance angiography and/or conventional angiography to identify the underlying etiology, particularly a vascular malformation or aneurysm that may require surgical intervention. (See 'Other neuroimaging studies' above.) Management Monitoring Because acute obstructive hydrocephalus often complicates IVH that involves the third and fourth ventricles, such patients should be closely monitored. When neurologic deterioration occurs, emergent CT scan should be done to exclude the development of obstructive hydrocephalus or recurrent hemorrhage. (See 'General measures' above and 'Computed tomography' above.) Blood pressure The optimal blood pressure management in patients with IVH is uncertain. For patients with IVH and elevated blood pressure, intravenous antihypertensives such as labetalol or nicardipine may be used to lower blood pressure gradually while maintaining adequate cerebral perfusion. Aggressive blood pressure lowering may minimize the risk of further hemorrhage but must be weighed against the risk of decreased cerebral perfusion in patients with increased ICP. (See 'Blood pressure management' above.) External ventricular drain We recommend external ventricular drainage (EVD) for patients with neurologic deterioration that occurs with ventricular enlargement over conservative management (Grade 1B). An EVD can reduce clot burden, treat hydrocephalus, and facilitate ICP monitoring. (See 'External ventricular drain' above.) Additional management options The use of intraventricular thrombolysis involves shared decision-making and after assessing individual risks and benefits and is reserved for patients at experienced centers with established protocols. (See 'Intraventricular thrombolysis' above and 'Lumbar drainage' above.) ACKNOWLEDGMENT https://www.uptodate.com/contents/intraventricular-hemorrhage/print 13/26 7/5/23, 11:57 AM Intraventricular hemorrhage - UpToDate The UpToDate editorial staff acknowledges James Pacelli Jr, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Darby DG, Donnan GA, Saling MA, et al. Primary intraventricular hemorrhage: clinical and neuropsychological findings in a prospective stroke series. Neurology 1988; 38:68. 2. Flint AC, Roebken A, Singh V. Primary intraventricular hemorrhage: yield of diagnostic angiography and clinical outcome. Neurocrit Care 2008; 8:330. 3. Hanley DF. Intraventricular hemorrhage: severity factor and treatment target in spontaneous intracerebral hemorrhage. Stroke 2009; 40:1533. 4. Nyquist P, Hanley DF. The use of intraventricular thrombolytics in intraventricular hemorrhage. J Neurol Sci 2007; 261:84. 5. 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Recombinant tissue plasminogen activator in the treatment of intraventricular hemorrhage secondary to periventricular arteriovenous malformation before surgery: case report. Neurosurgery 2003; 52:964. 18. Irie F, Fujimoto S, Uda K, et al. Primary intraventricular hemorrhage from dural arteriovenous fistula. J Neurol Sci 2003; 215:115. 19. Gerard E, Frontera JA, Wright CB. Vasospasm and cerebral infarction following isolated intraventricular hemorrhage. Neurocrit Care 2007; 7:257. 20. Okamura A, Goto S, Sato K, Ushio Y. Central neurocytoma with hemorrhagic onset. Surg Neurol 1995; 43:252. 21. Lee EJ, Choi KH, Kang SW, Lee IW. Intraventricular hemorrhage caused by lateral ventricular meningioma: a case report. Korean J Radiol 2001; 2:105. 22. Vates GE, Arthur KA, Ojemann SG, et al. A neurocytoma and an associated lenticulostriate artery aneurysm presenting with intraventricular hemorrhage: case report. Neurosurgery 2001; 49:721. 23. Lindboe CF, Stolt-Nielsen A, Dale LG. 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Curr Neurol Neurosci Rep 2007; 7:522. 41. Nishikawa T, Ueba T, Kajiwara M, et al. A priority treatment of the intraventricular hemorrhage (IVH) should be performed in the patients suffering intracerebral hemorrhage with large IVH. Clin Neurol Neurosurg 2009; 111:450. 42. Roh DJ, Asonye IS, Carvalho Poyraz F, et al. Intraventricular Hemorrhage Expansion in the CLEAR III Trial: A Post Hoc Exploratory Analysis. Stroke 2022; 53:1847. 43. Dull C, Torbey MT. Cerebral vasospasm associated with intraventricular hemorrhage. Neurocrit Care 2005; 3:150. 44. Maeda K, Kurita H, Nakamura T, et al. Occurrence of severe vasospasm following intraventricular hemorrhage from an arteriovenous malformation. Report of two cases. J Neurosurg 1997; 87:436. 45. Fluss R, Laarakker A, Nakhla J, et al. Prolonged delayed vasospasm in the setting of nonaneurysmal intraventricular hemorrhage. 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Greenberg SM, Ziai WC, Cordonnier C, et al. 2022 Guideline for the Management of Patients With Spontaneous Intracerebral Hemorrhage: A Guideline From the American Heart Association/American Stroke Association. Stroke 2022; 53:e282. 51. Narotam PK, Puri V, Roberts JM, et al. Management of hypertensive emergencies in acute brain disease: evaluation of the treatment effects of intravenous nicardipine on cerebral oxygenation. J Neurosurg 2008; 109:1065. 52. Findlay JM. Intraventricular Hemorrhage. In: Pathophysiology Diagnosis and Managment, 4t h ed, Mohr JPC D, Grotta J, Weir B, Wolf P (Eds). 53. Pfausler B, Beer R, Engelhardt K, et al. Cell index a new parameter for the early diagnosis of ventriculostomy (external ventricular drainage)-related ventriculitis in patients with intraventricular hemorrhage? Acta Neurochir (Wien) 2004; 146:477. 54. Nieuwkamp DJ, de Gans K, Rinkel GJ, Algra A. Treatment and outcome of severe intraventricular extension in patients with subarachnoid or intracerebral hemorrhage: a systematic review of the literature. J Neurol 2000; 247:117. 55. Vereecken KK, Van Havenbergh T, De Beuckelaar W, et al. Treatment of intraventricular hemorrhage with intraventricular administration of recombinant tissue plasminogen activator A clinical study of 18 cases. Clin Neurol Neurosurg 2006; 108:451. 56. Fountas KN, Kapsalaki EZ, Parish DC, et al. Intraventricular administration of rt-PA in patients with intraventricular hemorrhage. South Med J 2005; 98:767. 57. Staykov D, Huttner HB, Struffert T, et al. Intraventricular fibrinolysis and lumbar drainage for ventricular hemorrhage. Stroke 2009; 40:3275. 58. Gaberel T, Magheru C, Parienti JJ, et al. Intraventricular fibrinolysis versus external ventricular drainage alone in intraventricular hemorrhage: a meta-analysis. Stroke 2011; 42:2776. https://www.uptodate.com/contents/intraventricular-hemorrhage/print 17/26 7/5/23, 11:57 AM Intraventricular hemorrhage - UpToDate 59. Huttner HB, Tognoni E, Bardutzky J, et al. Influence of intraventricular fibrinolytic therapy with rt-PA on the long-term outcome of treated patients with spontaneous basal ganglia hemorrhage: a case-control study. Eur J Neurol 2008; 15:342. 60. Naff NJ, Hanley DF, Keyl PM, et al. Intraventricular thrombolysis speeds blood clot resolution: results of a pilot, prospective, randomized, double-blind, controlled trial. Neurosurgery 2004; 54:577. 61. Findlay JM, Grace MG, Weir BK. Treatment of intraventricular hemorrhage with tissue plasminogen activator. Neurosurgery 1993; 32:941. 62. Naff NJ, Carhuapoma JR, Williams MA, et al. Treatment of intraventricular hemorrhage with urokinase : effects on 30-Day survival. Stroke 2000; 31:841. 63. Coplin WM, Vinas FC, Agris JM, et al. A cohort study of the safety and feasibility of intraventricular urokinase for nonaneurysmal spontaneous intraventricular hemorrhage. Stroke 1998; 29:1573. 64. Rainov NG, Burkert WL. Urokinase infusion for severe intraventricular haemorrhage. Acta Neurochir (Wien) 1995; 134:55. 65. van Solinge TS, Muskens IS, Kavouridis VK, et al. Fibrinolytics and Intraventricular Hemorrhage: A Systematic Review and Meta-analysis. Neurocrit Care 2020; 32:262. 66. Hanley DF, Lane K, McBee N, et al. Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo- controlled CLEAR III trial. Lancet 2017; 389:603. 67. Naff N, Williams MA, Keyl PM, et al. Low-dose recombinant tissue-type plasminogen activator enhances clot resolution in brain hemorrhage: the intraventricular hemorrhage thrombolysis trial. Stroke 2011; 42:3009. 68. Schwarz S, Schwab S, Steiner HH, Hacke W. Secondary hemorrhage after intraventricular fibrinolysis: a cautionary note: a report of two cases. Neurosurgery 1998; 42:659. 69. Pollock GA, Shaibani A, Awad I, et al. Intraventricular hemorrhage secondary to intranidal aneurysm rupture-successful management by arteriovenous malformation embolization followed by intraventricular tissue plasminogen activator: case report. Neurosurgery 2011; 68:E581. 70. Varelas PN, Rickert KL, Cusick J, et al. Intraventricular hemorrhage after aneurysmal subarachnoid hemorrhage: pilot study of treatment with intraventricular tissue plasminogen activator. Neurosurgery 2005; 56:205. 71. Findlay JM, Jacka MJ. Cohort study of intraventricular thrombolysis with recombinant tissue plasminogen activator for aneurysmal intraventricular hemorrhage. Neurosurgery 2004; https://www.uptodate.com/contents/intraventricular-hemorrhage/print 18/26 7/5/23, 11:57 AM Intraventricular hemorrhage - UpToDate 55:532. 72. Mayfrank L, Rohde V, Gilsbach JM. Fibrinolytic treatment of intraventricular haemorrhage preceding surgical repair of ruptured aneurysms and arteriovenous malformations. Br J Neurosurg 1999; 13:128. 73. Herrick DB, Ziai WC, Thompson CB, et al. Systemic hematologic status following intraventricular recombinant tissue-type plasminogen activator for intraventricular hemorrhage: the CLEAR IVH Study Group. Stroke 2011; 42:3631. 74. Engelhard HH, Andrews CO, Slavin KV, Charbel FT. Current management of intraventricular hemorrhage. Surg Neurol 2003; 60:15. 75. Staykov D, Kuramatsu JB, Bardutzky J, et al. Efficacy and safety of combined intraventricular fibrinolysis with lumbar drainage for prevention of permanent shunt dependency after intracerebral hemorrhage with severe ventricular involvement: A randomized trial and individual patient data meta-analysis. Ann Neurol 2017; 81:93. 76. Staykov D, Volbers B, Wagner I, et al. Prognostic significance of third ventricle blood volume in intracerebral haemorrhage with severe ventricular involvement. J Neurol Neurosurg Psychiatry 2011; 82:1260. 77. Findlay JM. Intraventricular Hemorrhage. In: Stroke: Pathophysiology Diagnosis and Manag ement, 4th ed, Mohr JP, Choi DW, Grotta JC, Weir B, Wolf PA (Eds), Churchill Livingstone 2004. p.1231. 78. Vale FL, Bradley EL, Fisher WS 3rd. The relationship of subarachnoid hemorrhage and the need for postoperative shunting. J Neurosurg 1997; 86:462. 79. Graff-Radford NR, Torner J, Adams HP Jr, Kassell NF. Factors associated with hydrocephalus after subarachnoid hemorrhage. A report of the Cooperative Aneurysm Study. Arch Neurol 1989; 46:744. 80. Miller C, Tsivgoulis G, Nakaji P. Predictors of ventriculoperitoneal shunting after spontaneous intraparenchymal hemorrhage. Neurocrit Care 2008; 8:235. 81. Kobayashi E, Saeki N, Oishi H, et al. Long-term natural history of hemorrhagic moyamoya disease in 42 patients. J Neurosurg 2000; 93:976. Topic 1116 Version 23.0 https://www.uptodate.com/contents/intraventricular-hemorrhage/print 19/26 7/5/23, 11:57 AM Intraventricular hemorrhage - UpToDate GRAPHICS Glasgow Coma Scale (GCS) Score Eye opening Spontaneous 4 Response to verbal command 3 Response to pain 2 No eye opening 1 Best verbal response Oriented 5 Confused 4 Inappropriate words 3 Incomprehensible sounds 2 No verbal response 1 Best motor response Obeys commands 6 Localizing response to pain 5 Withdrawal response to pain 4 Flexion to pain 3 Extension to pain 2 No motor response 1 Total The GCS is scored between 3 and 15, 3 being the worst and 15 the best. It is composed of three parameters: best eye response (E), best verbal response (V), and best motor response (M). The components of the GCS should be recorded individually; for example, E2V3M4 results in a GCS score of 9. A score of 13 or higher correlates with mild brain injury, a score of 9 to 12 correlates with moderate injury, and a score of 8 or less represents severe brain injury. Graphic 81854 Version 9.0 https://www.uptodate.com/contents/intraventricular-hemorrhage/print 20/26 7/5/23, 11:57 AM Intraventricular hemorrhage - UpToDate Etiologies of thunderclap headache Most common causes of thunderclap headache: Subarachnoid hemorrhage Reversible cerebral vasoconstriction syndromes (RCVS) Conditions that less commonly cause thunderclap headache: Cerebral infection (eg, meningitis, acute complicated sinusitis) Cerebral venous thrombosis Cervical artery dissection Spontaneous intracranial hypotension Acute hypertensive crisis Posterior reversible leukoencephalopathy syndrome (PRES) Intracerebral hemorrhage Ischemic stroke Conditions that uncommonly or rarely cause thunderclap headache: Pituitary apoplexy Colloid cyst of the third ventricle Aortic arch dissection Aqueductal stenosis Brain tumor Giant cell arteritis Pheochromocytoma Pneumocephalus Retroclival hematoma Spinal epidural hematoma Varicella zoster virus vasculopathy Vogt-Koyanagi-Harada syndrome Disputed causes of thunderclap headache: Sentinel headache (unruptured intracranial aneurysm)* Primary thunderclap headache Sentinel headache due to an unruptured intracranial aneurysm is a possible cause of thunderclap headache, but supporting data are weak. https://www.uptodate.com/contents/intraventricular-hemorrhage/print 21/26 7/5/23, 11:57 AM Intraventricular hemorrhage - UpToDate There is controversy as to whether thunderclap headache can occur as a benign and potentially recurrent headache disorder in the absence of underlying organic intracranial pathology. Graphic 81710 Version 8.0 https://www.uptodate.com/contents/intraventricular-hemorrhage/print 22/26 7/5/23, 11:57 AM Intraventricular hemorrhage - UpToDate Intracerebral hemorrhage with intraventricular hemorrhage due to moyamoya syndrome Noncontrast head CT (A) showing hematoma in the right corpus striatum and lateral ventricles. Digital subtraction angiogram (B) showing critical stenosis of proximal right middle cerebral artery (arrow), prominent collateralization of both lenticulostriate vessels (circle), and branches of the anterior cerebral artery (thick arrows). CT: computed tomography. Courtesy of Glenn A Tung, MD, FACR. Graphic 132277 Version 1.0 https://www.uptodate.com/contents/intraventricular-hemorrhage/print 23/26 7/5/23, 11:57 AM Intraventricular hemorrhage - UpToDate Intraventricular hemorrhage due to ruptured periventricular arteriovenous malformation Noncontrast head CT (A) showing IVH. CT angiogram (B) showing abnormal tangle of vessels (circle) in the left perisplenial region. Digital subtraction angiogram (C) showing AVM nidus (circle). CT: computed tomography; IVH: intraventricular hemorrhage; AVM: arteriovenous malformation. Courtesy of Glenn A Tung, MD, FACR. Graphic 132281 Version 1.0 https://www.uptodate.com/contents/intraventricular-hemorrhage/print 24/26 7/5/23, 11:57 AM Intraventricular hemorrhage - UpToDate External ventricular drain An external ventricular drain (EVD) is a small catheter inserted through the skull usually into the lateral ventricle, which is typically connected to a closed collecting device to allow for drainage of cerebrospinal fluid. The EVD can also be connected to a transducer that records intracranial pressure. Graphic 56391 Version 2.0 https://www.uptodate.com/contents/intraventricular-hemorrhage/print 25/26 7/5/23, 11:57 AM Intraventricular hemorrhage - UpToDate Contributor Disclosures Brett L Cucchiara, MD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Alejandro A Rabinstein, MD Grant/Research/Clinical Trial Support: Chiesi [Small investigator-initiated project]. Consultant/Advisory Boards: AstraZeneca [Secondary stroke prevention]; Brainomix [AI for stroke diagnostics]; Novo Nordisk [Stroke risk]; Shionogi [Stroke neuroprotection]. Other Financial Interest: Boston Scientific [Adverse event adjudication committee member for stroke risk reduction device in patients with atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/intraventricular-hemorrhage/print 26/26

7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Posterior circulation cerebrovascular syndromes : Louis R Caplan, MD : Jos Biller, MD, FACP, FAAN, FAHA : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Apr 29, 2022. INTRODUCTION Twenty percent of ischemic events in the brain involve posterior circulation (vertebrobasilar) structures. This topic will review the major clinical syndromes associated with posterior circulation ischemia related to stenosis or occlusion of the large aortic arch, neck, and intracranial arteries. These arteries are the innominate and subclavian arteries in the chest, the vertebral arteries in the neck, and the intracranial vertebral, basilar, and posterior cerebral arteries. The evaluation and management of acute ischemic stroke (including stroke involving the posterior circulation) are discussed separately. (See "Initial assessment and management of acute stroke" and "Approach to reperfusion therapy for acute ischemic stroke" and "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".) SOURCE OF ISCHEMIA The most common causes of posterior circulation large artery ischemia are atherosclerosis, embolism, and dissection. Dolichoectasia (elongation and tortuosity) of the vertebral and basilar arteries is another occasional cause. About one-third of posterior circulation strokes are caused by occlusive disease within the large neck and intracranial arteries, which are the vertebral arteries in the neck and the intracranial vertebral, basilar, and posterior cerebral arteries [1-4]. https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 1/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate The proximal portion of the vertebral artery in the neck is the most common location of atherosclerotic occlusive disease within the posterior circulation [1-5]. Atherosclerosis of the intracranial vertebral arteries and of the basilar artery is also common. (See "Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis", section on 'Epidemiology'.) Dissection of the extracranial and intracranial vertebral arteries is another frequent cause of ischemia within the posterior circulation. Unlike the vertebral and basilar arteries, atherosclerosis and dissection of the posterior cerebral arteries is not common. Most infarcts in the posterior cerebral artery territory are due to embolism from the heart, aorta, or vertebral arteries. SUBCLAVIAN AND INNOMINATE ARTERIES Atherostenotic lesions of the innominate and subclavian arteries do cause arm ischemia and transient ischemic attacks (TIAs) but seldom cause strokes. Because the vertebral arteries in the neck originate from the proximal subclavian arteries, disease of the subclavian or innominate arteries proximal to the vertebral artery origin can cause reduction of vertebral artery flow. In the subclavian steal syndrome, obstruction of the proximal subclavian artery produces a low- pressure system within the ipsilateral vertebral artery and in blood vessels of the ipsilateral upper extremity. Blood from a higher-pressure system, the contralateral vertebral artery and basilar artery, is diverted and flows retrograde downward into the ipsilateral vertebral artery into the arm. (See "Subclavian steal syndrome", section on 'Clinical presentations' and "Subclavian steal syndrome", section on 'Upper extremity ischemia'.) Most often, subclavian artery disease is detected when patients with coronary or peripheral vascular occlusive disease are referred to ultrasound laboratories for noninvasive testing. Most patients with subclavian artery disease are asymptomatic. The most frequent symptoms of subclavian artery disease relate to the ipsilateral arm and hand. Coolness, weakness, and pain on use of the arm are common. Neurologic symptoms are uncommon unless there is accompanying carotid artery disease. Dizziness is by far the most common neurologic symptom of the subclavian steal syndrome, and usually has a spinning or vertiginous character. Diplopia, decreased vision, oscillopsia, and staggering all occur, but less frequently, often accompanying the dizziness. Attacks are brief and occasionally are brought on by exercising the ischemic arm. However, in most patients exercise https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 2/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate of the ischemic limb does not provoke neurologic symptoms or signs. (See "Subclavian steal syndrome", section on 'Clinical presentations' and "Subclavian steal syndrome", section on 'Upper extremity ischemia'.) Innominate artery disease is much less common than subclavian artery disease [1,3,6]. When the innominate artery becomes stenotic or occluded, signs and symptoms of decreased carotid artery flow may also develop. Ipsilateral monocular visual loss, ipsilateral cerebral hemisphere ischemia in the territories of the anterior and middle cerebral arteries, ipsilateral arm ischemia, and ischemic symptoms referable to the distal portion of the posterior circulation and/or the cerebellum may be due to innominate artery disease. Takayasu's disease and giant cell (temporal) arteritis can cause subclavian and innominate artery occlusive disease. Young women who smoke cigarettes and take oral contraceptives may develop occlusive disease of the aortic arch vessels that mimics Takayasu disease, except that it is not inflammatory. (See "Clinical features and diagnosis of Takayasu arteritis" and "Clinical manifestations of giant cell arteritis".) EXTRACRANIAL VERTEBRAL ARTERIES The vast majority of occlusive lesions of the proximal vertebral arteries are atherosclerotic. In a series of 100 patients with angiographically documented vertebral artery lesions, 92 percent were atherosclerotic in origin [7]. The most common location of atherosclerotic occlusive disease within the posterior circulation is the proximal portion of the vertebral artery in the neck [1-5]. Atherosclerotic plaques may begin in the subclavian artery and extend into the ostia of the proximal extracranial vertebral arteries (ECVAs), or begin within the most proximal portion of the ECVAs. Occlusions most often occur within the first inch (2 to 3 cm) of the ECVAs. In contrast, atherosclerotic disease rarely involves the more distal ECVAs within the cervical spine or near the penetration of the arteries into the skull ( figure 1). Another common cause of posterior circulation stroke is arterial dissection, which usually involves the ECVA just before it enters the foramen transversarium at C5 or C6, or in the very distal part of the artery in the neck before it penetrates the dura mater to enter the cranial cavity. CT angiography can show occlusive lesions at the origin of the vertebral arteries from the subclavian arteries as well as dissections. MR angiography often does not show the origins of the vertebral arteries well. https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 3/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate Proximal vertebral artery disease can cause sudden-onset strokes or transient ischemic attacks (TIAs). The most frequently reported symptom during TIAs is dizziness. These vertebral artery TIAs are indistinguishable from those described by patients with subclavian steal, except that vertebral artery TIAs are not precipitated by effort or by arm exertion. Although dizziness is the most common symptom, it is seldom the only neurologic symptom. Usually, in at least some attacks, dizziness is accompanied by other signs of hindbrain ischemia. Diplopia, oscillopsia, weakness of both legs, hemiparesis, and numbness are often reported. In patients with proximal ECVA disease, a bruit can often be heard over the supraclavicular region when auscultation is performed by moving the stethoscope bell over the posterior cervical muscles and the mastoid. Sometimes a bruit may be heard over the vertebral artery contralateral to the side of the stenotic vertebral artery because of increased collateral blood flow. Artery to artery embolism and low flow Embolization of white platelet-fibrin and red erythrocyte-fibrin thrombi from atherostenotic occlusive lesions is the most common presentation of ECVA origin disease [1-5,8]. The intraarterial emboli travel from the ECVA origin to reach the ipsilateral intracranial vertebral artery (ICVA), and sometimes travel on to block the rostral basilar artery and/or its branches. In support of this observation, patients presenting with ischemia in the distribution of the ICVA (the medulla and posterior inferior cerebellum) or the distal basilar artery (superior cerebellum, occipital and temporal lobes in the territory of the posterior cerebral arteries, or the thalamus or midbrain) show a high frequency of recent ECVA occlusions [1,3-5]. A situation analogous to that of ECVA origin disease is well known in the anterior circulation, where atherosclerotic disease of the internal carotid artery origin can cause distal ischemia by artery to artery embolization. As an example, it is not uncommon that a patient with a small, middle cerebral artery territory infarct is found to have an occlusion at the internal carotid artery origin by ultrasound or angiography. In most of these cases, it is likely that a recently formed occlusive thrombus in the internal carotid artery fragmented and embolized distally, causing the middle cerebral artery territory stroke. In patients with proximal ECVA stenosis, intraarterial (artery to artery) embolism is a much more frequent cause of ischemia to the intracranial posterior circulation arteries than hemodynamic insufficiency (ie, low flow). This point is illustrated by results from the New England Medical Center Posterior Circulation Registry, which evaluated a series of 407 patients who had posterior circulation TIAs or strokes within the prior six months and included 80 patients with severe stenosis or occlusion of the proximal ECVA [1]. In 45 (56 percent) of these 80 patients, https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 4/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate embolization from the vertebral artery lesion was the most likely cause of brain ischemia [1]. Only 13 patients (16 percent) had hemodynamic-related TIAs, and 12 of these 13 had severe bilateral vertebral artery occlusive disease. The only patient with unilateral vertebral artery disease had bilateral internal carotid artery occlusions. Dissection and other causes Dissection of the ECVA usually involves the distal portion of the ECVA as it winds around the upper cervical vertebrae [9]. Sometimes dissections involve the proximal ECVA between the origin of the artery and its entry into the vertebral column, usually at C5 or C6. Pain in the neck and/or occiput and TIAs or strokes involving the lateral medulla and cerebellum are the most common findings. (See "Cerebral and cervical artery dissection: Clinical features and diagnosis", section on 'Clinical manifestations'.) Ischemic symptoms due to ECVA dissection are most often vestibulocerebellar and include dizziness, vertigo, veering to one side, and loss of balance. When infarcts develop, they usually involve the inferior portion of the cerebellum, causing gait ataxia. Less common, are emboli to the distal posterior circulation, especially the posterior cerebral artery territories, causing a hemianopia. Occasionally cervical root pain and signs, and spinal cord ischemia can develop. In older patients, giant cell arteritis is an occasional cause of occlusive disease involving the distal extracranial vertebral artery just before it penetrates the dura to become intracranial. (See "Clinical manifestations of giant cell arteritis".) Rotational vertebral artery occlusion is an uncommon cause of transient posterior circulation ischemic symptoms, mainly paroxysmal vertigo or nonspecific dizziness, which may be accompanied by nystagmus, tinnitus, syncope, blurred vision, nausea, or vomiting [10,11]. The nystagmus typically has a prominent downbeat component, but may also include torsional and horizontal components [12]. The symptoms are due to dynamic compression of one (dominant) vertebral artery by bony elements of the cervical spine, triggered by head turning to one side, or less often by head turning to both sides or head tilting [10,11]. In most reported cases, there is associated hypoplasia or stenosis of the other vertebral artery. The symptoms are relieved by returning the head to the neutral position. Few if any cases result in infarction with permanent neurologic deficits from this mechanism. (See "Causes of vertigo", section on 'Rotational vertebral artery syndrome'.) INTRACRANIAL VERTEBRAL ARTERIES Atherostenotic disease can involve any portion of the intracranial vertebral arteries (ICVA) ( figure 2). The most common location of ICVA stenosis is the distal portion of the artery at or near the vertebral-basilar artery junction. Another common site of ICVA stenosis is the proximal https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 5/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate portion of the vertebral artery just after dural penetration and before giving off the posterior inferior cerebellar artery (PICA) branch. Dissection of the ICVA also occurs, and ischemic symptoms are usually accompanied by prominent headache [13]. ICVA dissections often extend into the basilar artery. Occlusive ICVA disease presents in a variety of different ways [4,14,15]: Asymptomatic occlusion Transient ischemic attacks (TIAs), usually including vestibulocerebellar symptoms or elements of the lateral medullary syndrome Lateral medullary infarcts Medial medullary infarction Infarction of one-half of the medulla (hemimedullary infarction) including the lateral and medial medulla on one side Cerebellar infarction in PICA territory Embolization of the ICVA thrombus to the distal basilar artery and its branches causing TIAs and/or strokes Propagation of the ICVA thrombus into the basilar artery causing a basilar artery syndrome Lateral medullary infarction Lateral medullary infarction (Wallenberg syndrome) is the most common and important syndrome related to intracranial vertebral artery occlusion ( figure 3) [4,15]. The diagnosis is often missed by non-neurologists, and so the features are very important to know and understand. Vestibulocerebellar symptoms and signs Vestibulocerebellar symptoms and signs are nearly always present in patients with lateral medullary infarcts [14]. These are related to involvement of the vestibular nuclei and their connections, and to involvement of the inferior cerebellar peduncle (restiform body). Common symptoms and signs are as follows: Feeling dizzy or off-balance, which may take a number of forms: Turning, rotating, whirling, or moving in relation to the environment Being pulled or falling towards one side, most often ipsilateral to the lesion Swaying or rolling as if moving from side to side https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 6/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate Tilting or leaning Difficulty sitting upright without support. Patients topple, lean, or veer to the ipsilateral side when they sit or stand. In many, standing or walking is impossible during the acute period without support. When they regain the ability to walk, patients often feel as if they are being pulled to the side of the lesion. They veer, list, or weave to the side, especially on turns. Hypotonia of the ipsilateral arm. This cerebellar sign can be demonstrated by having the patient quickly lower or raise the outstretched hands together, braking the ascent and descent suddenly. The symptomatic arm on the side ipsilateral to the infarct often overshoots and is not as quickly braked compared with the normal contralateral arm. In some patients, the ipsilateral arm also makes a slower ascent or descent. Blurred vision or diplopia. Some also describe oscillopsia, which is the appearance that objects in the visual field are in rhythmic motion or oscillation. Less common is tilting or inversion of the visual environment. Nystagmus. This is nearly always present, especially in patients who describe dizziness or vertigo. The nystagmus usually has both horizontal and rotational components. The rapid phase of the rotatory nystagmus usually moves the upper border of the iris towards the side of the lesion. Most often, larger amplitude, slower nystagmus is present on gaze to the side of the lesion, while smaller amplitude, quick nystagmus is found on gaze directed to the contralateral side. Ocular torsion. The eye and ear ipsilateral to the lateral medullary infarct may rest in a down position below the contralateral eye and ear [16]. At times, ocular torsion is accompanied by a head tilt and skew deviation with the ipsilateral eye positioned downward. This combination of findings is referred to as the ocular tilt reaction [4,17,18]. Limb ataxia ipsilateral to the lateral medullary infarct. Some patients cannot feed themselves using the ataxic arm. They overshoot targets and have difficulty pointing accurately to moving targets. Sensory symptoms and signs Sensory symptoms and signs are common in patients with lateral medullary infarcts. Pain or unpleasant feelings in the face are sometimes the earliest and most prominent feature of the lateral medullary syndrome and are diagnostic of a lateral tegmental brainstem localization. These are related to lesions of the spinal nucleus of V and the descending spinal tract of V. The facial pain is usually described as sharp jolts or stabs of https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 7/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate pain most often in the ipsilateral eye or face. Sometimes pain persists and is limited to the forehead and frontal scalp region. At times, the abnormal sensation is described as hot, burning, or scalding. Loss of pain and temperature sensation in the contralateral trunk and limbs is related to lesions of the lateral medullary spinothalamic tract. The most common pattern of sensory abnormality in patients with lateral medullary infarcts is loss of pain and temperature sensation in the ipsilateral face and the contralateral trunk and limbs. The next most frequent combination is hypalgesia in the ipsilateral face and contralateral face, trunk, and limbs. Less often, the hypalgesia can be solely contralateral, involving the face, arm, and leg, or sometimes only the face and arm [4,19]. The least common pattern of sensory loss is hypalgesia only involving the contralateral trunk, arm, and leg or portions thereof. Examination usually shows ipsilateral decreased pain and temperature sensation in the face. The corneal reflex is usually reduced in the ipsilateral eye. Although contralateral loss of pain and thermal sensation involving the body and limbs is usually found on examination, most patients with contralateral hypalgesia are unaware of their sensory loss until they are tested. However, some do notice loss of thermal sensation when they touch hot or cold objects with their contralateral upper and/or lower limbs. Bulbar muscle weakness Weakness of bulbar muscles innervated by the lower cranial nerves is a very prominent feature when lateral medullary infarcts extend medially. Usually, the abnormality is unilateral. Involvement of the nucleus ambiguus causes paralysis of the ipsilateral palate, pharynx, and larynx, resulting in hoarseness and dysphagia. Oropharyngeal muscle paralysis results in food being trapped in the piriform recess of the pharynx. Food and secretions have relatively free access into the air passages. Patients try to extricate the food with a cough or throat-clearing maneuver, which makes a characteristic crowing-like sound. Examination shows paralysis of the ipsilateral vocal cord and a lack of elevation of the ipsilateral palate on phonation. The uvula often deviates to the side contralateral to the lateral medullary infarct. Dysarthria and dysphonia are common. In some patients, dysphagia and aspiration are prominent. Aspiration and pneumonia are very important complications of abnormal pharyngeal function. Hiccups are also a relatively common and annoying complaint. https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 8/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate Respiratory dysfunction Respiratory dysfunction is an important feature of lateral medullary ischemia. Control of inspiration and expiration and their automaticity lies within the ventrolateral medullary tegmentum and the medullary reticular zone. The most common abnormality described in patients with lateral tegmental caudal brainstem lesions is failure of automatic respirations, a phenomenon especially apparent during sleep. This failure to initiate respiration has been referred to as Ondine's curse. (See "Disorders of ventilatory control", section on 'Ondine curse' and "Congenital central hypoventilation syndrome and other causes of sleep-related hypoventilation in children", section on 'Congenital central hypoventilation syndrome'.) Autonomic dysfunction Autonomic dysfunction may occur in lateral medullary infarction. The ipsilateral eye often shows features of Horner's syndrome due to lesions of the descending sympathetic nervous system. (See "Horner syndrome".) Cardiovascular abnormalities include tachycardia, orthostatic hypotension without cardiac rate acceleration, and intermittent bradycardia [4]. Some patients have labile blood pressures, tachycardia, unusual sweating, and arrhythmias. The anatomic basis is thought to be involvement of the dorsal motor nucleus of the vagus nerve. Medial medullary infarction The most consistent finding in patients with medial medullary ischemia is a contralateral hemiparesis [4,20]. Usually the hemiparesis is complete and flaccid at onset. Later, increased tone and spasticity develop. In approximately one-half of patients, the face is also involved. Facial weakness, when it occurs, is usually slight and transient and rarely persists. Sensory symptoms are related to ischemia of the medial lemniscus. Some patients report paresthesias or, less commonly, dysesthesias in the contralateral lower limb and trunk. Less often, sensory symptoms occur in the arm and hand. In many patients with sensory symptoms there are no objective signs of touch, vibration, or position sense loss. Proprioceptive dysfunction, with slight loss of position and vibration sense in the contralateral foot, is found in some patients. Ipsilateral tongue paralysis is the least common but most topographically localizing sign of medial medullary infarction, and is due to involvement of the hypoglossal nucleus. Tongue paresis causes slurring of speech, especially of lingual consonants. Hemimedullary infarction Occasional patients have infarction that involves both the lateral and medial medullary territories on one side (hemimedullary infarcts). Symptoms are identical to those found in patients with lateral medullary ischemia with the addition of a hemiparesis https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 9/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate contralateral to the lesion. The hemiparesis may develop concurrently with lateral medullary symptoms and signs or can occur later. (See 'Lateral medullary infarction' above and 'Medial medullary infarction' above.) Cerebellar infarction Cerebellar infarction in PICA distribution can involve just the vermis, or the lateral surface, or the full PICA territory ( figure 4). Full PICA territory infarcts are often accompanied by edema formation and mass effect (so-called pseudotumoral cerebellar infarcts). (See 'Pseudotumoral cerebellar infarction' below.) Approximately one-fifth of PICA territory cerebellar infarcts are accompanied by infarction in the dorsal or dorsolateral medulla [3,4]. The combination of lateral medullary and PICA cerebellar infarction occurs when the ICVA is occluded and blocks the orifice of both PICA and the lateral medullary penetrators. Sometimes medial PICA territory infarcts are accompanied by dorsal medullary infarcts since the medial PICA branch has some supply to the dorsal medulla [4,21,22]. Infarcts limited to the medial vermis in medial PICA territory usually cause a vertiginous labyrinthian syndrome that closely mimics a peripheral vestibulopathy. Severe vertigo and prominent nystagmus are the major findings. Some patients also have truncal lateropulsion characterized by feelings of magnetic pulling of the trunk to the ipsilateral side. Lateral cerebellar hemisphere PICA territory infarcts are usually characterized by minor degrees of dizziness and gait incoordination with veering to the side of the lesion. Minor limb hypotonia and incoordination are found. A common syndrome is acute unsteadiness with ataxia but without vertigo or dysarthria. Body sway towards the side of the lesion, ipsilateral limb ataxia, and abnormal rapid alternating movements are also common. When the full PICA cerebellar territory is involved, headache is usually present in the occiput or high neck on the ipsilateral side. The head may also be tilted with the occiput tending to tilt toward the ipsilateral side. Vomiting, gait ataxia, truncal lateropulsion, and limb incoordination are other common findings. The truncal dysfunction is similar to that found in the lateral medullary syndrome; the body is often tilted or pulled ipsilaterally upon sitting or standing. The limb incoordination consists mostly of hypotonia rather than a rhythmic intention tremor. Pseudotumoral cerebellar infarction The syndrome of pseudotumoral cerebellar infarction, with edema formation and mass effect, is most often associated with large full PICA territory infarcts. After the first day or so, patients with this form of cerebellar infarction typically https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 10/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate develop increased headache, vomiting, and decreased consciousness, with drowsiness followed by stupor. Bilateral Babinski signs are an early sign of cerebellar mass effect. Characteristic oculomotor abnormalities of large cerebellar space-taking infarcts can develop and include the following features: Most common are a conjugate gaze paresis to the side of the lesion or a paresis of abduction limited to the ipsilateral eye Bilateral sixth nerve paresis may occur Later bilateral horizontal gaze palsies may develop, often accompanied by ocular bobbing These signs are due to compression of the pontine tegmentum by the swollen cerebellar infarct. Stupor is followed by deep coma when the oculomotor abnormalities become bilateral. Dolichoectasia Dolichoectasia (dilatative arteriopathy) is a term that describes arterial elongation, widening, and tortuosity [23-29]. The intracranial vertebral and basilar arteries are most often affected. Dolichoectatic arteries are characterized by an abnormally large external diameter and a thin arterial wall that shows degeneration of the internal elastic lamina, and multiple gaps in the internal elastica. The media of dilated arteries becomes thin because of reticular fiber deficiency and smooth muscle atrophy. The most important clinical presentations of dilatative arteriopathy are as follows: Acute brain ischemia A progressive course related to compression of cranial nerves, the brainstem, or the third ventricle A catastrophic outcome caused by vascular rupture Flow in dilated arteries may become to-and-fro, causing reduced antegrade flow and thrombus formation. Elongation and angulation of arteries can stretch and distort the orifices of arterial branches leading to decreased blood flow, especially in penetrating branches. Dilated intracranial vertebral arteries can compress the medulla leading to the gradual onset of hemiparesis [26]. Distinguishing vertigo of brainstem and cerebellar ischemia from peripheral causes A composite three-part test entitled HINTS (Head-Impulse-Nystagmus-Test of Skew) is useful for distinguishing brainstem and cerebellar ischemia from vestibular neuritis or other peripheral causes of vertigo [30-33]. The test is most helpful in patients who have had continuous feelings https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 11/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate of vertigo or dizziness. It is not useful in patients with momentary position-related transient vertigo (often benign positional vertigo) or those with TIAs who are not dizzy when examined. Head Impulse For the head impulse test, also called head thrust test (see "Evaluation of the patient with vertigo", section on 'Other vestibular signs'), the patient is instructed to fix their gaze on a distant target while wearing his or her usual prescription eyeglasses. The head is then turned quickly and unpredictably by the examiner, about 15 ; the starting position should be about 10 from straight ahead. The normal response is that the eyes remain on the target ( figure 5). The abnormal response is that the eyes are dragged off of the target by the head turn (in one direction), followed by a saccade back to the target after the head turn; this response indicates a deficient vestibulo-ocular on the side of the head turn, implying a peripheral vestibular lesion (ie, the inner ear or vestibular nerve) on that side. This reflex is preserved in central lesions, except when cranial nerve (CN) VIII fascicles are affected in the lateral pons. Nystagmus Peripheral vestibular lesions often are accompanied by nystagmus that is always in the same direction (see "Evaluation of the patient with vertigo", section on 'Nystagmus'), while brainstem and cerebellar lesions are typically associated with nystagmus that changes direction with different positions of gaze. Test for Skew The test involves covering one eye and seeing if there is a vertical shift in the eye when uncovered. Brainstem and cerebellar lesions sometimes cause a slight skew deviation. Any of the following, whether present or untestable, suggest a brainstem or cerebellar lesion [30-33]: Normal head impulse test on both sides Direction-changing nystagmus Skew deviation The presence of all of the following suggests a peripheral lesion [30-33]: An abnormal head impulse test on one side Unidirectional, horizontal, torsional nystagmus that increases in intensity with gaze toward the fast phase Absent skew The importance of these oculomotor tests is that brain imaging with either CT or MRI may be normal during the acute phase of ischemic symptoms. In this regard, the HINTS test appears to https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 12/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate be more sensitive for the diagnosis of acute stroke than even brain MRI within the first two days after symptom onset [33]. One caveat is that there are rare examples of inner ear infarction (usually due to occlusion of the internal auditory artery, an anterior inferior cerebellar artery branch) causing an acute vestibular syndrome. These are typically associated with new hearing loss on the side of the vestibular lesion, which may be the only clue that the mechanism is stroke [32,33]. In such cases, the eye movements elicited on HINTS are indistinguishable from peripheral vestibular causes. BASILAR ARTERY The basilar artery begins at the medullopontine junction and ends at the junction of the pons and midbrain. Occlusive lesions may occur anywhere along the basilar artery [34]. Atherostenotic lesions are most common in the proximal and mid basilar artery; emboli have a predilection for stopping at the distal end of the basilar artery. Thrombi engrafted upon occlusive lesions within the distal intracranial vertebral artery (ICVA), for example, near or at the ICVA-basilar artery junction, can extend into the proximal basilar artery. Basilar artery occlusive disease most often presents as ischemia in the pons. The major burden of ischemia is in the middle of the pons, mostly in the paramedian base, and often also in the paramedian tegmentum ( picture 1). The reasons for this localization are as follows: The largest penetrating arteries supply the paramedian pons ( figure 6) and arise directly from the basilar artery. The pontine tegmentum is supplied mostly by arteries that arise from the distal basilar artery. When the distal basilar artery remains patent, the tegmentum is relatively spared. Collateral circulation comes mainly from the ICVAs through their posterior inferior cerebellar artery (PICA) branches that anastomose with anterior inferior cerebellar artery (AICA) and superior cerebellar artery (SCA) branches; these course around the lateral aspect of the pons, supplying the lateral tegmental and basal structures in the pons ( figure 4 and image 1). The paramedian pontine base contains descending long motor tract and crossing cerebellar fibers. The paramedian tegmentum contains mostly oculomotor fibers. As a result, the predominant symptoms and signs in patients with basilar artery occlusive disease are motor and oculomotor. Sensory and vestibular nuclei and tracts located in the lateral tegmentum are relatively spared. https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 13/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate Alteration in the level of consciousness is an important sign in patients with basilar artery occlusion. They may present with coma when the bilateral medial pontine tegmentum is ischemic. Motor symptoms and signs Most patients with symptomatic basilar artery occlusive disease and pontine ischemia have some transient or persistent degree of paresis and corticospinal tract abnormalities [3,4,14,35-38]. The initial motor weakness is often lateralized and has been referred to as the "herald hemiparesis" of basilar artery occlusion. Hemiparetic patients with basilar artery occlusion almost always show some motor or reflex abnormalities on the non-hemiparetic side. As examples, slight weakness, hyperreflexia, an extensor plantar reflex, or abnormal spontaneous movements such as shivering, twitching, shaking, or jerking may be present on the relatively spared side. Asymmetry but bilaterality of neurologic signs is the rule. Adventitious movements of the arms and/or legs are occasionally seen and can be prominent. These movements are variable and sometimes intermittent. Small movements may resemble fasciculations. Larger movements may resemble shivering, shuddering, or jerking; another variant is that of tremulous shaking. Voluntary or passive limb movements or painful stimuli may precipitate a flurry of abnormal movements. At times there are large repetitive jerking and twitching movements, especially in limbs contralateral to a hemiparesis. These movements are often misdiagnosed as seizures [39]. Incoordination of limb movements is another common motor finding. Ataxia is invariably combined with some degree of weakness. Incoordination is usually more severe in the legs. Toe- to-object and heel-to-shin testing usually shows clumsiness and diminished coordination due to cerebellar dysfunction. The ataxia is invariably bilateral but may be asymmetric and more severe on the weaker side. Intention tremor is not common. Bulbar involvement Weakness of bulbar muscles is very common and is an important cause of morbidity with pontine infarction due to basilar occlusive disease. Bulbar symptoms include facial weakness, dysphonia, dysarthria, dysphagia, and limited jaw movements. The face, pharynx, larynx, and tongue are most often involved. The pattern may be that of crossed motor loss, such as weakness involving one side of the face and the contralateral body, but more often the bulbar muscle weakness is bilateral. Some patients totally lose the ability to speak, open their mouth, protrude their tongue, swallow, or move their face at will or on command. Secretions pool in the pharynx; and aspiration is an important and serious complication. When all voluntary movements other than the eyes are lost https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 14/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate but consciousness is retained, the deficit is referred to as the "locked-in syndrome." (See "Locked-in syndrome".) Patients with infarction of the pontine base frequently have exaggerated crying and laughing spells and are hypersensitive to emotional stimulus, a condition known as pseudobulbar affect or emotional lability. Despite the loss of volitional muscle movement, reflexes of the jaw, face, and pharynx may be exaggerated. In addition, clonic jaw movements or clamping down on a tongue blade may occur as a response to attempts to pry the mouth open and to insert a tongue blade. Some patients with pontine ischemia develop palatal myoclonus (a rhythmic involuntary jerking movement of the soft palate and pharyngopalatine arch) that can involve the diaphragm and larynx. This movement disorder usually begins sometime after the brainstem infarct. The movements of the palate vary in rate between 40 and 200 beats per minute. The movements are readily seen by watching the palate and pharynx when the mouth is open. The movements involve the eustachian tube and make a click that the patient and clinician can hear. Oculomotor symptoms and signs Oculomotor symptoms and signs are common with symptomatic basilar artery occlusive disease and pontine ischemia, and few patients with this condition have normal eye movements. Abnormalities include: Complete bilateral horizontal gaze palsy Unilateral horizontal conjugate gaze palsy Unilateral or bilateral internuclear ophthalmoplegia (INO) One-and-a-half syndrome (a conjugate gaze palsy combined with an INO) Skew deviation of the eyes and ocular bobbing may also be present. Horizontal, gaze-paretic nystagmus is common and, when asymmetric, usually is more prominent when gaze is directed to the side of a unilateral pontine tegmental lesion. Dissociated nystagmus, that is nystagmus that is more severe in one eye and not rhythmically concordant in the two eyes, and vertical nystagmus are found in patients with an INO (see "Internuclear ophthalmoparesis"). Ptosis of the upper eyelids is also very frequent.

normal during the acute phase of ischemic symptoms. In this regard, the HINTS test appears to https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 12/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate be more sensitive for the diagnosis of acute stroke than even brain MRI within the first two days after symptom onset [33]. One caveat is that there are rare examples of inner ear infarction (usually due to occlusion of the internal auditory artery, an anterior inferior cerebellar artery branch) causing an acute vestibular syndrome. These are typically associated with new hearing loss on the side of the vestibular lesion, which may be the only clue that the mechanism is stroke [32,33]. In such cases, the eye movements elicited on HINTS are indistinguishable from peripheral vestibular causes. BASILAR ARTERY The basilar artery begins at the medullopontine junction and ends at the junction of the pons and midbrain. Occlusive lesions may occur anywhere along the basilar artery [34]. Atherostenotic lesions are most common in the proximal and mid basilar artery; emboli have a predilection for stopping at the distal end of the basilar artery. Thrombi engrafted upon occlusive lesions within the distal intracranial vertebral artery (ICVA), for example, near or at the ICVA-basilar artery junction, can extend into the proximal basilar artery. Basilar artery occlusive disease most often presents as ischemia in the pons. The major burden of ischemia is in the middle of the pons, mostly in the paramedian base, and often also in the paramedian tegmentum ( picture 1). The reasons for this localization are as follows: The largest penetrating arteries supply the paramedian pons ( figure 6) and arise directly from the basilar artery. The pontine tegmentum is supplied mostly by arteries that arise from the distal basilar artery. When the distal basilar artery remains patent, the tegmentum is relatively spared. Collateral circulation comes mainly from the ICVAs through their posterior inferior cerebellar artery (PICA) branches that anastomose with anterior inferior cerebellar artery (AICA) and superior cerebellar artery (SCA) branches; these course around the lateral aspect of the pons, supplying the lateral tegmental and basal structures in the pons ( figure 4 and image 1). The paramedian pontine base contains descending long motor tract and crossing cerebellar fibers. The paramedian tegmentum contains mostly oculomotor fibers. As a result, the predominant symptoms and signs in patients with basilar artery occlusive disease are motor and oculomotor. Sensory and vestibular nuclei and tracts located in the lateral tegmentum are relatively spared. https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 13/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate Alteration in the level of consciousness is an important sign in patients with basilar artery occlusion. They may present with coma when the bilateral medial pontine tegmentum is ischemic. Motor symptoms and signs Most patients with symptomatic basilar artery occlusive disease and pontine ischemia have some transient or persistent degree of paresis and corticospinal tract abnormalities [3,4,14,35-38]. The initial motor weakness is often lateralized and has been referred to as the "herald hemiparesis" of basilar artery occlusion. Hemiparetic patients with basilar artery occlusion almost always show some motor or reflex abnormalities on the non-hemiparetic side. As examples, slight weakness, hyperreflexia, an extensor plantar reflex, or abnormal spontaneous movements such as shivering, twitching, shaking, or jerking may be present on the relatively spared side. Asymmetry but bilaterality of neurologic signs is the rule. Adventitious movements of the arms and/or legs are occasionally seen and can be prominent. These movements are variable and sometimes intermittent. Small movements may resemble fasciculations. Larger movements may resemble shivering, shuddering, or jerking; another variant is that of tremulous shaking. Voluntary or passive limb movements or painful stimuli may precipitate a flurry of abnormal movements. At times there are large repetitive jerking and twitching movements, especially in limbs contralateral to a hemiparesis. These movements are often misdiagnosed as seizures [39]. Incoordination of limb movements is another common motor finding. Ataxia is invariably combined with some degree of weakness. Incoordination is usually more severe in the legs. Toe- to-object and heel-to-shin testing usually shows clumsiness and diminished coordination due to cerebellar dysfunction. The ataxia is invariably bilateral but may be asymmetric and more severe on the weaker side. Intention tremor is not common. Bulbar involvement Weakness of bulbar muscles is very common and is an important cause of morbidity with pontine infarction due to basilar occlusive disease. Bulbar symptoms include facial weakness, dysphonia, dysarthria, dysphagia, and limited jaw movements. The face, pharynx, larynx, and tongue are most often involved. The pattern may be that of crossed motor loss, such as weakness involving one side of the face and the contralateral body, but more often the bulbar muscle weakness is bilateral. Some patients totally lose the ability to speak, open their mouth, protrude their tongue, swallow, or move their face at will or on command. Secretions pool in the pharynx; and aspiration is an important and serious complication. When all voluntary movements other than the eyes are lost https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 14/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate but consciousness is retained, the deficit is referred to as the "locked-in syndrome." (See "Locked-in syndrome".) Patients with infarction of the pontine base frequently have exaggerated crying and laughing spells and are hypersensitive to emotional stimulus, a condition known as pseudobulbar affect or emotional lability. Despite the loss of volitional muscle movement, reflexes of the jaw, face, and pharynx may be exaggerated. In addition, clonic jaw movements or clamping down on a tongue blade may occur as a response to attempts to pry the mouth open and to insert a tongue blade. Some patients with pontine ischemia develop palatal myoclonus (a rhythmic involuntary jerking movement of the soft palate and pharyngopalatine arch) that can involve the diaphragm and larynx. This movement disorder usually begins sometime after the brainstem infarct. The movements of the palate vary in rate between 40 and 200 beats per minute. The movements are readily seen by watching the palate and pharynx when the mouth is open. The movements involve the eustachian tube and make a click that the patient and clinician can hear. Oculomotor symptoms and signs Oculomotor symptoms and signs are common with symptomatic basilar artery occlusive disease and pontine ischemia, and few patients with this condition have normal eye movements. Abnormalities include: Complete bilateral horizontal gaze palsy Unilateral horizontal conjugate gaze palsy Unilateral or bilateral internuclear ophthalmoplegia (INO) One-and-a-half syndrome (a conjugate gaze palsy combined with an INO) Skew deviation of the eyes and ocular bobbing may also be present. Horizontal, gaze-paretic nystagmus is common and, when asymmetric, usually is more prominent when gaze is directed to the side of a unilateral pontine tegmental lesion. Dissociated nystagmus, that is nystagmus that is more severe in one eye and not rhythmically concordant in the two eyes, and vertical nystagmus are found in patients with an INO (see "Internuclear ophthalmoparesis"). Ptosis of the upper eyelids is also very frequent. The pupils may remain normal or become small. In some patients, the pupils are bilaterally very small ("pinpoint"). Use of a magnifying glass can show that, despite their very small size, the pupillary response to light is preserved, although the amplitude of the response is slight. Sensory symptoms and signs Somatosensory abnormalities are generally not prominent in patients with basilar artery occlusions. Paresthesias on one side of the body and limbs reflect involvement of the contralateral medial lemniscus in the paramedian dorsal portion of the basis https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 15/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate pontis. Bilateral paramedian lesions that include the medial lemnisci on both sides can cause bilateral paresthesias. Proprioceptive loss is usually minimal or absent despite the paresthesias. Some patients with basilar artery occlusive disease have unusual burning pain in the face usually located in the center of the face near the midline. Tinnitus and hearing loss relate to involvement of the central auditory tracts and nuclei (auditory nuclei, lateral lemnisci, trapezoid bodies, inferior colliculi) or to ischemia of the eighth nerves or the cochlea. ROSTRAL BRAINSTEM ISCHEMIA AND "TOP OF THE BASILAR" SYNDROME Occlusion of the rostral portion of the basilar artery (the "top of the basilar") can cause ischemia of the midbrain, thalami, and temporal and occipital lobe hemispheral territories supplied by the posterior cerebral artery branches of the basilar artery. In most patients, infarction in this region (the top of the basilar) is caused by embolism from a more proximal source such as the heart, the aorta, the vertebral arteries in the neck, or the intracranial vertebral arteries. Less commonly, the syndrome is caused by intrinsic occlusive disease of the rostral portion of the basilar artery. In many patients infarction is limited to the rostral brainstem. The major abnormalities associated with rostral brainstem infarction involve alertness, behavior, memory, and oculomotor and pupillary functions. Oculomotor and pupillary abnormalities The most common abnormalities of eye position and movement involve vertical gaze and convergence [3,40,41]. Some patients lose all voluntary and reflex vertical eye movements. Reflex movements are sometimes preserved despite loss of voluntary vertical eye movements. Either upgaze or downgaze can be selectively involved, but in most patients both directions of vertical gaze are involved. Upgaze and vertical gaze palsies are more common than downgaze palsies. Asymmetric or unilateral lesions in the midbrain tegmentum and posterior thalami can cause ocular tilt reactions in which the contralateral eye and ear are down. Other abnormalities include skew deviation, ocular torsion, and abnormal estimation of the visual vertical [17]. Convergence abnormalities are also very common. Usually one or both eyes are hyperconverged. One or both eyes may rest inward or down and in at rest. On attempted upgaze, the eyes may show adductor contractions, causing convergence movements. A rostral mesencephalic lesion near the level of the posterior commissure can cause pathologic retraction of the upper eyelid with widening of the palpebral fissure (Collier sign). In some https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 16/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate patients, both lids are retracted but one eye may have a normal lid position or ptosis. Lesions in the rostral brainstem also often affect the pupillary light reflex so that the pupils react slowly and incompletely, or not at all, to light. In patients with diencephalic lesions, the pupils are often small at rest, and may be fixed and dilated if the lesions involve the third nerve Edinger-Westphal nuclei. A combination of diencephalic and midbrain lesions may cause mid- position fixed pupils. The constellation of neuroophthalmologic findings seen with midbrain (pretectal) lesions has been called Parinaud syndrome ( table 1). Altered alertness, behavior, and memory Abnormalities of alertness and behavior are common in patients with rostral brainstem infarcts [14]. Hypersomnolence and abulia are common. Patients may answer queries with replies that have no relation to reality. The patient may mislocate themselves in place, reporting that they are in a distant geographical location, and in the personal time dimension, saying that they are presently performing activities that they had actually done in childhood, adolescence, or much earlier in adult life. Thalamic or midbrain injury that "straddles the peduncles" can lead to peduncular hallucinations. These are predominantly visual, but there may be some minor tactile and auditory components. Visual hallucinations are often quite vivid and contain colors, objects, and scenes. The hallucinations occur predominantly after sundown [3,40]. (See "Approach to the patient with visual hallucinations", section on 'Peduncular hallucinosis'.) Prominent and sometimes persistent memory deficits may develop with rostral brainstem infarcts that include the thalamus. The amnesia involves both anterograde and retrograde memory and usually includes both verbal and nonverbal memory. Other findings Sensory and motor abnormalities are usually absent in patients with top of the basilar infarction. Movement disorders, especially hemiballism, have been described in some patients with small infarcts and hemorrhages involving the subthalamic nuclei, but hemiballism is rare in patients with well-documented "top of the basilar" infarcts. The superior portion of the cerebellum may also be infarcted, since the superior cerebellar arteries branch from the distal end of the basilar artery. Common symptoms are slight dizziness, vomiting, ipsilateral limb dysmetria, gait ataxia, and dysarthria. Vertigo is usually not prominent. Limb incoordination, intention tremor, and dysarthria are more common with superior cerebellar artery territory infarcts than with infarcts involving the territory of other cerebellar arteries. https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 17/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate POSTERIOR CEREBRAL ARTERIES Most posterior cerebral artery (PCA) territory infarcts are due to embolism from the heart, aorta, or vertebral arteries. Atherosclerosis and dissection of the PCAs is not common. Visual loss The most frequent finding in patients with PCA territory infarction is a hemianopia [1-4,42-44]. At times, the central or medial part of the field is spared, so-called macular sparing. A superior quadrant field defect results if the infarct involves just the lower bank of the calcarine fissure (the lingual gyrus). An inferior quadrantanopia results if the lesion affects the cuneus on the upper bank of the calcarine fissure. (See "Homonymous hemianopia".) When the full PCA territory is involved, visual neglect can accompany the hemianopia. However, patients are aware of the visual defect when infarcts are restricted to the striate cortex and do not extend into the adjacent parietal cortex. The visual defect is often described as a void, blackness, or a limitation of vision to one side, and patients usually recognize that they must focus extra attention to the hemianopic field. When given written material or pictures, patients with hemianopia due to occipital lobe infarction are able to see and interpret stimuli normally, although it may take somewhat longer to explore the hemianopic visual field. Clinicians can reliably map out the visual fields by confrontation in patients with occipital lobe infarcts. Optokinetic nystagmus is preserved. Some patients, although they accurately report motion or the presence of objects in their hemianopic field, cannot identify the nature, location, or color of those objects. Sensory and motor abnormalities In patients with PCA territory ischemia, lateral thalamic infarction is the major reason for somatosensory symptoms and signs [45]. Patients describe paresthesias or numbness in the face, limbs, and trunk. On examination, touch, pinprick, and position sense are reduced. The combination of hemisensory loss and hemianopia without paralysis is virtually diagnostic of infarction in the PCA territory. The occlusive lesion is within the PCA before the thalamogeniculate branches to the lateral thalamus. Rarely, occlusion of the proximal portion of the PCA causes a hemiplegia, which is probably due to infarction in the lateral midbrain [3,46- 48]. Involvement of the corticospinal and/or corticobulbar tracts in the cerebral peduncles is thought to cause hemiplegia in these cases. Left PCA territory symptoms and signs When the left PCA territory is infarcted, alexia without agraphia [49-52], anomic aphasia or transcortical sensory aphasia [53], and Gerstmann syndrome (acalculia, agraphia, finger agnosia, and right-left disorientation) may be found [3,49]. https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 18/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate Defective acquisition of new memories is common when both medial temporal lobes are damaged but also occurs in lesions limited to the left temporal lobe [3,49,54,55]. The memory deficit in patients with unilateral lesions is usually not permanent but may last up to six months. Patients cannot recall what has happened recently and, when given new information, they do not recall it moments later. They often repeat statements and questions spoken only minutes before. Some patients with left PCA territory infarction have difficulty in understanding the nature and use of objects presented visually (associative visual agnosia) [49,52]. They can trace with their fingers and copy objects, demonstrating that visual perception is preserved; they can name objects presented in their hand and explored by touch or when verbally described. Right PCA territory symptoms and signs Infarcts of the right PCA territory are often accompanied by prosopagnosia, which is difficulty in recognizing familiar faces [52,56]. Disorientation to place and an inability to recall routes or to read or visualize the location of places on maps are also common [57]. Patients with right occipitotemporal infarcts also may have difficulty visualizing what a given object or person look like. Dreams may be devoid of visual imagery. Visual neglect is much more common after lesions of the right than of the left PCA territory. SUMMARY Source of ischemia The most common causes of posterior circulation large artery ischemia are atherosclerosis, embolism, and dissection. Dolichoectasia (elongation and tortuosity) of the vertebral and basilar arteries is another occasional cause. (See 'Source of ischemia' above.) Subclavian and innominate arteries Atherostenotic lesions of these arteries cause arm ischemia and transient ischemic attacks (TIAs) but seldom cause strokes. (See 'Subclavian and innominate arteries' above.) Extracranial vertebral arteries The vast majority of occlusive lesions of the proximal vertebral arteries are atherosclerotic. The most common location of atherosclerotic occlusive disease within the posterior circulation is the proximal portion of the vertebral artery in the neck ( figure 1). In patients with proximal extracranial vertebral artery (ECVA) stenosis, intraarterial (artery-to-artery) embolism to the intracranial posterior circulation is a much more frequent cause of ischemia than hemodynamic insufficiency (ie, low flow). The most frequently reported symptom during TIAs is dizziness. Diplopia, https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 19/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate oscillopsia, bilateral leg weakness, hemiparesis, and numbness are often reported. Patients presenting with ischemia in the distribution of the intracranial vertebral arteries (the medulla and posterior inferior cerebellum) or the distal basilar artery (superior cerebellum, occipital and temporal lobes in the territory of the posterior cerebral arteries, or the thalamus or midbrain) show a high frequency of recent ECVA occlusions. Dissection of the ECVA usually involves the distal portion of the ECVA as it winds around the upper cervical vertebrae. (See 'Extracranial vertebral arteries' above.) Intracranial vertebral arteries Atherostenotic disease can involve any portion of the intracranial vertebral arteries (ICVA) ( figure 2). Occlusive ICVA disease presents in a variety of different ways (see 'Intracranial vertebral arteries' above): Asymptomatic occlusion TIAs, usually including vestibulocerebellar symptoms or elements of the lateral medullary syndrome Lateral medullary infarcts (see 'Lateral medullary infarction' above) Medial medullary infarction (see 'Medial medullary infarction' above) Infarction of one-half of the medulla including the lateral and medial medulla on one side (see 'Hemimedullary infarction' above) Cerebellar infarction in posterior inferior cerebellar artery territory (see 'Cerebellar infarction' above) Embolization of the ICVA thrombus to the distal basilar artery and its branches causing TIAs and/or strokes Propagation of the ICVA thrombus into the basilar artery causing a basilar artery syndrome Basilar artery and pontine ischemia Occlusive disease of the basilar artery most often presents as ischemia in the pons. The major burden of ischemia is in the middle of the pons, mostly in the paramedian base, and often also in the paramedian tegmentum ( picture 1). Most patients with symptomatic basilar artery occlusive disease and pontine ischemia have some transient or persistent degree of paresis and corticospinal tract abnormalities. Bulbar symptoms include facial weakness, dysphonia, dysarthria, dysphagia, and limited jaw movements. Oculomotor symptoms and signs are common. (See 'Basilar artery' above.) https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 20/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate Rostral basilar artery Occlusion of the rostral portion of the basilar artery (the "top of the basilar") can cause ischemia of the midbrain, thalami, and temporal and occipital lobe hemispheral territories supplied by the posterior cerebral artery branches of the basilar artery. Infarction in this region is typically caused by embolism from a more proximal source such as the heart, the aorta, the vertebral arteries in the neck, or the intracranial vertebral arteries. Less commonly, the syndrome is caused by intrinsic occlusive disease of the rostral portion of the basilar artery. The major abnormalities associated with rostral brainstem infarction involve alertness, behavior, memory, and oculomotor and pupillary functions. (See 'Rostral brainstem ischemia and "top of the basilar" syndrome' above.) Posterior cerebral artery territory Most posterior cerebral artery (PCA) territory infarcts are due to embolism from the heart, aorta, or vertebral arteries. Atherosclerosis and dissection of the PCAs is not common. The most frequent finding in patients with PCA territory infarction is a hemianopia. Lateral thalamic infarction is the major reason for somatosensory symptoms and signs. Additional neurologic syndromes found with infarction of the left PCA territory include alexia without agraphia, anomic aphasia or transcortical sensory aphasia, and Gerstmann syndrome (acalculia, agraphia, finger agnosia, and right-left disorientation). Syndromes observed with right PCA territory infarction include prosopagnosia, which is difficulty in recognizing familiar faces, spatial disorientation, and visual neglect. (See 'Posterior cerebral arteries' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Caplan LR, Wityk RJ, Glass TA, et al. New England Medical Center Posterior Circulation registry. Ann Neurol 2004; 56:389. 2. Savitz SI, Caplan LR. Vertebrobasilar disease. N Engl J Med 2005; 352:2618. 3. Caplan LR. Vertebrobasilar Ischemia and Hemorrhage: Clinical Findings, Diagnosis and Man agement of Posterior Circulation Disease, 2nd edition, Cambridge University Press, Cambrid ge 2015. 4. Caplan L. Posterior circulation ischemia: then, now, and tomorrow. 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Arch Neurol 1982; 39:33. https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 24/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate Topic 1102 Version 22.0 https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 25/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate GRAPHICS Anatomy of extracranial vertebral arteries Graphic 59642 Version 3.0 https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 26/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate Posterior circulation to the brain Graphic 66585 Version 3.0 https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 27/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate Medulla oblongata The usual location of lateral medullary infarcts is hatch-marked in the upper right of the figure. The anatomical structures are labeled on the diagram. Graphic 62175 Version 1.0 https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 28/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate Major cerebellar arterial branches The intracranial vertebral and basilar arteries are depicted with their major cerebellar arterial branches, including PICA (posterior inferior and cerebellar artery), AICA (anterior inferior cerebellar artery), and SCA (superior cerebellar artery). Reproduced with permission from Caplan, LR. Posterior circulation disease. Clinical ndings, diagnosis, and management. Blackwell Science, Boston 1996. Copyright 1996 Blackwell Science. Graphic 73656 Version 1.0 https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 29/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate Head impulse test At rest, the patient is asked to fixate on a distant target. The patient's head is rotated rapidly by the examiner, first to the left (A to B), then to the right (C to D). In a normal response, the eyes remain on target (B). In an abnormal response, the eyes are dragged off target (D), followed by a saccade back to the target (E). This response implies a peripheral vestibular lesion on the right. Graphic 52022 Version 5.0 https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 30/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate Myelin stain of the pons at necropsy after stroke due to basilar artery occlusive disease A large infarct (shown in white) involves the bilateral basis pontis and extends into the ventral portion of the pontine tegmentum. Reproduced with permission from: Caplan LR. Posterior circulation disease. Clinical ndings, diagnosis, and management. Blackwell Science, Boston 1996. Copyright 1996 Blackwell Science. Graphic 81264 Version 5.0 https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 31/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate Vascular supply of the pons The major penetrating arteries from the basilar artery are depicted. A) Large paired median arteries. B) Paramedian arteries lying slightly laterally. C) Arteries that branch at a right angle from the long circumferential artery (the superior cerebellar artery) into the lateral pontine tegmentum. Reproduced with permission from: Caplan LR. Posterior circulation disease. Clinical ndings, diagnosis, and management. Blackwell Science, Boston 1996. Copyright 1996 Blackwell Science. Graphic 69507 Version 3.0 https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 32/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate Collateral blood flow in a patient with a proximal basilar artery occlusion Vertebral artery angiogram, lateral view. The proximal portion of the basilar artery is occluded. Blood flow is seen in the intracranial vertebral artery (A), which gives off the posterior inferior cerebellar artery (PICA) (B), which in turn anastamoses with the superior cerebellar artery (SCA) (C). From there, blood flows over the cerebellum to fill the rostral portion of the basilar artery (D). Reproduced with permission from: Caplan LR. Posterior circulation disease. Clinical ndings, diagnosis, and management. Blackwell Science, Boston 1996. Copyright 1996 Blackwell Science. Graphic 61444 Version 4.0 https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 33/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate Ophthalmic findings in the Parinaud syndrome Vertical gaze abnormalities, especially upgaze Downward gaze preference or tonic downward deviation of the eyes ("setting-sun sign") Primary position upbeat or downbeat nystagmus Impaired convergence and divergence Excessive convergence tone Convergence-retraction nystagmus Skew deviation, often with the higher eye on the side of the lesion Alternating adduction hypertropia or alternating adduction hypotropia Bilateral upper eyelid retraction (Collier "tucked-lid" sign) Bilateral ptosis Pupillary abnormalities (large with light-near dissociation) Modi ed with permission from: Lee AG, Brazis PW. Clinical Pathways in Neuro-ophthalmology: An Evidence-based Approach, Thieme, New York 1998. Graphic 81227 Version 4.0 https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 34/35 7/5/23, 11:58 AM Posterior circulation cerebrovascular syndromes - UpToDate Contributor Disclosures Louis R Caplan, MD No relevant financial relationship(s) with ineligible companies to disclose. Jos Biller, MD, FACP, FAAN, FAHA No relevant financial relationship(s) with ineligible companies to disclose. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/posterior-circulation-cerebrovascular-syndromes/print 35/35

7/5/23, 11:59 AM Spinal cord infarction: Clinical presentation and diagnosis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Spinal cord infarction: Clinical presentation and diagnosis : Michael T Mullen, MD, Michael L McGarvey, MD : Scott E Kasner, MD, Glenn A Tung, MD, FACR : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Sep 03, 2021. INTRODUCTION Spinal cord infarction is a rare but often devastating disorder caused by a wide array of pathologic states. Patients typically present with acute paraparesis or quadriparesis, depending on the level of the spinal cord involved. The diagnosis is generally made clinically, with neuroimaging to confirm the diagnosis and exclude other conditions. This topic discusses the clinical features and diagnosis of spinal cord infarction. The vascular anatomy of the spinal cord, and the etiologies, prognosis, treatment, and chronic complications of spinal cord infarction are discussed separately. Other causes of myelopathy are also discussed separately. (See "Spinal cord infarction: Epidemiology and etiologies" and "Spinal cord infarction: Prognosis and treatment" and "Chronic complications of spinal cord injury and disease" and "Disorders affecting the spinal cord" and "Anatomy and localization of spinal cord disorders".) CLINICAL PRESENTATION Onset and precipitating factors While the onset of spinal cord infarction may be abrupt, similar to cerebral infarction, a significant proportion experience a decline over a few to several hours [1,2]. In one case series of 133 patients with spinal cord infarction, the time from symptom onset to nadir deficit was more than four hours in 44 percent of patients, and greater than 12 hours in 23 percent [3]. In this same cohort, lifting, Valsalva, or other physical activity was described at or preceding symptom onset in 25 percent of cases. Most patients (72 percent) had severe back or limb pain at symptom onset. https://www.uptodate.com/contents/spinal-cord-infarction-clinical-presentation-and-diagnosis/print 1/17 7/5/23, 11:59 AM Spinal cord infarction: Clinical presentation and diagnosis - UpToDate Neurologic syndromes The neurologic presentation of spinal cord infarction is largely defined by the vascular territory involved. The severity of the impairments can vary widely, from paraplegia to minor weakness. The involved cord level can be anywhere along the cord's length, depending in part on the underlying etiology. Back or neck pain often accompanies spinal cord ischemia, and has been reported in as many as 70 percent of patients, typically occurring at the level of the lesion [1-9]. Anterior spinal artery syndrome The most common clinical presentation of a spinal cord infarction is anterior spinal artery (ASA) syndrome [1,6,10]. Consistent with its functional neuroanatomy, an ASA infarct typically presents as loss of motor function and pain/temperature sensation, with relative sparing of proprioception and vibratory sense below the level of the lesion [11]. The acute stages are characterized by flaccidity and loss of deep tendon reflexes; spasticity and hyperreflexia develop over ensuing days and weeks. Autonomic dysfunction may be present and can manifest as hypotension (either orthostatic or frank hypotension), sexual dysfunction, and/or bowel and bladder dysfunction [5,12,13]. Chest pain with electrocardiogram (ECG) changes has been reported in a patient with C7 to T1 spinal cord infarction [14]. In the acute evaluation of patients, it is important to recognize that hypotension may be both a cause as well as a manifestation of spinal cord ischemia. If the lesion is in the rostral cervical cord, respiration is compromised. While bilateral presentations are more common, unilateral ASA deficits are frequently reported [1,3-6,15]. This occurs either because of occlusion of a unilateral sulcal artery, or because incomplete collateralization with the posterior spinal artery (PSA) maintains perfusion on one side of the cord. Very rostral ASA infarctions produce sensory loss in all modalities because of involvement of the medial lemniscus in the medulla [4]. Posterior spinal artery syndrome PSA infarction produces loss of proprioception and vibratory sense below the level of the injury and total anesthesia at the level of the injury. Weakness has been described, but is typically mild and transient. Unilateral involvement is more common, but bilateral presentations have been described ( image 1) [1]. Other presentations Atypical presentations of spinal cord infarction that do not fit a well- defined vascular distribution include Brown-Sequard syndrome, full transverse lesions similar to that found in cord transection, and central cord syndrome [1,6] (see "Anatomy and localization of spinal cord disorders"). Additionally, we have observed cases of lower extremity weakness (unilateral and bilateral) without sensory loss. The etiology for this is unknown but likely relates to incomplete collateralization from the complex network of anastomosis that make up the spinal vascular supply. Among case series, these atypical, seemingly nonvascular syndromes compose one-third of patients [6]. https://www.uptodate.com/contents/spinal-cord-infarction-clinical-presentation-and-diagnosis/print 2/17 7/5/23, 11:59 AM Spinal cord infarction: Clinical presentation and diagnosis - UpToDate Transient symptoms lasting a few minutes to several hours, so-called spinal transient ischemic attacks (TIAs), have also been described in a variety of clinical settings, but these are unusual [1,5,16,17]. Venous infarction of the spinal cord has been described, usually in association with spinal vascular malformations. These infarcts may be either hemorrhagic or nonhemorrhagic. In nonhemorrhagic venous infarcts, venous hypertension decreases the arterial-venous pressure gradient leading to decreased perfusion ( image 2). Nonhemorrhagic venous infarction typically presents with a gradual onset of progressive neurologic decline, whereas hemorrhage is associated with the sudden onset of pain and flaccid paraparesis [12]. (See "Disorders affecting the spinal cord", section on 'Vascular malformations'.) DIFFERENTIAL DIAGNOSIS While there are many potential causes of myelopathy, only a few are characterized by an abrupt symptom onset. (See "Disorders affecting the spinal cord".) Compressive myelopathy from neoplasm, epidural or subdural hematoma, or abscess are important diagnostic considerations and typically mandate urgent neuroimaging to identify findings that may require urgent surgical decompression. While these lesions typically develop over time, the clinical presentation can be fairly abrupt and mimic spinal cord infarction. (See "Disorders affecting the spinal cord", section on 'Neoplasms' and "Clinical features and diagnosis of neoplastic epidural spinal cord compression" and "Spinal epidural abscess".) Transverse myelitis is more typically associated with an evolution of myelopathic symptoms over hours and days, but these can develop in as short a period as 10 minutes [18,19]. A history of recent vaccination or viral illness may suggest this diagnosis, but these are often absent. Symptoms isolated to the anterior spinal artery (ASA) territory suggest infarction over inflammation, but this is not definitive. Other diagnostic studies (lumbar puncture, brain imaging) may be required. Because individual clinical and diagnostic features are not sensitive or specific for either diagnosis, clinicians must consider the preponderance of the evidence when determining the more likely diagnosis. Clinical and diagnostic features that favor transverse myelitis over infarction include progression of symptoms over at least a few hours, symptoms and magnetic resonance imaging (MRI) lesions that extend beyond a vascular territory, gadolinium enhancement, and cerebrospinal fluid (CSF) findings of pleocytosis or elevated immunoglobulin G (IgG) levels [20]. (See "Disorders affecting the spinal cord", section on 'Transverse myelitis'.) https://www.uptodate.com/contents/spinal-cord-infarction-clinical-presentation-and-diagnosis/print 3/17 7/5/23, 11:59 AM Spinal cord infarction: Clinical presentation and diagnosis - UpToDate Acute polyneuropathy (eg, Guillain-Barr syndrome [GBS]) can be confused with acute myelopathy because both are associated with flaccidity and loss of reflexes in the acute stage [21] (see 'Clinical presentation' above). Contributing to potential diagnostic confusion is that back pain is a common feature in both GBS and acute spinal cord infarction. A history of ascending symptoms over time suggests GBS, while a sensory level and impaired bladder function suggest spinal cord infarction. In some cases, differentiating these diagnoses requires diagnostic tests (MRI, electromyography) and the passage of time to allow upper motor neuron signs to emerge. (See "Guillain-Barr syndrome in adults: Pathogenesis, clinical features, and diagnosis".) Epidural hematoma is an important cause of acute paraplegia in the postoperative setting, especially if the patient has had either a lumbar drain or epidural anesthesia. Although epidural hematoma usually has a more subacute presentation with evolution over time, this presentation may be obscured in the perioperative period [22]. Aortic dissection or rupture may cause paraplegia from impaired perfusion of the brain and lower extremities, as well as from spinal ischemia. It is also possible for all these mechanisms to occur simultaneously. DIAGNOSIS The diagnosis of spinal cord infarction is made in the setting of a compatible clinical syndrome: rapidly developing myelopathic deficits in the absence of another identifiable etiology by history, examination, magnetic resonance imaging (MRI), or other testing (when indicated) [3]. Spinal MRI MRI is required in the diagnosis of spinal cord infarction. Perhaps its most important role is to rule out the alternative diagnosis of compressive myelopathy. MRI can also provide confirmatory evidence of spinal cord infarction and may provide information as to the underlying etiology. In most cases, this test should be performed urgently, although it may be deferred if the patient requires urgent aortic surgery or another life-saving intervention. MRI changes associated with spinal cord ischemia include hyperintensities on T2-weighted and short-tau inversion recovery images( image 3 and image 1 and image 2 and image 4). The sensitivity of standard MRI is limited, particularly in the first several hours. The percentage of patients with T2 changes on MRI scan in published reports ranges from 45 to 73 percent depending in part on the scan's timing [1,3,5,6,12,23,24]. If clinical suspicion is high and the initial MRI is normal, follow-up imaging should be obtained. However, a significant minority of patients (14 percent in one series) will also have normal follow-up MRI scans [7,24]. A finding of restricted diffusion on diffusion-weighted images (DWI-MRI) appears to be significantly more https://www.uptodate.com/contents/spinal-cord-infarction-clinical-presentation-and-diagnosis/print 4/17 7/5/23, 11:59 AM Spinal cord infarction: Clinical presentation and diagnosis - UpToDate sensitive than standard T2 images ( image 5) [25-29]. While the limited number of case reports precludes a definitive estimate of its sensitivity, in one series of 19 patients with spinal cord infarction, restricted diffusion was found in all patients [29]. A finding of T2 signal abnormality, even with restricted diffusion, is not specific for ischemia and can be seen in transverse myelitis and other intrinsic cord pathologies. The finding of T2- hyperintense signal restricted to a spinal vascular territory or the ventral horns ("owl's eyes" or "snake eyes" sign) is more specific for spinal cord infarction ( image 1 and image 2 and image 4). A finding of vertebral body infarction adjacent to a cord signal abnormality on MRI is a specific indicator of ischemia and a useful confirmatory sign if present [30]. However, this is found in only 4 to 35 percent of patients, and its absence does not exclude spinal cord infarction [1,3,6,8]. MRI may also help define the underlying etiology: Intervertebral disc disease at the level of infarction may suggest possible fibrocartilaginous embolism. Spondylotic disease may suggest a possible bony compression mechanism, particularly if the onset of symptoms is associated with activity involving twisting or torquing of the spine [8]. Spinal cord vascular malformations also have distinct patterns of abnormalities that may be seen on MRI [31]. (See "Disorders affecting the spinal cord", section on 'Vascular malformations'.) In one case series, vertebral body infarction was highly associated with aortic disease pathology [8]. Other tests Further testing is not always necessary. As an example, in the setting of paraplegia after aortic surgery, a patient with typical spine MRI findings will likely not require further testing. However, depending on the clinical presentation, other tests should be ordered to further exclude alternative diagnoses (see 'Differential diagnosis' above) and to identify an underlying etiology ( table 1). Aortic dissection can be identified by multiplane transesophageal echocardiography (TEE), chest computed tomography (CT), and MRI. Descending aortic dissection is a known cause of spinal cord infarction; it can lead to morbidity if unrecognized. Therefore, this should be considered and specifically excluded in all at-risk patients including those who present with prominent pain, abnormal distal pulses, known aortic aneurysm, and/or an underlying collagen disorder (Marfan syndrome). A low threshold for this diagnosis should also include https://www.uptodate.com/contents/spinal-cord-infarction-clinical-presentation-and-diagnosis/print 5/17 7/5/23, 11:59 AM Spinal cord infarction: Clinical presentation and diagnosis - UpToDate older adults with vascular risk factors in whom the underlying cause of spinal cord infarction is not immediately known. In patients with hemodynamic instability, this evaluation will take priority over spine imaging. (See "Clinical features and diagnosis of acute aortic dissection".) Vascular imaging, either CT angiography or magnetic resonance angiography, should be performed to exclude a vertebral artery dissection in a patient with a rostral cervical cord infarction. A gadolinium-enhanced MRI of the brain may be helpful to exclude multiple sclerosis if the clinical presentation is consistent with transverse myelitis. Echocardiography can be performed to look for a source of embolism. A lumbar puncture and cerebrospinal fluid (CSF) analysis should be performed in younger patients to look for signs of infection or inflammatory diseases. CSF testing should include cell count, protein, glucose, Gram stain and culture, cytology/flow cytometry, oligoclonal bands, as well as tests for syphilis, Lyme, herpes, varicella, and cytomegalovirus. Serum tests for syphilis, Lyme, HIV, enterovirus, coxsackie A and B, adenovirus, and Epstein-Barr virus may be of value. CSF analysis in spinal cord infarction is typically normal, but there can be pleocytosis (rarely more than 100 white blood cell count [WBC]) and an elevated protein (usually less than 119 mg/dL) [3-5,7,24]. Blood tests to evaluate a possible hypercoagulable condition should be performed when the cause of spinal cord infarction is obscure, particularly in younger patients and those without vascular risk factors. Urine or blood toxicology screen should exclude cocaine and other drugs of abuse. Rheumatologic tests are likely of low yield if there are no other suggestive clinical features, but these tests (sedimentation rate, antinuclear antibody, antineutrophil cytoplasmic antibodies, and SSA/B antibodies) could be considered. Initial vascular imaging with contrast-enhanced MR- or CT-angiography should be performed when there is either clinical concern for a vascular malformation, dural arteriovenous fistula, or suspicious findings on MRI (eg, evidence of venous infarction or enlarged venous collateral vessels surrounding a cord with abnormal T2- or STIR- hyperintense signal) ( image 2). Digital subtraction angiography (DSA) is performed with abnormal noninvasive vascular imaging to further characterize lesions. In addition, DSA is performed in patients with https://www.uptodate.com/contents/spinal-cord-infarction-clinical-presentation-and-diagnosis/print 6/17 7/5/23, 11:59 AM Spinal cord infarction: Clinical presentation and diagnosis - UpToDate normal noninvasive vascular imaging when clinical suspicion for a vascular malformation is high. (See "Disorders affecting the spinal cord", section on 'Vascular malformations'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) SUMMARY AND RECOMMENDATIONS Spinal cord infarction is a rare condition caused by a wide array of pathologic conditions. Clinical presentation Most patients with spinal cord infarction present with acute neurologic deficits attributable to the anterior spinal artery (ASA) territory. However, one- third of patients may have less typical presentations including posterior spinal artery (PSA), central cord, and complete cord transection syndromes. (See 'Clinical presentation' above.) Differential diagnosis Acute spinal cord infarction must be distinguished from lesions compressing the spinal cord. Transverse myelitis and acute demyelinating polyneuropathy are other important diagnostic considerations, depending on the clinical setting. (See 'Differential diagnosis' above.) Diagnosis The diagnosis of spinal cord infarction is made in the setting of a compatible clinical syndrome: rapidly developing myelopathic deficits in the absence of another identifiable etiology by history, examination, magnetic resonance imaging (MRI), or other testing. (See 'Diagnosis' above.) MRI of the spine is performed to exclude a compressive myelopathy, as well as to provide evidence supporting the diagnosis of infarction. Spine MRI findings have imperfect sensitivity and specificity for ischemia. However, diffusion-weighted images (DWI-MRI) improve the sensitivity of MRI to detect acute spinal ischemia. (See 'Spinal MRI' above.) Additional testing Other tests are used to further exclude alternative diagnoses and to identify an underlying etiology ( table 1). The choice of tests is tailored to the clinical situation and may include echocardiography, brain imaging, vascular imaging, and laboratory tests to identify for a hypercoagulable condition. (See 'Other tests' above.) https://www.uptodate.com/contents/spinal-cord-infarction-clinical-presentation-and-diagnosis/print 7/17 7/5/23, 11:59 AM Spinal cord infarction: Clinical presentation and diagnosis - UpToDate Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Novy J, Carruzzo A, Maeder P, Bogousslavsky J. Spinal cord ischemia: clinical and imaging patterns, pathogenesis, and outcomes in 27 patients. Arch Neurol 2006; 63:1113. 2. Cheng MY, Lyu RK, Chang YJ, et al. Spinal cord infarction in Chinese patients. Clinical features, risk factors, imaging and prognosis. Cerebrovasc Dis 2008; 26:502. 3. Zalewski NL, Rabinstein AA, Krecke KN, et al. Characteristics of Spontaneous Spinal Cord Infarction and Proposed Diagnostic Criteria. JAMA Neurol 2019; 76:56. 4. Sandson TA, Friedman JH. Spinal cord infarction. Report of 8 cases and review of the literature. Medicine (Baltimore) 1989; 68:282. 5. Cheshire WP, Santos CC, Massey EW, Howard JF Jr. Spinal cord infarction: etiology and outcome. Neurology 1996; 47:321. 6. Nedeltchev K, Loher TJ, Stepper F, et al. Long-term outcome of acute spinal cord ischemia syndrome. Stroke 2004; 35:560. 7. Masson C, Pruvo JP, Meder JF, et al. Spinal cord infarction: clinical and magnetic resonance imaging findings and short term outcome. J Neurol Neurosurg Psychiatry 2004; 75:1431. 8. Cheng MY, Lyu RK, Chang YJ, et al. Concomitant spinal cord and vertebral body infarction is highly associated with aortic pathology: a clinical and magnetic resonance imaging study. J Neurol 2009; 256:1418. 9. Hsu CY, Cheng CY, Lee JD, et al. Clinical features and outcomes of spinal cord infarction following vertebral artery dissection: a systematic review of the literature. Neurol Res 2013; 35:676. 10. Weidauer S, Nichtweiss M, Lanfermann H, Zanella FE. Spinal cord infarction: MR imaging and clinical features in 16 cases. Neuroradiology 2002; 44:851. 11. Foo D, Rossier AB. Anterior spinal artery syndrome and its natural history. Paraplegia 1983; 21:1. 12. Mohr JP, Benavente O, Barnett HJ. Spinal Cord Ischemia. In: Stroke Pathophysiology, Diagno sis, and Management, Barnett HJ, Mohr JP, Stein BM, Yatsu FM (Eds), Churchill Livingstone, P hiladelphia 1998. p.423. 13. Cheung AT, Weiss SJ, McGarvey ML, et al. Interventions for reversing delayed-onset postoperative paraplegia after thoracic aortic reconstruction. Ann Thorac Surg 2002; 74:413. 14. Nakae Y, Johkura K, Kudo Y, Kuroiwa Y. Spinal cord infarction with cervical angina. J Neurol Sci 2013; 324:195. https://www.uptodate.com/contents/spinal-cord-infarction-clinical-presentation-and-diagnosis/print 8/17 7/5/23, 11:59 AM Spinal cord infarction: Clinical presentation and diagnosis - UpToDate 15. STEEGMANN AT. Syndrome of the anterior spinal artery. Neurology 1952; 2:15. 16. Hussain MS, Shuaib A, Siddiqi ZA. Spinal cord transient ischemic attacks: a possible role for abciximab. Neurology 2005; 64:761. 17. English SW, Rabinstein AA, Flanagan EP, Zalewski NL. Spinal cord transient ischemic attack: Insights from a series of spontaneous spinal cord infarction. Neurol Clin Pract 2020; 10:480. 18. Transverse Myelitis Consortium Working Group. Proposed diagnostic criteria and nosology of acute transverse myelitis. Neurology 2002; 59:499. 19. Wilmshurst JM, Walker MC, Pohl KR. Rapid onset transverse myelitis in adolescence: implications for pathogenesis and prognosis. Arch Dis Child 1999; 80:137. 20. Nance JR, Golomb MR. Ischemic spinal cord infarction in children without vertebral fracture. Pediatr Neurol 2007; 36:209. 21. Hui AC, Wong KS, Fu M, Kay R. Ischaemic myelopathy presenting as Guillain-Barr syndrome. Int J Clin Pract 2000; 54:340. 22. SreeHarsha CK, Rajasekaran S, Dhanasekararaja P. Spontaneous complete recovery of paraplegia caused by epidural hematoma complicating epidural anesthesia: a case report and review of literature. Spinal Cord 2006; 44:514. 23. Salvador de la Barrera S, Barca-Buyo A, Montoto-Marqu s A, et al. Spinal cord infarction: prognosis and recovery in a series of 36 patients. Spinal Cord 2001; 39:520. 24. Robertson CE, Brown RD Jr, Wijdicks EF, Rabinstein AA. Recovery after spinal cord infarcts: long-term outcome in 115 patients. Neurology 2012; 78:114. 25. Thurnher MM, Bammer R. Diffusion-weighted MR imaging (DWI) in spinal cord ischemia. Neuroradiology 2006; 48:795. 26. Beslow LA, Ichord RN, Zimmerman RA, et al. Role of diffusion MRI in diagnosis of spinal cord infarction in children. Neuropediatrics 2008; 39:188. 27. K ker W, Weller M, Klose U, et al. Diffusion-weighted MRI of spinal cord infarction high resolution imaging and time course of diffusion abnormality. J Neurol 2004; 251:818. 28. Shinoyama M, Takahashi T, Shimizu H, et al. Spinal cord infarction demonstrated by diffusion-weighted magnetic resonance imaging. J Clin Neurosci 2005; 12:466. 29. Nogueira RG, Ferreira R, Grant PE, et al. Restricted diffusion in spinal cord infarction demonstrated by magnetic resonance line scan diffusion imaging. Stroke 2012; 43:532. 30. Faig J, Busse O, Salbeck R. Vertebral body infarction as a confirmatory sign of spinal cord ischemic stroke: report of three cases and review of the literature. Stroke 1998; 29:239. 31. Hurst RW. Spinal vascular disorders. In: Resonance Imaging of the Brain and Spine, 2nd ed, https://www.uptodate.com/contents/spinal-cord-infarction-clinical-presentation-and-diagnosis/print 9/17 7/5/23, 11:59 AM Spinal cord infarction: Clinical presentation and diagnosis - UpToDate Atlas SW (Ed), Lippincott, Philadelphia 2006. p.1387. Topic 1117 Version 17.0 https://www.uptodate.com/contents/spinal-cord-infarction-clinical-presentation-and-diagnosis/print 10/17 7/5/23, 11:59 AM Spinal cord infarction: Clinical presentation and diagnosis - UpToDate GRAPHICS Spinal cord infarction in the distribution of the posterior spinal artery Sagittal T2-weighted MRI image (A) shows hyperintensity in dorsal thoracic spinal cord (arrow). Axial turbo spin-echo T2-weighted MRI images (B, C) show hyperintensities consistent with infarction in the distribution of the posterior spinal arteries (arrowheads). Courtesy of Glenn A Tung, MD. Graphic 132591 Version 1.0 https://www.uptodate.com/contents/spinal-cord-infarction-clinical-presentation-and-diagnosis/print 11/17 7/5/23, 11:59 AM Spinal cord infarction: Clinical presentation and diagnosis - UpToDate Venous infarction of the spinal cord from a spinal AVF Sagittal T2-weighted MRI image (A) shows hyperintensity in the lower half of the thoracic spinal cord (arrows). Axial turbo spin-echo T2-weighted MRI images (B, C, D) shows hyperintensity in greater than half of the spinal cord in a pattern atypical for arterial infarction (smaller arrowhead) as well as linear hypodensities in the subarachnoid space consistent with small vessels (short arrows). Spinal angiogram (E) shows catheter (thick arrow), spinal dural AVF (dashed arrow), and dilated intradural veins (larger arrowheads). AVF: arteriovenous fistula; MRI: magnetic resonance imaging. Courtesy of Glenn A Tung, MD. Graphic 132592 Version 1.0 https://www.uptodate.com/contents/spinal-cord-infarction-clinical-presentation-and-diagnosis/print 12/17 7/5/23, 11:59 AM Spinal cord infarction: Clinical presentation and diagnosis - UpToDate MRI findings in spinal cord ischemia Magnetic resonance images (MRI) of the thoracolumbar spine demonstrating spinal cord infarction in a patient with paraplegia after thoracoabdominal aneurysm repair. T2 weighted sagittal imaging through the center of the spinal cord (left panel) showed central infarction extending from the high thoracic level into the lumbar segments. T2 weighted axial images of the spinal cord at the thoracic level demonstrated central infraction (right panel). Courtesy of Michael L McGarvy, MD and Michael Mullen, MD. Graphic 72280 Version 4.0 https://www.uptodate.com/contents/spinal-cord-infarction-clinical-presentation-and-diagnosis/print 13/17 7/5/23, 11:59 AM Spinal cord infarction: Clinical presentation and diagnosis - UpToDate Spinal cord infarction in the distribution of the anterior spinal artery Sagittal STIR MRI image (A) shows hyperintensity in lower cervical and upper thoracic cord (arrows). Axial turbo spin-echo T2-weighted images (B, C) show hyperintensities in the ventral horns of the central gray matter ("owl's eyes sign") consistent with acute cervicothoracic cord infarction (arrowheads). STIR: short tau inversion recovery; MRI: magnetic resonance imaging. Courtesy of Glenn A Tung, MD. Graphic 132593 Version 1.0 https://www.uptodate.com/contents/spinal-cord-infarction-clinical-presentation-and-diagnosis/print 14/17 7/5/23, 11:59 AM Spinal cord infarction: Clinical presentation and diagnosis - UpToDate MRI sequences showing acute spinal cord infarction Sagittal MRI images showing contrast enhancement (arrow) on post-contrast T1-weighted image (A) and reduced diffusivity (arrowheads) on DWI image (B) and ADC map image (C). MRI: magnetic resonance imaging; DWI: diffusion-weighted imaging; ADC: apparent diffusion coefficient. Courtesy of Glenn A Tung, MD. Graphic 132595 Version 1.0 https://www.uptodate.com/contents/spinal-cord-infarction-clinical-presentation-and-diagnosis/print 15/17 7/5/23, 11:59 AM Spinal cord infarction: Clinical presentation and diagnosis - UpToDate Causes of spinal cord infarction Aorta disease, procedures Infection Aortic surgery Bacterial meningitis Thoracic endovascular aortic repair (TEVAR) Syphilis Aortic dissection Mucormycosis Traumatic rupture of the aorta Hematologic disease Aortic thrombosis Hypercoagulable conditions Aortic aneurysm Sickle cell anemia Coarctation of the aorta Non-aortic surgeries Aortography Spine disease Systemic hypoperfusion Spine surgery Cardiac arrest Cervical spondylosis Systemic bleeding Fibrocartilaginous embolism Cardiogenic embolism Epidural steroid injections Atrial myxoma Miscellaneous Mitral valve disease Cocaine abuse Patent foramen ovale Vertebral artery dissection Bacterial endocarditis Spinal vascular malformation Cardiac catheterization Decompression sickness Vasculitis Systemic lupus erythematosus Polyarteritis nodosa Behcet syndrome Giant cell arteritis Graphic 57862 Version 7.0 https://www.uptodate.com/contents/spinal-cord-infarction-clinical-presentation-and-diagnosis/print 16/17 7/5/23, 11:59 AM Spinal cord infarction: Clinical presentation and diagnosis - UpToDate Contributor Disclosures Michael T Mullen, MD Grant/Research/Clinical Trial Support: NINDS [Asymptomatic carotid disease]. All of the relevant financial relationships listed have been mitigated. Michael L McGarvey, MD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Glenn A Tung, MD, FACR No relevant financial relationship(s) with ineligible companies to disclose. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/spinal-cord-infarction-clinical-presentation-and-diagnosis/print 17/17

7/5/23, 11:59 AM Spinal cord infarction: Epidemiology and etiologies - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Spinal cord infarction: Epidemiology and etiologies : Michael T Mullen, MD, Michael L McGarvey, MD : Scott E Kasner, MD : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Oct 06, 2021. INTRODUCTION Spinal cord infarction is a rare but often devastating disorder caused by a wide array of pathologic states. Patients typically present with acute paraparesis or quadriparesis, depending on the level of the spinal cord involved. The diagnosis is generally made clinically, with neuroimaging to confirm the diagnosis and exclude other conditions. This topic discusses the vascular anatomy of the spinal cord as well as the epidemiology and causes of spinal cord infarction. The clinical features, diagnosis, prognosis, treatment, and chronic complications of spinal cord infarction are discussed separately. Other causes of myelopathy are also discussed separately. (See "Spinal cord infarction: Clinical presentation and diagnosis" and "Spinal cord infarction: Prognosis and treatment" and "Chronic complications of spinal cord injury and disease" and "Disorders affecting the spinal cord" and "Anatomy and localization of spinal cord disorders".) EPIDEMIOLOGY The incidence of spinal cord infarction has not been specifically reported. It has been estimated that spinal cord infarction accounts for approximately 1 percent of all strokes [1,2]. Extrapolating from estimates of total stroke incidence in the United States, which range from 540,000 to 780,000 per year, it is expected that 5000 to 8000 cases of spontaneous spinal cord infarction occur per year [3,4]. This may be an underestimate, as these figures likely do not include spinal https://www.uptodate.com/contents/spinal-cord-infarction-epidemiology-and-etiologies/print 1/16 7/5/23, 11:59 AM Spinal cord infarction: Epidemiology and etiologies - UpToDate cord infarction complicating major surgery, which is the most common cause of spinal cord infarction. Spinal cord infarction typically occurs in adults; this is expected, as it is usually a direct or indirect complication of atherosclerotic vascular disease; in one series, the mean age was 64 years [5]. However, children, even neonates, can develop spinal cord infarction in specific circumstances [6]. (See 'Etiologies' below.) VASCULAR ANATOMY Three major vessels arising from the vertebral arteries in the neck supply the spinal cord ( figure 1) [7]. There is one anterior spinal artery (ASA) and a pair of posterior spinal arteries (PSAs). The ASA supplies the anterior two-thirds of the spinal cord. The ASA and PSAs anastomose distally at the conus medullaris [8]. Anterior spinal artery The ASA arises from the vertebral arteries at the level of the foramen magnum. It runs along the center of the anterior aspect of the spinal cord in the anterior median sulcus from the foramen magnum to the conus medullaris, making it the longest artery in the body [8]. Although it is typically continuous throughout its course, the diameter of the ASA varies considerably throughout its length [9]. It is smallest in the thoracic segment and largest in the lumbosacral region [10]. Along its course, the ASA is augmented by radicular arteries. These small arteries enter the spinal canal through the intervertebral foramen and supply blood to the emerging nerve roots. They originate from the vertebral arteries, intercostal arteries, or in rare instances, directly from the aorta. Typically, just 6 to 10 of the 31 pairs of radicular arteries (one pair at each spinal level) contribute to the ASA [11]. These arteries usually enter the spinal canal from the left neural foramen, but may be bilateral, particularly in the cervical spine. The thoracic spinal cord is particularly dependent on radicular contributions and may be the most vulnerable to infarction [10,11]. The most prominent thoracic radicular artery is the artery of Adamkiewicz, also known as the artery of the lumbar enlargement. The artery of Adamkiewicz contributes to the ASA between the T9 to T12 level in 75 percent of individuals, but may be found above and below this level [8]. From the ASA, sulcal arteries run into the center of the cord and then branch to the right or the left to supply the deep structures of the spinal cord. The ASA also contributes to a peripheral arterial plexus, which gives off radial branches to supply the periphery of the cord. The ASA supplies blood to the anterior horns of the gray matter, spinothalamic tracts, and corticospinal tracts. https://www.uptodate.com/contents/spinal-cord-infarction-epidemiology-and-etiologies/print 2/16 7/5/23, 11:59 AM Spinal cord infarction: Epidemiology and etiologies - UpToDate Posterior spinal artery The PSAs originate from the vertebral arteries and travel the length of the cord in the posterior lateral sulci bilaterally. The PSAs vary greatly in diameter throughout their course and may even be discontinuous. The PSAs are supported by a greater number of radicular arteries than the ASA, commonly between 10 and 23 [11]. These radicular arteries typically originate from the left but are more frequently bilateral than those contributing to the ASA. The PSAs frequently anastomose with each other and are heavily connected to the peripheral and posterolateral plexuses [8,10]. The PSAs supply the dorsal columns and the posterior horns [10]. Venous system Two major spinal veins, one anterior and one posterior, drain into a series of radicular veins, then into intravertebral and paravertebral plexuses, and finally into the azygous and pelvic venous systems [12]. Because spinal veins contain no valves, Valsalva and increased intra-abdominal pressure can lead to increased venous pressure and decreased spinal cord perfusion [10]. Factors that modulate blood flow As in the brain, spinal blood flow is influenced by metabolic demand and responds to both hypoxia and hypercapnia with increased blood flow [12]. Metabolic demand and blood flow is highest in the gray matter, which is most abundant in the cervical and lumbar enlargements [13,14]. Blood flow to the spinal cord is also influenced by perfusion pressure, which is the difference between mean arterial and intraspinal canal pressure. Through autoregulation, spinal blood flow is maintained at a constant level over a range of mean arterial pressures. However, there are lower and upper limits of systemic blood pressure beyond which autoregulation fails [13,15]. As a result, systemic hypotension or increased intraspinal canal pressure may decrease perfusion and put the cord at risk. Because the spinal cord exists in a fixed space, intraspinal canal pressure is sensitive to changes in the contents of the spinal canal and may rise significantly in pathologic states. ETIOLOGIES A broad spectrum of diseases can cause spinal cord infarction ( table 1) [10]. The mechanisms underlying these can be broadly categorized: Diseases or procedures involving the thoracoabdominal aorta Intrinsic arterial occlusion resulting from arteriosclerosis, vasculitis, infection, embolic occlusion, thrombosis Hypoperfusion Venous infarction https://www.uptodate.com/contents/spinal-cord-infarction-epidemiology-and-etiologies/print 3/16 7/5/23, 11:59 AM Spinal cord infarction: Epidemiology and etiologies - UpToDate Aortic surgery Surgery to repair thoracic and thoracoabdominal aortic aneurysms is the most common cause of spinal cord infarction [1,5,10,12,16-18]. Rates of spinal cord ischemia following thoracic aortic surgery have been reported to be as high as 29 percent, but are more usually reported as 10 to 11 percent [19]. Both open surgery and endovascular repair are associated with spinal cord ischemia. Risks may be lower with an endovascular approach, but data are conflicting and selection bias of patients may play a role in this finding [20-23]. Spinal cord ischemia after thoracic aortic surgery may be clinically apparent immediately after surgery, or after a period of normal neurologic functioning [24]. Delayed spinal cord ischemia has been reported as late as 27 days after surgical repair [25]. Many factors may play a role in this complication. These include systemic hypotension, before, during, or after the procedure; aortic cross-clamping causing decreased arterial perfusion and increased spinal canal pressure; and occlusion of important feeding arteries such as the artery of Adamkiewicz or other intercostal arteries either by ligation, resection, or embolization. Episodes of systemic hypotension in many cases appear to be temporally associated with delayed onset of ischemia [24,25]. Risk factors for spinal cord ischemia following aneurysm repair have been reported to include advanced age, aortic rupture, history of cerebrovascular disease, prior aortic surgery, more extensive aortic disease (eg, Crawford II/III repairs), postoperative bleeding, long cross-clamp duration, intraoperative hypotension, sacrifice of intercostal vessels, renal insufficiency, and atrial fibrillation [19,25-27]. Efforts to reduce the risk of spinal cord ischemia have included placement of lumbar drains, reimplantation of intercostal arteries, intraoperative neurophysiologic monitoring, epidural cooling, use of distal aortic perfusion, and arterial blood pressure augmentation [16,19,24,26- 30]. While these interventions appear to improve outcomes, these have not been studied in a randomized or carefully controlled fashion. Aortic dissection Acute dissection of the descending aorta is often a catastrophic event and is associated with a high mortality (10 to 50 percent). Survivors of the acute event often contend with complications resulting from acute occlusion of branch vessels that include celiac, superior mesenteric, and renal arteries, as well as radicular arterial supply to the spinal cord. The incidence of spinal cord infarction with aortic dissection is reported to be 4 percent; spinal cord ischemia as the presenting symptom of aortic dissection is more unusual, but has been described in a number of cases [31-35]. Typically, spinal cord infarction in this setting involves the mid and lower thoracic cord levels. Severe "tearing" pain and abnormal distal pulses suggest this diagnosis [32,36]. However, 5 to 15 https://www.uptodate.com/contents/spinal-cord-infarction-epidemiology-and-etiologies/print 4/16 7/5/23, 11:59 AM Spinal cord infarction: Epidemiology and etiologies - UpToDate percent of acute aortic dissections are painless, requiring a high degree of suspicion for this diagnosis [33,34,37]. Chronic hypertension, underlying atherosclerotic vascular disease, and Marfan syndrome are among the risk factors for aortic dissection [38]. (See "Clinical features and diagnosis of acute aortic dissection".) Other aortic pathologies Spinal cord infarction can complicate traumatic aortic rupture [12]. Other pathologies involving the descending aorta, such as aneurysm formation and thrombosis, have also been presumed to be causative in some patients with acute spinal cord infarction [12,17,39-41]. Coarctation of the aorta and its corrective surgery is a less common cause of spinal cord infarction [42]. Spinal cord infarction can also complicate aortography [43]. Nonaortic surgeries A number of other surgical procedures are associated with spinal cord ischemia. Of these, spine surgery is the most common; however, bowel resection, hepatectomy, caesarean section, hip and prostate surgery, and many other open procedures have also been associated with spinal cord infarction [5,10,12,17,44-46]. Spinal cord infarction has also been reported after endovascular procedures including percutaneous coronary intervention, neurointerventional procedures, and others [47-51]. Surgical injury to a radicular feeding artery probably plays a role in many of these cases. Others have wondered about the role of epidural anesthesia possibly causing direct injury to an artery or inducing vasospasm in some cases [39,45]. In some patients, intra- or perioperative hypotension appeared to be contributory. Others have noted that many patients with perioperative spinal cord infarction have underlying aortic disease and/or prior aortic surgery, perhaps increasing their susceptibility to this complication. Fibrocartilaginous embolism Fibrocartilaginous embolism (FCE) is a rare phenomenon that can cause spinal cord infarction. FCE originates from herniated intervertebral discs. A temporal relationship to minor head or neck injury or heavy lifting is a clue to this etiology, but is not always present. A broad age range of patients (7 to 78 years) can be affected by this phenomenon [52-56]. Most cases involve the cervical cord; some involve the lower medulla or upper thoracic cord. Neck pain typically precedes neurologic symptoms by 15 minutes to 48 hours [54,56-59]. Magnetic resonance imaging (MRI) may show a collapsed intervertebral disc at the appropriate level. Because the upper cervical cord is involved, case fatality rates appear to be relatively high. The pathogenesis of this phenomenon is uncertain. It is hypothesized that axial loading forces on the spinal column produce a high intradisc pressure causing the injection of semifluid disc material into the disc vasculature and/or to the bone marrow and venous sinuses of the vertebral bodies [56]. This material may then spread retrograde to involve blood vessels https://www.uptodate.com/contents/spinal-cord-infarction-epidemiology-and-etiologies/print 5/16 7/5/23, 11:59 AM Spinal cord infarction: Epidemiology and etiologies - UpToDate supplying the spinal cord. Autopsy has shown fibrocartilaginous material occluding local arteries and/or veins in some cases; however, autopsy is rarely performed, and it has also been postulated that spinal hyperextension can cause vascular compression and spinal infarction without FCE [56,60-62]. Systemic hypotension The spinal cord is vulnerable to ischemic injury during episodes of systemic hypotension (eg, cardiopulmonary arrest, systemic bleeding, etc). One autopsy series found evidence of ischemic myelopathy in 46 percent of adults who died after a cardiac arrest or severe hypotensive episode [63]. The predominant level of involvement was the lumbosacral cord. This phenomenon is also described in neonates, particularly premature neonates, after episodes of hypotension in the perinatal period [64]. Among survivors, ischemic myelopathy can be obscured by hypoxic-ischemic encephalopathy; however, in a number of cases, spinal cord infarction is the principal complication [12,39,65]. Vascular malformation The most common presentation of a spinal vascular malformation is that of a progressive, step-wise myelopathy. However, some patients may have a more abrupt or stroke-like presentation [12,66]. (See "Disorders affecting the spinal cord", section on 'Vascular malformations'.) Other causes Among case series, between 44 to 74 percent of patients with spinal cord infarction do not have an identified etiology [1,5,6,17,39,40,67-71]. In many of these cases, atherosclerotic risk factors are prevalent, and atherothrombotic disease is presumed to be responsible for at least some of these cases. However, this pathology has not been specifically described. Moreover, a small percentage of patients in many series includes patients with no identifiable etiology and no vascular risk factors [39,40]. Other causes of spinal cord infarction are numerous ( table 1) [10]. A few of the more common of these rare conditions include: Vasculitis resulting from bacterial or syphilitic infection, systemic lupus erythematosus, polyarteritis nodosa, and giant cell arteritis, which can be a cause of spinal cord infarction [1,12,67,68,72,73]. Vertebral artery atheroma and dissection, which has been associated with rostral cervical cord infarction [17,40,74,75]. Both inherited and acquired hypercoagulable conditions as well as sickle cell disease, which appear to underlie some cases of spinal cord infarction [12,76-81]. Cervical spondylosis, which has been postulated to be a cause of spinal cord infarction, perhaps by causing dissection or compression of a radicular artery [12,39,82]. https://www.uptodate.com/contents/spinal-cord-infarction-epidemiology-and-etiologies/print 6/16 7/5/23, 11:59 AM Spinal cord infarction: Epidemiology and etiologies - UpToDate Umbilical artery catheters used in newborns, which can rarely cause occlusion of the artery of Adamkiewicz, resulting in spinal cord infarction [83,84]. Cocaine-related arteriopathy, which has been thought to cause spinal cord infarction in a few patients [17]. Emboli from a variety of cardiogenic sources (artificial valves, vegetations), which have also been implicated as the cause of spinal cord infarction in a number of cases [17,39,67,85- 87]. Decompression sickness myelopathy, which may have a vascular pathogenesis. (See "Disorders affecting the spinal cord", section on 'Decompression sickness myelopathy'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) SUMMARY Epidemiology Spinal cord infarction is a rare condition caused by a wide array of pathologic conditions ( table 1). (See 'Epidemiology' above.) Vascular anatomy Three major vessels arising from the vertebral arteries in the neck supply the spinal cord ( figure 1). There is one anterior spinal artery (ASA) and a pair of posterior spinal arteries (PSAs). The ASA supplies the anterior two-thirds of the spinal cord. Along its course, the ASA and PSAs are augmented by radicular arteries. The thoracic spinal cord is particularly dependent on radicular contributions and may be the most vulnerable to infarction. (See 'Vascular anatomy' above.) Common etiologies The most common cause of spinal cord infarction is surgical repair of the thoracoabdominal aorta. (See 'Aortic surgery' above.) Spinal cord ischemia can also result from other pathologies involving the aorta, including aortic dissection. (See 'Aortic dissection' above and 'Other aortic pathologies' above.) Less common causes Spinal cord infarction can also complicate other nonaortic surgeries, as well as episodes of profound systemic hypotension such as those occurring https://www.uptodate.com/contents/spinal-cord-infarction-epidemiology-and-etiologies/print 7/16 7/5/23, 11:59 AM Spinal cord infarction: Epidemiology and etiologies - UpToDate during cardiopulmonary arrest. (See 'Nonaortic surgeries' above and 'Systemic hypotension' above.) Other causes of spinal cord infarction are diverse ( table 1). A large proportion of spontaneous spinal cord infarction does not have an identified etiology; many of these are presumably secondary to atherothrombotic disease. (See 'Other causes' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Sandson TA, Friedman JH. 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Surfers' myelopathy: a case series of 19 novice surfers with nontraumatic myelopathy. Neurology 2012; 79:2171. 63. Duggal N, Lach B. Selective vulnerability of the lumbosacral spinal cord after cardiac arrest and hypotension. Stroke 2002; 33:116. 64. Sladky JT, Rorke LB. Perinatal hypoxic/ischemic spinal cord injury. Pediatr Pathol 1986; 6:87. 65. Lin CC, Chen SY, Lan C, et al. Spinal cord infarction caused by cardiac tamponade. Am J Phys Med Rehabil 2002; 81:68. 66. Salamon E, Patsalides A, Gobin YP, et al. Dural arteriovenous fistula at the craniocervical junction mimicking acute brainstem and spinal cord infarction. JAMA Neurol 2013; 70:796. 67. Novy J, Carruzzo A, Maeder P, Bogousslavsky J. Spinal cord ischemia: clinical and imaging patterns, pathogenesis, and outcomes in 27 patients. Arch Neurol 2006; 63:1113. 68. Salvador de la Barrera S, Barca-Buyo A, Montoto-Marqu s A, et al. Spinal cord infarction: prognosis and recovery in a series of 36 patients. Spinal Cord 2001; 39:520. 69. Martinelli V, Comi G, Rovaris M, et al. Acute myelopathy of unknown aetiology: a clinical, neurophysiological and MRI study of short- and long-term prognostic factors. J Neurol 1995; 242:497. 70. Cheng MY, Lyu RK, Chang YJ, et al. Spinal cord infarction in Chinese patients. Clinical features, risk factors, imaging and prognosis. Cerebrovasc Dis 2008; 26:502. 71. Cheng MY, Lyu RK, Chang YJ, et al. Concomitant spinal cord and vertebral body infarction is highly associated with aortic pathology: a clinical and magnetic resonance imaging study. J Neurol 2009; 256:1418. 72. Rathore MF, Gill ZA, Malik AA, Farooq F. Acute flaccid paraplegia: a rare complication of meningococcal meningitis. Spinal Cord 2008; 46:314. https://www.uptodate.com/contents/spinal-cord-infarction-epidemiology-and-etiologies/print 12/16 7/5/23, 11:59 AM Spinal cord infarction: Epidemiology and etiologies - UpToDate 73. Mustafa KN, Hadidy A, Joudeh A, et al. Spinal cord infarction in giant cell arteritis associated with scalp necrosis. Rheumatol Int 2015; 35:377. 74. Laufs H, Weidauer S, Heller C, et al. Hemi-spinal cord infarction due to vertebral artery dissection in congenital afibrinogenemia. Neurology 2004; 63:1522. 75. Hsu CY, Cheng CY, Lee JD, et al. Clinical features and outcomes of spinal cord infarction following vertebral artery dissection: a systematic review of the literature. Neurol Res 2013; 35:676. 76. Hakimi KN, Massagli TL. Anterior spinal artery syndrome in two children with genetic thrombotic disorders. J Spinal Cord Med 2005; 28:69. 77. Young G, Krohn KA, Packer RJ. Prothrombin G20210A mutation in a child with spinal cord infarction. J Pediatr 1999; 134:777. 78. Ramelli GP, Wyttenbach R, von der Weid N, Ozdoba C. Anterior spinal artery syndrome in an adolescent with protein S deficiency. J Child Neurol 2001; 16:134. 79. Rothman SM, Nelson JS. Spinal cord infarction in a patient with sickle cell anemia. Neurology 1980; 30:1072. 80. M rquez JC, Granados AM, Castillo M. MRI of cervical spinal cord infarction in a patient with sickle cell disease. Clin Imaging 2012; 36:595. 81. Edwards A, Clay EL, Jewells V, et al. A 19-year-old man with sickle cell disease presenting with spinal infarction: a case report. J Med Case Rep 2013; 7:210. 82. Ram S, Osman A, Cassar-Pullicino VN, et al. Spinal cord infarction secondary to intervertebral foraminal disease. Spinal Cord 2004; 42:481. 83. Lemke RP, Idiong N, al-Saedi S, et al. Spinal cord infarct after arterial switch associated with an umbilical artery catheter. Ann Thorac Surg 1996; 62:1532. 84. Brown MS, Phibbs RH. Spinal cord injury in newborns from use of umbilical artery catheters: report of two cases and a review of the literature. J Perinatol 1988; 8:105. 85. Mori S, Sadoshima S, Tagawa K, et al. Massive spinal cord infarction with multiple paradoxical embolism: a case report. Angiology 1993; 44:251. 86. Hirose G, Kosoegawa H, Takado M, et al. Spinal cord ischemia and left atrial myxoma. Arch Neurol 1979; 36:439. 87. Petruzzellis M, Fraddosio A, Giorelli M, et al. Posterior spinal artery infarct due to patent foramen ovale: a case report. Spine (Phila Pa 1976) 2010; 35:E155. Topic 1125 Version 13.0 https://www.uptodate.com/contents/spinal-cord-infarction-epidemiology-and-etiologies/print 13/16 7/5/23, 11:59 AM Spinal cord infarction: Epidemiology and etiologies - UpToDate GRAPHICS Arterial supply of the spinal cord Reproduced with permission from: Prasad S, Price RS, Kranick SM, et al. Clinical Reasoning: A 59-year-old woman with acute paraplegia. Neurology 2007; 69:E41. Copyright 2007 Lippincott Williams & Wilkins. Graphic 62845 Version 10.0 https://www.uptodate.com/contents/spinal-cord-infarction-epidemiology-and-etiologies/print 14/16 7/5/23, 11:59 AM Spinal cord infarction: Epidemiology and etiologies - UpToDate Causes of spinal cord infarction Aorta disease, procedures Infection Aortic surgery Bacterial meningitis Thoracic endovascular aortic repair (TEVAR) Syphilis Aortic dissection Mucormycosis Traumatic rupture of the aorta Hematologic disease Aortic thrombosis Hypercoagulable conditions Aortic aneurysm Sickle cell anemia Coarctation of the aorta Non-aortic surgeries Aortography Spine disease Systemic hypoperfusion Spine surgery Cardiac arrest Cervical spondylosis Systemic bleeding Fibrocartilaginous embolism Cardiogenic embolism Epidural steroid injections Atrial myxoma Miscellaneous Mitral valve disease Cocaine abuse Patent foramen ovale Vertebral artery dissection Bacterial endocarditis Spinal vascular malformation Cardiac catheterization Decompression sickness Vasculitis Systemic lupus erythematosus Polyarteritis nodosa Behcet syndrome Giant cell arteritis Graphic 57862 Version 7.0 https://www.uptodate.com/contents/spinal-cord-infarction-epidemiology-and-etiologies/print 15/16 7/5/23, 11:59 AM Spinal cord infarction: Epidemiology and etiologies - UpToDate Contributor Disclosures Michael T Mullen, MD Grant/Research/Clinical Trial Support: NINDS [Asymptomatic carotid disease]. All of the relevant financial relationships listed have been mitigated. Michael L McGarvey, MD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/spinal-cord-infarction-epidemiology-and-etiologies/print 16/16

7/5/23, 12:00 PM Spinal cord infarction: Prognosis and treatment - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Spinal cord infarction: Prognosis and treatment : Michael T Mullen, MD, Michael L McGarvey, MD : Scott E Kasner, MD : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Sep 28, 2021. INTRODUCTION Spinal cord infarction is a rare disorder caused by a wide variety of pathologies. Patients typically present with acute paraparesis or quadriparesis depending on the level of the spinal cord involved. The severity can vary, and while many patients make some functional recovery, permanent and disabling neurologic deficits remain in most. Specific treatment options are unfortunately limited. This topic discusses the prognosis and acute treatment of spinal cord infarction. The causes, clinical symptoms, and diagnosis of spinal cord infarction are discussed separately. The management of chronic complications of spinal cord infarction is also discussed separately. (See "Spinal cord infarction: Epidemiology and etiologies" and "Spinal cord infarction: Clinical presentation and diagnosis" and "Disorders affecting the spinal cord" and "Chronic complications of spinal cord injury and disease".) TREATMENT General medical care Depending on the level and severity of spinal cord ischemia, patients are at risk for a number of systemic as well as neurologic complications in the first days and weeks. Some of these are potentially life-threatening and can exacerbate the neurologic injury. Early intervention can avoid and ameliorate many of these. Patients with moderate to severe deficits resulting from a high thoracic or cervical cord infarct should be admitted to an intensive care unit with close monitoring of vital signs and neurologic status. https://www.uptodate.com/contents/spinal-cord-infarction-prognosis-and-treatment/print 1/11 7/5/23, 12:00 PM Spinal cord infarction: Prognosis and treatment - UpToDate Cardiovascular complications Neurogenic shock refers to hypotension, usually with bradycardia, attributed to interruption of autonomic pathways in the spinal cord causing decreased vascular resistance. Patients with spinal cord infarction may also have hemodynamic instability related to the underlying etiology. An adequate blood pressure is believed to be critical in maintaining adequate perfusion to the ischemic, but not yet infarcted, spinal cord. Bradycardia can occur in severe, high cervical (C1 through C5) lesions and may require external pacing or administration of atropine. Autonomic dysreflexia, a phenomenon characterized by episodic paroxysmal hypertension with headache, bradycardia, flushing, and sweating, is most often described after a traumatic spinal cord injury, but may be a potential concern after spinal cord infarction involving the cervical and upper thoracic cord as well. (See "Chronic complications of spinal cord injury and disease", section on 'Autonomic dysreflexia'.) Respiratory complications The incidence of pulmonary complications (respiratory failure, pulmonary edema, pneumonia, and pulmonary embolism) is highest with higher cervical lesions and is also common with thoracic lesions. Weakness of the diaphragm and chest wall muscles leads to impaired clearance of secretions, ineffective cough, atelectasis, and hypoventilation (see "Respiratory physiologic changes following spinal cord injury"). Signs of impending respiratory failure, such as increased respiratory rate, declining forced vital capacity, rising pCO , or falling pO , indicate urgent 2 2 intubation and ventilation with positive pressure support. With a goal of preventing atelectasis and pneumonia, chest physiotherapy should be instituted as soon as possible; patients may also need frequent suctioning. (See "Respiratory complications in the adult patient with chronic spinal cord injury", section on 'Respiratory insufficiency' and "Respiratory complications in the adult patient with chronic spinal cord injury", section on 'Pulmonary infection'.) Venous thromboembolism and pulmonary embolism Patients with significant paraparesis after spinal cord infarction should be treated to prevent deep venous thrombosis. We consider patients with acute spinal cord infarction to have a similar risk to those with spinal cord injury and treat accordingly. Specific recommendations are provided separately. (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".) Pressure sores Pressure sores are most common on the buttocks and heels and can develop quickly in immobilized patients. Such patients should be turned side to side (log-rolled) every https://www.uptodate.com/contents/spinal-cord-infarction-prognosis-and-treatment/print 2/11 7/5/23, 12:00 PM Spinal cord infarction: Prognosis and treatment - UpToDate two to three hours to avoid pressure sores. Special mattresses can also be used to ameliorate this complication. Urinary catheterization Initially, an indwelling urinary catheter should be placed to avoid bladder distension. Three or four days after injury, intermittent catheterization should be substituted, as this reduces the incidence of bladder infections. (See "Chronic complications of spinal cord injury and disease", section on 'Bladder dysfunction'.) Gastrointestinal stress ulceration Patients with spinal cord infarction, particularly those that affect the cervical cord, are at high risk for stress ulceration and should receive prophylaxis with proton pump inhibitors. (See "Stress ulcers in the intensive care unit: Diagnosis, management, and prevention".) Temperature control Patients with a cervical spinal cord injury may lack vasomotor control and cannot sweat below the lesion. Their temperature may vary with the environment and need to be maintained. Functional recovery Occupational and physiotherapy should be started as soon as possible. Psychological counseling should also be offered to patients and relatives as early as possible. Specific treatments Thrombolysis Thrombolytic therapy for spinal cord ischemia remains investigational at this time. Thrombolytic therapy has been utilized with apparent success in only a few published case reports of spinal cord infarction [1,2]. A significant barrier to thrombolytic treatment in this situation is the initial diagnostic uncertainty that can delay diagnosis beyond the treatment window; this includes the need to exclude aortic dissection and vascular malformations, which are contraindications to thrombolytic agents. Corticosteroids Systemic corticosteroids have not been studied in acute ischemic injury to the spinal cord and are not recommended in acute ischemic stroke involving the brain [3]. We do not recommend the use of steroids to treat spinal cord infarction; however, in rare cases when it is not clear whether a patient has an ischemic versus a demyelinating spinal cord lesion, it may be reasonable to use corticosteroids pending a firm diagnosis. (See "Treatment of acute exacerbations of multiple sclerosis in adults", section on 'Initial therapy with glucocorticoids'.) Following aortic surgery or endovascular repair A specific protocol has been developed that appears to be effective in reversing or limiting the neurologic deficits from spinal cord ischemia after aortic surgery and thoracic endovascular aortic repair (TEVAR) [4-7]. This employs https://www.uptodate.com/contents/spinal-cord-infarction-prognosis-and-treatment/print 3/11 7/5/23, 12:00 PM Spinal cord infarction: Prognosis and treatment - UpToDate a combination of blood pressure support and reduction of spinal cord canal pressure with lumbar drains ( algorithm 1): Mean arterial pressure is increased in increments of 10 mmHg every five minutes (with volume and vasopressor agents) until symptoms resolve, bleeding complications ensue, or additional blood pressure augmentation would cause an unacceptably high risk of bleeding at the surgical bed. If a lumbar drain is in place, it should be opened and set to drain at 8 to 12 mmHg. If not in place, a lumbar drain should be placed if there is no response to blood pressure augmentation within 10 to 20 minutes. If there is no response to treatment, spinal imaging is performed to exclude epidural hematoma. Magnetic resonance imaging (MRI) is preferred, but in cases where MRI is contraindicated or the patient is not stable enough to undergo MRI, computed tomography (CT) is acceptable. Vasopressors are slowly weaned over the ensuing 24 to 48 hours, with close monitoring of neurologic function. After vasopressor support is weaned, the lumbar drain should be capped, and then removed 24 hours later if neurologic function remains stable. While this protocol has not been evaluated in a controlled study, the temporal association of the intervention with the observation of improvement provides evidence of its efficacy. Nonetheless, the number of patients in whom this treatment has been reported is small [8]. The use of this treatment protocol in spinal cord infarction due to other causes has not been studied. While these interventions could be considered, the benefit is questionable, particularly given the usually long delay from onset of symptoms to initiation of therapy in these settings. Other underlying cause If an underlying etiology is found, it should be treated (ie, systemic vasculitis, aortic dissection, cardiogenic embolism), usually with a goal toward preventing further deterioration and secondary events rather than treating the primary injury. Vascular malformations of the spinal cord should be repaired if present. Repair of the malformation may prevent further neurologic decline, and in some instances lead to improved neurologic function [9,10]. The use of antiplatelet treatment in patients with underlying vascular risk factors or comorbid vascular disease is recommended to prevent other secondary atherothrombotic events. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".) https://www.uptodate.com/contents/spinal-cord-infarction-prognosis-and-treatment/print 4/11 7/5/23, 12:00 PM Spinal cord infarction: Prognosis and treatment - UpToDate PROGNOSIS Small case series have attempted to define the range of outcomes following spinal cord infarction. Case fatality The case fatality rate varies depending on the case mix included in the series, but is often reported between 10 and 20 percent [8,11-14]. Patients presenting in the setting of cardiac arrest and acute aortic rupture or dissection and those with high cervical lesions are at greatest risk of dying. Patients with spinal cord infarction have a higher mortality rate after hospital discharge, in part related to the high prevalence of underlying vascular risk factors [15]. Functional outcomes Among survivors, most make some improvement in functional deficits. Independent gait is achieved by 11 to 46 percent, while 20 to 57 percent do not achieve ambulatory status [8,11-13,16-19]. One case series with prolonged follow-up noted that gradual improvement occurred in many patients long after hospital discharge [14]. Poor prognostic factors for recovery include severe impairment at presentation, female sex, advanced age, and lack of improvement in the first 24 hours [11,13,14,16-18,20,21]. Patients with residual deficits after spinal cord infarction must often contend with a variety of other complications including bladder, bowel, and sexual dysfunction, spasticity, and chronic pain. The management of these conditions is discussed separately. (See "Chronic complications of spinal cord injury and disease".) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) SUMMARY AND RECOMMENDATIONS Acute medical care Depending on the level and severity of spinal cord ischemia, patients are at risk for potentially life-threatening complications. Patients with moderate to severe deficits resulting from a high thoracic or cervical cord infarct should be admitted to an intensive care unit with close monitoring of vital signs and neurologic status. (See 'General medical care' above.) https://www.uptodate.com/contents/spinal-cord-infarction-prognosis-and-treatment/print 5/11 7/5/23, 12:00 PM Spinal cord infarction: Prognosis and treatment - UpToDate Similar to patients with traumatic spinal cord injury, patients with significant paraparesis after spinal cord infarction are at high risk of venous thromboembolism and should receive interventions to prevent this complication. Specific recommendations are provided separately. (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".) Specific therapies There are no therapies proven to reverse or limit ischemic spinal cord injury. A protocol for managing patients in the setting of thoracoabdominal aneurysm surgery is presented ( algorithm 1), but this requires independent, prospective demonstration of its safety and efficacy. (See 'Specific treatments' above.) Secondary prevention Underlying causes should be treated in order to prevent secondary events. As an example, patients with atherosclerotic risk factors or underlying comorbid atherosclerotic vascular disease will benefit from antiplatelet therapy and management of atherosclerotic risk factors to prevent future stroke and myocardial infarction. Specific recommendations are provided separately. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".) Prognosis Mortality after spinal cord infarction is primarily influenced by the underlying etiology; however, patients with high cervical cord lesions are at risk of potentially life- threatening complications. Survivors of spinal cord infarction often make some functional improvements, but most have significant, residual neurologic deficits. (See 'Prognosis' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Restrepo L, Guttin JF. Acute spinal cord ischemia during aortography treated with intravenous thrombolytic therapy. Tex Heart Inst J 2006; 33:74. 2. Baba H, Tomita K, Kawagishi T, Imura S. Anterior spinal artery syndrome. Int Orthop 1993; 17:353. 3. Adams HP Jr, del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and https://www.uptodate.com/contents/spinal-cord-infarction-prognosis-and-treatment/print 6/11 7/5/23, 12:00 PM Spinal cord infarction: Prognosis and treatment - UpToDate Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Circulation 2007; 115:e478. 4. Cheung AT, Weiss SJ, McGarvey ML, et al. Interventions for reversing delayed-onset postoperative paraplegia after thoracic aortic reconstruction. Ann Thorac Surg 2002; 74:413. 5. Cheung AT, Pochettino A, McGarvey ML, et al. Strategies to manage paraplegia risk after endovascular stent repair of descending thoracic aortic aneurysms. Ann Thorac Surg 2005; 80:1280. 6. McGarvey ML, Mullen MT, Woo EY, et al. The treatment of spinal cord ischemia following thoracic endovascular aortic repair. Neurocrit Care 2007; 6:35. 7. McGarvey ML, Cheung AT, Szeto W, Messe SR. Management of neurologic complications of thoracic aortic surgery. J Clin Neurophysiol 2007; 24:336. 8. Zalewski NL, Rabinstein AA, Krecke KN, et al. Spinal cord infarction: Clinical and imaging insights from the periprocedural setting. J Neurol Sci 2018; 388:162. 9. Hurst RW. Spinal vascular disorders. In: Magnetic Resonance Imaging of the Brain and Spin e, 2nd ed, Atlas SW (Ed), Lippincott, Philadelphia 2006. p.1387. 10. Van Dijk JM, TerBrugge KG, Willinsky RA, et al. Multidisciplinary management of spinal dural arteriovenous fistulas: clinical presentation and long-term follow-up in 49 patients. Stroke 2002; 33:1578. 11. Cheshire WP, Santos CC, Massey EW, Howard JF Jr. Spinal cord infarction: etiology and outcome. Neurology 1996; 47:321. 12. Novy J, Carruzzo A, Maeder P, Bogousslavsky J. Spinal cord ischemia: clinical and imaging patterns, pathogenesis, and outcomes in 27 patients. Arch Neurol 2006; 63:1113. 13. Masson C, Pruvo JP, Meder JF, et al. Spinal cord infarction: clinical and magnetic resonance imaging findings and short term outcome. J Neurol Neurosurg Psychiatry 2004; 75:1431. 14. Robertson CE, Brown RD Jr, Wijdicks EF, Rabinstein AA. Recovery after spinal cord infarcts: long-term outcome in 115 patients. Neurology 2012; 78:114. 15. Lato T, Markiewicz R, Gaszczyk G. [Spirographic studies and measurement of airflow resistance in evaluation of bronchial hyperreactivity in children with asthma]. Pneumonol Pol 1990; 58:107. 16. Nedeltchev K, Loher TJ, Stepper F, et al. Long-term outcome of acute spinal cord ischemia syndrome. Stroke 2004; 35:560. https://www.uptodate.com/contents/spinal-cord-infarction-prognosis-and-treatment/print 7/11 7/5/23, 12:00 PM Spinal cord infarction: Prognosis and treatment - UpToDate 17. Salvador de la Barrera S, Barca-Buyo A, Montoto-Marqu s A, et al. Spinal cord infarction: prognosis and recovery in a series of 36 patients. Spinal Cord 2001; 39:520. 18. Iseli E, Cavigelli A, Dietz V, Curt A. Prognosis and recovery in ischaemic and traumatic spinal cord injury: clinical and electrophysiological evaluation. J Neurol Neurosurg Psychiatry 1999; 67:567. 19. Ros Castell V, S nchez S nchez A, Natera Villalba E, et al. Spinal cord infarction: aetiology, imaging findings, and prognostic factors in a series of 41 patients. Neurologia (Engl Ed) 2023; 38:391. 20. Geldmacher DS, Bowen BC. Vascular disease of the nervous system. In: Neurology in Clinical Practice, 4th ed, Bradley WG, Daroff RB, Fenichel GM, Jankovic J (Eds), Butterworth Heinema nn, Philadelphia 2004. p.1313. 21. Cheng MY, Lyu RK, Chang YJ, et al. Spinal cord infarction in Chinese patients. Clinical features, risk factors, imaging and prognosis. Cerebrovasc Dis 2008; 26:502. Topic 1115 Version 11.0 https://www.uptodate.com/contents/spinal-cord-infarction-prognosis-and-treatment/print 8/11 7/5/23, 12:00 PM Spinal cord infarction: Prognosis and treatment - UpToDate GRAPHICS Algorithm for the treatment of spinal cord ischemia after thoracic aortic repair Reproduced with permission from: McGarvey ML, Cheung AT, Szeto W, et al. Management of Neurologic Complications of Thoracic Aortic Surgery. J Clin Neurophysiol 2007; 24:336. Copyright 2007 Lippincott Williams & Wilkins. https://www.uptodate.com/contents/spinal-cord-infarction-prognosis-and-treatment/print 9/11 7/5/23, 12:00 PM Spinal cord infarction: Prognosis and treatment - UpToDate Graphic 51097 Version 11.0 https://www.uptodate.com/contents/spinal-cord-infarction-prognosis-and-treatment/print 10/11 7/5/23, 12:00 PM Spinal cord infarction: Prognosis and treatment - UpToDate Contributor Disclosures Michael T Mullen, MD Grant/Research/Clinical Trial Support: NINDS [Asymptomatic carotid disease]. All of the relevant financial relationships listed have been mitigated. Michael L McGarvey, MD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/spinal-cord-infarction-prognosis-and-treatment/print 11/11

7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Stroke: Etiology, classification, and epidemiology : Louis R Caplan, MD : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 15, 2022. INTRODUCTION The two broad categories of stroke, hemorrhage and ischemia, are diametrically opposite conditions: hemorrhage is characterized by too much blood within the closed cranial cavity, while ischemia is characterized by too little blood to supply an adequate amount of oxygen and nutrients to a part of the brain [1]. Each of these categories can be divided into subtypes that have somewhat different causes, clinical pictures, clinical courses, outcomes, and treatment strategies. As an example, intracranial hemorrhage can be caused by intracerebral hemorrhage (ICH, also called parenchymal hemorrhage), which involves bleeding directly into brain tissue, and subarachnoid hemorrhage (SAH), which involves bleeding into the cerebrospinal fluid that surrounds the brain and spinal cord [1]. This topic will review the classification of stroke. The clinical diagnosis of stroke subtypes and an overview of stroke evaluation are discussed separately. (See "Clinical diagnosis of stroke subtypes" and "Overview of the evaluation of stroke".) DEFINITIONS Stroke is classified into two major types: Brain ischemia due to thrombosis, embolism, or systemic hypoperfusion https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 1/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate Brain hemorrhage due to intracerebral hemorrhage (ICH) or subarachnoid hemorrhage (SAH) A stroke is the acute neurologic injury that occurs as a result of one of these pathologic processes. Approximately 80 percent of strokes are due to ischemic cerebral infarction and 20 percent to brain hemorrhage. (See 'Epidemiology' below.) An infarcted brain is pale initially. Within hours to days, the gray matter becomes congested with engorged, dilated blood vessels and minute petechial hemorrhages. When an embolus blocking a major vessel migrates, lyses, or disperses within minutes to days, recirculation into the infarcted area can cause a hemorrhagic infarction and may aggravate edema formation due to disruption of the blood-brain barrier. Transient ischemic attack (TIA) is defined clinically by the temporary nature of the associated neurologic symptoms, which last less than 24 hours by the classic definition. The definition is changing with recognition that transient neurologic symptoms are frequently associated with permanent brain tissue injury. The definition of TIA is discussed in more detail separately. (See "Definition, etiology, and clinical manifestations of transient ischemic attack", section on 'Definition of TIA'.) A primary ICH damages the brain directly at the site of the hemorrhage by compressing the surrounding tissue. Physicians must initially consider whether the patient with suspected cerebrovascular disease is experiencing symptoms and signs suggestive of ischemia or hemorrhage. The great majority of ischemic strokes are caused by a diminished supply of arterial blood, which carries sugar and oxygen to brain tissue. Another cause of stroke that is difficult to classify is stroke due to occlusion of veins that drain the brain of blood. Venous occlusion causes a backup of fluid resulting in brain edema, and in addition it may cause both brain ischemia and hemorrhage into the brain. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".) BRAIN ISCHEMIA There are three main subtypes of brain ischemia [2]: Thrombosis (see 'Thrombosis' below) generally refers to local in situ obstruction of an artery. The obstruction may be due to disease of the arterial wall, such as arteriosclerosis, dissection, or fibromuscular dysplasia; there may or may not be superimposed thrombosis. https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 2/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate Embolism (see 'Embolism' below) refers to particles of debris originating elsewhere that block arterial access to a particular brain region [3]. Since the process is not local (as with thrombosis), local therapy only temporarily solves the problem; further events may occur if the source of embolism is not identified and treated. Systemic hypoperfusion (see 'Systemic hypoperfusion' below) is a more general circulatory problem, manifesting itself in the brain and perhaps other organs. Blood disorders (see 'Blood disorders' below) are an uncommon primary cause of stroke. However, increased blood coagulability can result in thrombus formation and subsequent cerebral embolism in the presence of an endothelial lesion located in the heart, aorta, or large arteries that supply the brain. Thrombosis Thrombotic strokes are those in which the pathologic process giving rise to thrombus formation in an artery produces a stroke either by reduced blood flow distally (low flow) or by an embolic fragment that breaks off and travels to a more distant vessel (artery-to- artery embolism). Thrombotic strokes can be divided into either large or small vessel disease ( table 1). These two subtypes of thrombosis are worth distinguishing since the causes, outcomes, and treatments are different. Large vessel disease Large vessels include both the extracranial (common and internal carotids, vertebral) and intracranial arterial system (Circle of Willis and proximal branches) ( figure 1 and figure 2). Intrinsic lesions in large extracranial and intracranial arteries cause symptoms by reducing blood flow beyond obstructive lesions, and by serving as the source of intra-arterial emboli. At times a combination of mechanisms is operant. Severe stenosis promotes the formation of thrombi which can break off and embolize, and the reduced blood flow caused by the vascular obstruction makes the circulation less competent at washing out and clearing these emboli. Pathologies affecting large extracranial vessels include: Atherosclerosis Dissection Takayasu arteritis Giant cell arteritis Fibromuscular dysplasia Pathologies affecting large intracranial vessels include: Atherosclerosis https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 3/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate Dissection Arteritis/vasculitis Noninflammatory vasculopathy Moyamoya syndrome Vasoconstriction Atherosclerosis is by far the most common cause of in situ local disease within the large extracranial and intracranial arteries that supply the brain. White platelet-fibrin and red erythrocyte-fibrin thrombi are often superimposed upon the atherosclerotic lesions, or they may develop without severe vascular disease in patients with hypercoagulable states. Vasoconstriction (eg, with migraine) is probably the next most common, followed in frequency by arterial dissection (a disorder much more common than previously recognized) and traumatic occlusion. Fibromuscular dysplasia is an uncommon arteriopathy, while arteritis is frequently mentioned in the differential diagnosis, but it is an extremely rare cause of thrombotic stroke. Aortic disease is really a form of proximal extracranial large vessel disease, but it is often considered together with cardioembolic sources because of anatomic proximity. (See 'Aortic atherosclerosis' below.) Identification of the specific focal vascular lesion, including its nature, severity, and localization, is important for treatment since local therapy may be effective (eg, surgery, angioplasty, intraarterial thrombolysis). It should be possible clinically in most patients to determine whether the local vascular disease is within the anterior (carotid) or posterior (vertebrobasilar) circulation and whether the disorder affects large or penetrating arteries. (See "Clinical diagnosis of stroke subtypes", section on 'Neurologic examination'.) Delivery of adequate blood through a blocked or partially blocked artery depends upon many factors, including blood pressure, blood viscosity, and collateral flow. Local vascular lesions also may throw off emboli, which can cause transient symptoms. In patients with thrombosis, the neurologic symptoms often fluctuate, remit, or progress in a stuttering fashion ( figure 3). (See "Clinical diagnosis of stroke subtypes", section on 'Clinical course of symptoms and signs' and "Definition, etiology, and clinical manifestations of transient ischemic attack", section on 'Mechanisms and clinical manifestations'.) Small vessel disease Small vessel disease affects the intracerebral arterial system, specifically penetrating arteries that arise from the distal vertebral artery, the basilar artery, the middle cerebral artery stem, and the arteries of the circle of Willis. These arteries thrombose due to: https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 4/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate Lipohyalinosis (a lipid hyaline build-up distally secondary to hypertension) and fibrinoid degeneration Atheroma formation at their origin or in the parent large artery The most common cause of obstruction of the smaller arteries and arterioles that penetrate at right angles to supply the deeper structures within the brain (eg, basal ganglia, internal capsule, thalamus, pons) is lipohyalinosis (ie, blockage of an artery by medial hypertrophy and lipid admixed with fibrinoid material in the hypertrophied arterial wall). A stroke due to obstruction of these vessels is referred to as a lacunar stroke (see "Lacunar infarcts"). Lipohyalinosis is most often related to hypertension, but aging may play a role. Microatheromas can also block these small penetrating arteries, as can plaques within the larger arteries that block or extend into the orifices of the branches (called atheromatous branch disease) [1]. Penetrating artery occlusions usually cause symptoms that develop during a short period of time, hours or at most a few days ( figure 4), compared with large artery-related brain ischemia, which can evolve over a longer period. Embolism Embolic strokes are divided into four categories ( table 1) [3]. Those with a known source that is cardiac Those with a possible cardiac or aortic source based upon transthoracic and/or transesophageal echocardiographic findings Those with an arterial source (artery to artery embolism) Those with a truly unknown source in which tests for embolic sources are negative The symptoms depend upon the region of brain rendered ischemic [4,5]. The embolus suddenly blocks the recipient site so that the onset of symptoms is abrupt and usually maximal at the start ( figure 5). Unlike thrombosis, multiple sites within different vascular territories may be affected when the source is the heart (eg, left atrial appendage or left ventricular thrombus) or aorta. Treatment will depend upon the source and composition of the embolus. (See "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack".) Cardioembolic strokes usually occur abruptly, although they occasionally present with stuttering, fluctuating symptoms. The symptoms may clear entirely since emboli can migrate and lyse, particularly those composed of thrombus. When this occurs, infarction generally also occurs but is silent; the area of infarction is smaller than the area of ischemia that gave rise to the https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 5/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate symptoms. This process is often referred to as a TIA due to embolism, although it is more correctly termed an embolic infarction or stroke in which the symptoms clear within 24 hours. High-risk cardiac source The diagnosis of embolic strokes with a known cardiac source is generally agreed upon by physicians ( table 2) [6,7]; included in this category are those due to: Atrial fibrillation and paroxysmal atrial fibrillation Rheumatic mitral or aortic valve disease Bioprosthetic and mechanical heart valves Atrial or ventricular thrombus Sinus node dysfunction Sustained atrial flutter Recent myocardial infarction (within one month) Chronic myocardial infarction together with ejection fraction <28 percent Symptomatic congestive heart failure with ejection fraction <30 percent Dilated cardiomyopathy Fibrous nonbacterial endocarditis as found in patients with systemic lupus (ie, Libman- Sacks endocarditis), antiphospholipid syndrome, and cancer (marantic endocarditis) Infective endocarditis Papillary fibroelastoma Left atrial myxoma Coronary artery bypass graft (CABG) surgery With CABG, for example, the incidence of postoperative neurologic sequelae is approximately 2 to 6 percent, most of which is due to stroke [8]. Atheroemboli associated with ascending aortic atherosclerosis is probably the most common cause. (See "Neurologic complications of cardiac surgery".) Potential cardiac source Embolic strokes considered to have a potential cardiac source ( table 2) are ones in which a possible source is detected (usually) by echocardiographic methods [6,7,9], including: Patent foramen ovale Atrial septal aneurysm Atrial septal aneurysm with patent foramen ovale Atrial cardiopathy (large or malfunctioning left atrium) Left ventricular aneurysm without thrombus Isolated left atrial smoke on echocardiography (no mitral stenosis or atrial fibrillation) https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 6/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate Complex atheroma in the ascending aorta or proximal arch (see 'Aortic atherosclerosis' below) In this group, the association of the cardiac or aortic lesion and the rate of embolism is often uncertain, since some of these lesions do not have a high frequency of embolism and are often incidental findings unrelated to the stroke event [10]. Thus, they are considered potential sources of embolism. A truly unknown source represents embolic strokes in which no clinical evidence of heart disease is present ( table 1). Aortic atherosclerosis In longitudinal population studies with nonselected patients, complex aortic atherosclerosis does not appear to be associated with any increased primary ischemic stroke risk [11-13]. However, most studies evaluating secondary stroke risk have found that complex aortic atherosclerosis is a risk factor for recurrent stroke [14-17]. The range of findings is illustrated by the following studies: A prospective case-control study examined the frequency and thickness of atherosclerotic plaques in the ascending aorta and proximal arch in 250 patients admitted to the hospital with ischemic stroke and 250 consecutive controls, all over the age of 60 years [15]. Atherosclerotic plaques 4 mm in thickness were found in 14 percent of patients compared with 2 percent of controls, and the odds ratio for ischemic stroke among patients with such plaques was 9.1 after adjustment for atherosclerotic risk factors. In addition, aortic atherosclerotic plaques 4 mm were much more common in patients with brain infarcts of unknown cause (relative risk 4.7). In contrast, a population-based study of 1135 subjects who had transesophageal echocardiography (TEE) found that complex atherosclerotic plaque (>4 mm with or without mobile debris) in the ascending and transverse aortic arch was not a significant risk factor for cryptogenic ischemic stroke or TIA after adjusting for age, sex, and other clinical risk factors [12]. However, there was an association between complex aortic plaque and noncryptogenic stroke. The investigators concluded that complex aortic arch debris is a marker for the presence of generalized atherosclerosis. Methodologic differences are a potential explanation for the discrepant results of these reports assessing the risk of ischemic stroke related to aortic atherosclerosis, as the earlier case-control studies may have been skewed by selection and referral bias. However, many patients with aortic atherosclerosis also have cardiac or large artery lesions, a problem that may confound purely epidemiologic studies. https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 7/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate In the author's opinion, there is no question that large protruding plaques in the ascending aorta and arch, particularly mobile plaques, are an important cause of stroke [18]. (See "Thromboembolism from aortic plaque".) Systemic hypoperfusion Reduced blood flow is more global in patients with systemic hypoperfusion and does not affect isolated regions. The reduced perfusion can be due to cardiac pump failure caused by cardiac arrest or arrhythmia, or to reduced cardiac output related to acute myocardial ischemia, pulmonary embolism, pericardial effusion, or bleeding. Hypoxemia may further reduce the amount of oxygen carried to the brain. Symptoms of brain dysfunction typically are diffuse and nonfocal in contrast to the other two categories of ischemia. Most affected patients have other evidence of circulatory compromise and hypotension such as pallor, sweating, tachycardia or severe bradycardia, and low blood pressure. The neurologic signs are typically bilateral, although they may be asymmetric when there is preexisting asymmetrical craniocerebral vascular occlusive disease. The most severe ischemia may occur in border zone (watershed) regions between the major cerebral supply arteries since these areas are most vulnerable to systemic hypoperfusion. The signs that may occur with borderzone infarction include cortical blindness, or at least bilateral visual loss; stupor; and weakness of the shoulders and thighs with sparing of the face, hands, and feet (a pattern likened to a "man-in-a-barrel"). Blood disorders Blood and coagulation disorders are an uncommon primary cause of stroke and TIA, but they should be considered in patients younger than age 45, patients with a history of clotting dysfunction, and in patients with a history of cryptogenic stroke [10]. The blood disorders associated with arterial cerebral infarction include: Sickle cell anemia Polycythemia vera Essential thrombocytosis Heparin induced thrombocytopenia Protein C or S deficiency, acquired or congenital Prothrombin gene mutation Factor V Leiden (resistance to activated protein C) Antithrombin III deficiency Antiphospholipid syndrome Hyperhomocysteinemia Thrombotic thrombocytopenic purpura (TTP) https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 8/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate Factor V Leiden mutation and prothrombin 20210 mutations are associated mostly with venous rather than arterial thrombosis. They can result in cerebral venous thrombosis or deep venous thrombosis with paradoxical emboli. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".) Infectious and inflammatory disease such as pneumonia, urinary tract infections, Crohn disease, ulcerative colitis, HIV/AIDS, and cancers result in a rise in acute phase reactants such as fibrinogen, C-reactive protein, and coagulation factors VII and VIII. In the presence of an endothelial cardiac or vascular lesion, this increase can promote active thrombosis and embolism. CLASSIFICATION SYSTEMS FOR ISCHEMIC STROKE TOAST classification The TOAST classification scheme for ischemic stroke is widely used and has good interobserver agreement [19]. The TOAST system ( table 3) attempts to classify ischemic strokes according to the major pathophysiologic mechanisms that are recognized as the cause of most ischemic strokes ( table 1). It assigns ischemic strokes to five subtypes based upon clinical features and the results of ancillary studies including brain imaging, neurovascular evaluations, cardiac tests, and laboratory evaluations for a prothrombotic state. The five TOAST subtypes of ischemic stroke are: Large artery atherosclerosis Cardioembolism Small vessel occlusion Stroke of other determined etiology Stroke of undetermined etiology The last subtype, stroke of undetermined etiology, involves cases where the cause of a stroke cannot be determined with any degree of confidence, and by definition includes those with two or more potential causes identified, those with a negative evaluation, and those with an incomplete evaluation. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)".) SSS-TOAST and CCS classification Since the original TOAST classification scheme was developed in the early 1990s, advances in stroke evaluation and diagnostic imaging have allowed more frequent identification of potential vascular and cardiac causes of stroke [6]. These advances could cause an increasing proportion of ischemic strokes to be classified as https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 9/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate "undetermined" if the strict definition of this category (cases with two or more potential causes) is applied. As a result, an evidenced-based modification of the TOAST criteria called SSS-TOAST was developed [6]. The SSS-TOAST system divides each of the original TOAST subtypes into three subcategories as "evident," "probable," or "possible" based upon the weight of diagnostic evidence as determined by predefined clinical and imaging criteria. In a further refinement, an automated version of the SSS-TOAST called the Causative Classification System (CCS) was devised ( table 4) to improve its usefulness and accuracy for stroke subtyping [20]. The CCS is a computerized algorithm that consists of questionnaire-style classification scheme. The CCS appears to have good inter-rater reliability among multiple centers [21]. It is available online at https://ccs.mgh.harvard.edu/ccs_title.php. The overall agreement between the original TOAST and CCS classification systems appears to be moderate at best, suggesting that two methods often classify stroke cases into different categories despite having categories with similar names [22]. BRAIN HEMORRHAGE There are two main subtypes of brain hemorrhage [2]: Intracerebral hemorrhage (ICH) refers to bleeding directly into the brain parenchyma Subarachnoid hemorrhage (SAH) refers to bleeding into the cerebrospinal fluid within the subarachnoid space that surrounds the brain Intracerebral hemorrhage Bleeding in ICH is usually derived from arterioles or small arteries. The bleeding is directly into the brain, forming a localized hematoma that spreads along white matter pathways. Accumulation of blood occurs over minutes or hours; the hematoma gradually enlarges by adding blood at its periphery like a snowball rolling downhill. The hematoma continues to grow until the pressure surrounding it increases enough to limit its spread or until the hemorrhage decompresses itself by emptying into the ventricular system or into the cerebrospinal fluid (CSF) on the pial surface of the brain [23,24]. The most common causes of ICH are hypertension, trauma, bleeding diatheses, amyloid angiopathy, illicit drug use (mostly amphetamines and cocaine), and vascular malformations [23,24] (see "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis"). Less frequent causes include bleeding into tumors, aneurysmal rupture, and vasculitis. https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 10/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate The earliest symptoms of ICH relate to dysfunction of the portion of the brain that contains the hemorrhage [23,24]. As examples: Bleeding into the right putamen and internal capsule region causes left limb motor and/or sensory signs Bleeding into the cerebellum causes difficulty walking Bleeding into the left temporal lobe presents as aphasia The neurologic symptoms usually increase gradually over minutes or a few hours. In contrast to brain embolism and SAH, the neurologic symptoms related to ICH may not begin abruptly and are not maximal at onset ( figure 6) (and see below). Headache, vomiting, and a decreased level of consciousness develop if the hematoma becomes large enough to increase intracranial pressure or cause shifts in intracranial contents ( figure 7) [23,24]. These symptoms are absent with small hemorrhages; the clinical presentation in this setting is that of a gradually progressing stroke. ICH destroys brain tissue as it enlarges. The pressure created by blood and surrounding brain edema is life threatening; large hematomas have a high mortality and morbidity. The goal of treatment is to contain and limit the bleeding. Recurrences are unusual if the causative disorder is controlled (eg, hypertension or bleeding diathesis). Subarachnoid hemorrhage The two major causes of SAH are rupture of arterial aneurysms that lie at the base of the brain and bleeding from vascular malformations that lie near the pial surface. Bleeding diatheses, trauma, amyloid angiopathy, and illicit drug use are less common. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) Rupture of an aneurysm releases blood directly into the CSF under arterial pressure. The blood spreads quickly within the CSF, rapidly increasing intracranial pressure. Death or deep coma ensues if the bleeding continues. The bleeding usually lasts only a few seconds but rebleeding is very common. With causes of SAH other than aneurysm rupture, the bleeding is less abrupt and may continue over a longer period of time. Symptoms of SAH begin abruptly in contrast to the more gradual onset of ICH. The sudden increase in pressure causes a cessation of activity (eg, loss of memory or focus or knees buckling). Headache is an invariable symptom and is typically instantly severe and widespread; the pain may radiate into the neck or even down the back into the legs. Vomiting occurs soon after onset. There are usually no important focal neurologic signs unless bleeding occurs into the brain and CSF at the same time (meningocerebral hemorrhage). Onset headache is more common than in ICH, and the combination of onset headache and vomiting is infrequent in https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 11/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate ischemic stroke ( figure 7) [25]. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) Approximately 30 percent of patients have a minor hemorrhage manifested only by sudden and severe headache (the so-called sentinel headache) that precedes a major SAH ( figure 7) [25]. The complaint of the sudden onset of severe headache is sufficiently characteristic that SAH should always be considered. In a prospective study of 148 patients presenting with sudden and severe headache, for example, SAH was present in 25 percent overall and 12 percent in patients in whom headache was the only symptom [26]. EPIDEMIOLOGY Globally, ischemia accounts for 62 percent, intracerebral hemorrhage 28 percent, and subarachnoid hemorrhage 10 percent of all incident strokes, reflecting a higher incidence of hemorrhagic stroke in low- and middle-income countries [27,28]. In the United States, the proportion of all strokes due to ischemia, intracerebral hemorrhage, and subarachnoid hemorrhage is 87, 10, and 3 percent, respectively [29]. The lifetime risk of stroke for adult men and women (25 years of age and older) is approximately 25 percent [30]. The highest risk of stroke is found in East Asia, Central Europe, and Eastern Europe. Worldwide, stroke is the second most common cause of mortality and the second most common cause of disability [31]. In China, which has the greatest burden of stroke in the world, the age-standardized prevalence, incidence, and mortality rates are estimated to be 1115, 247, and 115 per 100,000 person-years, respectively [32]. These data suggest that the stroke prevalence in China is relatively low compared with the prevalence in high-income countries, but the stroke incidence and mortality rates in China are among the highest in the world. While the incidence of stroke is decreasing in high-income countries, including the United States [33-35], the incidence is increasing in low-income countries [36]. The overall rate of stroke-related mortality is decreasing in high and low income countries, but the absolute number of people with stroke, stroke survivors, stroke-related deaths, and the global burden of stroke-related disability is high and increasing [37]. In the United States, the annual incidence of new or recurrent stroke is about 795,000, of which about 610,000 are first-ever strokes, and 185,000 are recurrent strokes [29]. There is a higher regional incidence and prevalence of stroke and a higher stroke mortality rate in the southeastern United States (sometimes referred to as the "stroke belt") than in the rest of the country [38-42]. The lifetime risk of stroke is higher for females compared with males [29]. https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 12/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate Black and Hispanic Americans have an increased risk of stroke compared with White Americans, as illustrated by the following observations: The Northern Manhattan Study reported that the age-adjusted incidence of first ischemic stroke among White, Hispanic, and Black Americans was 88, 149, and 191 per 100,000 respectively [43]. Among Black compared with White Americans, the relative rate of stroke attributed to intracranial atherosclerosis, extracranial atherosclerosis, lacunes, and cardioembolism was 5.85, 3.18, 3.09, and 1.58 respectively. Among Hispanic compared with White Americans, the relative rate of stroke attributed to intracranial atherosclerosis, extracranial atherosclerosis, lacunes, and cardioembolism was 5.00, 1.71, 2.32, and 1.42. The Greater Cincinnati/Northern Kentucky Stroke Study showed that small vessel strokes and strokes of undetermined origin were nearly twice as common, and large vessel strokes were 40 percent more common, among Black compared with White patients [44]. The incidence of cardioembolic strokes was not significantly different. An increased incidence of stroke has also been found among Mexican Americans compared with non-Hispanic White Americans [45]. INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Hemorrhagic stroke (The Basics)" and "Patient education: Stroke (The Basics)") Beyond the Basics topics (see "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)") https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 13/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate SUMMARY Classification Stroke is classified into two major types (see 'Definitions' above): Brain ischemia due to thrombosis, embolism, or systemic hypoperfusion Brain hemorrhage due to intracerebral hemorrhage (ICH) or subarachnoid hemorrhage (SAH) Ischemia - There are three main subtypes of brain ischemia ( table 1): Thrombosis generally refers to local in situ obstruction of an artery. The obstruction may be due to disease of the arterial wall, such as atherosclerosis, arteriosclerosis, dissection, or fibromuscular dysplasia; there may or may not be superimposed thrombosis. Thrombotic strokes can be divided into either large or small vessel disease. These two subtypes of thrombosis are worth distinguishing since the causes, outcomes, and treatments are different. (See 'Thrombosis' above.) Embolism refers to particles of debris originating elsewhere that block arterial access to a particular brain region. The source of embolism is most often from the heart or from an artery (artery-to-artery embolism). (See 'Embolism' above.) Systemic hypoperfusion is a more general circulatory problem, manifesting itself in the brain and perhaps other organs. (See 'Systemic hypoperfusion' above.) Blood disorders are an uncommon primary cause of stroke. However, increased blood coagulability can result in thrombus formation and subsequent cerebral embolism in the presence of an endothelial lesion located in the heart, aorta, or large arteries that supply the brain. (See 'Blood disorders' above.) Ischemic stroke classification The TOAST classification scheme for ischemic stroke ( table 3) is widely used and has good interobserver agreement. The SSS-TOAST system divides each of the original TOAST subtypes into three subcategories as "evident," "probable," or "possible" based upon the weight of diagnostic. The Causative Classification System (CCS) ( table 4) is an automated version of the SSS-TOAST. (See 'Classification systems for ischemic stroke' above.) Brain hemorrhage There are two main subtypes of brain hemorrhage: ICH refers to bleeding directly into the brain parenchyma. Accumulation of blood occurs over minutes or hours. The most common causes of ICH are hypertension, trauma, https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 14/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate bleeding diatheses, amyloid angiopathy, illicit drug use (mostly amphetamines and cocaine), and vascular malformations. Less frequent causes include bleeding into tumors, aneurysmal rupture, and vasculitis. (See 'Intracerebral hemorrhage' above.) SAH refers to bleeding into the cerebrospinal fluid within the subarachnoid space that surrounds the brain. The two major causes of SAH are rupture of arterial aneurysms that lie at the base of the brain and bleeding from vascular malformations that lie near the pial surface. Bleeding diatheses, trauma, amyloid angiopathy, and illicit drug use are less common. Rupture of an aneurysm releases blood directly into the cerebrospinal fluid (CSF) under arterial pressure. The blood spreads quickly within the CSF, rapidly increasing intracranial pressure. Death or deep coma ensues if the bleeding continues. (See 'Subarachnoid hemorrhage' above.) Epidemiology Globally, ischemia accounts for 62 percent, intracerebral hemorrhage 28 percent, and subarachnoid hemorrhage 10 percent of all incident strokes, reflecting a higher incidence of hemorrhagic stroke in low- and middle-income countries. In the United States, the proportion of all strokes due to ischemia, intracerebral hemorrhage, and subarachnoid hemorrhage is 87, 10, and 3 percent, respectively. (See 'Epidemiology' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Caplan LR. Intracranial branch atheromatous disease: a neglected, understudied, and underused concept. Neurology 1989; 39:1246. 2. Caplan LR. Basic pathology, anatomy, and pathophysiology of stroke. In: Caplan's Stroke: A Clinical Approach, 4th ed, Saunders Elsevier, Philadelphia 2009. p.22. 3. Brain embolism, Caplan LR, Manning W (Eds), Informa Healthcare, New York 2006. 4. Caplan LR. Brain embolism, revisited. Neurology 1993; 43:1281. 5. Caplan LR. Brain embolism. In: Clinical Neurocardiology, Caplan LR, Hurst JW, Chimowitz M (Eds), Marcel Dekker, New York 1999. p.35. 6. Ay H, Furie KL, Singhal A, et al. An evidence-based causative classification system for acute ischemic stroke. Ann Neurol 2005; 58:688. 7. Doufekias E, Segal AZ, Kizer JR. Cardiogenic and aortogenic brain embolism. J Am Coll Cardiol 2008; 51:1049. https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 15/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate 8. Roach GW, Kanchuger M, Mangano CM, et al. Adverse cerebral outcomes after coronary bypass surgery. Multicenter Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation Investigators. N Engl J Med 1996; 335:1857. 9. Kamel H, Bartz TM, Elkind MSV, et al. Atrial Cardiopathy and the Risk of Ischemic Stroke in the CHS (Cardiovascular Health Study). Stroke 2018; 49:980. 10. Flemming KD, Brown RD Jr, Petty GW, et al. Evaluation and management of transient ischemic attack and minor cerebral infarction. Mayo Clin Proc 2004; 79:1071. 11. Meissner I, Khandheria BK, Sheps SG, et al. Atherosclerosis of the aorta: risk factor, risk marker, or innocent bystander? A prospective population-based transesophageal echocardiography study. J Am Coll Cardiol 2004; 44:1018. 12. Petty GW, Khandheria BK, Meissner I, et al. Population-based study of the relationship between atherosclerotic aortic debris and cerebrovascular ischemic events. Mayo Clin Proc 2006; 81:609. 13. Russo C, Jin Z, Rundek T, et al. Atherosclerotic disease of the proximal aorta and the risk of vascular events in a population-based cohort: the Aortic Plaques and Risk of Ischemic Stroke (APRIS) study. Stroke 2009; 40:2313. 14. Amarenco P, Duyckaerts C, Tzourio C, et al. The prevalence of ulcerated plaques in the aortic arch in patients with stroke. N Engl J Med 1992; 326:221. 15. Amarenco P, Cohen A, Tzourio C, et al. Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. N Engl J Med 1994; 331:1474. 16. Cohen A, Tzourio C, Bertrand B, et al. Aortic plaque morphology and vascular events: a follow-up study in patients with ischemic stroke. FAPS Investigators. French Study of Aortic Plaques in Stroke. Circulation 1997; 96:3838. 17. Di Tullio MR, Russo C, Jin Z, et al. Aortic arch plaques and risk of recurrent stroke and death. Circulation 2009; 119:2376. 18. Caplan LR. The aorta as a donor source of brain embolism. In: Brain embolism, Caplan, LR, Manning, WJ (Eds), Informa Healthcare, New York 2006. p.187. 19. Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic

th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Hemorrhagic stroke (The Basics)" and "Patient education: Stroke (The Basics)") Beyond the Basics topics (see "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)") https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 13/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate SUMMARY Classification Stroke is classified into two major types (see 'Definitions' above): Brain ischemia due to thrombosis, embolism, or systemic hypoperfusion Brain hemorrhage due to intracerebral hemorrhage (ICH) or subarachnoid hemorrhage (SAH) Ischemia - There are three main subtypes of brain ischemia ( table 1): Thrombosis generally refers to local in situ obstruction of an artery. The obstruction may be due to disease of the arterial wall, such as atherosclerosis, arteriosclerosis, dissection, or fibromuscular dysplasia; there may or may not be superimposed thrombosis. Thrombotic strokes can be divided into either large or small vessel disease. These two subtypes of thrombosis are worth distinguishing since the causes, outcomes, and treatments are different. (See 'Thrombosis' above.) Embolism refers to particles of debris originating elsewhere that block arterial access to a particular brain region. The source of embolism is most often from the heart or from an artery (artery-to-artery embolism). (See 'Embolism' above.) Systemic hypoperfusion is a more general circulatory problem, manifesting itself in the brain and perhaps other organs. (See 'Systemic hypoperfusion' above.) Blood disorders are an uncommon primary cause of stroke. However, increased blood coagulability can result in thrombus formation and subsequent cerebral embolism in the presence of an endothelial lesion located in the heart, aorta, or large arteries that supply the brain. (See 'Blood disorders' above.) Ischemic stroke classification The TOAST classification scheme for ischemic stroke ( table 3) is widely used and has good interobserver agreement. The SSS-TOAST system divides each of the original TOAST subtypes into three subcategories as "evident," "probable," or "possible" based upon the weight of diagnostic. The Causative Classification System (CCS) ( table 4) is an automated version of the SSS-TOAST. (See 'Classification systems for ischemic stroke' above.) Brain hemorrhage There are two main subtypes of brain hemorrhage: ICH refers to bleeding directly into the brain parenchyma. Accumulation of blood occurs over minutes or hours. The most common causes of ICH are hypertension, trauma, https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 14/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate bleeding diatheses, amyloid angiopathy, illicit drug use (mostly amphetamines and cocaine), and vascular malformations. Less frequent causes include bleeding into tumors, aneurysmal rupture, and vasculitis. (See 'Intracerebral hemorrhage' above.) SAH refers to bleeding into the cerebrospinal fluid within the subarachnoid space that surrounds the brain. The two major causes of SAH are rupture of arterial aneurysms that lie at the base of the brain and bleeding from vascular malformations that lie near the pial surface. Bleeding diatheses, trauma, amyloid angiopathy, and illicit drug use are less common. Rupture of an aneurysm releases blood directly into the cerebrospinal fluid (CSF) under arterial pressure. The blood spreads quickly within the CSF, rapidly increasing intracranial pressure. Death or deep coma ensues if the bleeding continues. (See 'Subarachnoid hemorrhage' above.) Epidemiology Globally, ischemia accounts for 62 percent, intracerebral hemorrhage 28 percent, and subarachnoid hemorrhage 10 percent of all incident strokes, reflecting a higher incidence of hemorrhagic stroke in low- and middle-income countries. In the United States, the proportion of all strokes due to ischemia, intracerebral hemorrhage, and subarachnoid hemorrhage is 87, 10, and 3 percent, respectively. (See 'Epidemiology' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Caplan LR. Intracranial branch atheromatous disease: a neglected, understudied, and underused concept. Neurology 1989; 39:1246. 2. Caplan LR. Basic pathology, anatomy, and pathophysiology of stroke. In: Caplan's Stroke: A Clinical Approach, 4th ed, Saunders Elsevier, Philadelphia 2009. p.22. 3. Brain embolism, Caplan LR, Manning W (Eds), Informa Healthcare, New York 2006. 4. Caplan LR. Brain embolism, revisited. Neurology 1993; 43:1281. 5. Caplan LR. Brain embolism. In: Clinical Neurocardiology, Caplan LR, Hurst JW, Chimowitz M (Eds), Marcel Dekker, New York 1999. p.35. 6. Ay H, Furie KL, Singhal A, et al. An evidence-based causative classification system for acute ischemic stroke. Ann Neurol 2005; 58:688. 7. Doufekias E, Segal AZ, Kizer JR. Cardiogenic and aortogenic brain embolism. J Am Coll Cardiol 2008; 51:1049. https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 15/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate 8. Roach GW, Kanchuger M, Mangano CM, et al. Adverse cerebral outcomes after coronary bypass surgery. Multicenter Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation Investigators. N Engl J Med 1996; 335:1857. 9. Kamel H, Bartz TM, Elkind MSV, et al. Atrial Cardiopathy and the Risk of Ischemic Stroke in the CHS (Cardiovascular Health Study). Stroke 2018; 49:980. 10. Flemming KD, Brown RD Jr, Petty GW, et al. Evaluation and management of transient ischemic attack and minor cerebral infarction. Mayo Clin Proc 2004; 79:1071. 11. Meissner I, Khandheria BK, Sheps SG, et al. Atherosclerosis of the aorta: risk factor, risk marker, or innocent bystander? A prospective population-based transesophageal echocardiography study. J Am Coll Cardiol 2004; 44:1018. 12. Petty GW, Khandheria BK, Meissner I, et al. Population-based study of the relationship between atherosclerotic aortic debris and cerebrovascular ischemic events. Mayo Clin Proc 2006; 81:609. 13. Russo C, Jin Z, Rundek T, et al. Atherosclerotic disease of the proximal aorta and the risk of vascular events in a population-based cohort: the Aortic Plaques and Risk of Ischemic Stroke (APRIS) study. Stroke 2009; 40:2313. 14. Amarenco P, Duyckaerts C, Tzourio C, et al. The prevalence of ulcerated plaques in the aortic arch in patients with stroke. N Engl J Med 1992; 326:221. 15. Amarenco P, Cohen A, Tzourio C, et al. Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. N Engl J Med 1994; 331:1474. 16. Cohen A, Tzourio C, Bertrand B, et al. Aortic plaque morphology and vascular events: a follow-up study in patients with ischemic stroke. FAPS Investigators. French Study of Aortic Plaques in Stroke. Circulation 1997; 96:3838. 17. Di Tullio MR, Russo C, Jin Z, et al. Aortic arch plaques and risk of recurrent stroke and death. Circulation 2009; 119:2376. 18. Caplan LR. The aorta as a donor source of brain embolism. In: Brain embolism, Caplan, LR, Manning, WJ (Eds), Informa Healthcare, New York 2006. p.187. 19. Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993; 24:35. 20. Ay H, Benner T, Arsava EM, et al. A computerized algorithm for etiologic classification of ischemic stroke: the Causative Classification of Stroke System. Stroke 2007; 38:2979. 21. Arsava EM, Ballabio E, Benner T, et al. The Causative Classification of Stroke system: an international reliability and optimization study. Neurology 2010; 75:1277. https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 16/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate 22. McArdle PF, Kittner SJ, Ay H, et al. Agreement between TOAST and CCS ischemic stroke classification: the NINDS SiGN study. Neurology 2014; 83:1653. 23. Caplan LR. Intracerebral haemorrhage. Lancet 1992; 339:656. 24. Kase CS, Caplan LR. Intracerebral Hemorrhage, Butterworth-Heinemann, Boston 1996. 25. Gorelick PB, Hier DB, Caplan LR, Langenberg P. Headache in acute cerebrovascular disease. Neurology 1986; 36:1445. 26. Linn FH, Wijdicks EF, van der Graaf Y, et al. Prospective study of sentinel headache in aneurysmal subarachnoid haemorrhage. Lancet 1994; 344:590. 27. Krishnamurthi RV, Feigin VL, Forouzanfar MH, et al. Global and regional burden of first-ever ischaemic and haemorrhagic stroke during 1990-2010: findings from the Global Burden of Disease Study 2010. Lancet Glob Health 2013; 1:e259. 28. GBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol 2021; 20:795. 29. Tsao CW, Aday AW, Almarzooq ZI, et al. Heart Disease and Stroke Statistics-2022 Update: A Report From the American Heart Association. Circulation 2022; 145:e153. 30. GBD 2016 Lifetime Risk of Stroke Collaborators, Feigin VL, Nguyen G, et al. Global, Regional, and Country-Specific Lifetime Risks of Stroke, 1990 and 2016. N Engl J Med 2018; 379:2429. 31. GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019; 18:459. 32. Wang W, Jiang B, Sun H, et al. Prevalence, Incidence, and Mortality of Stroke in China: Results from a Nationwide Population-Based Survey of 480 687 Adults. Circulation 2017; 135:759. 33. Koton S, Schneider AL, Rosamond WD, et al. Stroke incidence and mortality trends in US communities, 1987 to 2011. JAMA 2014; 312:259. 34. Vangen-L nne AM, Wilsgaard T, Johnsen SH, et al. Declining Incidence of Ischemic Stroke: What Is the Impact of Changing Risk Factors? The Troms Study 1995 to 2012. Stroke 2017; 48:544. 35. Madsen TE, Khoury JC, Leppert M, et al. Temporal Trends in Stroke Incidence Over Time by Sex and Age in the GCNKSS. Stroke 2020; 51:1070. 36. Feigin VL, Forouzanfar MH, Krishnamurthi R, et al. Global and regional burden of stroke during 1990-2010: findings from the Global Burden of Disease Study 2010. Lancet 2014; 383:245. https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 17/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate 37. GBD 2016 Stroke Collaborators. Global, regional, and national burden of stroke, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019; 18:439. 38. Lanska DJ. Geographic distribution of stroke mortality in the United States: 1939-1941 to 1979-1981. Neurology 1993; 43:1839. 39. Casper ML, Wing S, Anda RF, et al. The shifting stroke belt. Changes in the geographic pattern of stroke mortality in the United States, 1962 to 1988. Stroke 1995; 26:755. 40. Centers for Disease Control and Prevention (CDC). Disparities in deaths from stroke among persons aged <75 years United States, 2002. MMWR Morb Mortal Wkly Rep 2005; 54:477. 41. Rich DQ, Gaziano JM, Kurth T. Geographic patterns in overall and specific cardiovascular disease incidence in apparently healthy men in the United States. Stroke 2007; 38:2221. 42. Glymour MM, Kosheleva A, Boden-Albala B. Birth and adult residence in the Stroke Belt independently predict stroke mortality. Neurology 2009; 73:1858. 43. White H, Boden-Albala B, Wang C, et al. Ischemic stroke subtype incidence among whites, blacks, and Hispanics: the Northern Manhattan Study. Circulation 2005; 111:1327. 44. Schneider AT, Kissela B, Woo D, et al. Ischemic stroke subtypes: a population-based study of incidence rates among blacks and whites. Stroke 2004; 35:1552. 45. Morgenstern LB, Smith MA, Lisabeth LD, et al. Excess stroke in Mexican Americans compared with non-Hispanic Whites: the Brain Attack Surveillance in Corpus Christi Project. Am J Epidemiol 2004; 160:376. Topic 1089 Version 33.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 18/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate GRAPHICS Pathophysiologic ischemic stroke classification Large vessel atherothrombotic stroke More common Bifurcation of the common carotid artery Siphon portion of the common carotid artery Middle cerebral artery stem Intracranial vertebral arteries proximal to middle basilar artery Origin of the vertebral arteries Less common Origin of the common carotid artery Posterior cerebral artery stem Origin of the major branches of the basilar-vertebral arteries Origin of the branches of the anterior, middle, and posterior cerebral arteries Small vessel (lacunar) stroke Mechanism Lipohyalinotic occlusion Less frequently proximal atherothrombotic occlusion Least likely embolic occlusion Most common locations Penetrating branches of the anterior, middle, and posterior cerebral and basilar arteries Cardioaortic embolic stroke Cardiac sources definite - antithrombotic therapy generally used Left atrial thrombus Left ventricular thrombus Atrial fibrillation and paroxysmal atrial fibrillation Sustained atrial flutter Recent myocardial infarction (within one month) Rheumatic mitral or aortic valve disease Bioprosthetic and mechanical heart valve https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 19/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate Chronic myocardial infarction with ejection fraction <28 percent Symptomatic heart failure with ejection fraction <30 percent Dilated cardiomyopathy Cardiac sources definite - anticoagulation hazardous Bacterial endocarditis (exception nonbacterial) Atrial myxoma Cardiac sources possible Mitral annular calcification Patent foramen ovale Atrial septal aneurysm Atrial septal aneurysm with patent foramen ovale Left ventricular aneurysm without thrombus Isolated left atrial spontaneous echo contrast ("smoke") without mitral stenosis or atrial fibrillation Mitral valve strands Ascending aortic atheromatous disease (>4 mm) True unknown source embolic stroke Other Dissection Moyamoya Binswanger's disease Primary thrombosis Cerebral mass Graphic 55099 Version 4.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 20/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate Anatomy of the cerebral arterial circulation Frontal view of the carotid arteries, vertebral arteries, and intracranial vessels and their communication with each other via the circle of Willis. Reproduced with permission from: U acker R. Atlas Of Vascular Anatomy: An Angiographic Approach, Second Edition. Philadelphia: Lippincott Williams & Wilkins, 2006. Copyright 2006 Lippincott Williams & Wilkins. Graphic 51410 Version 6.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 21/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate Major cerebral vascular territories Representation of the territories of the major cerebral vessels shown in a coronal section of the brain. Reproduced with permission from Kistler, JP, et al, Cerebrovascular Diseases. Harrison's Principles of Internal Medicine, 13th ed, McGraw-Hill, New York 1994. Copyright 1994 McGraw-Hill Companies, Inc. Graphic 65199 Version 2.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 22/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate Stuttering time course of thrombotic stroke The course of weakness of the right limb in a patient with a thrombotic stroke reveals fluctuating symptoms, varying between normal and abnormal, progressing in a stepwise or stuttering fashion with some periods of improvement. Graphic 64107 Version 2.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 23/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate Time course of lacunar infarction Penetrating artery occlusions usually cause symptoms that develop over a short period of time, hours or at most a few days, compared to large artery-related brain ischemia which can evolve over a longer period. A stuttering course may ensue, as with large artery thrombosis. This patient had a pure motor hemiparesis. Graphic 52246 Version 1.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 24/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate Time course of embolic stroke Embolic stroke occurs suddenly, with symptoms maximal at onset. This patient had multiple embolic events with different clinical symptoms (initially weakness, followed by paresthesias). Graphic 73261 Version 1.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 25/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate Cardioaortic sources of cerebral embolism Sources with high primary risk for ischemic stroke Sources with low or uncertain primary risk for ischemic stroke Atrial fibrillation Cardiac sources of embolism: Paroxysmal atrial fibrillation Mitral annular calcification Left atrial thrombus Patent foramen ovale Left ventricular thrombus Atrial septal aneurysm Sick sinus syndrome Atrial septal aneurysm and patent foramen ovale Atrial flutter Left ventricular aneurysm without thrombus Recent myocardial infarction (within one month prior to stroke) Left atrial spontaneous echo contrast ("smoke") Mitral stenosis or rheumatic valve disease Congestive heart failure with ejection fraction <30% Mechanical heart valves Bioprosthetic heart valves Chronic myocardial infarction together with low ejection fraction (<28%) Apical akinesia Dilated cardiomyopathy (prior established Wall motion abnormalities (hypokinesia, diagnosis or left ventricular dilatation with an akinesia, dyskinesia) other than apical akinesia ejection fraction of <40% or fractional shortening of <25%) Nonbacterial thrombotic endocarditis Hypertrophic cardiomyopathy Infective endocarditis Left ventricular hypertrophy Papillary fibroelastoma Left ventricular hypertrabeculation/non- compaction Left atrial myxoma Recent aortic valve replacement or coronary artery bypass graft surgery Presence of left ventricular assist device Paroxysmal supraventricular tachycardia Aortic sources of embolism: Complex atheroma in the ascending aorta or proximal arch (protruding with >4 mm thickness, or mobile debris, or plaque ulceration) The high- and low-risk cardioaortic sources in this table are separated using an arbitrary 2% annual https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 26/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate or one-time primary stroke risk threshold. Data from: 1. Ay H, Benner T, Arsava EM, et al. A computerized algorithm for etiologic classi cation of ischemic stroke: the Causative Classi cation of Stroke System. Stroke 2007; 38:2979. 2. Ay H, Furie KL, Singhal A, et al. An evidence-based causative classi cation system for acute ischemic stroke. Ann Neurol 2005; 58:688. 3. Arsava EM, Ballabio E, Benner T, et al. The Causative Classi cation of Stroke system: an international reliability and optimization study. Neurology 2010; 75:1277. 4. Kamel H, Elkind MS, Bhave PD, et al. Paroxysmal supraventricular tachycardia and the risk of ischemic stroke. Stroke 2013; 44:1550. 5. Kirklin JK, Pagani FD, Kormos RL, et al. Eighth annual INTERMACS report: Special focus on framing the impact of adverse events. J Heart Lung Transplant 2017; 36:1080. Reproduced and modi ed with permission from: Ay H, Furie KL, Singhal A, et al. An evidence-based causative classi cation system for acute ischemic stroke. Ann Neurol 2005; 58:688. Copyright 2005 American Neurological Association. Graphic 60843 Version 11.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 27/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate TOAST classification of subtypes of acute ischemic stroke Large-artery atherosclerosis Cardioembolism Small-vessel occlusion Stroke of other determined etiology Stroke of undetermined etiology Two or more causes identified Negative evaluation Incomplete evaluation Graphic 62571 Version 1.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 28/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate Causative Classification System (CCS) of ischemic stroke etiology Stroke Level of Criteria mechanism confidence 1. Either occlusive or stenotic ( 50 percent diameter reduction or <50 percent diameter reduction with plaque ulceration or Large artery Evident atherosclerosis thrombosis) vascular disease judged to be caused by atherosclerosis in the clinically relevant extracranial or intracranial arteries, and 2. The absence of acute infarction in vascular territories other than the stenotic or occluded artery 1. History of 1 transient monocular blindness (TMB), TIA, or stroke from the territory of index artery affected by atherosclerosis within the last month, or Probable 2. Evidence of near-occlusive stenosis or nonchronic complete occlusion judged to be caused by atherosclerosis in the clinically relevant extracranial or intracranial arteries (except for the vertebral arteries), or 3. The presence of ipsilateral and unilateral internal watershed infarctions or multiple, temporally separate, infarctions exclusively within the territory of the affected artery Possible 1. The presence of an atherosclerotic plaque protruding into the lumen and causing mild stenosis (<50 percent) in the absence of any detectable plaque ulceration or thrombosis in a clinically relevant extracranial or intracranial artery and history of 2 TMB, TIA, or stroke from the territory of index artery affected by atherosclerosis, at least one event within the last month, or 2. Evidence for evident large artery atherosclerosis in the absence of complete diagnostic investigation for other mechanisms https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 29/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate Cardio-aortic embolism Evident The presence of a high-risk cardiac source of cerebral embolism Probable 1. Evidence of systemic embolism, or 2. The presence of multiple acute infarctions that have occurred closely related in time within both right and left anterior or both anterior and posterior circulations in the absence of occlusion or near-occlusive stenosis of all relevant vessels. Other diseases that can cause multifocal ischemic brain injury such as vasculitides, vasculopathies, and hemostatic or hemodynamic disturbances must not be present. Possible 1. The presence of a cardiac condition with low or uncertain primary risk of cerebral embolism, or 2. Evidence for evident cardio-aortic embolism in the absence of complete diagnostic investigation for other mechanisms Small artery Evident Imaging evidence of a single and clinically relevant acute infarction occlusion <20 mm in greatest diameter within the territory of basal or brainstem penetrating arteries in the absence of any other pathology in the parent artery at the site of the origin of the penetrating artery (focal atheroma, parent vessel dissection, vasculitis, vasospasm, etc) Probable 1. The presence of stereotypic lacunar transient ischemic attacks within the past week, or 2. The presence of a classical lacunar syndrome Possible 1. Presenting with a classical lacunar syndrome in the absence of imaging that is sensitive enough to detect small infarctions, or 2. Evidence for evident small artery occlusion in the absence of complete diagnostic investigation for other mechanisms Other causes Evident The presence of a specific disease process that involves clinically appropriate brain arteries Probable A specific disease process that has occurred in clear and close temporal or spatial relationship to the onset of brain infarction such as arterial dissection, cardiac or arterial surgery, and cardiovascular interventions Possible Evidence for an evident other cause in the absence of complete diagnostic investigation for mechanisms listed above https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 30/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate Undetermined Unknown (no Cryptogenic embolism: causes evident, probable, or 1. Angiographic evidence of abrupt cut-off consistent with a blood clot within otherwise angiographically normal looking intracranial arteries, or possible criteria for 2. Imaging evidence of complete recanalization of previously the causes occluded artery, or above) 3. The presence of multiple acute infarctions that have occurred closely related in time without detectable abnormality in the relevant vessels Other cryptogenic: Those not fulfilling the criteria for cryptogenic embolism Incomplete evaluation: The absence of diagnostic tests that, under the examiner's judgment, would have been essential to uncover the underlying etiology Unclassified The presence of >1 evident mechanism in which there is either probable evidence for each, or no probable evidence to be able to establish a single cause Reproduced with permission from: Ay H, Benner T, Arsava EM. A computerized algorithm for etiologic classi cation of ischemic stroke: the Causative Classi cation of Stroke System. Stroke 2007; 38:2979. Graphic 57732 Version 4.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 31/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate Time course of neurologic changes in intracerebral hemorrhage Schematic representation of rapid downhill course in terms of unusual behavior (solid line), hemimotor function (dotted line), and consciousness (dash-dotted line) in a patient with intracerebral (intraparenchymal) hemorrhage. Graphic 61491 Version 3.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 32/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate Headache and vomiting in stroke subtypes The frequency of sentinel headache, onset headache, and vomiting in three subtypes of stroke: subarachnoid hemorrhage, intraparenchymal (intracerebral) hemorrhage, and ischemic stroke. Onset headache was present in virtually all patients with SAH and about one-half of those with IPH; all of these symptoms were infrequent in patients with IS. SAH: subarachnoid hemorrhage; IPH: intraparenchymal (intracerebral) hemorrhage; IS: ischemic stroke. Data from: Gorelick PB, Hier DB, Caplan LR, Langenberg P. Headache in acute cerebrovascular disease. Neurology 1986; 36:1445. Graphic 60831 Version 4.0 https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 33/34 7/5/23, 12:00 PM Stroke: Etiology, classification, and epidemiology - UpToDate Contributor Disclosures Louis R Caplan, MD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/stroke-etiology-classification-and-epidemiology/print 34/34

7/5/23, 12:01 PM Subarachnoid hemorrhage grading scales - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Subarachnoid hemorrhage grading scales : Robert J Singer, MD, Christopher S Ogilvy, MD, Guy Rordorf, MD : Jos Biller, MD, FACP, FAAN, FAHA, Alejandro A Rabinstein, MD : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Sep 07, 2021. INTRODUCTION Subarachnoid hemorrhage (SAH) is often a devastating event. The appropriate therapy for SAH depends in part upon the severity of hemorrhage. Level of consciousness on admission, patient age, and the amount of blood on initial head computed tomography (CT) scan are the most important prognostic factors for SAH at presentation [1]. A number of grading systems are used in practice to standardize the clinical classification of patients with SAH based upon the initial neurologic examination and the appearance of blood on the initial head CT. This topic will provide an overview of the more commonly used clinical and radiologic grading scales for SAH. Treatment and other aspects of SAH are discussed separately. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis" and "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) INDIVIDUAL GRADING SCALES An ideal SAH grading scale would provide the following capabilities [2-4]: Guide management decisions that are influenced by the severity of SAH Provide prognosis for clinicians, patients, and family members Assist practitioners in their ability to compare individual patients and groups of similar patients regarding studies that examine the impact of new treatments https://www.uptodate.com/contents/subarachnoid-hemorrhage-grading-scales/print 1/17 7/5/23, 12:01 PM Subarachnoid hemorrhage grading scales - UpToDate Enable practitioners to detect and quantify changes in disease severity while following an individual patient While a number of SAH grading scales have been proposed, none meets all of these requirements or is universally accepted [4,5]. Results for an individual patient may vary depending on the interval between symptom onset and assessment of the patient. Furthermore, there is a paucity of validation studies, and no prospective controlled comparison studies have been performed. Glasgow Coma Scale The Glasgow Coma Scale (GCS) ( table 1) was devised in the early 1970s [6]. The GCS is not a true SAH grading scale, but is rather a standardized method for evaluating the level of consciousness in a number of neurologic conditions including SAH. The GCS assigns points based on three parameters of neurologic function: Eye opening (spontaneous = 4, response to verbal command = 3, response to pain = 2, no eye opening = 1) Best verbal response (oriented = 5, confused = 4, inappropriate words = 3, incomprehensible sounds = 2, no verbal response = 1) Best motor response (obeys commands = 6, localizing response to pain = 5, withdrawal response to pain = 4, flexion to pain = 3, extension to pain = 2, no motor response = 1) In a prospective series of 765 patients with SAH, a higher GCS correlated with better outcome after aneurysm surgery [7]. However, a significant difference in outcome was observed only between patients with GCS scores of 15 and 14, while no significant differences were found between the remaining adjacent GCS scores. The interobserver variability of the GCS for patients with SAH is moderate (kappa 0.46) [8]. The GCS has been incorporated into several additional SAH grading systems. (See 'World Federation of Neurological Surgeons grading scale' below and 'Ogilvy and Carter grading system' below.) It should be recognized that sedating medications and intubation can confound interpretation of the clinical SAH scales, particularly the GCS and those that incorporate it, since such interventions will reduce the level of consciousness and impair verbal responses. Hunt and Hess grading system The grading system proposed by Hunt and Hess in 1968 ( table 2) [9] is one of the most widely used [10]. The scale was intended as an index of surgical risk. The initial clinical grade correlates with the severity of hemorrhage. Grade 1: Asymptomatic or mild headache and slight nuchal rigidity https://www.uptodate.com/contents/subarachnoid-hemorrhage-grading-scales/print 2/17 7/5/23, 12:01 PM Subarachnoid hemorrhage grading scales - UpToDate Grade 2: Moderate to severe headache, stiff neck, no neurologic deficit except cranial nerve palsy Grade 3: Drowsy or confused, mild focal neurologic deficit Grade 4: Stupor, moderate or severe hemiparesis Grade 5: Deep coma, decerebrate posturing The grade is advanced one level for the presence of serious systemic disease (eg, hypertension, diabetes, severe arteriosclerosis, chronic pulmonary disease) or vasospasm on angiography. A subsequent modification proposed by Hunt and Kosnik added a grade 0 for unruptured aneurysms and a grade 1a for a fixed neurologic deficit without other signs of SAH [11]. Although the Hunt and Hess scale is easy to administer, the classifications are arbitrary, some of the terms are vague (eg, drowsy, stupor, and deep coma) and some patients may present with initial features that defy placement within a single grade [4]. As an example, a rare presentation of SAH may include severe headache (ie, grade 2), normal level of consciousness, and severe hemiparesis (ie, grade 4). In such cases, the clinician must subjectively decide which of the presenting features is most important for determining the grade. A systematic review of SAH grading scales found conflicting data regarding the utility of the Hunt and Hess scale for prognosis [4]. Furthermore, it is unclear if there are significant differences in outcome for adjacent Hunt and Hess grades. Some studies evaluating Hunt and Hess grades found significant differences in outcome for some adjacent grades and not others [8,12] A study of 230 patients with SAH found a significant difference in outcome for compressed but not adjacent Hunt and Hess grades; patients with grades 1 to 3 had better outcomes compared with those with grades 4 and 5 [13] Another study of 405 patients with SAH found no significant difference for the risk of poor outcome or death between patients with Hunt and Hess grades 0 to 2 [2]. Furthermore, the risk was significantly different only when comparing patients with Hunt and Hess grade 3 to those with grade 0. The interobserver variability for the Hunt and Hess scale is moderate (kappa 0.41 to 0.48) [8,14,15]. https://www.uptodate.com/contents/subarachnoid-hemorrhage-grading-scales/print 3/17 7/5/23, 12:01 PM Subarachnoid hemorrhage grading scales - UpToDate World Federation of Neurological Surgeons grading scale The grading system of the World Federation of Neurological Surgeons (WFNS) ( table 3) was proposed in 1988 [16]. It is based on the GCS score (see 'Glasgow Coma Scale' above) and the presence of motor deficits. Grade 1: GCS score 15, no motor deficit Grade 2: GCS score 13 to 14, no motor deficit Grade 3: GCS score 13 to 14, with motor deficit Grade 4: GCS score 7 to 12, with or without motor deficit Grade 5: GCS score 3 to 6, with or without motor deficit Unlike the Hunt and Hess scale, the WFNS scale uses objective terminology to assign grades [4]. However, it may be more complex to administer than the Hunt and Hess scale because it requires assessment of both motor function and GCS. One study of 50 patients with SAH found that the interobserver variability for the WFNS scale was moderate (kappa of 0.6) [15]. A systematic review of SAH grading scales found conflicting data regarding the prognostic power of the WFNS grades [4]; two studies showed a stepwise increase in the likelihood of poor outcome with increasing WFNS grade [8,17], while others did not find consistent significant differences in outcome between adjacent WFNS grades [7,12,18]. In a study assessing a series of 185 patients with SAH, the Hunt and Hess score correlated more strongly with outcome at six months than the GCS or World Federation of Neurological Surgeons Scale (WFNS) [19]. However, individual grades for all three scales demonstrated suboptimal sensitivity, specificity, and predictive value. In addition, nearly half of the patients with poor scale grades on admission had a good outcome. The WFNS in conjunction with the Japan Neurosurgical Society proposed a modification to the scale such that the presence of motor deficit as outlined above is excluded. In two studies, this modified scale appeared to have better discriminatory value compared with the original WFNS scale, but broader validation studies are required [20-22]. Fisher scale The Fisher scale ( table 4) was devised in 1980 as an index of vasospasm risk (but not clinical outcome) based upon the hemorrhage pattern seen on initial head CT scan [23]. Group 1: No blood detected Group 2: Diffuse deposition or thin layer with all vertical layers of blood (in interhemispheric fissure, insular cistern, or ambient cistern) less than 1 mm thick Group 3: Localized clots and/or vertical layers of blood 1 mm or more in thickness Group 4: Intracerebral or intraventricular clots with diffuse or no subarachnoid blood https://www.uptodate.com/contents/subarachnoid-hemorrhage-grading-scales/print 4/17 7/5/23, 12:01 PM Subarachnoid hemorrhage grading scales - UpToDate The Fisher scale was validated in a small prospective series of 41 patients with SAH [24]. The interobserver variability for the Fisher scale indicates excellent agreement between observers (kappa 0.90) [2]. The Fisher scale has also been incorporated into other SAH grading systems. (See 'The VASOGRADE' below and 'Ogilvy and Carter grading system' below.) Modified Fisher scale Like the Fisher scale, the modified Fisher scale (also known as the Claassen grading system) proposed in 2001 is an index of the risk of delayed cerebral ischemia due to vasospasm after SAH ( table 5) [25,26]. It does not address clinical outcome. Unlike the Fisher scale, the modified Fisher scale takes into account the separate and additive risk of SAH and intraventricular hemorrhage (IVH). Ten cisterns or fissures are evaluated for blood with the modified Fisher scale. These include the frontal interhemispheric fissure, the quadrigeminal cistern, the bilateral suprasellar and ambient cisterns, and the bilateral basal sylvian and lateral sylvian fissures. The scale is graded as follows: Grade 0: No SAH or IVH Grade 1: Minimal SAH and no IVH Grade 2: Minimal SAH with bilateral IVH Grade 3: Thick SAH (completely filling one or more cistern or fissure) without bilateral IVH Grade 4: Thick SAH (completely filling one or more cistern or fissure) with bilateral IVH The modified Fisher scale was derived from analysis of data from 276 patients with SAH who had a head computed tomography (CT) scan within 72 hours of onset [25]. The best predictors of delayed cerebral ischemia due to vasospasm were thick SAH completely filling any cistern or fissure (odds ratio [OR] 2.3, 95% CI 1.5-9.5) and bilateral IVH (OR 4.1, 95% CI 1.7-9.8). Interrater reliability has been reported to be suboptimal [27]. While the modified Fisher scale has been validated in retrospectively, prospective validation is awaited [28,29]. The VASOGRADE The VASOGRADE grading scale was developed to predict the risk of delayed cerebral ischemia following SAH [30]. It is based on the WFNS scale and modified Fisher scale (mFS) at time of admission. The scale is divided into three categories: Green WFNS 1 or 2 and mFS 1 or 2 Yellow WFNS 1 to 3 and mFS 3 or 4 Red WFNS 4 or 5 and any mFS Compared with patients classified as "green," patients classified as "red" had a higher risk for delayed cerebral ischemia (OR 3.19; 95% CI 2.07-4.50) [30]. Patients classified as "yellow" had a https://www.uptodate.com/contents/subarachnoid-hemorrhage-grading-scales/print 5/17 7/5/23, 12:01 PM Subarachnoid hemorrhage grading scales - UpToDate similar risk as those classified as "green" (OR 1.31; 95% CI 0.77-2.23). Ogilvy and Carter grading system A SAH classification system to predict outcome for surgical management of SAH due to ruptured aneurysm was proposed by Ogilvy and Carter ( table 6) in 1998. It stratifies patients based upon age, Hunt and Hess grade (clinical condition), Fisher grade (SAH volume and vasospasm risk), and aneurysm size [2]. (See 'Hunt and Hess grading system' above and 'Fisher scale' above.) One point is given for each of the following variables: Age greater than 50 Hunt and Hess grade 4 to 5 (in coma) Fisher grade score 3 to 4 Aneurysm size >10 mm An additional point is added for a giant posterior circulation aneurysm ( 25 mm) The total score ranges from 0 to 5, corresponding to grades 0 to 5. The Ogilvy and Carter scale mitigates the potential subjectivity inherent in the Hunt and Hess system by compressing it into two grades (coma or no coma). Similarly, it compresses the Fisher scale into two grades. Nonetheless, it is more complex to administer than the Hunt and Hess scale, and requires knowledge of aneurysm size. In a prospective evaluation of this system in 72 patients with SAH, the authors reported good to excellent outcomes in greater than 78 percent of patients with grades 0 to 2 [2]. In comparison, good outcomes were seen in 67 percent of grade 3 and 25 percent of grade 4 patients. Of note, there was no statistical difference in outcomes between grades 0 and 1. However, patients with grades 2, 3, and 4 had statistically worse outcomes compared with those in the adjacent lower grade. Only surgically treated patients were included in the study, and none with grade 5 had surgery. The interobserver variability for the Ogilvy and Carter scale is very good, reflecting substantial observer agreement (kappa 0.69) [2]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) https://www.uptodate.com/contents/subarachnoid-hemorrhage-grading-scales/print 6/17 7/5/23, 12:01 PM Subarachnoid hemorrhage grading scales - UpToDate SUMMARY Grading scale selection Several subarachnoid hemorrhage (SAH) grading scales are available, but the selection of any grading scale is based on individual or institutional preference. No scale is optimal to help direct management, detect clinical changes over time, and guide prognosis. In addition, there are few validation studies of these scales and no prospective controlled comparison studies. (See 'Individual grading scales' above.) Glasgow Coma Scale The Glasgow Coma Scale (GCS) ( table 1) is a standardized scale for evaluating the level of consciousness. It is widely known and has utility for predicting outcome after SAH. Sedating medications and intubation can confound interpretation of the GCS. It has moderate interobserver variability. (See 'Glasgow Coma Scale' above.) Hunt and Hess grading scale The Hunt and Hess grading scale ( table 2) assesses severity of SAH. It is widely used and is easy to administer, but the terminology is subjective and atypical presentations of SAH may be difficult to classify. The interobserver variability is moderate. (See 'Hunt and Hess grading system' above.) World Federation of Neurological Surgeons grading scale The World Federation of Neurological Surgeons (WFNS) grading scale ( table 3) assesses severity of SAH. It uses the GCS score and objective terminology to assign grades. Interobserver variability for the WFNS scale is fair. (See 'World Federation of Neurological Surgeons grading scale' above.) Fisher and modified Fisher scales The Fisher scale ( table 4) is an index of vasospasm risk (but not clinical outcome) based upon the hemorrhage pattern seen on initial head computed tomography (CT) scan. It has been validated prospectively, and interobserver variability is excellent. (See 'Fisher scale' above.) The modified Fisher scale ( table 5) is an index of the risk of delayed cerebral ischemia due to vasospasm after SAH. Unlike the Fisher scale, the modified Fisher scale takes into account the separate and additive risk of SAH and intraventricular hemorrhage (IVH). (See 'Modified Fisher scale' above.) VASOGRADE scale The VASOGRADE is a three-category grading scale using the WFNS and modified Fisher scales to predict the risk of delayed cerebral ischemia following SAH. (See 'The VASOGRADE' above.) Ogilvy and Carter scale The Ogilvy and Carter scale ( table 6) system was developed to predict outcome for surgical management of SAH due to ruptured aneurysm. It incorporates patient age, Hunt and Hess, Fisher grade, and aneurysm size. It is more https://www.uptodate.com/contents/subarachnoid-hemorrhage-grading-scales/print 7/17 7/5/23, 12:01 PM Subarachnoid hemorrhage grading scales - UpToDate complex to administer than Hunt and Hess. Interobserver variability for the Ogilvy and Carter scale is very good. (See 'Ogilvy and Carter grading system' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Hijdra A, van Gijn J, Nagelkerke NJ, et al. Prediction of delayed cerebral ischemia, rebleeding, and outcome after aneurysmal subarachnoid hemorrhage. Stroke 1988; 19:1250. 2. Ogilvy CS, Carter BS. A proposed comprehensive grading system to predict outcome for surgical management of intracranial aneurysms. Neurosurgery 1998; 42:959. 3. Takagi K, Tamura A, Nakagomi T, et al. How should a subarachnoid hemorrhage grading scale be determined? A combinatorial approach based solely on the Glasgow Coma Scale. J Neurosurg 1999; 90:680. 4. Rosen DS, Macdonald RL. Subarachnoid hemorrhage grading scales: a systematic review. Neurocrit Care 2005; 2:110. 5. Dengler NF, Sommerfeld J, Diesing D, et al. Prediction of cerebral infarction and patient outcome in aneurysmal subarachnoid hemorrhage: comparison of new and established radiographic, clinical and combined scores. Eur J Neurol 2018; 25:111. 6. Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet 1974; 2:81. 7. Gotoh O, Tamura A, Yasui N, et al. Glasgow Coma Scale in the prediction of outcome after early aneurysm surgery. Neurosurgery 1996; 39:19. 8. Oshiro EM, Walter KA, Piantadosi S, et al. A new subarachnoid hemorrhage grading system based on the Glasgow Coma Scale: a comparison with the Hunt and Hess and World Federation of Neurological Surgeons Scales in a clinical series. Neurosurgery 1997; 41:140. 9. Hunt WE, Hess RM. Surgical risk as related to time of intervention in the repair of intracranial aneurysms. J Neurosurg 1968; 28:14. 10. van Gijn J, Bromberg JE, Lindsay KW, et al. Definition of initial grading, specific events, and overall outcome in patients with aneurysmal subarachnoid hemorrhage. A survey. Stroke 1994; 25:1623. 11. Hunt WE, Kosnik EJ. Timing and perioperative care in intracranial aneurysm surgery. Clin Neurosurg 1974; 21:79. 12. Hirai S, Ono J, Yamaura A. Clinical grading and outcome after early surgery in aneurysmal subarachnoid hemorrhage. Neurosurgery 1996; 39:441. https://www.uptodate.com/contents/subarachnoid-hemorrhage-grading-scales/print 8/17 7/5/23, 12:01 PM Subarachnoid hemorrhage grading scales - UpToDate 13. Proust F, Hannequin D, Langlois O, et al. Causes of morbidity and mortality after ruptured aneurysm surgery in a series of 230 patients. The importance of control angiography. Stroke 1995; 26:1553. 14. Lindsay KW, Teasdale GM, Knill-Jones RP. Observer variability in assessing the clinical features of subarachnoid hemorrhage. J Neurosurg 1983; 58:57. 15. Degen LA, Dorhout Mees SM, Algra A, Rinkel GJ. Interobserver variability of grading scales for aneurysmal subarachnoid hemorrhage. Stroke 2011; 42:1546. 16. Report of World Federation of Neurological Surgeons Committee on a Universal Subarachnoid Hemorrhage Grading Scale. J Neurosurg 1988; 68:985. 17. Rosen DS, Macdonald RL. Grading of subarachnoid hemorrhage: modification of the world World Federation of Neurosurgical Societies scale on the basis of data for a large series of patients. Neurosurgery 2004; 54:566. 18. Lagares A, G mez PA, Lobato RD, et al. Prognostic factors on hospital admission after spontaneous subarachnoid haemorrhage. Acta Neurochir (Wien) 2001; 143:665. 19. Aulmann C, Steudl WI, Feldmann U. [Validation of the prognostic accuracy of neurosurgical admission scales after rupture of cerebral aneurysms]. Zentralbl Neurochir 1998; 59:171. 20. Sano H, Satoh A, Murayama Y, et al. Modified World Federation of Neurosurgical Societies subarachnoid hemorrhage grading system. World Neurosurg 2015; 83:801. 21. Sano H, Inamasu J, Kato Y, et al. Modified world federation of neurosurgical societies subarachnoid hemorrhage grading system. Surg Neurol Int 2016; 7:S502. 22. Fung C, Inglin F, Murek M, et al. Reconsidering the logic of World Federation of Neurosurgical Societies grading in patients with severe subarachnoid hemorrhage. J Neurosurg 2016; 124:299. 23. Fisher CM, Kistler JP, Davis JM. Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning. Neurosurgery 1980; 6:1. 24. Kistler JP, Crowell RM, Davis KR, et al. The relation of cerebral vasospasm to the extent and location of subarachnoid blood visualized by CT scan: a prospective study. Neurology 1983; 33:424. 25. Claassen J, Bernardini GL, Kreiter K, et al. Effect of cisternal and ventricular blood on risk of delayed cerebral ischemia after subarachnoid hemorrhage: the Fisher scale revisited. Stroke 2001; 32:2012. 26. Frontera JA, Claassen J, Schmidt JM, et al. Prediction of symptomatic vasospasm after subarachnoid hemorrhage: the modified fisher scale. Neurosurgery 2006; 59:21. https://www.uptodate.com/contents/subarachnoid-hemorrhage-grading-scales/print 9/17 7/5/23, 12:01 PM Subarachnoid hemorrhage grading scales - UpToDate 27. Melinosky C, Kincaid H, Claassen J, et al. The Modified Fisher Scale Lacks Interrater Reliability. Neurocrit Care 2021; 35:72. 28. Kramer AH, Hehir M, Nathan B, et al. A comparison of 3 radiographic scales for the prediction of delayed ischemia and prognosis following subarachnoid hemorrhage. J Neurosurg 2008; 109:199. 29. van der Steen WE, Leemans EL, van den Berg R, et al. Radiological scales predicting delayed cerebral ischemia in subarachnoid hemorrhage: systematic review and meta-analysis. Neuroradiology 2019; 61:247. 30. de Oliveira Manoel AL, Jaja BN, Germans MR, et al. The VASOGRADE: A Simple Grading Scale for Prediction of Delayed Cerebral Ischemia After Subarachnoid Hemorrhage. Stroke 2015; 46:1826. Topic 1094 Version 20.0 https://www.uptodate.com/contents/subarachnoid-hemorrhage-grading-scales/print 10/17 7/5/23, 12:01 PM Subarachnoid hemorrhage grading scales - UpToDate GRAPHICS Glasgow Coma Scale (GCS) Score Eye opening Spontaneous 4 Response to verbal command 3 Response to pain 2 No eye opening 1 Best verbal response Oriented 5 Confused 4 Inappropriate words 3 Incomprehensible sounds 2 No verbal response 1 Best motor response Obeys commands 6 Localizing response to pain 5 Withdrawal response to pain 4 Flexion to pain 3 Extension to pain 2 No motor response 1 Total The GCS is scored between 3 and 15, 3 being the worst and 15 the best. It is composed of three parameters: best eye response (E), best verbal response (V), and best motor response (M). The components of the GCS should be recorded individually; for example, E2V3M4 results in a GCS score of 9. A score of 13 or higher correlates with mild brain injury, a score of 9 to 12 correlates with moderate injury, and a score of 8 or less represents severe brain injury. Graphic 81854 Version 9.0 https://www.uptodate.com/contents/subarachnoid-hemorrhage-grading-scales/print 11/17 7/5/23, 12:01 PM Subarachnoid hemorrhage grading scales - UpToDate Hunt and Hess grading system for patients with subarachnoid hemorrhage Grade Neurologic status 1 Asymptomatic or mild headache and slight nuchal rigidity 2 Severe headache, stiff neck, no neurologic deficit except cranial nerve palsy 3 Drowsy or confused, mild focal neurologic deficit 4 Stuporous, moderate or severe hemiparesis 5 Coma, decerebrate posturing Based upon initial neurologic examination. Adapted from: Hunt W, Hess R. Surgical risk as related to time of intervention in the repair of intracranial aneurysms. J Neurosurg 1968; 28:14. Graphic 69179 Version 5.0 https://www.uptodate.com/contents/subarachnoid-hemorrhage-grading-scales/print 12/17 7/5/23, 12:01 PM Subarachnoid hemorrhage grading scales - UpToDate World Federation of Neurological Surgeons subarachnoid hemorrhage grading scale Grade GCS score Motor deficit 1 15 Absent 2 13 to 14 Absent 3 13 to 14 Present 4 7 to 12 Present or absent 5 3 to 6 Present or absent GCS: Glasgow Coma Scale. Data from: Report of World Federation of Neurological Surgeons Committee on a Universal Subarachnoid Hemorrhage Grading Scale. J Neurosurg 1988; 68:985. Graphic 65468 Version 3.0 https://www.uptodate.com/contents/subarachnoid-hemorrhage-grading-scales/print 13/17 7/5/23, 12:01 PM Subarachnoid hemorrhage grading scales - UpToDate [1] Fisher grade of cerebral vasospasm risk in subarachnoid hemorrhage Group Appearance of blood on head CT scan 1 No blood detected 2 Diffuse deposition or thin layer with all vertical layers (in interhemispheric fissure, insular cistern, ambient cistern) less than 1 mm thick 3 Localized clot and/or vertical layers 1 mm or more in thickness 4 Intracerebral or intraventricular clot with diffuse or no subarachnoid blood CT: computed tomography. Reference: 1. Fisher CM, Kistler JP, Davis JM. Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by CT scanning. Neurosurgery 1980; 6:1. Graphic 81122 Version 4.0 https://www.uptodate.com/contents/subarachnoid-hemorrhage-grading-scales/print 14/17 7/5/23, 12:01 PM Subarachnoid hemorrhage grading scales - UpToDate Modified Fisher (Claassen) subarachnoid hemorrhage CT rating scale Grade Head CT criteria 0 No SAH or IVH 1 Minimal SAH and no IVH 2 Minimal SAH with bilateral IVH 3 Thick SAH (completely filling one or more cistern or fissure) without bilateral IVH 4 Thick SAH (completely filling one or more cistern or fissure) with bilateral IVH CT: computed tomography; SAH: subarachnoid hemorrhage; IVH: intraventricular hemorrhage. From: Claassen J, Bernardini GL, Kreiter K, et al. E ect of cisternal and ventricular blood on risk of delayed cerebral ischemia after subarachnoid hemorrhage: the Fisher scale revisited. Stroke 2001; 32:2012. Graphic 57558 Version 5.0 https://www.uptodate.com/contents/subarachnoid-hemorrhage-grading-scales/print 15/17 7/5/23, 12:01 PM Subarachnoid hemorrhage grading scales - UpToDate Ogilvy and Carter grading system to predict outcome for surgical management of intracranial aneurysms Criteria Points Age 50 or less 0 Age greater than 50 1 Hunt and Hess grade 0 to 3 (no coma) 0 Hunt and Hess grade 4 and 5 (in coma) 1 Fisher scale score 0 to 2 0 Fisher scale score 3 and 4 1 Aneurysm size 10 mm or less 0 Aneurysm size greater than 10 mm 1 Giant posterior circulation aneurysm size 25 mm or more 1 The total score ranges from 0 to 5, corresponding to grades 0 to 5 Adapted from: Ogilvy CS, Carter BS. A proposed comprehensive grading system to predict outcome for surgical management of intracranial aneurysms. Neurosurgery 1998; 42:959. Graphic 70705 Version 4.0 https://www.uptodate.com/contents/subarachnoid-hemorrhage-grading-scales/print 16/17 7/5/23, 12:01 PM Subarachnoid hemorrhage grading scales - UpToDate Contributor Disclosures Robert J Singer, MD No relevant financial relationship(s) with ineligible companies to disclose. Christopher S Ogilvy, MD Consultant/Advisory Boards: Cerevasc [Hydrocephalus]; Contour [Aneurysms]; Medtronic [Chronic subdural hematoma]. All of the relevant financial relationships listed have been mitigated. Guy Rordorf, MD No relevant financial relationship(s) with ineligible companies to disclose. Jos Biller, MD, FACP, FAAN, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Alejandro A Rabinstein, MD Grant/Research/Clinical Trial Support: Chiesi [Small investigator- initiated project]. Consultant/Advisory Boards: AstraZeneca [Secondary stroke prevention]; Brainomix [AI for stroke diagnostics]; Novo Nordisk [Stroke risk]; Shionogi [Stroke neuroprotection]. Other Financial Interest: Boston Scientific [Adverse event adjudication committee member for stroke risk reduction device in patients with atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/subarachnoid-hemorrhage-grading-scales/print 17/17

7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Subdural hematoma in adults: Etiology, clinical features, and diagnosis : William McBride, MD : Jos Biller, MD, FACP, FAAN, FAHA, Alejandro A Rabinstein, MD, Glenn A Tung, MD, FACR : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Sep 20, 2021. INTRODUCTION Subdural hematoma (SDH) is a form of intracranial hemorrhage characterized by bleeding into the space between the dural and arachnoid membranes surrounding the brain. The pathophysiology, etiology, clinical features, and diagnostic evaluation of SDH will be discussed here. A rapid overview summarizes clinical features, evaluation, and management of SDH in adults ( table 1). Other aspects of SDH are reviewed separately. (See "Subdural hematoma in adults: Management and prognosis".) (See "Intracranial subdural hematoma in children: Epidemiology, anatomy, and pathophysiology".) (See "Intracranial subdural hematoma in children: Clinical features, evaluation, and management".) Other forms of intracranial hemorrhage and intracerebral hemorrhage are discussed elsewhere. (See "Intracranial epidural hematoma in adults".) (See "Intracranial epidural hematoma in children: Epidemiology, anatomy, and pathophysiology" and "Intracranial epidural hematoma in children: Clinical features, https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 1/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate diagnosis, and management".) (See "Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis" and "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis" and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".) (See "Nonaneurysmal subarachnoid hemorrhage".) (See "Perimesencephalic nonaneurysmal subarachnoid hemorrhage".) (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis" and "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis".) PATHOPHYSIOLOGY AND ETIOLOGY Anatomy SDH forms between the dural and the arachnoid membranes overlying the brain ( image 1 and figure 1 and figure 2). Anatomic distinctions between the different forms of brain hemorrhage may be visible by imaging and may be used to help guide treatment and to identify underlying mechanisms. SDH is often crescent shaped because bleeding follows the contour of the overlying dura. SDH will typically span overlying epidural sutural margins but not the interhemispheric falx. Most SDH occur along the cerebral convexities. However, SDH may also occur in the subdural spaces between cerebral and cerebellar hemispheres or circumferentially around the brainstem [1]. Extracranial SDH along the spinal column is a rare site of bleeding [2,3]. Other forms of intracranial hemorrhage are defined by their distinct anatomic sites of bleeding: Subarachnoid hemorrhage (SAH) occurs between the arachnoid and pial membranes ( image 2). Blood from SAH closely follows the contour of the overlying pial membrane and cortical gyri of the brain. Intraventricular blood may be seen in SAH because the subarachnoid space communicates with intraventricular foramen in the fourth ventricle. (See "Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis".) Epidural hematomas arise in the potential space between the dura and the inner table of the skull ( image 3). Epidural hematomas often have a lens-shaped appearance because bleeding is typically restricted by calvarial sutures where the dura attaches to the skull. Epidural hematomas can span the underlying dural attachments including the interhemispheric falx. (See "Intracranial epidural hematoma in adults".) https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 2/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate Intracerebral hemorrhage describes bleeding within the brain tissue ( image 4). (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis".) Pathophysiology Acute SDH occurs due to bleeding within the subdural space and may resolve by resorption or become chronic by membranous encapsulation and hygroma formation. Vascular injury in acute subdural hematoma Acute SDH is usually caused by tearing of the veins located between the arachnoid membranes and the dura in most cases. These bridging veins drain from the surface of the brain into the dural sinuses [4]. Venous bleeding at this site is usually arrested by the rising intracranial pressure or compartmental tamponade by the clot itself. Arterial rupture can also result in SDH in approximately 20 to 30 percent of SDH cases [5-7]. In an autopsy study of 46 patients with isolated SDH that included 23 caused by arterial injury, most were caused by injuries to small cortical arteries of <1 mm diameter [7]. Both arterial and venous SDHs had generally similar postmortem characteristics, although SDHs caused by arterial rupture were predominately located in the temporoparietal region, while those caused by bridging vein rupture were predominately frontoparietal. Development of chronic subdural hematoma Following the initial dural trauma and development of an acute SDH, the process of blood resorption begins with breakdown of erythrocytes and other cellular components. In addition, collagen synthesis is induced and fibroblasts spread over the inner surface of the dura to form a thick outer membrane [8,9]. Subsequently, a thinner inner membrane develops, resulting in complete encapsulation of the clot. This process typically occurs over a time course of approximately two weeks [9]. (See 'Imaging features' below.) Some chronic SDH are subsequently resorbed completely. However, others may expand during this time. This may be due either to spontaneous or triggered recurrent bleeding ("acute-on- chronic" SDH) or to the formation of a subdural hygroma. Development of subdural hygroma Communication between the subdural and subarachnoid space may allow cerebrospinal fluid to accumulate and form a subdural hygroma. Membrane permeability during SDH resolution, an osmotic draw of water into the protein-rich SDH fluid, and injury to the arachnoid membrane may contribute to this process [9,10]. More than one-half of all subdural hygromas grow in size and may result in greater mass effect than the initial SDH [4]. Although the reason for this observation is unknown, a larger initial clot size appears to be related to a greater likelihood of subsequent expansion [11]. https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 3/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate Most subdural hygromas will resolve slowly over several weeks with adequate reexpansion of the intracranial contents. However, some will persist [10]. The persistence of hygromas appears to be related to the formation of pseudomembranes that line the space created between the arachnoid and the dura during the acute phase. These subsequently become vascularized by abnormally permeable capillaries that allow for further accumulation of subdural fluid. Specific etiologies SDH may be spontaneous or triggered by an inciting event. Trauma Head trauma is the most common cause of SDH, with the majority of cases related to motor vehicle accidents, falls, and assaults [12]. The linear translation of acceleration along the diameter of the skull in the lateral direction can produce injury to veins, arteries, meninges, or brain parenchyma, resulting in multiple forms of intracranial hemorrhage, including SDH [13]. A retrospective cohort study of emergency department administrative claims data involving 27,502 patients with SDH identified a traumatic source in 71 percent [14]. (See "Traumatic brain injury: Epidemiology, classification, and pathophysiology".) In addition, trivial or minor head trauma is frequently identified as an antecedent to acute or chronic SDH in susceptible patients with cerebral atrophy or other risk factors [15,16]. (See 'Cerebral atrophy' below.) Intentional or inflicted head trauma is also a source for SDH, typically seen in infants and children. (See "Child abuse: Epidemiology, mechanisms, and types of abusive head trauma in infants and children", section on 'Intracranial bleeding' and "Intracranial subdural hematoma in children: Epidemiology, anatomy, and pathophysiology", section on 'Type of injury'.) Intracranial hypotension Low cerebrospinal fluid pressure (intracranial hypotension) is another mechanism that can result in SDH. Intracranial hypotension may be caused by a spontaneous or iatrogenic cerebrospinal fluid leak such as following lumbar puncture or ventriculostomy, lumboperitoneal shunt placement, or other neurosurgical procedures [17]. As the cerebrospinal fluid pressure decreases, reduction in the buoyancy (ie, sagging) of the brain causes traction on bridging veins and leads to tearing and rupture of these vessels. In addition, intracranial hypotension may lead to engorgement of cerebral veins and subsequent leakage of fluid into the subdural space ( image 5). (See "Spontaneous intracranial hypotension: Pathophysiology, clinical features, and diagnosis" and "Normal pressure hydrocephalus", section on 'Shunt complications'.) Less common causes Arterial sources Arterial injury may coexist with venous injury in traumatic and other causes of SDH. In addition, arterial injuries occurring in the subdural space may be a cause https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 4/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate of spontaneous SDH. Specific underlying arterial causes of SDH include: Intracerebral hemorrhage Primary intracerebral hemorrhage may be accompanied by SDH when bleeding through the cortical surface extends into the subdural space. Intracerebral hemorrhages with SDH involving the cerebellum have been attributed to hypertension and those in lobar regions have been associated with cerebral amyloid angiopathy [18,19]. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis".) Ruptured cerebral aneurysm A ruptured cerebral aneurysm causing SAH that extends into the subdural space occurs in approximately 0.5 up to 7.9 percent of cases [20-24]. Bleeding is typically visible on imaging at both sites. Very rarely, aneurysm rupture causes isolated SDH without visible SAH [24]. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) Cerebral vascular malformations Rupture of an arteriovenous malformation, arteriovenous fistula, or cavernous malformation at the cortical surface may rarely present with isolated acute SDH [25-28]. (See "Brain arteriovenous malformations" and "Vascular malformations of the central nervous system".) Vasculopathy Cocaine abuse with associated hypertension and vasospasm has been proposed as a rare cause of spontaneous SDH presumably via cortical vessel injury in the setting of vasospasm [29,30]. Neoplasm Neoplastic lesions may lead to SDH by vessel injury from mass effect or from neovascular rupture. SDH associated with dural (pachymeningeal) metastasis are commonly defined by clinical history and identification of dural nodules on magnetic resonance imaging or pathologic specimen [31-37]. The most common malignancies associated with dural metastases are breast, prostate, lung, and lymphoma [38]. (See "Brain metastases in breast cancer" and "Initial staging and evaluation of males with newly diagnosed prostate cancer", section on 'Metastasis (M)' and "Brain metastases in non-small cell lung cancer" and "Secondary central nervous system lymphoma: Clinical features and diagnosis".) Rarely, primary brain tumors such as meningiomas may also be complicated by SDH [39,40]. (See "Epidemiology, pathology, clinical features, and diagnosis of meningioma".) EPIDEMIOLOGY https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 5/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate While the exact incidence of SDH is unknown, acute SDH is found in approximately 11 percent of mild to moderate head injuries that require hospitalization [12,41,42] and approximately 20 percent of severe traumatic brain injuries [12,43-46]. The mean age of patients with SDH caused by head injuries is between approximately 30 and 50 years old, the majority of whom are males [12,41,42,47,48]. Motor vehicle accidents are the most common cause of traumatic SDH among younger adults, while falls are the most common cause among older adults [49]. SDH is a more common complication of trauma than epidural hematoma [50]. The incidence of chronic SDH ranges from 1.7 up to 20.6 per 100,000 persons/year [51]. This risk appears to be increasing over time, likely as a consequence of an aging population and the increased use of antiplatelet and anticoagulant medications [52]. Chronic SDH is more common in older than younger patients, who are likelier to have cerebral atrophy. RISK FACTORS Cerebral atrophy Patients with significant cerebral atrophy are at an elevated risk for SDH. Cerebral atrophy results in a larger space between the dural membrane and cortical surface of the brain, which increases tension on bridging veins. Bleeding in the subdural space may occur when this tension leads to venous injury. Cerebral atrophy is common in older adults, those with a history of chronic alcohol abuse, and those with previous traumatic brain injury. In such patients, trivial head trauma or even pure whiplash injury in the absence of physical impact may produce an SDH [9,53]. Antithrombotic therapy The use of antithrombotic agents increases the risk of SDH, as illustrated by a case-control study of 10,010 patients with a first-ever SDH [54]. An increased risk of SDH was associated with the use of the following antithrombotic medications: Aspirin (cases and controls 26.7 and 22.4 percent; adjusted odds ratio [OR] 1.24, 95% CI 1.15-1.33) Clopidogrel (cases and controls 5.0 and 2.2 percent; OR 1.87, 95% CI 1.57-2.24) Direct oral anticoagulant (cases and controls 1.0 and 0.6 percent; OR 1.73, 95% CI 1.31-2.28) Vitamin K antagonist (cases and controls 14.3 and 4.9 percent; OR 3.69, 95% CI 3.38-4.03) The risk of SDH appears highest among patients taking warfarin and increases with the intensity of anticoagulation. A case-control analysis compared 121 consecutive adults who developed intracranial hemorrhage while taking warfarin (including 44 with SDH) with 363 matched controls managed by the outpatient anticoagulation clinic [55]. The risk of SDH was significantly https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 6/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate associated with a prothrombin time ratio of >2, approximately equivalent to an international normalized ratio (INR) >4. The increased risk of SDH with direct oral anticoagulants may be similar to aspirin. A clinical trial involving 27,395 patients randomized to rivaroxaban, aspirin, or low-dose rivaroxaban plus aspirin showed a similarly low incidence of SDH (0.04 to 0.06 per 100 patient-years) among the treatment arms [56]. A meta-analysis likewise showed that the risk of SDH for patients taking factor Xa inhibitors was similar to those taking aspirin (OR 0.97, 95% CI 0.52-1.81) [56]. Dual antiplatelet or combination antiplatelet plus anticoagulation therapy confers a higher risk of SDH than monotherapy [57,58]. In a meta-analysis of more than 23,000 patients from trials testing the addition of clopidogrel to aspirin, dual therapy was associated with an elevated risk (risk ratio 2.0, 95% CI 1.0-3.8) [57]. However, the absolute risk was low (1.1 per 1000 patient- years). Other coagulopathies The risk of traumatic and spontaneous SDH may be increased in patients with thrombocytopenia and those with liver disease [59-61]. (See "Approach to the adult with a suspected bleeding disorder".) SDH is a reported complication of systemic thrombolysis, although the incidence is quite low. One trial reported that treatment with heparin, aspirin, and intravenous recombinant tissue-type plasminogen activator (rt-PA) at doses of either 150 or 100 mg was complicated by SDH in 0.2 and 0.1 percent of patients, respectively [62]. Another study found that SDH occurring in patients receiving rt-PA for acute myocardial infarction was associated with other risk factors such as a history of preexisting head trauma or older age [63]. CLINICAL MANIFESTATIONS The initial presentation of SDH has a wide spectrum of manifestations. Patients with severe head trauma and SDH may present with symptoms related to coexisting epidural hematoma, subarachnoid hemorrhage, cerebral contusion, diffuse brain swelling, and fractures. Any of these injuries may coexist in a given patient following trauma, and their clinical manifestations can be difficult to distinguish [4,12,41,42]. Such patients may also present with coma due to the overall insult to the brain. The clinical features of patients with traumatic brain injury are discussed in greater detail separately. (See "Acute mild traumatic brain injury (concussion) in adults", section on 'Clinical features'.) By contrast, patients with a mild or trivial trauma and those with spontaneous SDH are likelier to present with signs and symptoms due to the mass effect of the SDH alone. https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 7/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate SDH may also be asymptomatic, found incidentally on imaging obtained for unrelated symptoms. Focal neurologic signs Specific presenting symptoms may vary according to the location of the bleeding overlying the brain structures impacted. Frontal lobe Hemiparesis, speech impairment (dominant hemisphere), executive dysfunction (nondominant hemisphere) [64] Parietal lobe Speech impairment (dominant hemisphere), sensory impairment (nondominant hemisphere) [65] Posterior fossa Headache, vomiting, anisocoria, dysphagia, cranial nerve palsies, nuchal rigidity, ataxia [66] Interhemispheric Headache, paraparesis without facial weakness (falx syndrome) [67,68] Focal deficits may be either ipsilateral or contralateral to the side of the SDH. Contralateral hemiparesis can occur due to direct compression of cortex underlying the hematoma, whereas ipsilateral hemiparesis can occur with lateral displacement of the midbrain caused by the mass effect of the hematoma. Such midbrain displacement results in compression of the contralateral cerebral peduncle against the free edge of the tentorium ( image 6) [4,69]. Bilateral chronic SDH may present with intermittent paraparesis that is proximal and painless [70,71]. Headaches are commonly reported in alert patients with SDH, due to activation of nociceptors within the dura [72,73]. Seizures Patients with acute or chronic SDH may also present with seizures or status epilepticus [74,75]. The incidence of early seizures (within seven days of onset) appears higher for patients with acute SDH than those with chronic SDH (28 versus 5 percent) [76]. Risk factors for seizures associated with acute SDH include lower Glasgow coma scale (GCS) score and the need for surgical evacuation with craniotomy [77]. For patients with chronic SDH, risks for seizures are related to premorbid conditions including prior alcohol use and prior stroke. Acute large hematoma Those with large SDH may present with more severe or progressive symptoms including stupor or herniation syndromes ( table 2) due to shifting of midline brain structures [1]. Approximately 50 percent of patients may be comatose upon presentation. Up to https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 8/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate one-third of these patients have an initial transient "lucid interval" after the acute injury that is followed by a progressive neurologic decline to coma [4,12]. In rare instances of SDH, cerebral hypoperfusion due to increased intracranial pressure or mass effect may culminate in cerebral infarction [78]. Chronic subdural hematoma Patients who become symptomatic with chronic SDH are more likely to present with nonfocal symptoms than those with acute SDH. The onset of bleeding may be difficult to establish, and symptoms may not become evident until weeks after the injury or other inciting source. Vague or mild, nonfocal symptoms may become clinically apparent when persistent or progressive. Such symptoms may include new or unexplained, progressive symptoms such as: Headache [79,80] Light-headedness Cognitive impairment [4,81] Apathy or depression [82,83] Parkinsonism (eg, tremor, rigidity) [84,85] Gait ataxia [86] Somnolence [87] Seizures [4,12,78,79] DIAGNOSIS AND EVALUATION The diagnosis of SDH is made by neuroimaging, typically computed tomography (CT) of the head, as part of the evaluation of a patient with a head injury or work-up for other symptoms. (See 'Clinical manifestations' above.) Other diagnostic imaging and laboratory testing may be indicated when the cause of the bleeding is not apparent. Imaging features Noncontrast head CT is the first-choice imaging study to rapidly diagnose SDH [88]. Brain magnetic resonance imaging (MRI) may also be used but typically takes longer to perform than CT and is less readily available in many facilities on an emergent basis. In addition, MRI may not be feasible for some patients with implanted metallic or electrical devices. (See "Patient evaluation for metallic or electrical implants, devices, or foreign bodies before magnetic resonance imaging".) SDH may be categorized clinically by the time since onset of bleeding. https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 9/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate Acute SDH presents 1 to 2 days after onset. Subacute SDH presents 3 to 14 days after onset. Chronic SDH presents 15 or more days after onset. However, these categories of acute, subacute, and chronic SDH are defined somewhat arbitrarily as there is no consensus in the literature regarding time thresholds. When there is no history of trauma or other inciting event prior to the clinical presentation of SDH, the age of the bleeding may be approximated by imaging features, described immediately below. Head CT Computed tomography (CT) of the head is the most widely used imaging study for acute head trauma owing to its speed, relative simplicity, and widespread availability [88,89]. Specific imaging characteristics can also help identify acute and chronic SDH. Acute SDH is readily visualized on head CT as a uniformly high-density crescentic collection ( image 7). Chronic SDH and hygromas appear as isodense to hypodense crescent-shaped lesions that may contain friable, vascularized pseudomembranes that enhance with intravenous contrast ( image 8 and image 9). Mixed-density SDH (also called "hematohygroma") contain both hyperdense and hypodense components. They may be acute or chronic. Within days after onset of bleeding, an acute SDH may have a mixed density on CT due to sedimentation of erythrocytes in the hemorrhage. In addition, spontaneous or triggered rebleeding in a chronic SDH may appear as a mixed-density SDH. Unilateral SDH with mass effect will typically distort brain anatomy on CT ( image 10). However, careful evaluation may be needed to identify cases with subtle imaging features. Bilateral SDH may be missed, as the brain parenchyma can appear symmetric, while a resolving SDH may be isointense relative to brain ( image 11) [4]. Head CT can also be used to help distinguish SDH from an epidural hematoma and other forms of intracranial hemorrhage by the pattern and shape of bleeding. (See 'Anatomy' above.) In a study published in 1988, approximately 91 percent of SDHs 5 mm in thickness were identified on initial head CT [90]. By contrast, SDHs 3 mm in thickness were often missed initially but noted to be present retrospectively. With improvements in resolution, modern- generation CT scanners may provide even greater sensitivity for the detection of SDH. However, there have been no published data to confirm this impression. https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 10/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate Brain MRI Brain magnetic resonance imaging (MRI) may be performed for the initial diagnosis of SDH. In a study of 40 patients with traumatic brain injury, MRI was as sensitive as CT for detecting acute hemorrhagic lesions including SDH [90]. Brain MRI may be the preferred imaging modality for the initial diagnosis or subsequent evaluation of SDH in specific circumstances: Identifying small bleeds Small chronic SDH on head CT may be mistaken for brain tissue or cerebrospinal fluid (CSF) but may be more easily identified on MRI ( image 11). For these patients, MRI may be preferred. Specific MRI sequences are sensitive for blood and may help identify small SDH: On fluid-attenuated inversion recovery (FLAIR) sequences, blood is typically hyperintense compared with CSF ( image 12). On T2* (eg, gradient echo or susceptibility-weighted image) sequences, blood is typically hypointense. Determining the age of the bleed Specific MRI sequences (eg, T1, T2, and T2* sequences) may help identify the age of a hemorrhagic lesion. The signal intensity of blood evolves as oxyhemoglobin in erythrocytes degrades to deoxyhemoglobin, methemoglobin, and finally hemosiderin. However, these imaging patterns used more commonly for intracerebral hemorrhage do not apply as well for SDH and other forms of extra-axial intracranial bleeding. The timing of MRI findings of an evolving SDH for an individual patient may vary by the size of the bleeding, presence of rebleeding, and extent of pseudomembrane formation [91]. Evaluating for secondary causes MRI can provide additional information regarding the presence and extent of associated intraparenchymal lesions such as intracerebral hemorrhage, arteriovenous malformations, or dural neoplasms [89,90]. (See 'Evaluation for underlying causes' below.) Confirming that the subdural lesion is hemorrhagic MRI may be useful to identify the rare instances when a subdural lesion may be caused by a nonhemorrhagic source. Such patients typically lack a history of trauma or other risk factors for SDH or have atypical imaging findings on CT. In a review of 48 patients with SDH mimics, the most common causes of the subdural lesions were lymphoma, metastasis, sarcoma, and infection [92]. Follow-up imaging Urgent repeat neuroimaging, typically with CT, is indicated for patients with clinical deterioration to assess for hematoma expansion or rebleeding and guide treatment options. Surveillance imaging is also performed for stable patients to confirm the SDH is stable https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 11/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate by imaging. The role of imaging in the management of SDH is discussed in greater detail separately. (See "Subdural hematoma in adults: Management and prognosis", section on 'Follow- up imaging'.) Evaluation for underlying causes Patients with SDH attributed to trauma or in the setting of common risk factors (eg, older patient with baseline severe cerebral atrophy and chronic subdural hematoma) may not require additional imaging. Other patients without antecedent trauma or obvious risk factors for SDH should be evaluated for secondary causes. Brain and vascular imaging We prefer brain MRI with contrast to evaluate for secondary causes such as intracranial hypotension, associated intracerebral hemorrhage, or neoplasm. Repeat head CT with contrast may be performed as an alternative. (See 'Brain MRI' above.) Noninvasive angiography (eg, magnetic resonance angiography [MRA] or CT angiography [CTA]) may be indicated to evaluate for a vascular etiology when the history and initial imaging reveal no other obvious cause [24]. Digital subtraction angiography is performed when there is suspicion for an underlying vascular lesion that was not detected by noninvasive MRA or CTA. As an example, spontaneous SDH can rarely occur as a consequence of intracranial aneurysmal rupture, and angiography may be necessary to fully evaluate the possibility of an underlying vascular lesion [93]. (See 'Less common causes' above.) Laboratory testing A complete blood count, liver function tests, and prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) testing may identify patients with SDH due to coagulopathy. Electrolytes are useful to identify hyponatremia or other derangements which may increase the risk of seizures. Lumbar puncture is contraindicated due to the risk of herniation for patients with a space- occupying lesions such as an SDH. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 12/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Subdural hematoma (The Basics)") SUMMARY AND RECOMMENDATIONS Anatomy Subdural hematoma (SDH) forms between the dural and the arachnoid membranes overlying the brain ( figure 2 and image 1). SDH often has a crescent- shaped appearance because bleeding follows the contour of the overlying dura. Most SDHs occur along the cerebral convexities but may also occur in the subdural spaces between cerebral and cerebellar hemispheres or circumferentially around the brainstem ( figure 1). (See 'Anatomy' above.) Pathophysiology Acute SDH is usually caused by tearing of the veins located between the arachnoid membranes and the dura in most cases. An arterial source may be found in approximately 20 to 30 percent of SDH cases. Etiologies SDH may be spontaneous or triggered by an inciting event. (See 'Specific etiologies' above.) Head trauma is the most common cause of SDH, with most cases related to motor vehicle accidents, falls, and assaults. Low cerebrospinal fluid pressure (intracranial hypotension) may cause SDH by a spontaneous or iatrogenic cerebrospinal fluid leak such as following lumbar puncture or ventriculostomy, lumboperitoneal shunt placement, or other neurosurgical procedures. Arterial causes of SDH include trauma, intracerebral hemorrhage, ruptured cerebral aneurysm, cerebral arteriovenous malformation, or vasculopathy. https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 13/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate Neoplastic lesions may lead to SDH by mass effect or neovascular rupture. SDH associated with dural (pachymeningeal) metastasis are breast, prostate, lung, and lymphoma. Primary brain tumors are a rare source of SDH. Epidemiology Acute SDH complicates approximately 11 percent of mild to moderate head injuries that require hospitalization and approximately 20 percent of severe traumatic brain injuries. The incidence of chronic SDH ranges from 1.7 up to 20.6 per 100,000 persons/year. (See 'Epidemiology' above.) Risk factors Patients with significant cerebral atrophy, those who use antithrombotic medications, or who have other sources of coagulopathy are at an elevated risk for SDH. (See 'Risk factors' above.) Clinical manifestations The initial presentation of SDH has a wide spectrum of manifestations. Patients with severe head trauma and SDH may present with coma due to the overall insult to the brain, while those with a mild or trivial trauma and those with spontaneous SDH are likelier to present with symptoms due to the SDH alone ( table 1). (See 'Clinical manifestations' above.) Symptoms of acute SDH include weakness, numbness, visual impairment, and seizures. Patients who become symptomatic with chronic SDH are more likely to present with nonfocal symptoms than those with acute SDH. SDH may also be asymptomatic, found incidentally on imaging obtained for unrelated symptoms. Imaging features Noncontrast head computed tomography (CT) is the first-choice imaging study to rapidly diagnose SDH. Brain magnetic resonance imaging (MRI) may also be used but typically takes longer to perform than CT and is less readily available in many facilities. However, MRI may be preferred for small chronic SDH and to identifying possible underlying causes ( image 11). (See 'Imaging features' above.) Evaluation for underlying etiology Patients without antecedent trauma or obvious risk factors for SDH should be evaluated for secondary causes. This may include brain MRI or other imaging, angiography in selected cases, and laboratory evaluation for coagulopathy. (See 'Evaluation for underlying causes' above.) ACKNOWLEDGMENT https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 14/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate The UpToDate editorial staff acknowledges David Brock, MD, CIP, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Finger G, Martins OG, Basso LS, et al. Acute Spontaneous Subdural Hematoma in Posterior Fossa: Great Outcome. World Neurosurg 2018; 119:146. 2. de Beer MH, Eysink Smeets MM, Koppen H. Spontaneous Spinal Subdural Hematoma. Neurologist 2017; 22:34. 3. Benyaich Z, Laghmari M, Lmejjati M, et al. Acute Lumbar Spinal Subdural Hematoma Inducing Paraplegia After Lumbar Spinal Manipulation: Case Report and Literature Review. World Neurosurg 2019; 128:182. 4. Ropper AH, Samuels MA, Klein JP, Prasad S. Craniocerebral trauma. In: Adams and Victor's Pr inciples of Neurology, 11th ed, Ropper AH, Samuels MA, Klein JP, Prasad S (Eds), McGraw-Hil l, New York 2019. p.906. 5. Gennarelli TA, Thibault LE. Biomechanics of acute subdural hematoma. J Trauma 1982; 22:680. 6. Haselsberger K, Pucher R, Auer LM. Prognosis after acute subdural or epidural haemorrhage. Acta Neurochir (Wien) 1988; 90:111. 7. Maxeiner H, Wolff M. Pure subdural hematomas: a postmortem analysis of their form and bleeding points. Neurosurgery 2002; 50:503. 8. Sajanti J, Majamaa K. High concentrations of procollagen propeptides in chronic subdural haematoma and effusion. J Neurol Neurosurg Psychiatry 2003; 74:522. 9. Louis ED, Mayer SA, Rowland LP. Traumatic brain injury. In: Merritt's Neurology, 13th ed, Lou is ED, Mayer SA, Rowland LP (Eds), Lippincott Williams & Wilkins, Philadelphia 2016. p.367. 10. Lee KS. The pathogenesis and clinical significance of traumatic subdural hygroma. Brain Inj 1998; 12:595. 11. Labadie EL, Glover D. Physiopathogenesis of subdural hematomas. Part 1: Histological and biochemical comparisons of subcutaneous hematoma in rats with subdural hematoma in man. J Neurosurg 1976; 45:382. 12. Bullock MR, Chesnut R, Ghajar J, et al. Surgical management of acute subdural hematomas. Neurosurgery 2006; 58:S16. 13. Besenski N. Traumatic injuries: imaging of head injuries. Eur Radiol 2002; 12:1237. https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 15/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate 14. Morris NA, Merkler AE, Parker WE, et al. Adverse Outcomes After Initial Non-surgical Management of Subdural Hematoma: A Population-Based Study. Neurocrit Care 2016; 24:226. 15. Kuhn EN, Erwood MS, Oster RA, et al. Outcomes of Subdural Hematoma in the Elderly with a History of Minor or No Previous Trauma. World Neurosurg 2018; 119:e374. 16. Edlmann E, Giorgi-Coll S, Whitfield PC, et al. Pathophysiology of chronic subdural haematoma: inflammation, angiogenesis and implications for pharmacotherapy. J Neuroinflammation 2017; 14:108. 17. Beck J, Gralla J, Fung C, et al. Spinal cerebrospinal fluid leak as the cause of chronic subdural hematomas in nongeriatric patients. J Neurosurg 2014; 121:1380. 18. Vega RA, Valadka AB. Natural History of Acute Subdural Hematoma. Neurosurg Clin N Am 2017; 28:247. 19. Patel PV, FitzMaurice E, Nandigam RN, et al. Association of subdural hematoma with increased mortality in lobar intracerebral hemorrhage. Arch Neurol 2009; 66:79. 20. Barton E, Tudor J. Subdural haematoma in association with intracranial aneurysm. Neuroradiology 1982; 23:157. 21. Nowak G, Schwachenwald S, Kehler U, et al. Acute subdural haematoma from ruptured intracranial aneurysms. Acta Neurochir (Wien) 1995; 136:163. 22. Inamasu J, Saito R, Nakamura Y, et al. Acute subdural hematoma caused by ruptured cerebral aneurysms: diagnostic and therapeutic pitfalls. Resuscitation 2002; 52:71. 23. Gelabert-Gonzalez M, Iglesias-Pais M, Fern ndez-Villa J. Acute subdural haematoma due to ruptured intracranial aneurysms. Neurosurg Rev 2004; 27:259.

Basics topic (see "Patient education: Subdural hematoma (The Basics)") SUMMARY AND RECOMMENDATIONS Anatomy Subdural hematoma (SDH) forms between the dural and the arachnoid membranes overlying the brain ( figure 2 and image 1). SDH often has a crescent- shaped appearance because bleeding follows the contour of the overlying dura. Most SDHs occur along the cerebral convexities but may also occur in the subdural spaces between cerebral and cerebellar hemispheres or circumferentially around the brainstem ( figure 1). (See 'Anatomy' above.) Pathophysiology Acute SDH is usually caused by tearing of the veins located between the arachnoid membranes and the dura in most cases. An arterial source may be found in approximately 20 to 30 percent of SDH cases. Etiologies SDH may be spontaneous or triggered by an inciting event. (See 'Specific etiologies' above.) Head trauma is the most common cause of SDH, with most cases related to motor vehicle accidents, falls, and assaults. Low cerebrospinal fluid pressure (intracranial hypotension) may cause SDH by a spontaneous or iatrogenic cerebrospinal fluid leak such as following lumbar puncture or ventriculostomy, lumboperitoneal shunt placement, or other neurosurgical procedures. Arterial causes of SDH include trauma, intracerebral hemorrhage, ruptured cerebral aneurysm, cerebral arteriovenous malformation, or vasculopathy. https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 13/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate Neoplastic lesions may lead to SDH by mass effect or neovascular rupture. SDH associated with dural (pachymeningeal) metastasis are breast, prostate, lung, and lymphoma. Primary brain tumors are a rare source of SDH. Epidemiology Acute SDH complicates approximately 11 percent of mild to moderate head injuries that require hospitalization and approximately 20 percent of severe traumatic brain injuries. The incidence of chronic SDH ranges from 1.7 up to 20.6 per 100,000 persons/year. (See 'Epidemiology' above.) Risk factors Patients with significant cerebral atrophy, those who use antithrombotic medications, or who have other sources of coagulopathy are at an elevated risk for SDH. (See 'Risk factors' above.) Clinical manifestations The initial presentation of SDH has a wide spectrum of manifestations. Patients with severe head trauma and SDH may present with coma due to the overall insult to the brain, while those with a mild or trivial trauma and those with spontaneous SDH are likelier to present with symptoms due to the SDH alone ( table 1). (See 'Clinical manifestations' above.) Symptoms of acute SDH include weakness, numbness, visual impairment, and seizures. Patients who become symptomatic with chronic SDH are more likely to present with nonfocal symptoms than those with acute SDH. SDH may also be asymptomatic, found incidentally on imaging obtained for unrelated symptoms. Imaging features Noncontrast head computed tomography (CT) is the first-choice imaging study to rapidly diagnose SDH. Brain magnetic resonance imaging (MRI) may also be used but typically takes longer to perform than CT and is less readily available in many facilities. However, MRI may be preferred for small chronic SDH and to identifying possible underlying causes ( image 11). (See 'Imaging features' above.) Evaluation for underlying etiology Patients without antecedent trauma or obvious risk factors for SDH should be evaluated for secondary causes. This may include brain MRI or other imaging, angiography in selected cases, and laboratory evaluation for coagulopathy. (See 'Evaluation for underlying causes' above.) ACKNOWLEDGMENT https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 14/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate The UpToDate editorial staff acknowledges David Brock, MD, CIP, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Finger G, Martins OG, Basso LS, et al. Acute Spontaneous Subdural Hematoma in Posterior Fossa: Great Outcome. World Neurosurg 2018; 119:146. 2. de Beer MH, Eysink Smeets MM, Koppen H. Spontaneous Spinal Subdural Hematoma. Neurologist 2017; 22:34. 3. Benyaich Z, Laghmari M, Lmejjati M, et al. Acute Lumbar Spinal Subdural Hematoma Inducing Paraplegia After Lumbar Spinal Manipulation: Case Report and Literature Review. World Neurosurg 2019; 128:182. 4. Ropper AH, Samuels MA, Klein JP, Prasad S. Craniocerebral trauma. 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Topic 1105 Version 21.0 https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 21/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate GRAPHICS Subdural hematoma in adults: Rapid overview of emergency management Clinical manifestations When to suspect: Trauma Unexplained acute or subacute progressive neurologic symptoms New neurologic symptoms in an older patient (especially if taking anticoagulants) Common symptoms: New and persistent headache, focal or bilateral weakness, confusion, subacute cognitive decline, seizures Signs of elevated intracranial pressure: Dilated pupil(s) Progressive drowsiness Cushing triad (bradycardia, respiratory depression, hypertension) Evaluation Assess airway, breathing, circulation, and disability to initiate supportive care Determine GCS and neurologic deficits (eg, hemiparesis, numbness, speech or vision impairment) Identify exposure to anticoagulant medications (eg, warfarin, DOACs, heparinoids) Obtain emergency imaging (eg, head CT or fast MRI) Laboratory evaluation: Complete blood count, PT, PTT, INR, basic electrolytes, pregnancy test in female of childbearing age Initial serial monitoring: Neurologic examination (hourly) for signs of deterioration Repeat head CT 6 to 8 hours after initial study and for any clinical signs of deterioration Treatment Manage trauma patients according to principles of advanced trauma life support* Perform tracheal intubation for any patient unable to protect their airway, with rapidly deteriorating mental status, or with GCS 8 https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 22/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate Obtain immediate neurosurgical consultation as indicated by clinical signs or imaging: Hemispheric SDH >10 mm thickness or midline shift >5 mm SDH causing brainstem compression or pupillary abnormalities SDH causing progressive neurologic deterioration (eg, GCS drop 2 points) Reverse anticoagulation (agent specific): Warfarin Reverse with 4-factor PCC and IV vitamin K Dabigatran Reverse with idarucizumab Factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) Reverse with 4-factor PCC or andexanet alfa Heparin (unfractionated) Reverse with protamine sulfate Low molecular weight heparin Reverse with andexanet alfa; protamine sulfate is an alternative Medical management of intracranial pressure: Blood pressure control: Prevent HYPOtension to maintain SBP >100 mmHg: fluid resuscitation with isotonic IV fluids; phenylephrine for refractory symptoms Initial dose 0.5 to 2 mcg/kg per minute IV; maintenance dose 0.25 to 5 mcg/kg per minute Treat HYPERtension: Initial treatment to rapidly reduce SBP to <220 mmHg: nicardipine 5 mg/hour IV, titrate by 2.5 mg/hour every 5 to 15 minutes (maximum dose: 15 mg/hour); alternate: labetalol 20 mg IV bolus, may repeat every 10 minutes Subsequent treatment to reduce SBP to <160 mmHg while monitoring for stability of neurologic status Elevate head of bed >30 degrees Give antipyretics for temperature >38 degrees Celsius (eg, acetaminophen [paracetamol] 325 to 650 mg orally or PR every 4 to 6 hours or 650 mg IV every 4 hours) Repeat imaging (eg, head CT) for signs of new or progressive elevated intracranial pressure: Obtain immediate neurosurgical consultation for surgical indications (refer to above) Osmotic therapy (mannitol or hypertonic saline) or hyperventilation as temporary treatment measures https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 23/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate GCS: Glasgow coma scale; DOAC: direct oral anticoagulant; CT: computed tomography; MRI: magnetic resonance imaging; PT: prothrombin time; PTT: partial thromboplastin time; INR: international normalized ratio; SDH: subdural hematoma; PCC: prothrombin complex concentrate; IV: intravenous; SBP: systolic blood pressure; PR: per rectum. Refer to the UpToDate topics on trauma management in adults. Refer to the UpToDate topics on management of elevated intracranial pressure in adults. Graphic 132691 Version 5.0 https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 24/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate Head CT of subdural hemorrhage and cerebral edema CT image (axial view) of acute-hyperacute right subdural hemorrhage (arrows) and asymmetric cerebral edema in an eight- month-old male infant who sustained nonaccidental injury (child abuse). CT: computed tomography. Graphic 51782 Version 4.0 https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 25/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate Possible locations of subdural hematoma (SDH) Graphic 132721 Version 1.0 https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 26/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate Distinct forms of intracranial hemorrhage (ICH) Graphic 132722 Version 1.0 https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 27/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate Various radiologic patterns of subarachnoid hemorrhage on noncontrast compu tomography (CT) of the head (A) Obvious large SAH: hyperdense blood in all the basal cisterns, with some dilatation of the temporal horn the lateral ventricles, suggesting early hydrocephalus. (B) More subtle, smaller SAH: small hyperdense collection of blood in the basal cistern adjacent to the left p and suprasellar cistern (short solid arrow). (C) Perimesencephalic SAH: the long solid arrows indicate a perimesencephalic (sometimes called a pretrun SAH. These hemorrhages represent approximately 10% of nontraumatic SAHs. They are thought to be caused venous bleeding, will have a negative CTA result, and usually have an excellent outcome. However, the radiographic pattern is also observed with posterior circulation aneurysms, so all of these patients require neurosurgical consultation and vascular imaging. (D) Convexal SAH: the arrowheads indicate a high convexal SAH. This pattern is observed in two groups of patients. In younger patients, it is usually due to RCVS, but in older ones, it often indicates amyloid angiopath a patient presenting with a severe rapid-onset headache, RCVS would be the likely diagnosis. (E) Traumatic SAH: the history usually suggests a traumatic SAH (the most common cause). However, if this pattern (dashed arrows indicate small amounts of SAH abutting bone, often in the anterior frontal and temp bones) is observed in a patient without a clear history of trauma, the likely cause is a traumatic SAH. https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 28/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate SAH: subarachnoid hemorrhage; CTA: computed tomography angiography; RCVS: reversible cerebral vasoconstriction syndrome. Reproduced from: Edlow JA. Managing Patients With Nontraumatic, Severe, Rapid-Onset Headache. Ann Emerg Med 2018; 71:400. Illus used with the permission of Elsevier Inc. All rights reserved. Graphic 121315 Version 1.0 https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 29/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate Non contrast head CT demonstrates an acute traumatic epidural hematoma over the left parietal region Courtesy of Neuroradiology Department, Thomas Je erson University, Philadelphia, PA. Graphic 60726 Version 4.0 https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 30/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate CT and MRI scans of hyperacute intracerebral hemorrhage CT and MRI studies were obtained less than six hours from symptom onset in a patient with spontaneous acute intracerebral hemorrhage. The CT scan shows a hyperdense hemorrhage predominantly in the left frontal lobe. On MRI, the central portion of the hematoma is isointense to brain parenchyma on the T1-weighted image and hyperintense on the T2-weighted and T2* gradient echo images, consistent with hemorrhage containing oxyhemoglobin. On the T2-weighted and T2* gradient echo images, the periphery of the hemorrhage is hypointense, consistent with deoxygenation that occurs more rapidly at the borders. On the T2 weighted image, tissue adjacent to and surrounding the hematoma is hyperintense, consistent with vasogenic edema. CT: computed tomography; MRI: magnetic resonance imaging; ICH: https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 31/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate intracerebral hemorrhage. Graphic 81767 Version 2.0 https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 32/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate Bilateral subdural hematomas from spontaneous intracranial hypotension FLAIR image on brain MRI (A) shows bilateral hyperintense subdural hematomas (arrows) that compress underlying cerebral cortex. Axial post-contrast T1-weighted image (B) shows uniform enhancement of the dura (arrowheads). Sagittal post-contrast T1-weighted image (C) shows diffuse dural enhancement (dashed arrows), pituitary hyperemia (circle), and brain sagging, suggestive of intracranial hypotension. FLAIR: fluid-attenuated inversion recovery; MRI: magnetic resonance imaging. https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 33/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate Courtesy of Glenn A Tung, MD, FACR. Graphic 132680 Version 1.0 https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 34/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate Uncal herniation from subdural hematoma Noncontrast head CT shows a large right holohemispheric subdural hematoma on axial (A) and coronal (B) images. Mass effect from hematoma causes a right-to-left midline shift (line) and subfalcine herniation (arrowhead). Axial image through the temporal lobes (C) shows uncal herniation with compression of the cerebral peduncles (arrow). CT: computed tomography. https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 35/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate Courtesy of Glenn A Tung, MD, FACR. Graphic 132682 Version 1.0 https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 36/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate Clinical progression of transtentorial herniation Headache Altered level of consciousness Dilation of ipsilateral pupil Cranial nerve III palsy Ptosis Loss of medial gaze Decerebrate posturing Hemiparesis Dilation of opposite pupil Alteration of respiration Bradycardia Hypertension Respiratory arrest Graphic 70683 Version 2.0 https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 37/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate Non contrast head CT demonstrates a traumatic acute subdural hematoma over the left hemisphere and a smaller subacute subdural hematoma over the right hemisphere Courtesy of Neuroradiology Department, Thomas Je erson University, Philadelphia, PA. Graphic 68424 Version 3.0 https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 38/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate Non contrast head CT demonstrates a subacute subdural hematoma over the right cerebral hemisphere CT: computed tomography. Courtesy of Neuroradiology Department, Thomas Je erson University, Philadelphia, PA. Graphic 80783 Version 4.0 https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 39/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate Pseudomembranes in chronic subdural hematomas Noncontrast head CT images (A, B, C) show chronic subdural hematoma (arrows) with pseudomembranes (arrowheads) that appear as linear or nodular densities. CT: computed tomography. Courtesy of Glenn A Tung, MD, FACR. https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 40/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate Graphic 132683 Version 1.0 https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 41/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate Traumatic subdural hematoma (SDH) CT scan showing a left acute SDH (arrow). SDHs are typically crescent shaped. In this case the SDH is causing significant mass effect and shift of midline structures to the right. CT: computed tomography. Reproduced with permission from: J Claude Hemphill III, MD and Nicholas Phan, MD, FRCSC. Graphic 68102 Version 5.0 https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 42/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate Bilateral isodense subdural hematomas Noncontrast head CT shows mass effect on left lateral ventricle and subtle isodense subdural hematoma (arrow) in axial (A) and coronal (C) images. Subdural hematomas are demonstrated on transverse axial T1-weighted (B) and coronal T2-weighted (D) MRI sequences by markedly different signal intensity than compressed brain tissue. CT: computed tomography; MRI: magnetic resonance imaging. https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 43/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate Courtesy of Glenn A Tung, MD, FACR. Graphic 132684 Version 1.0 https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 44/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate MRI of the brain demonstrates a spontaneous subdural hematoma over the right cerebral hemisphere MRI: magnetic resonance imaging. Courtesy of Neuroradiology Department, Thomas Je erson University, Philadelphia, PA. Graphic 50871 Version 4.0 https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 45/46 7/5/23, 12:02 PM Subdural hematoma in adults: Etiology, clinical features, and diagnosis - UpToDate Contributor Disclosures William McBride, MD No relevant financial relationship(s) with ineligible companies to disclose. Jos Biller, MD, FACP, FAAN, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Alejandro A Rabinstein, MD Grant/Research/Clinical Trial Support: Chiesi [Small investigator- initiated project]. Consultant/Advisory Boards: AstraZeneca [Secondary stroke prevention]; Brainomix [AI for stroke diagnostics]; Novo Nordisk [Stroke risk]; Shionogi [Stroke neuroprotection]. Other Financial Interest: Boston Scientific [Adverse event adjudication committee member for stroke risk reduction device in patients with atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. Glenn A Tung, MD, FACR No relevant financial relationship(s) with ineligible companies to disclose. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/subdural-hematoma-in-adults-etiology-clinical-features-and-diagnosis/print 46/46

7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Subdural hematoma in adults: Management and prognosis : William McBride, MD : Jos Biller, MD, FACP, FAAN, FAHA, Alejandro A Rabinstein, MD : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 23, 2023. INTRODUCTION Subdural hematoma (SDH) is a form of intracranial hemorrhage characterized by bleeding into the space between the dural and arachnoid membranes surrounding the brain. The management and prognosis of SDH will be discussed here. A rapid overview summarizes the clinical features, evaluation, and management of SDH in adults ( table 1). Other aspects of SDH are reviewed separately. (See "Subdural hematoma in adults: Etiology, clinical features, and diagnosis".) (See "Intracranial subdural hematoma in children: Epidemiology, anatomy, and pathophysiology".) (See "Intracranial subdural hematoma in children: Clinical features, evaluation, and management".) Other forms of intracranial hemorrhage are discussed elsewhere. (See "Intracranial epidural hematoma in adults".) (See "Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis".) (See "Nonaneurysmal subarachnoid hemorrhage".) (See "Perimesencephalic nonaneurysmal subarachnoid hemorrhage".) https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 1/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis".) (See "Traumatic brain injury: Epidemiology, classification, and pathophysiology".) INITIAL MANAGEMENT SDH can be a neurologic emergency that may cause irreversible brain injury and death caused by hematoma expansion, elevated intracranial pressure (ICP), or brain herniation. Patients with acute or chronic SDH require urgent initial assessment of clinical status to determine the need for surgery and the medical interventions needed to mitigate adverse outcomes ( algorithm 1). Initial assessment and emergency management The initial assessment of SDH includes airway management for patients with drowsiness or severe bulbar symptoms. Patients with SDH associated with trauma should also undergo a structured primary survey to identify and prioritize management of other injuries. The initial evaluation of adult patients with trauma is discussed in greater detail separately. (See "Initial management of trauma in adults", section on 'Primary evaluation and management'.) A neurologic examination is performed to determine the severity of initial neurologic deficits and provide a baseline to assess subsequent deterioration. The clinical assessment typically includes the Glasgow Coma Scale ( table 2), a simple clinical scale to quantify deficits for patients with brain injury. Management of antithrombotic medications Reversing anticoagulation For most patients with SDH who are taking anticoagulants, we discontinue these medications and give agents to reverse anticoagulant effects. We balance the hemorrhagic risks of anticoagulation with the thrombotic risks of reversal at an individual level. Reversal of anticoagulation is required for patients with acute or chronic SDH prior to surgical intervention. In addition, for most patients with acute SDH who are managed nonoperatively, we reverse anticoagulation to reduce the risk of SDH enlargement. By contrast, for some patients with a chronic or small acute SDH and no signs of increased ICP who are receiving anticoagulation for a compelling indication such as a mechanical heart valve, the risk-benefit calculation may favor continued anticoagulation with close observation of neurologic status. For such patients, we anticoagulate with heparin during the acute setting whenever possible because it is typically quicker to reverse in the event of hematoma expansion. https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 2/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate (See "Anticoagulation for prosthetic heart valves: Management of bleeding and invasive procedures", section on 'Management of bleeding'.) If reversal of anticoagulation is indicated, the appropriate intervention depends upon the anticoagulant the patient is taking, the time since last dosage, and the urgency with which reversal is needed. Some patients prescribed anticoagulant medications may not require reversal agents if laboratory testing or the time interval since last dose indicates they are effectively not anticoagulated. For other patients with a medication-related coagulopathy: Warfarin Four-factor prothrombin complex concentrate (4F PCC) along with intravenous vitamin K is preferred for patients with serious or life-threatening bleeding; the dose of 4F PCC may need to be repeated while awaiting the effects of drug discontinuation ( table 3). If a 4F PCC is not available, a three-factor product may be used with recombinant activated factor VII or fresh frozen plasma (FFP). Reversal of anticoagulation in this setting is discussed separately. (See "Reversal of anticoagulation in intracranial hemorrhage", section on 'Warfarin'.) Dabigatran We use the reversal agent idarucizumab for patients with potentially life- threatening bleeding including SDH. If idarucizumab is not available, an activated PCC such as factor eight inhibitor bypassing agent (FEIBA) can be used ( table 4). (See "Reversal of anticoagulation in intracranial hemorrhage", section on 'Dabigatran'.) Direct factor Xa inhibitors (eg, apixaban, edoxaban, rivaroxaban) We use either andexanet alfa or a 4F PCC to reverse the effects of direct factor Xa inhibitors ( table 4). (See "Reversal of anticoagulation in intracranial hemorrhage", section on 'Apixaban, edoxaban, and rivaroxaban'.) Unfractionated heparin and low molecular weight heparins Protamine sulfate is used to reverse the effect of heparin agents. The dose depends upon the type of heparin used (unfractionated versus low molecular weight agents), the dose of heparin given, and the time elapsed since that dose. Andexanet alfa may be used for patients taking low molecular weight heparin. (See "Reversal of anticoagulation in intracranial hemorrhage", section on 'Unfractionated heparin' and "Reversal of anticoagulation in intracranial hemorrhage", section on 'LMW heparin'.) Patients on antiplatelets Antiplatelet medications are typically stopped at the time of diagnosis for most patients with either acute SDH or large or symptomatic chronic SDH to reduce the risk of hematoma enlargement. However, we balance the thrombotic risks of discontinuation with the hemorrhagic risks of continuing antiplatelets at an individual level. We may continue antiplatelet medications during acute monitoring for selected patients at low risk https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 3/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate of hematoma expansion and high risk of thrombosis such as those with established atherosclerotic disease or who have undergone intravascular stent placement and who have small or chronic SDH. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk" and "Antithrombotic therapy for elective percutaneous coronary intervention: General use" and "Overview of carotid artery stenting" and "Endovascular techniques for lower extremity revascularization", section on 'Antiplatelet therapy'.) We do not give platelet transfusion to most patients taking antiplatelet medications who present with SDH. The available data from trials of patients with spontaneous intracerebral hemorrhage suggest that platelet transfusions may be hazardous and should be avoided. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Reverse anticoagulation'.) We reserve platelet transfusions for those with specific indications, including those with a thrombocytopenia (<100,000/microL) or a known platelet defect. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Platelet function disorders'.) Identifying patients with an indication for surgery Some patients with SDH require urgent surgical treatment at the time of initial presentation based on severity of imaging findings or clinical exam. Surgery may help to prevent irreversible brain injury and death caused by hematoma expansion, elevated ICP, and brain herniation. The benefits of surgery for patients with SDH are based on the severity of the lesion, the likelihood of subsequent deterioration, and the potential for recovery with surgery [1]. The indications for and timing of surgery and operative approaches for patients with SDH are discussed below. (See 'Surgical indications and approaches' below.) SURGICAL INDICATIONS AND APPROACHES Neurosurgical consultation Neurosurgical consultation may be obtained for most patients with acute or symptomatic chronic SDH. Immediate neurosurgical consultation for urgent surgical evacuation is required for patients with SDH and any of the following clinical and imaging features: Clinical features Dilated pupil(s) Rapid or progressive deterioration (including new drowsiness) on examination https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 4/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate Drop of 2 points on Glasgow Coma Scale (GCS) score ( table 2) Cushing triad (bradycardia, respiratory depression, hypertension) Imaging features Maximal clot thickness >10 mm Shift of midline structures >5 mm, measured at the septum pellucidum ( image 1) Hydrocephalus or brainstem compression ( image 2) SDH associated with structural brain lesion (eg, skull fracture, arteriovenous malformation) For other patients with acute SDH, we monitor nonoperatively with close neurologic examinations and surveillance imaging for clinical or radiographic deterioration. (See 'Nonoperative management' below.) Acute subdural hematoma Urgent surgical hematoma evacuation is required for patients with acute SDH and clinical signs attributable to brain herniation or elevated intracranial pressure (ICP) and for such patients who have evidence of neurologic deterioration since the time of injury. We suggest urgent surgical hematoma evacuation for patients with SDH thickness >10 mm or midline shift >5 mm on initial brain scan ( algorithm 1). The benefits of surgery for those with an indication based on SDH size alone may be less certain for patients with significant cerebral atrophy and/or with minimal midline shift, patients older than 75 years of age, and those with medical comorbidities that are at elevated surgical risk [2]. For other patients with acute SDH, we monitor nonoperatively with close neurologic examinations and surveillance imaging for clinical or radiographic deterioration. (See 'Nonoperative management' below.) Guidelines from an expert panel published in 2006 recommended surgical evacuation to reduce the risk of mortality or further morbidity for patients with severe or progressive symptoms and those with large acute SDH [1]. Clinical thresholds for surgery included a drop in the GCS score by 2 points from the time of injury to hospital admission and the presence of asymmetric or fixed and dilated pupils [1]. Imaging thresholds for surgery included an SDH clot thickness >10 mm or >5 mm midline shift, regardless of clinical findings. Larger SDH volumes are associated with worse outcomes. In a retrospective study of 174 patients undergoing surgery for SDH, the mortality rate increased with size of clot thickness from 10 percent for patients when SDH <10 mm to 90 percent when SDH >30 mm [3]. In another study of initial nonoperative management of 31 patients with acute SDH, hematoma thickness >10 mm and midline shift >5 mm on initial imaging were associated with subsequent neurologic deterioration and need for surgery [4]. https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 5/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate Common surgical options for acute SDH include craniotomy, craniostomy (eg, burr hole trephination), and decompressive craniectomy [1]. Craniotomy Craniotomy is often the preferred surgical technique for patients with acute SDH without underlying brain swelling who undergo hematoma evacuation. The procedure involves removal of a small section of skull to expose and drain the SDH. The skull flap is replaced and secured at the end of the procedure. Craniotomy provides better access and more effective drainage of acute SDH than the more limited burr hole craniostomy. Craniectomy Decompressive craniectomy involves removal of a section of the skull to permit wide exposure of the underlying dura mater overlying the SDH. This technique facilitates SDH evacuation and can help reduce morbidity from associated or anticipated brain swelling [5]. The removed skull flap is replaced in a delayed fashion. Craniostomy Craniostomy involves drilling a small hole through the skull to gain rapid access to SDH and/or to minimize incision size. It may be performed using burr hole trephination or twist drill techniques [6]. Craniostomy is less invasive than craniotomy techniques and can be performed at the bedside for emergency situations. It may also be used to reduce SDH volume in patients with mixed-density (acute-on-chronic) SDH [7]. Surgical technique for SDH evacuation varies by severity of injury, surgeon experience/preference, and available resources. Craniotomy may be preferred to minimize operative time and wound complications while craniectomy may be preferred to reduce risk of morbidity or reoperation from subsequent brain swelling [5]. In a multicenter trial of 462 patients with symptomatic acute SDH who were randomized to craniotomy or craniectomy, the functional outcomes were similar between groups at both 6 and 12 months [8]. However, reoperation within two weeks was more frequent in those assigned to craniotomy (15 versus 7 percent) and wound complications were more common among patients assigned to craniectomy (12 versus 4 percent). Limited observational data suggest that craniotomy is associated with better outcomes than craniostomy [1]. In a surgical series of 60 patients with SDH, 25 patients underwent craniotomies, 24 were treated with burr holes, 8 had craniotomies with dural grafting, and 3 had decompressive craniectomies [9]. In a subgroup of severely affected patients, patients treated with craniotomy had a lower mortality and greater functional recovery rates than those treated with burr hole surgery. However, these results should be interpreted with caution due to small patient numbers, nonrandomized treatment allocation, and differences between treatment groups [1]. https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 6/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate Chronic subdural hematoma Urgent recommended hematoma evacuation is required for patients with large and symptomatic chronic SDH and the potential for recovery who develop signs attributable to brain herniation or elevated ICP including for such patients with evidence of moderate to severe cognitive impairment or progressive neurologic deterioration attributable to the chronic SDH. We suggest surgical evacuation of chronic SDH for patients with clot thickness >10 mm or midline shift >5 mm on brain scan ( algorithm 1). Nonoperative management is warranted for patients with small chronic SDH that are asymptomatic or causing minimal symptoms. In addition, nonoperative management may be preferred for older patients with chronic SDH not causing elevated ICP or severe symptoms as surgical outcomes may be worse in patients age 75 years or older [2]. (See 'Monitoring' below.) There are no expert guidelines for the management of symptomatic chronic SDH. Some authors recommend surgery for patients with acute or chronic when SDH thickness is >10 mm or midline shift is >5 mm based on risk of subsequent deterioration and poor outcome [10]. In addition, surgical evacuation of chronic SDH improves outcome for symptomatic patients with evidence of brain herniation or elevated ICP [10]. Surgical evacuation may improve symptoms when chronic SDH causes severe cognitive impairment [11,12]. However, some authors advocate a trial of conservative management for older adult patients with chronic SDH but no evidence of increased ICP, even when the SDH is thought to be causing or contributing to cognitive impairment. In one small series, five patients older than 70 years with persistent SDH four to five weeks after minor head trauma were observed for 30 to 45 days. These patients were symptomatic with headache and decreased cognition on the Mini Mental Status Exam at the outset of the study. Serial head computed tomography (CT) scans revealed complete disappearance or marked reduction in SDH size by 30 to 45 days, and clinical recovery was complete [13]. The benefits of surgical evacuation of chronic SDH need to be balanced with surgical risks and the nonoperative natural history of chronic SDH. Chronic SDH may resolve spontaneously with nonoperative management in many cases, typically over a period of several weeks. In addition, subdural fluid can reaccumulate after surgery for chronic SDH and may lead to repeat surgery, increase risk of seizures, and higher overall treatment costs [14]. (See "Subdural hematoma in adults: Etiology, clinical features, and diagnosis", section on 'Pathophysiology'.) Available surgical options for symptomatic chronic SDH include burr hole trephination, craniotomy, and decompressive craniectomy [1]. Endovascular treatment with middle meningeal artery embolization may be used to prevent chronic SDH recurrence or as a primary treatment for symptomatic patients who are at high risk for surgical options. In most cases, burr hold https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 7/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate trephination is pursued. When indicated, identification and ligation of the bleeding vessel must be undertaken. Burr hole and drainage Burr hole trephination is performed for most patients undergoing surgery for symptomatic chronic SDH to facilitate fluid drainage and reexpansion of underlying brain tissue. One or more burr holes can be placed to allow drainage of the hematoma. A flexible catheter (Jackson Pratt drain) is usually placed in the subdural space until the drainage subsides [15]. The use of a drain after burr hole placement was found in one trial to reduce SDH recurrence (9 versus 24 percent) and six- month mortality (9 versus 18 percent) without an excess in medical or surgical complications [16]. The optimal time for catheter drainage is uncertain. In a trial of 420 patients with chronic SDH assigned to burr hole drainage for either 24 or 48 hours, outcomes were similar when assessing SDH recurrence (14 versus 13 percent), as well as length of hospital stay, postoperative infections, and mortality [17]. A subdural evacuating port system is a less invasive alternative to craniectomy and burr hole decompression that appears safe and similarly effective in small observational studies [18,19]. Middle meningeal artery embolization Endovascular middle meningeal artery (MMA) embolization represents a minimally invasive treatment option for the management of chronic SDH [20,21]. MMA embolization may be used as an adjunctive option along with open techniques to decrease the likelihood of hematoma reaccumulation, including for patients with a coagulopathy and those with multiple prior SDH recurrences. It may also be performed as a sole intervention in patients deemed high surgical risk. A 2021 meta-analysis of 17 retrospective and 3 prospective studies including 1416 patients with chronic SDH, those who had MMA embolization with or without initial surgical evacuation had lower rates of hematoma recurrence than those who had surgical or nonoperative management without MMA (4.8 percent versus 21.5 percent; odds ratio 0.15, 95% CI 0.03-0.75) and similar complication rates [22,23]. Subsequent rescue surgery due to treatment failure after MMA embolization has been reported in 1 to 9 percent of patients in various case series [20,21,24,25]. As an example, in a multicenter series of 138 patients with chronic SDH selected for MMA embolization, more than 70 percent achieved at least 50 percent improvement on imaging and only 7 percent underwent additional subsequent treatment [20]. Predictors of treatment failure include pretreatment anticoagulation and MMA diameter <1.5 mm [25]. https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 8/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate Other surgical techniques A craniotomy with resection of membranes that surround the clot is typically performed in patients with chronic SDH that rebleed after burr hole drainage to prevent reaccumulation of fluid [26-28]. Timing of surgery Urgent surgical hematoma evacuation (within two to four hours) is required for patients with acute or chronic SDH and signs of brain herniation or elevated ICP and for patients who develop acute neurologic deterioration. We suggest urgent surgical hematoma evacuation for patients with clot thickness >10 mm or midline shift >5 mm on initial brain scan. Surgery performed within two to four hours after the onset of neurologic deterioration may be associated with a lower mortality than delayed surgery [1,29-32]. Data from observational studies have found mortality rates between 30 and 47 percent with urgent surgery compared with 80 to 90 percent when intervention was delayed beyond four hours [1]. However, other observational studies evaluating the time between injury and surgery have reported no significant relationship with outcome [33-38], and some reports found that early intervention appeared to have a worse outcome than delayed surgery [1,9,35,39]. These data may be confounded by selection bias, since patients who had immediate surgery tended to have more severe injuries and lower initial GCS scores than those in whom intervention was delayed [1]. NONOPERATIVE MANAGEMENT Monitoring For all patients with SDH managed nonoperatively, we use serial neurologic examinations and repeat imaging, typically with head computed tomography (CT), to assess for subsequent deterioration and the development of increased intracranial pressure (ICP). No randomized trials have compared surgery with conservative management for patients with SDH, but limited observational data suggest that patients with acute SDH who are clinically stable and have small hematomas can be managed nonoperatively [4,40,41]. In a series of 65 comatose patients with acute SDH, 15 patients were selected for nonoperative management because they were clinically stable or improved from the time of injury to evaluation, had hematoma thickness <10 mm and midline shift <5 mm on initial head CT, and had no evidence of uncompensated ICP elevation with invasive monitoring [40]. A good functional outcome was achieved in 10 of 15 patients (67 percent) initially managed nonoperatively compared with 13 of 50 patients (26 percent) who initially required with surgery. Only two patients in the nonoperative group had delayed surgical evacuation due to the development of parenchymal hematomas or elevated ICP. https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 9/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate Serial clinical examinations Clinical setting Patients with an acute or symptomatic chronic SDH should be monitored in an inpatient setting with neurosurgical expertise. Those at risk for respiratory failure with impairment of alertness, coma, or other severe neurologic deficits should be admitted to an intensive care unit. Other patients with small, asymptomatic chronic SDH that are found incidentally on imaging may be monitored in the ambulatory setting with initial clinical exam and follow- up imaging to document resolution of the hematoma. (See 'Follow-up imaging' below.) Parameters to monitor Neurologic examinations should include assessments of alertness, pupillary and other bulbar functions, and sensorimotor functions. For patients with baseline impairment of alertness or weakness, serial testing with Glasgow Coma Scale (GCS) score ( table 2) is also performed. Invasive monitoring of ICP is indicated for patients with SDH due to trauma and those with other risk factors for developing elevated ICP. This is presently separately. (See "Evaluation and management of elevated intracranial pressure in adults", section on 'Indications'.) Monitoring frequency For patients hospitalized with acute or chronic SDH, serial neurologic examinations should be performed at baseline and every one to two hours for at least the first 24 hours after presentation. The frequency of examinations may be reduced to every four hours for stable patients. A longer interval of initial monitoring or more frequent examinations may be performed for those at higher risk for hematoma expansion. Risk factors for hematoma expansion include [41-43]: Older age History of hypertension History of ischemic heart disease Antithrombotic medication exposure Impaired consciousness on examination SDH associated with additional intracranial injuries Larger SDH volume Presence of intraventricular hemorrhage The risk of hematoma enlargement and neurologic deterioration may be highest in the first 36 hours after SDH onset [44]. However, SDH expansion or clinical deterioration may occur hours to weeks after injury in patients with SDH. In a study of 31 patients with https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 10/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate traumatic SDH who were initially managed nonoperatively, surgery for neurologic deterioration was required in six patients within three days of injury [4]. Follow-up imaging We suggest that surveillance follow-up head CT be obtained within six to eight hours of the initial scan for all patients hospitalized with acute and symptomatic chronic SDH who are managed nonoperatively [40]. The incidence of hematoma expansion is highest in the initial several hours after onset [42,44]. Hematoma expansion may precede clinical deterioration and patients selected for initial nonoperative management may develop an indication for surgery due to progressive findings on follow-up imaging. (See 'Identifying patients with an indication for surgery' above.) For patients with stable findings on initial follow-up head CT, subsequent imaging may be performed at transitions of care (eg, prior to hospital discharge) to document stability. In addition, for patients resuming antithrombotic medications that were discontinued during initial management, follow-up head CT is typically obtained prior to resuming antithrombotic medications to document resolution of the hematoma. (See 'Resumption of antithrombotic medications' below.) Follow-up imaging is also performed for patients with acute or chronic SDH to document resolution after recovery. The timing of imaging varies by size and acuity of the SDH. Resolution of acute bleeding may be found several days up to two weeks from onset, while resolution of chronic SDH may occur several weeks after onset. (See "Subdural hematoma in adults: Etiology, clinical features, and diagnosis", section on 'Imaging features' and "Subdural hematoma in adults: Etiology, clinical features, and diagnosis", section on 'Pathophysiology'.) Urgent repeat head CT is warranted for all patients with clinical deterioration. (See 'Management of patients who deteriorate' below.) Management of patients who deteriorate Urgent repeat imaging to assess for indication for surgery Urgent repeat imaging with head CT is warranted to assess for progression of the hematoma, brain compression, or hydrocephalus in all patients with SDH who have an acute deterioration in clinical status. Patients with progression of hematoma We recommend surgical evacuation when repeat head CT shows progression that meets imaging criteria for surgery. (See 'Surgical indications and approaches' above.) For patients with clinical deterioration and modest SDH progression on repeat head CT (eg, SDH that is larger than prior study but <10 mm thickness) that does not meet imaging https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 11/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate criteria for surgical evacuation, we use clinical status to guide subsequent therapy. (See 'Surgical indications and approaches' above.) We recommend surgical evacuation for patients with rapid or significant clinical deterioration that is attributable to hematoma expansion (eg, pupillary changes, progressive hemiparesis contralateral to SDH). We also recommend surgical evacuation for patients with evidence of elevated ICP such as new drowsiness, development of the Cushing triad, or a drop of 2 points on GCS score ( table 2). (See 'Surgical indications and approaches' above.) For those with minor clinical changes and modest progression on repeat head CT, we may continue close nonoperative monitoring. (See 'Monitoring' above.) For patients with clinical deterioration that is not attributable to hematoma expansion or elevated ICP, we pursue additional testing to identify the source. As an example, a patient with new isolated aphasia in the setting of a right hemisphere SDH that progressed from 4 mm to 6 mm maximal thickness may require additional testing for seizure or ischemic stroke. (See 'Testing for other causes of deterioration when repeat imaging is stable' below.) Patients with elevated intracranial pressure Patients with SDH may develop elevated ICP requiring urgent intervention. For patients managed nonoperatively with an ICP monitor, we recommend urgent surgical evacuation if the ICP is persistently >20 mmHg. Definitive therapy for elevated ICP is usually hematoma evacuation; medical resuscitation used as a temporizing measure for patients awaiting surgery includes head elevation, hyperventilation, and osmotic diuresis with intravenous mannitol or hypertonic saline. The management of elevated ICP is reviewed elsewhere. (See "Evaluation and management of elevated intracranial pressure in adults".) Testing for other causes of deterioration when repeat imaging is stable Patients with SDH are at risk of clinical deterioration due to neurologic events other than hematoma expansion or elevated ICP. Additional testing is warranted for patients with SDH and evidence of clinical deterioration not accounted for by findings on repeat head CT. Specific testing is determined by clinical features and patient risk factors. Seizures SDH may cause seizures due to compression of underlying cerebral cortex. Seizures may accompany acute SDH in the setting of mild or severe traumatic brain injury. (See "Posttraumatic seizures and epilepsy".) https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 12/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate Patients with a persistent impairment in alertness not due to elevated ICP, those with fluctuating changes in neurologic examination, and those with witnessed convulsions warrant evaluation for seizures with electroencephalography. Ischemic stroke SDH may be complicated by ischemic stroke in patients with thromboembolic risk factors such as atrial fibrillation due to the reversal of anticoagulation to manage the SDH. In addition, ischemic stroke may infrequently occur in nonambulatory patients in the setting of embolization of a deep venous thrombosis. (See "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults", section on 'Paradoxical emboli'.) Ischemic stroke should be suspected in at-risk patients with SDH who have a sudden clinical deterioration consistent with ischemic stroke ( table 5) and stable head CT. Brain magnetic resonance imaging (MRI) is the preferred imaging modality because acute ischemic stroke may not be visible on initial repeat head CT. The treatment of acute ischemic stroke is discussed separately. (See "Initial assessment and management of acute stroke".) Acute toxic-metabolic encephalopathy Patients with SDH may develop delirium due several causes including preexisting medical conditions, pain, or medications. The evaluation of patients with delirium is discussed separately. (See "Diagnosis of delirium and confusional states".) Evaluation for underlying causes Some patients with spontaneous SDH not associated with trauma or other obvious cause may warrant brain and/or vascular imaging and other testing to identify possible secondary causes. The evaluation of underlying causes of SDH is discussed separately. (See "Subdural hematoma in adults: Etiology, clinical features, and diagnosis", section on 'Evaluation for underlying causes'.) Prevention and management of medical complications Patients with acute or chronic SDH are at risk for medical complications due to immobility or direct effects of the SDH. These complications can be associated with worse outcomes based on data from patients with intracerebral hemorrhage [45]. Seizure prophylaxis and management Patients with SDH are at risk for seizure or status epilepticus [46]. We do not routinely start antiseizure medicine prophylaxis for patients who have not had a seizure. In systematic reviews and observational studies, the seizure rate appears similar whether or not patients with SDH receive antiseizure medication prophylaxis [46-49]. https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 13/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate For patients with impairment of consciousness not attributed to mass effect from the SDH, we evaluate for other causes of symptoms. This includes electroencephalography to assess for nonconvulsive seizures or status epilepticus. (See 'Evaluation for underlying causes' above.) Antiseizure medications are typically reserved for patients with SDH who have clinical or electrographic seizures. The choice of initial antiseizure medication is guided by medical comorbidities, drug interactions, side effect drug profile, and contraindications ( table 6). (See "Evaluation and management of the first seizure in adults".) Prevention of venous thromboembolism Patients hospitalized with an acute illness and those with a neurologic condition that impairs mobility are at risk for venous thromboembolism. Intermittent pneumatic compression should be started on the first day of hospital admission for patients with SDH and impaired mobility. We add chemical prophylaxis for most patients one to four days after SDH stability is documented. An exception would be some patients being evaluated for urgent surgery for whom chemical prophylaxis may be temporarily withheld. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults".) Therapies not recommended or of uncertain benefit Statin medications Limited data suggest that low-dose statin medications may reduce hematoma size for patients with chronic SDH. In a systematic review that identified 156 patients with chronic SDH from three observational studies, atorvastatin 20 mg daily for one to six months was associated with reduced hematoma volume and low rates of recurrence [50]. In a trial of 196 patients with chronic SDH from China, those assigned atorvastatin 20 mg daily had better outcomes at eight weeks than those assigned to placebo, including greater reduction in SDH volumes (29 versus 17 mL) and lower rates of surgery for hematoma enlargement or deterioration (11 versus 24 percent; hazard ratio 0.47, 95% CI 0.24-0.92) [51]. Additional studies are needed to better identify the role of statin medications in the nonoperative management of patients with chronic SDH. Tranexamic acid The role of tranexamic acid (TXA) in the nonoperative management of patients with SDH is uncertain. TXA is an antifibrinolytic agent used in some patients with chronic SDH to reduce the rate of rebleeding after surgery or to promote resorption [52]. In a systematic review of 105 patients from four studies, only low-quality evidence was identified showing that tranexamic acid was associated with reduction in hematoma volume [53]. Data were limited by small numbers and variability in patient characteristics. In addition, TXA was used as an adjunctive therapy to surgical evacuation in most cases. In https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 14/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate an observational study of 27 patients with chronic SDH managed nonoperatively including TXA for a mean of 65 days, resolution occurred in all patients and no complications were reported [54]. Additional trial data are needed to clarify the role of TXA for patients with chronic SDH. Glucocorticoids We avoid glucocorticoid therapy for patients with SDH. In a trial of 748 patients with symptomatic chronic SDH, those assigned to a two-week course of dexamethasone were less likely to achieve a good functional outcome at six months than those assigned to placebo (84 versus 90 percent) [55]. Glucocorticoid therapy has also been associated with increased acute mortality following head injury. This issue is discussed separately. (See "Management of acute moderate and severe traumatic brain injury", section on 'Glucocorticoids'.) PROGNOSIS AND LONG-TERM MANAGEMENT The prognosis of SDH depends on severity of SDH and associated medical comorbidities. In a study that included 746 procedures of patients with SDH who underwent surgery between 2005 and 2012, the 30-day mortality rate was 17 percent [56]. In another study assessing outcome of patients undergoing surgery for acute SDH that included 462 patients (median age 49 years old), mortality at six months was 31 percent [8]. The estimated mortality rate for patients with more severe injuries who require surgery for SDH is as high as 60 percent in some small studies [1,3,9,29,33,40]. For patients who presented with coma prior to surgical evacuation, mortality rates were 57 to 68 percent [1,34,57]. Risk factors for poor outcome Age greater than 60 years and severe neurologic impairment

clinical deterioration not accounted for by findings on repeat head CT. Specific testing is determined by clinical features and patient risk factors. Seizures SDH may cause seizures due to compression of underlying cerebral cortex. Seizures may accompany acute SDH in the setting of mild or severe traumatic brain injury. (See "Posttraumatic seizures and epilepsy".) https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 12/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate Patients with a persistent impairment in alertness not due to elevated ICP, those with fluctuating changes in neurologic examination, and those with witnessed convulsions warrant evaluation for seizures with electroencephalography. Ischemic stroke SDH may be complicated by ischemic stroke in patients with thromboembolic risk factors such as atrial fibrillation due to the reversal of anticoagulation to manage the SDH. In addition, ischemic stroke may infrequently occur in nonambulatory patients in the setting of embolization of a deep venous thrombosis. (See "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults", section on 'Paradoxical emboli'.) Ischemic stroke should be suspected in at-risk patients with SDH who have a sudden clinical deterioration consistent with ischemic stroke ( table 5) and stable head CT. Brain magnetic resonance imaging (MRI) is the preferred imaging modality because acute ischemic stroke may not be visible on initial repeat head CT. The treatment of acute ischemic stroke is discussed separately. (See "Initial assessment and management of acute stroke".) Acute toxic-metabolic encephalopathy Patients with SDH may develop delirium due several causes including preexisting medical conditions, pain, or medications. The evaluation of patients with delirium is discussed separately. (See "Diagnosis of delirium and confusional states".) Evaluation for underlying causes Some patients with spontaneous SDH not associated with trauma or other obvious cause may warrant brain and/or vascular imaging and other testing to identify possible secondary causes. The evaluation of underlying causes of SDH is discussed separately. (See "Subdural hematoma in adults: Etiology, clinical features, and diagnosis", section on 'Evaluation for underlying causes'.) Prevention and management of medical complications Patients with acute or chronic SDH are at risk for medical complications due to immobility or direct effects of the SDH. These complications can be associated with worse outcomes based on data from patients with intracerebral hemorrhage [45]. Seizure prophylaxis and management Patients with SDH are at risk for seizure or status epilepticus [46]. We do not routinely start antiseizure medicine prophylaxis for patients who have not had a seizure. In systematic reviews and observational studies, the seizure rate appears similar whether or not patients with SDH receive antiseizure medication prophylaxis [46-49]. https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 13/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate For patients with impairment of consciousness not attributed to mass effect from the SDH, we evaluate for other causes of symptoms. This includes electroencephalography to assess for nonconvulsive seizures or status epilepticus. (See 'Evaluation for underlying causes' above.) Antiseizure medications are typically reserved for patients with SDH who have clinical or electrographic seizures. The choice of initial antiseizure medication is guided by medical comorbidities, drug interactions, side effect drug profile, and contraindications ( table 6). (See "Evaluation and management of the first seizure in adults".) Prevention of venous thromboembolism Patients hospitalized with an acute illness and those with a neurologic condition that impairs mobility are at risk for venous thromboembolism. Intermittent pneumatic compression should be started on the first day of hospital admission for patients with SDH and impaired mobility. We add chemical prophylaxis for most patients one to four days after SDH stability is documented. An exception would be some patients being evaluated for urgent surgery for whom chemical prophylaxis may be temporarily withheld. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults".) Therapies not recommended or of uncertain benefit Statin medications Limited data suggest that low-dose statin medications may reduce hematoma size for patients with chronic SDH. In a systematic review that identified 156 patients with chronic SDH from three observational studies, atorvastatin 20 mg daily for one to six months was associated with reduced hematoma volume and low rates of recurrence [50]. In a trial of 196 patients with chronic SDH from China, those assigned atorvastatin 20 mg daily had better outcomes at eight weeks than those assigned to placebo, including greater reduction in SDH volumes (29 versus 17 mL) and lower rates of surgery for hematoma enlargement or deterioration (11 versus 24 percent; hazard ratio 0.47, 95% CI 0.24-0.92) [51]. Additional studies are needed to better identify the role of statin medications in the nonoperative management of patients with chronic SDH. Tranexamic acid The role of tranexamic acid (TXA) in the nonoperative management of patients with SDH is uncertain. TXA is an antifibrinolytic agent used in some patients with chronic SDH to reduce the rate of rebleeding after surgery or to promote resorption [52]. In a systematic review of 105 patients from four studies, only low-quality evidence was identified showing that tranexamic acid was associated with reduction in hematoma volume [53]. Data were limited by small numbers and variability in patient characteristics. In addition, TXA was used as an adjunctive therapy to surgical evacuation in most cases. In https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 14/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate an observational study of 27 patients with chronic SDH managed nonoperatively including TXA for a mean of 65 days, resolution occurred in all patients and no complications were reported [54]. Additional trial data are needed to clarify the role of TXA for patients with chronic SDH. Glucocorticoids We avoid glucocorticoid therapy for patients with SDH. In a trial of 748 patients with symptomatic chronic SDH, those assigned to a two-week course of dexamethasone were less likely to achieve a good functional outcome at six months than those assigned to placebo (84 versus 90 percent) [55]. Glucocorticoid therapy has also been associated with increased acute mortality following head injury. This issue is discussed separately. (See "Management of acute moderate and severe traumatic brain injury", section on 'Glucocorticoids'.) PROGNOSIS AND LONG-TERM MANAGEMENT The prognosis of SDH depends on severity of SDH and associated medical comorbidities. In a study that included 746 procedures of patients with SDH who underwent surgery between 2005 and 2012, the 30-day mortality rate was 17 percent [56]. In another study assessing outcome of patients undergoing surgery for acute SDH that included 462 patients (median age 49 years old), mortality at six months was 31 percent [8]. The estimated mortality rate for patients with more severe injuries who require surgery for SDH is as high as 60 percent in some small studies [1,3,9,29,33,40]. For patients who presented with coma prior to surgical evacuation, mortality rates were 57 to 68 percent [1,34,57]. Risk factors for poor outcome Age greater than 60 years and severe neurologic impairment are important prognostic indicators in patients with acute SDH [9,34]. Clinical features associated with poor outcome after SDH include the following: Older age [34,56] Lower Glasgow Coma Scale score [9,39] Coma at presentation [56,57] Coagulopathy [1,56,58] In addition, several studies have identified head computed tomography (CT) findings that correlate with poor outcome after acute SDH, including the following: Hematoma thickness [3,35] Hematoma volume [36] Presence and/or degree of midline brain shift [3,34-36] https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 15/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate Reduced patency of the basal cisterns [35] Coexisting intraparenchymal injury [33,58] Arterial source to SDH [59,60] However, some studies have not confirmed these relationships [61]. Risk of recurrence Recurrence of an acute SDH after initial resolution is uncommon and usually associated with an underlying fixed bleeding source such as a dural arteriovenous malformation, metastases, liver failure, hematological malignancies, or intracranial hypotension [62-65]. The risk of recurrence may be higher in patients with spontaneous SDH than those with a clear precipitant such as trauma. Recurrence of chronic SDH has been described in 5 up to 30 percent of patients [66-68]. Older age, thicker hematoma width, and bilateral presentation have been linked to higher rates of recurrence [68-73]. Ongoing antiplatelet and anticoagulant therapy may also increase the risk of recurrent SDH, although this has not been consistently found [72,74,75]. The use of postoperative drainage is associated with a lower risk of secondary recurrence. Resumption of antithrombotic medications The decision to resume anticoagulant or antiplatelet medications that were discontinued during initial SDH management should be individualized balancing the strength of the specific indication for therapy with the risk of SDH recurrence. We suggest resuming antiplatelet therapy after SDH resolution for most patients with a specific indication for such therapy. In one study of 2939 patients with SDH, the risk of subsequent arterial ischemic events was elevated in the first four weeks after SDH (hazard ratio 3.6, 95% CI 1.9-5.5), driven largely by patients with strong indications for antithrombotic therapy [76]. Accordingly, the risk-benefit analysis might favor resumption of antiplatelet therapy in a patient with active coronary or vascular disease, particularly after a SDH related to a traumatic injury that was not likely to recur. Many patients will benefit from resuming anticoagulation when the thromboembolic risk is higher than the risk of recurrent SDH. The specific risks and benefits should be weighed for individual patients. As examples: Anticoagulation may be resumed for selected patients with a traumatic SDH and atrial fibrillation with an elevated risk of thromboembolism after follow-up head CT shows resolution of the hematoma. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 16/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate Anticoagulation may be resumed for selected patients with a spontaneous SDH and a history of deep venous thrombosis and a high recurrence risk after follow-up head CT shows resolution of the hematoma. (See "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation", section on 'High recurrence risk'.) Anticoagulation may be withheld for selected patients with SDH and a high risk of recurrence, such as those with SDH due to a secondary source such as an unsecured arteriovenous malformation that has bled or cerebral amyloid angiopathy. (See "Brain arteriovenous malformations", section on 'Ruptured AVMs' and "Cerebral amyloid angiopathy", section on 'Managing anticoagulant and antiplatelet medications'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Subdural hematoma (The Basics)") SUMMARY AND RECOMMENDATIONS Initial management Subdural hematoma (SDH) can be a neurologic emergency that may cause irreversible brain injury and death caused by hematoma expansion, elevated https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 17/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate intracranial pressure (ICP), and brain herniation. Patients with SDH require urgent assessment of clinical status, the management of any antithrombotic medications, and evaluation of the need for immediate surgery ( table 1). (See 'Initial management' above.) Surgical management Urgent surgical hematoma evacuation is required for patients with SDH and signs attributable to brain herniation or elevated ICP and for those with clinical deterioration due to hematoma expansion ( algorithm 1). (See 'Surgical indications and approaches' above.) We also suggest surgical hematoma evacuation for patients with clot thickness >10 mm or midline shift >5 mm on initial brain scan especially if there is neurologic deterioration (Grade 2C). For other patients, we monitor nonoperatively with close neurologic monitoring for clinical or radiographic deterioration. Nonoperative management for all others Nonoperative management of SDH may be appropriate for patients who are clinically stable and have small hematomas with no signs of brain herniation (ie, midline shift <5 mm) or elevated ICP. Patients with SDH managed nonoperatively are closely monitored to assess for subsequent deterioration ( algorithm 1). (See 'Nonoperative management' above.) Monitoring Neurologic examinations should be performed at baseline and every one to two hours for at least the first 24 hours. Examinations include assessments of alertness, pupillary and other bulbar functions, sensorimotor functions, and Glasgow Coma Scale scoring ( table 2). (See 'Monitoring' above.) Repeat imaging Surveillance follow-up imaging with head computed tomography (CT) should be obtained within six to eight hours of the initial scan for all patients with SDH. Urgent repeat head CT is warranted for all patients who have an acute deterioration in clinical status. (See 'Follow-up imaging' above and 'Urgent repeat imaging to assess for indication for surgery' above.) Patients who deteriorate Surgical evacuation is indicated when clinical deterioration is due to significant progression of the hematoma. Testing for other causes is warranted for patients with SDH and evidence of clinical deterioration not accounted for by findings on repeat head CT. (See 'Management of patients who deteriorate' above.) Resumption of antithrombotic medications The decision should be individualized balancing the strength of the specific indication for therapy with the risk of SDH recurrence. Many patients will benefit from resuming anticoagulation when the https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 18/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate thromboembolic risk is higher than the risk of recurrent SDH. (See 'Resumption of antithrombotic medications' above.) Prognosis The 30-day mortality rate in patients with SDH who underwent surgery is approximately 17 percent but may be higher in patients who present with clinical features such as older age, preexisting coagulopathy, severe deficits on exam, and imaging features such as larger SDH volume, brain compression, or coexisting intraparenchymal injury. (See 'Risk factors for poor outcome' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Bullock MR, Chesnut R, Ghajar J, et al. Surgical management of acute subdural hematomas. Neurosurgery 2006; 58:S16. 2. Uno M, Toi H, Hirai S. Chronic Subdural Hematoma in Elderly Patients: Is This Disease Benign? Neurol Med Chir (Tokyo) 2017; 57:402. 3. Zumkeller M, Behrmann R, Heissler HE, Dietz H. Computed tomographic criteria and survival rate for patients with acute subdural hematoma. Neurosurgery 1996; 39:708. 4. Wong CW. Criteria for conservative treatment of supratentorial acute subdural haematomas. Acta Neurochir (Wien) 1995; 135:38. 5. Phan K, Moore JM, Griessenauer C, et al. Craniotomy Versus Decompressive Craniectomy for Acute Subdural Hematoma: Systematic Review and Meta-Analysis. World Neurosurg 2017; 101:677. 6. Yagnik KJ, Goyal A, Van Gompel JJ. Twist drill craniostomy vs burr hole drainage of chronic subdural hematoma: a systematic review and meta-analysis. Acta Neurochir (Wien) 2021; 163:3229. 7. Choi YH, Han SR, Lee CH, et al. Delayed Burr Hole Surgery in Patients with Acute Subdural Hematoma: Clinical Analysis. J Korean Neurosurg Soc 2017; 60:717. 8. Hutchinson PJ, Adams H, Mohan M, et al. Decompressive Craniectomy versus Craniotomy for Acute Subdural Hematoma. N Engl J Med 2023; 388:2219. 9. Hatashita S, Koga N, Hosaka Y, Takagi S. Acute subdural hematoma: severity of injury, surgical intervention, and mortality. Neurol Med Chir (Tokyo) 1993; 33:13. 10. Mehta V, Harward SC, Sankey EW, et al. Evidence based diagnosis and management of chronic subdural hematoma: A review of the literature. J Clin Neurosci 2018; 50:7. https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 19/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate 11. Gill M, Maheshwari V, Narang A, Lingaraju TS. Impact on Cognitive Improvement Following Burr Hole Evacuation of Chronic Subdural Hematoma: A Prospective Observational Study. J Neurosci Rural Pract 2018; 9:457. 12. Blaauw J, Boxum AG, Jacobs B, et al. Prevalence of Cognitive Complaints and Impairment in Patients with Chronic Subdural Hematoma and Recovery after Treatment: A Systematic Review. J Neurotrauma 2021; 38:159. 13. Parlato C, Guarracino A, Moraci A. Spontaneous resolution of chronic subdural hematoma. Surg Neurol 2000; 53:312. 14. Rauhala M, Hel n P, Huhtala H, et al. Chronic subdural hematoma-incidence, complications, and financial impact. Acta Neurochir (Wien) 2020; 162:2033. 15. Mayer S, Rowland L. Head injury. In: Merritt's Neurology, Rowland L (Ed), Lippincott Williams & Wilkins, 2000. p.401. 16. Santarius T, Kirkpatrick PJ, Ganesan D, et al. Use of drains versus no drains after burr-hole evacuation of chronic subdural haematoma: a randomised controlled trial. Lancet 2009; 374:1067. 17. Jensen TSR, Haldrup M, Hjortdal Gr nh j M, et al. National randomized clinical trial on subdural drainage time after chronic subdural hematoma evacuation. J Neurosurg 2021; :1. 18. Singla A, Jacobsen WP, Yusupov IR, Carter DA. Subdural evacuating port system (SEPS) minimally invasive approach to the management of chronic/subacute subdural hematomas. Clin Neurol Neurosurg 2013; 115:425. 19. Safain M, Roguski M, Antoniou A, et al. A single center's experience with the bedside subdural evacuating port system: a useful alternative to traditional methods for chronic subdural hematoma evacuation. J Neurosurg 2013; 118:694. 20. Kan P, Maragkos GA, Srivatsan A, et al. Middle Meningeal Artery Embolization for Chronic Subdural Hematoma: A Multi-Center Experience of 154 Consecutive Embolizations. Neurosurgery 2021; 88:268. 21. Link TW, Boddu S, Paine SM, et al. Middle Meningeal Artery Embolization for Chronic Subdural Hematoma: A Series of 60 Cases. Neurosurgery 2019; 85:801. 22. Ironside N, Nguyen C, Do Q, et al. Middle meningeal artery embolization for chronic subdural hematoma: a systematic review and meta-analysis. J Neurointerv Surg 2021; 13:951. 23. Srivatsan A, Mohanty A, Nascimento FA, et al. Middle Meningeal Artery Embolization for Chronic Subdural Hematoma: Meta-Analysis and Systematic Review. World Neurosurg 2019; 122:613. https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 20/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate 24. Ban SP, Hwang G, Byoun HS, et al. Middle Meningeal Artery Embolization for Chronic Subdural Hematoma. Radiology 2018; 286:992. 25. Salem MM, Kuybu O, Nguyen Hoang A, et al. Middle Meningeal Artery Embolization for Chronic Subdural Hematoma: Predictors of Clinical and Radiographic Failure from 636 Embolizations. Radiology 2023; 307:e222045. 26. Victor M, Ropper A. Craniocerebral trauma. In: Adams and Victor's Principles of Neurology, 7 th ed, Victor M, Ropper A (Eds), McGraw-Hill, 2001. p.925. 27. Lee JY, Ebel H, Ernestus RI, Klug N. Various surgical treatments of chronic subdural hematoma and outcome in 172 patients: is membranectomy necessary? Surg Neurol 2004; 61:523. 28. Moon HG, Shin HS, Kim TH, et al. Ossified chronic subdural hematoma. Yonsei Med J 2003; 44:915. 29. Haselsberger K, Pucher R, Auer LM. Prognosis after acute subdural or epidural haemorrhage. Acta Neurochir (Wien) 1988; 90:111. 30. Seelig JM, Becker DP, Miller JD, et al. Traumatic acute subdural hematoma: major mortality reduction in comatose patients treated within four hours. N Engl J Med 1981; 304:1511. 31. Wilberger JE Jr, Harris M, Diamond DL. Acute subdural hematoma: morbidity, mortality, and operative timing. J Neurosurg 1991; 74:212. 32. Sakas DE, Bullock MR, Teasdale GM. One-year outcome following craniotomy for traumatic hematoma in patients with fixed dilated pupils. J Neurosurg 1995; 82:961. 33. Ko RK, Akdemir H, Oktem IS, et al. Acute subdural hematoma: outcome and outcome prediction. Neurosurg Rev 1997; 20:239. 34. Kotwica Z, Brzezi ski J. Acute subdural haematoma in adults: an analysis of outcome in comatose patients. Acta Neurochir (Wien) 1993; 121:95. 35. Servadei F, Nasi MT, Giuliani G, et al. CT prognostic factors in acute subdural haematomas: the value of the 'worst' CT scan. Br J Neurosurg 2000; 14:110. 36. Howard MA 3rd, Gross AS, Dacey RG Jr, Winn HR. Acute subdural hematomas: an age- dependent clinical entity. J Neurosurg 1989; 71:858. 37. Massaro F, Lanotte M, Faccani G, Triolo C. One hundred and twenty-seven cases of acute subdural haematoma operated on. Correlation between CT scan findings and outcome. Acta Neurochir (Wien) 1996; 138:185. 38. Uzan M, Yent r E, Hanci M, et al. Is it possible to recover from uncal herniation? Analysis of 71 head injured cases. J Neurosurg Sci 1998; 42:89. https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 21/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate 39. Dent DL, Croce MA, Menke PG, et al. Prognostic factors after acute subdural hematoma. J Trauma 1995; 39:36. 40. Servadei F, Nasi MT, Cremonini AM, et al. Importance of a reliable admission Glasgow Coma Scale score for determining the need for evacuation of posttraumatic subdural hematomas: a prospective study of 65 patients. J Trauma 1998; 44:868. 41. Mathew P, Oluoch-Olunya DL, Condon BR, Bullock R. Acute subdural haematoma in the conscious patient: outcome with initial non-operative management. Acta Neurochir (Wien) 1993; 121:100. 42. Givner A, Gurney J, O'Connor D, et al. Reimaging in pediatric neurotrauma: factors associated with progression of intracranial injury. J Pediatr Surg 2002; 37:381. 43. Gaonkar VB, Garg K, Agrawal D, et al. Risk Factors for Progression of Conservatively Managed Acute Traumatic Subdural Hematoma: A Systematic Review and Meta-Analysis. World Neurosurg 2021; 146:332. 44. Oertel M, Kelly DF, McArthur D, et al. Progressive hemorrhage after head trauma: predictors and consequences of the evolving injury. J Neurosurg 2002; 96:109. 45. Zhang Y, Wang Y, Ji R, et al. In-hospital complications affect short-term and long-term mortality in ICH: a prospective cohort study. Stroke Vasc Neurol 2021; 6:201. 46. Pruitt P, Naidech A, Van Ornam J, Borczuk P. Seizure frequency in patients with isolated subdural hematoma and preserved consciousness. Brain Inj 2019; 33:1059. 47. Nachiappan DS, Garg K. Role of prophylactic antiepileptic drugs in chronic subdural hematoma-a systematic review and meta-analysis. Neurosurg Rev 2021; 44:2069. 48. Lavergne P, Labidi M, Brunet MC, et al. Efficacy of antiseizure prophylaxis in chronic subdural hematoma: a cohort study on routinely collected health data. J Neurosurg 2019; :1. 49. Khor D, Wu J, Hong Q, et al. Early Seizure Prophylaxis in Traumatic Brain Injuries Revisited: A Prospective Observational Study. World J Surg 2018; 42:1727. 50. Qiu S, Zhuo W, Sun C, et al. Effects of atorvastatin on chronic subdural hematoma: A systematic review. Medicine (Baltimore) 2017; 96:e7290. 51. Jiang R, Zhao S, Wang R, et al. Safety and Efficacy of Atorvastatin for Chronic Subdural Hematoma in Chinese Patients: A Randomized ClinicalTrial. JAMA Neurol 2018; 75:1338. 52. Yamada T, Natori Y. Prospective Study on the Efficacy of Orally Administered Tranexamic Acid and Goreisan for the Prevention of Recurrence After Chronic Subdural Hematoma Burr Hole Surgery. World Neurosurg 2020; 134:e549. 53. Scerrati A, Visani J, Ricciardi L, et al. To drill or not to drill, that is the question: nonsurgical treatment of chronic subdural hematoma in the elderly. A systematic review. Neurosurg https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 22/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate Focus 2020; 49:E7. 54. Kutty RK, Leela SK, Sreemathyamma SB, et al. The Outcome of Medical Management of Chronic Subdural Hematoma with Tranexamic Acid - A Prospective Observational Study. J Stroke Cerebrovasc Dis 2020; 29:105273. 55. Hutchinson PJ, Edlmann E, Bulters D, et al. Trial of Dexamethasone for Chronic Subdural Hematoma. N Engl J Med 2020; 383:2616. 56. Lukasiewicz AM, Grant RA, Basques BA, et al. Patient factors associated with 30-day morbidity, mortality, and length of stay after surgery for subdural hematoma: a study of the American College of Surgeons National Surgical Quality Improvement Program. J Neurosurg 2016; 124:760. 57. Gennarelli TA, Spielman GM, Langfitt TW, et al. Influence of the type of intracranial lesion on outcome from severe head injury. J Neurosurg 1982; 56:26. 58. Hlatky R, Valadka AB, Goodman JC, Robertson CS. Evolution of brain tissue injury after evacuation of acute traumatic subdural hematomas. Neurosurgery 2004; 55:1318. 59. Kaur G, Dakay K, Sursal T, et al. Acute subdural hematomas secondary to aneurysmal subarachnoid hemorrhage confer poor prognosis: a national perspective. J Neurointerv Surg 2021; 13:426. 60. Mulcahy MJ, Chaganti J, Dower A, Al-Khawaja D. Spontaneous Acute Arterial Subdural Hematoma. World Neurosurg 2018; 110:403. 61. van den Brink WA, Zwienenberg M, Zandee SM, et al. The prognostic importance of the volume of traumatic epidural and subdural haematomas revisited. Acta Neurochir (Wien) 1999; 141:509. 62. Maiuri F, Iaconetta G, Sardo L, Briganti F. Dural arteriovenous malformation associated with recurrent subdural haematoma and intracranial hypertension. Br J Neurosurg 2001; 15:273. 63. Mizuno J, Mummaneni PV, Rodts GE, Barrow DL. Recurrent subdural hematoma caused by cerebrospinal fluid leakage. Case report. J Neurosurg Spine 2006; 4:183. 64. Garc a-Morales I, Porta-Etessam J, Gal n L, et al. Recurrent subdural haematomas in a patient with spontaneous intracranial hypotension. Cephalalgia 2001; 21:703. 65. Schievink WI, Maya MM, Pikul BK, Louy C. Spontaneous spinal cerebrospinal fluid leaks as the cause of subdural hematomas in elderly patients on anticoagulation. J Neurosurg 2010; 112:295. 66. Santarius T, Qureshi HU, Sivakumaran R, et al. The role of external drains and peritoneal conduits in the treatment of recurrent chronic subdural hematoma. World Neurosurg 2010; 73:747. https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 23/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate 67. Carlsen JG, Cortnum S, S rensen JC. Recurrence of chronic subdural haematomata with and without post-operative drainage. Br J Neurosurg 2011; 25:388. 68. Yu GJ, Han CZ, Zhang M, et al. Prolonged drainage reduces the recurrence of chronic subdural hematoma. Br J Neurosurg 2009; 23:606. 69. Escosa Ba M, Wessling H, Salca HC, de Las Heras Echeverr a P. Use of twist-drill craniostomy with drain in evacuation of chronic subdural hematomas: independent predictors of recurrence. Acta Neurochir (Wien) 2011; 153:1097. 70. Oh HJ, Lee KS, Shim JJ, et al. Postoperative course and recurrence of chronic subdural hematoma. J Korean Neurosurg Soc 2010; 48:518. 71. Kung WM, Hung KS, Chiu WT, et al. Quantitative assessment of impaired postevacuation brain re-expansion in bilateral chronic subdural haematoma: possible mechanism of the higher recurrence rate. Injury 2012; 43:598. 72. Torihashi K, Sadamasa N, Yoshida K, et al. Independent predictors for recurrence of chronic subdural hematoma: a review of 343 consecutive surgical cases. Neurosurgery 2008; 63:1125. 73. Yamamoto H, Hirashima Y, Hamada H, et al. Independent predictors of recurrence of chronic subdural hematoma: results of multivariate analysis performed using a logistic regression model. J Neurosurg 2003; 98:1217. 74. Forster MT, Math AK, Senft C, et al. The influence of preoperative anticoagulation on outcome and quality of life after surgical treatment of chronic subdural hematoma. J Clin Neurosci 2010; 17:975. 75. Lindvall P, Koskinen LO. Anticoagulants and antiplatelet agents and the risk of development and recurrence of chronic subdural haematomas. J Clin Neurosci 2009; 16:1287. 76. Murthy SB, Wu X, Diaz I, et al. Non-Traumatic Subdural Hemorrhage and Risk of Arterial Ischemic Events. Stroke 2020; 51:1464. Topic 1110 Version 26.0 https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 24/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate GRAPHICS Subdural hematoma in adults: Rapid overview of emergency management Clinical manifestations When to suspect: Trauma Unexplained acute or subacute progressive neurologic symptoms New neurologic symptoms in an older patient (especially if taking anticoagulants) Common symptoms: New and persistent headache, focal or bilateral weakness, confusion, subacute cognitive decline, seizures Signs of elevated intracranial pressure: Dilated pupil(s) Progressive drowsiness Cushing triad (bradycardia, respiratory depression, hypertension) Evaluation Assess airway, breathing, circulation, and disability to initiate supportive care Determine GCS and neurologic deficits (eg, hemiparesis, numbness, speech or vision impairment) Identify exposure to anticoagulant medications (eg, warfarin, DOACs, heparinoids) Obtain emergency imaging (eg, head CT or fast MRI) Laboratory evaluation: Complete blood count, PT, PTT, INR, basic electrolytes, pregnancy test in female of childbearing age Initial serial monitoring: Neurologic examination (hourly) for signs of deterioration Repeat head CT 6 to 8 hours after initial study and for any clinical signs of deterioration Treatment Manage trauma patients according to principles of advanced trauma life support* Perform tracheal intubation for any patient unable to protect their airway, with rapidly deteriorating mental status, or with GCS 8 https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 25/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate Obtain immediate neurosurgical consultation as indicated by clinical signs or imaging: Hemispheric SDH >10 mm thickness or midline shift >5 mm SDH causing brainstem compression or pupillary abnormalities SDH causing progressive neurologic deterioration (eg, GCS drop 2 points) Reverse anticoagulation (agent specific): Warfarin Reverse with 4-factor PCC and IV vitamin K Dabigatran Reverse with idarucizumab Factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) Reverse with 4-factor PCC or andexanet alfa Heparin (unfractionated) Reverse with protamine sulfate Low molecular weight heparin Reverse with andexanet alfa; protamine sulfate is an alternative Medical management of intracranial pressure: Blood pressure control: Prevent HYPOtension to maintain SBP >100 mmHg: fluid resuscitation with isotonic IV fluids; phenylephrine for refractory symptoms Initial dose 0.5 to 2 mcg/kg per minute IV; maintenance dose 0.25 to 5 mcg/kg per minute Treat HYPERtension: Initial treatment to rapidly reduce SBP to <220 mmHg: nicardipine 5 mg/hour IV, titrate by 2.5 mg/hour every 5 to 15 minutes (maximum dose: 15 mg/hour); alternate: labetalol 20 mg IV bolus, may repeat every 10 minutes Subsequent treatment to reduce SBP to <160 mmHg while monitoring for stability of neurologic status Elevate head of bed >30 degrees Give antipyretics for temperature >38 degrees Celsius (eg, acetaminophen [paracetamol] 325 to 650 mg orally or PR every 4 to 6 hours or 650 mg IV every 4 hours) Repeat imaging (eg, head CT) for signs of new or progressive elevated intracranial pressure: Obtain immediate neurosurgical consultation for surgical indications (refer to above) Osmotic therapy (mannitol or hypertonic saline) or hyperventilation as temporary treatment measures https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 26/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate GCS: Glasgow coma scale; DOAC: direct oral anticoagulant; CT: computed tomography; MRI: magnetic resonance imaging; PT: prothrombin time; PTT: partial thromboplastin time; INR: international normalized ratio; SDH: subdural hematoma; PCC: prothrombin complex concentrate; IV: intravenous; SBP: systolic blood pressure; PR: per rectum. Refer to the UpToDate topics on trauma management in adults. Refer to the UpToDate topics on management of elevated intracranial pressure in adults. Graphic 132691 Version 5.0 https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 27/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate Management of acute and symptomatic chronic subdural hematoma SDH: subdural hematoma; CT: computed tomography; EEG: electroencephalogram; MRI: magnetic resonance imaging. For patients with trauma, follow principles of advanced trauma life support. https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 28/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate Refer to the UpToDate on reversal of anticoagulation in intracranial hemorrhage for additional details. Glasgow Coma Scale drop 2+ points; worsening of neurologic exam including pupillary abnormalities, cranial nerve palsies, and limb weakness. Includes patients with nontraumatic SDH without cerebral atrophy, coagulopathy, or other risk factors to explain SDH. Refer to the UpToDate topic on the etiology, clinical features, and diagnosis of subdural hematoma in adults for additional details. Graphic 134178 Version 1.0 https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 29/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate Glasgow Coma Scale (GCS) Score Eye opening Spontaneous 4 Response to verbal command 3 Response to pain 2 No eye opening 1 Best verbal response Oriented 5 Confused 4 Inappropriate words 3 Incomprehensible sounds 2 No verbal response 1 Best motor response Obeys commands 6 Localizing response to pain 5 Withdrawal response to pain 4 Flexion to pain 3 Extension to pain 2 No motor response 1 Total The GCS is scored between 3 and 15, 3 being the worst and 15 the best. It is composed of three parameters: best eye response (E), best verbal response (V), and best motor response (M). The components of the GCS should be recorded individually; for example, E2V3M4 results in a GCS score of 9. A score of 13 or higher correlates with mild brain injury, a score of 9 to 12 correlates with moderate injury, and a score of 8 or less represents severe brain injury. Graphic 81854 Version 9.0 https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 30/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate Emergency reversal of anticoagulation from warfarin for life-threatening hemorrhage in adults: Suggested approaches based upon available resources A. If 4-factor prothrombin complex concentrate (4F PCC) is available (preferred approach): 1. Give 4F PCC* 1500 to 2000 units IV over 10 minutes. Check INR 15 minutes after completion of the infusion. If INR is not 1.5, give additional 4F PCC (refer to topic or drug reference for details). 2. Give vitamin K 10 mg IV over 10 to 20 minutes. B. If 3-factor prothrombin complex concentrate (3F PCC) is available but 4F PCC is not available: 1. Give 3F PCC* 1500 to 2000 units IV over 10 minutes. Check INR 15 minutes after completion of the infusion. If INR is not 1.5, give additional 3F PCC (refer to topic or drug reference for details). 2. Give Factor VIIa 20 mcg/kg IV OR give FFP 2 units IV by rapid infusion. Factor VIIa may be preferred if volume overload is a concern. 3. Give vitamin K 10 mg IV over 10 to 20 minutes. C. If neither 3F PCC nor 4F PCC is available: 1. Give FFP 2 units IV by rapid infusion. Check INR 15 minutes after completion of infusion. If INR 1.5, administer 2 additional units of FFP IV rapid infusion. Repeat process until INR 1.5. May wish to administer loop diuretic between FFP infusions if volume overload is a concern. 2. Give vitamin K 10 mg IV over 10 to 20 minutes. These products and doses are for use in life-threatening bleeding only. Evidence of life-threatening bleeding and over-anticoagulation with a vitamin K antagonist (eg, warfarin) are required. Anaphylaxis and transfusion reactions can occur. It may be reasonable to thaw 4 units of FFP while awaiting the PT/INR. The transfusion service may substitute other plasma products for FFP (eg, Plasma Frozen Within 24 Hours After Phlebotomy

subacute cognitive decline, seizures Signs of elevated intracranial pressure: Dilated pupil(s) Progressive drowsiness Cushing triad (bradycardia, respiratory depression, hypertension) Evaluation Assess airway, breathing, circulation, and disability to initiate supportive care Determine GCS and neurologic deficits (eg, hemiparesis, numbness, speech or vision impairment) Identify exposure to anticoagulant medications (eg, warfarin, DOACs, heparinoids) Obtain emergency imaging (eg, head CT or fast MRI) Laboratory evaluation: Complete blood count, PT, PTT, INR, basic electrolytes, pregnancy test in female of childbearing age Initial serial monitoring: Neurologic examination (hourly) for signs of deterioration Repeat head CT 6 to 8 hours after initial study and for any clinical signs of deterioration Treatment Manage trauma patients according to principles of advanced trauma life support* Perform tracheal intubation for any patient unable to protect their airway, with rapidly deteriorating mental status, or with GCS 8 https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 25/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate Obtain immediate neurosurgical consultation as indicated by clinical signs or imaging: Hemispheric SDH >10 mm thickness or midline shift >5 mm SDH causing brainstem compression or pupillary abnormalities SDH causing progressive neurologic deterioration (eg, GCS drop 2 points) Reverse anticoagulation (agent specific): Warfarin Reverse with 4-factor PCC and IV vitamin K Dabigatran Reverse with idarucizumab Factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) Reverse with 4-factor PCC or andexanet alfa Heparin (unfractionated) Reverse with protamine sulfate Low molecular weight heparin Reverse with andexanet alfa; protamine sulfate is an alternative Medical management of intracranial pressure: Blood pressure control: Prevent HYPOtension to maintain SBP >100 mmHg: fluid resuscitation with isotonic IV fluids; phenylephrine for refractory symptoms Initial dose 0.5 to 2 mcg/kg per minute IV; maintenance dose 0.25 to 5 mcg/kg per minute Treat HYPERtension: Initial treatment to rapidly reduce SBP to <220 mmHg: nicardipine 5 mg/hour IV, titrate by 2.5 mg/hour every 5 to 15 minutes (maximum dose: 15 mg/hour); alternate: labetalol 20 mg IV bolus, may repeat every 10 minutes Subsequent treatment to reduce SBP to <160 mmHg while monitoring for stability of neurologic status Elevate head of bed >30 degrees Give antipyretics for temperature >38 degrees Celsius (eg, acetaminophen [paracetamol] 325 to 650 mg orally or PR every 4 to 6 hours or 650 mg IV every 4 hours) Repeat imaging (eg, head CT) for signs of new or progressive elevated intracranial pressure: Obtain immediate neurosurgical consultation for surgical indications (refer to above) Osmotic therapy (mannitol or hypertonic saline) or hyperventilation as temporary treatment measures https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 26/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate GCS: Glasgow coma scale; DOAC: direct oral anticoagulant; CT: computed tomography; MRI: magnetic resonance imaging; PT: prothrombin time; PTT: partial thromboplastin time; INR: international normalized ratio; SDH: subdural hematoma; PCC: prothrombin complex concentrate; IV: intravenous; SBP: systolic blood pressure; PR: per rectum. Refer to the UpToDate topics on trauma management in adults. Refer to the UpToDate topics on management of elevated intracranial pressure in adults. Graphic 132691 Version 5.0 https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 27/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate Management of acute and symptomatic chronic subdural hematoma SDH: subdural hematoma; CT: computed tomography; EEG: electroencephalogram; MRI: magnetic resonance imaging. For patients with trauma, follow principles of advanced trauma life support. https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 28/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate Refer to the UpToDate on reversal of anticoagulation in intracranial hemorrhage for additional details. Glasgow Coma Scale drop 2+ points; worsening of neurologic exam including pupillary abnormalities, cranial nerve palsies, and limb weakness. Includes patients with nontraumatic SDH without cerebral atrophy, coagulopathy, or other risk factors to explain SDH. Refer to the UpToDate topic on the etiology, clinical features, and diagnosis of subdural hematoma in adults for additional details. Graphic 134178 Version 1.0 https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 29/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate Glasgow Coma Scale (GCS) Score Eye opening Spontaneous 4 Response to verbal command 3 Response to pain 2 No eye opening 1 Best verbal response Oriented 5 Confused 4 Inappropriate words 3 Incomprehensible sounds 2 No verbal response 1 Best motor response Obeys commands 6 Localizing response to pain 5 Withdrawal response to pain 4 Flexion to pain 3 Extension to pain 2 No motor response 1 Total The GCS is scored between 3 and 15, 3 being the worst and 15 the best. It is composed of three parameters: best eye response (E), best verbal response (V), and best motor response (M). The components of the GCS should be recorded individually; for example, E2V3M4 results in a GCS score of 9. A score of 13 or higher correlates with mild brain injury, a score of 9 to 12 correlates with moderate injury, and a score of 8 or less represents severe brain injury. Graphic 81854 Version 9.0 https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 30/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate Emergency reversal of anticoagulation from warfarin for life-threatening hemorrhage in adults: Suggested approaches based upon available resources A. If 4-factor prothrombin complex concentrate (4F PCC) is available (preferred approach): 1. Give 4F PCC* 1500 to 2000 units IV over 10 minutes. Check INR 15 minutes after completion of the infusion. If INR is not 1.5, give additional 4F PCC (refer to topic or drug reference for details). 2. Give vitamin K 10 mg IV over 10 to 20 minutes. B. If 3-factor prothrombin complex concentrate (3F PCC) is available but 4F PCC is not available: 1. Give 3F PCC* 1500 to 2000 units IV over 10 minutes. Check INR 15 minutes after completion of the infusion. If INR is not 1.5, give additional 3F PCC (refer to topic or drug reference for details). 2. Give Factor VIIa 20 mcg/kg IV OR give FFP 2 units IV by rapid infusion. Factor VIIa may be preferred if volume overload is a concern. 3. Give vitamin K 10 mg IV over 10 to 20 minutes. C. If neither 3F PCC nor 4F PCC is available: 1. Give FFP 2 units IV by rapid infusion. Check INR 15 minutes after completion of infusion. If INR 1.5, administer 2 additional units of FFP IV rapid infusion. Repeat process until INR 1.5. May wish to administer loop diuretic between FFP infusions if volume overload is a concern. 2. Give vitamin K 10 mg IV over 10 to 20 minutes. These products and doses are for use in life-threatening bleeding only. Evidence of life-threatening bleeding and over-anticoagulation with a vitamin K antagonist (eg, warfarin) are required. Anaphylaxis and transfusion reactions can occur. It may be reasonable to thaw 4 units of FFP while awaiting the PT/INR. The transfusion service may substitute other plasma products for FFP (eg, Plasma Frozen Within 24 Hours After Phlebotomy [PF24]); these products are considered clinically interchangeable. PCC will reverse anticoagulation within minutes of administration; FFP administration can take hours due to the volume required; vitamin K effect takes 12 to 24 hours, but administration of vitamin K is needed to counteract the long half-life of warfarin. Subsequent monitoring of the PT/INR is needed to guide further therapy. Refer to topics on warfarin reversal in individual situations for further management. PCC: unactivated prothrombin complex concentrate; 4F PCC: PCC containing coagulation factors II, VII, IX, X, protein S and protein C; 3F PCC: PCC containing factors II, IX, and X and only trace factor VII; FFP: fresh frozen plasma; PT: prothrombin time; INR: international normalized ratio; FEIBA: factor eight inhibitor bypassing agent. Before use, check product label to confirm factor types (3 versus 4 factor) and concentration. Activated complexes and single-factor IX products (ie, FEIBA, AlphaNine, Mononine, Immunine, BeneFix) are NOT used for warfarin reversal. https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 31/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate PCC doses shown are those suggested for initial treatment of emergency conditions. Subsequent treatment is based on INR and patient weight if available. Refer to topic and Lexicomp drug reference included with UpToDate for INR-based dosing. Graphic 89478 Version 10.0 https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 32/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate Direct oral anticoagulant reversal agents for life-threatening bleeding (imminent risk of death from bleeding) Reversal agent (all are given Anticoagulant intravenously) Dabigatran (Pradaxa; oral thrombin inhibitor) Idarucizumab (Praxbind). Dose: 5 grams* Oral factor Xa inhibitors: Andexanet alfa (AndexXa). Dosing for the initial bolus and subsequent infusion depend Apixaban (Eliquis) on the dose level of the factor Xa inhibitor and Edoxaban (Lixiana, Savaysa) the interval since it was last taken. Rivaroxaban (Xarelto) OR- 4-factor PCC (Kcentra, Beriplex P/N, Octaplex). Dosing can be done with a fixed dose of 2000 units OR a weight-based dose of 25 to 50 units per kg. Reversal agents carry a risk of life-threatening thrombosis and should only be used under the direction of a specialist with expertise in their use and/or in a patient at imminent risk of death from bleeding. In general, a single dose is given; dosing may be repeated in rare situations in which the oral anticoagulant persists for longer in the circulation, such as severe kidney dysfunction. Andexanet dosing is as follows: If the patient took rivaroxaban >10 mg, apixaban >5 mg, or dose unknown within the previous 8 hours: Andexanet 800 mg bolus at 30 mg/minute followed by 960 mg infusion at 8 mg/minute for up to 120 minutes. OR- If the patient took rivaroxaban 10 mg or apixaban 5 mg, or if 8 hours have elapsed since the last dose of a factor Xa inhibitor: Andexanet 400 mg bolus at 30 mg/minute followed by 480 mg infusion at 4 mg/minute for up to 120 minutes. Refer to UpToDate topics on treatment of bleeding in patients receiving a DOAC or perioperative management of patients receiving a DOAC for additional information on administration, risks, and alternative therapies. DOAC: direct oral anticoagulant; PCC: prothrombin complex concentrate; FEIBA: factor eight inhibitor bypassing activity. If idarucizumab is unavailable, an activated PCC (FEIBA, 50 to 80 units per kg intravenously) may be a reasonable alternative. Graphic 112299 Version 9.0 https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 33/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate Traumatic subdural hematoma (SDH) CT scan showing a left acute SDH (arrow). SDHs are typically crescent shaped. In this case the SDH is causing significant mass effect and shift of midline structures to the right. CT: computed tomography. Reproduced with permission from: J Claude Hemphill III, MD and Nicholas Phan, MD, FRCSC. Graphic 68102 Version 5.0 https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 34/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate Uncal herniation from subdural hematoma Noncontrast head CT shows a large right holohemispheric subdural hematoma on axial (A) and coronal (B) images. Mass effect from hematoma causes a right-to-left midline shift (line) and subfalcine herniation (arrowhead). Axial image through the temporal lobes (C) shows uncal herniation with compression of the cerebral peduncles (arrow). CT: computed tomography. https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 35/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate Courtesy of Glenn A Tung, MD, FACR. Graphic 132682 Version 1.0 https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 36/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate Symptoms of transient ischemic attacks and the vascular territories involved ICA/MCA VA/BA PCA SVD Visual abnormalities Transient ++++ monocular blindness Hemianopia + +++ Blindness ++ ++ Motor abnormalities Hemiparesis + + ++ Quadriparesis ++++ Single part weakness Face + ++ + Arm/hand +++ + Thigh/leg/foot ++ + + Crossed weakness* ++++ Limb ++ ++ ataxia/weakness Gait ataxia +++ + Sensory abnormalities Hemisensory + ++ ++ Single part sensory Face + ++ + ++ Arm/hand ++ ++ + Thigh/leg/foot + + + + Crossed sensory* ++++ Cognitive abnormalities Aphasia ++++ + Amnesia + +++ Alexia +++ +++ https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 37/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate Abulia ++ + + Brainstem and cranial nerve symptoms Dizziness/vertigo + +++ Diplopia ++++ Dysarthria + ++ ++ Dysphagia ++ ++ Tinnitus/hearing loss ++++ ICA: internal carotid arteries; MCA: middle cerebral arteries; VA: vertebral arteries; BA: basilar artery; PCA: posterior cerebral arteries; SVD: small vessel disease. Crossed weakness or crossed sensory refers to one side of the cranial structures and the opposite side limbs and trunk. Graphic 71676 Version 5.0 https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 38/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate Pharmacologic properties of antiseizure medications Enzyme or Metabolism and Protein binding Half-lif transporter clearance (%) adults (h induction/inhibition* 20 Brivaracetam Metabolized Inhibits epoxide 9 primarily by CYP- hydroxylase independent hydrolysis (60%) and CYP2C19 (30%) Dose adjustment is needed in hepatic impairment Cannabidiol Hepatic (primarily) and gut by CYP2C19, CYP3A4, UGT1A7, UGT1A9, and UGT2B7 to Inhibits BCRP/ABCG2, BSEP/ABCB11, CYP2C19 (moderate) >94 56 to 61 May increase serum concentration of clobazam and the active metabolite(s) of clobazam active metabolite 7- OH-CBD and then to inactive metabolite 7-COOH-CBD Dose adjustment is needed in moderate to severe hepatic impairment Carbamazepine >90% metabolized by CYPs 3A4 (major) Potent and broad- spectrum inducer of CYP, 75 25 to 65 (init enzyme-ind and 1A2/2C8 (minor) to active (epoxide) UGT-glucuronidation, and P-gp naive patien 8 to 22 (afte and inactive weeks due t induction) metabolites Dose adjustment is needed in severe renal impairment; use is not recommended in moderate or severe hepatic impairment Cenobamate Primarily May increase serum 60 50 to 60 hou metabolized by glucuronidation via concentrations of clobazam, phenobarbital, https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 39/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate UGT2B7 and to a phenytoin, and CYP2C19 lesser extent by substrates UGT2B4, and by oxidation via May decrease serum concentrations of carbamazepine, CYP2E1, CYP2A6, CYP2B6, and to a lamotrigine, and CYP2B6 and CYP3A substrates lesser extent by CYP2C19 and CYP3A4/5 Dose adjustment is needed for hepatic impairment; not recommended for patients with severe hepatic impairment or end-stage renal disease Clobazam >90% metabolized by CYPs 3A4, 2C19, 2B6 and non-CYP transformations to active (N- Inhibits CYP2D6 (weak) 80 to 90 (clobazam, parent drug) 36 to 42 (clo parent drug 70 (N- 71 to 82 (N- desmethylclobazam, active metabolite) desmethylcl active metab desmethylclobazam) and inactive metabolites Active metabolite is primarily metabolized by CYP2C19 Dose adjustment is needed in hepatic impairment Eslicarbazepine Prodrug; <33% of active form Induces CYP3A4 (moderate) <40 13 to 20 (pro in renal undergoes UGT- insufficiency Inhibits CYP2C19 (weak) glucuronidation (including <5% metabolized to oxcarbazepine); 66% is excreted renally as unchanged drug Dose adjustment is needed for renal impairment; not https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 40/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate recommended in patients with severe hepatic impairment Ethosuximide ~80% metabolized by CYP3A4 (major) None <5 40 to 60 and non-CYP transformations to inactive metabolites Felbamate 50% metabolized by CYPs 3A4, 2E1 Increases conversion of carbamazepine to active 25 13 to 22 (pro in renal (minor); ~50% epoxide metabolite; insufficiency renally excreted as unchanged drug mechanism not established Dose adjustment is needed in renal impairment Inhibits CYP2C19 (weak) Gabapentin >95% renally None <5 5 to 7 (prolo excreted as unchanged drug (ie, does not undergo hepatic metabolism) renal insuffi >130 hours anuria) Dose adjustment is needed in renal impairment Lacosamide 40% renally excreted as unchanged drug; 30% metabolized by non-CYP transformations None <15 13 (including methylation) to inactive metabolite Dose adjustment is needed in hepatic and renal impairment Lamotrigine >90% metabolized by UGT- May induce its own metabolism by UGT- 55 12 to 62 glucuronidation and other non-CYP glucuronidation (minor) transformations to inactive metabolites https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 41/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate Dose adjustment is needed in moderate to severe renal or hepatic impairment Levetiracetam >65% renally None <10 6 to 8 excreted as unchanged drug; 24% metabolized by non-CYP transformation (including amidase hydrolysis) to inactive metabolites Dose adjustment is needed in renal impairment Oxcarbazepine Prodrug; 70% of Induces CYP3A4 (weak) 40 9 (active me active (MHD) form undergoes UGT- glucuronidation; 30% is renally excreted as unchanged active drug and UGT-glucuronidation but does not induce its own metabolism prolonged in insufficiency Dose adjustment is needed in severe renal impairment Perampanel >70% metabolized Appears to induce 95 105 by CYPs 3A4, 3A5 and non-CYP transformations to metabolism of progestin- containing hormonal contraceptives inactive metabolites Dose adjustment is needed in mild or moderate hepatic impairment Phenobarbital 75% metabolized by Potent and broad- 55 75 to 110 CYPs 2C19, 2C9 (minor) and spectrum inducer of CYP and UGT-glucuronidation glucosidase hydrolysis and 2E1 (minor) to inactive metabolites; 25% https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 42/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate excreted renally as unchanged drug Dose adjustment is needed in severe renal or hepatic impairment Phenytoin >90% metabolized Potent and broad- 90 to 95 9 to >42 (do by CYPs 2C9, 2C19, 3A4 (minor) and spectrum inducer of CYP and UGT-glucuronidation dependent) non-CYP transformations to inactive metabolites; clearance is dose dependent, saturable, and may be subject to genetic polymorphism Dose adjustment is needed in severe renal or hepatic insufficiency; monitoring of free (unbound) concentrations also suggested Pregabalin >95% excreted None <5 6 renally as unchanged drug Dose adjustment is needed in renal impairment Primidone 75% metabolized by CYPs 2C19, 2C9 Potent and broad- spectrum inducer of CYP 0 to 20 10 to 15 (pa 29 to 100 (ac (minor) and 2E1 metabolite) (minor) to active intermediates; ~25% excreted renally as unchanged drug Dose adjustment is needed in moderate and severe renal or hepatic impairment; https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 43/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate close monitoring of plasma levels suggested Rufinamide >90% metabolized by non-CYP Induces CYP3A4 (weak) 35 6 to 10 transformations (hydrolysis) to inactive metabolites Stiripentol Metabolized Inhibits CYP3A4, 99 4.5 to 13 primarily in the liver by CYP450 enzymes CYP2C19, CYP3A4, CYP2C19, P-gp, and BCRP and glucuronidation Tiagabine >90% metabolized None 95 7 to 9 by CYP3A4 and non- CYP transformations to inactive metabolites 2 to 5 (with inducing an medications Topiramate >65% excreted renally as unchanged drug; None 9 to 17 12 to 24 <30% metabolized by non-CYP transformations to inactive metabolites; extent of metabolism is increased ~50% in patients receiving enzyme-inducing antiseizure medications Dose adjustment is needed in moderate and severe renal or hepatic impairment Valproate >95% undergoes None 80 to 95 7 to 16 complex transformations including CYPs 2C9, 2C19, 2A6, UGT- glucuronidation and other non-CYP transformation https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 44/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate Dose adjustment is needed in hepatic impairment Vigabatrin >90% excreted renally as None 0 5 to 13 (unre duration of unchanged drug Dose adjustment is needed in renal impairment Zonisamide >65% metabolized None 50 63 by CYPs 3A4, 2C19 (minor) and non- CYP transformations Dose adjustment and/or slower titration is needed in mild renal impairment or hepatic impairment; not recommended in patients with moderate or severe renal impairment CYP: cytochrome P450; MHD: monohydroxy derivative active form of oxcarbazepine; P-gp: membrane P-glycoprotein multidrug resistance transporter; UGT-glucuronidation: metabolism by uridine 5'diphosphate-glucuronyltransferases. The inhibitors and inducers of CYP or UGT drug metabolism and P-gp transporters listed in this table can alter serum concentrations of drugs that are dependent upon these enzymes or transporters for elimination, activation, or bioavailability. Classifications are based on US Food and Drug Administration guidance [4, 5]. Other sources may use a different classification system resulting in some agents being classified differently. Specific interactions should be assessed using a drug interaction program such as Lexicomp interactions included within UpToDate. Highly protein-bound antiseizure medications exhibit altered pharmacokinetics, including greater therapeutic and toxic effects and drug interactions, when given in usual doses to patients with low serum albumin or protein-binding affinity (eg, due to nephrotic syndrome or acidosis). Dose alteration is needed and monitoring of unbound (free) antiseizure medication serum concentrations is suggested. Refer to UpToDate topic for additional information. Inhibitors of epoxide hydroxylase (eg, brivaracetam) can decrease metabolism of phenytoin and active metabolite of carbamazepine; refer to UpToDate topic. Data from: Lexicomp Online. Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. Additional data from: https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 45/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate 1. Bazil CW. Antiepileptic drugs in the 21st century. CNS Spectr 2001; 6:756. 2. Lacerda G, Krummel T, Sabourdy C, et al. Optimizing therapy of seizures in patients with renal or hepatic dysfunction. Neurology 2006; 67:S28. 3. Anderson GD, Hakimian S. Pharmacokinetic of antiepileptic drugs in patients with hepatic or renal impairment. Clin Pharmacokinet 2014; 53:29. 4. US Food and Drug Administration. Clinical drug interaction studies Cytochrome P450 enzyme- and transporter- mediated drug interactions guidance for industry, January 2020. Available at: https://www.fda.gov/regulatory- information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and- transporter-mediated-drug-interactions (Accessed on June 5, 2020). 5. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Available at: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug- interactions-table-substrates-inhibitors-and-inducers (Accessed on June 12, 2019). Graphic 60182 Version 35.0 https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 46/47 7/5/23, 12:02 PM Subdural hematoma in adults: Management and prognosis - UpToDate Contributor Disclosures William McBride, MD No relevant financial relationship(s) with ineligible companies to disclose. Jos Biller, MD, FACP, FAAN, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Alejandro A Rabinstein, MD Grant/Research/Clinical Trial Support: Chiesi [Small investigator- initiated project]. Consultant/Advisory Boards: AstraZeneca [Secondary stroke prevention]; Brainomix [AI for stroke diagnostics]; Novo Nordisk [Stroke risk]; Shionogi [Stroke neuroprotection]. Other Financial Interest: Boston Scientific [Adverse event adjudication committee member for stroke risk reduction device in patients with atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/subdural-hematoma-in-adults-management-and-prognosis/print 47/47

7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Use and utility of stroke scales and grading systems : Larry B Goldstein, MD, FAAN, FANA, FAHA : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Mar 09, 2023. INTRODUCTION This topic will review stroke scales and grading systems that are used for ischemic and hemorrhagic stroke. Grading systems used to classify patients with subarachnoid hemorrhage are reviewed separately. (See "Subarachnoid hemorrhage grading scales".) Categorization systems used in the classification and etiology of stroke are also discussed elsewhere. (See "Stroke: Etiology, classification, and epidemiology", section on 'TOAST classification' and "Stroke: Etiology, classification, and epidemiology", section on 'SSS-TOAST and CCS classification'.) ROLE OF SCALES IN STROKE ASSESSMENT In addition to their importance for assessing the impact of therapeutic interventions in clinical trials, stroke scales are useful in the routine clinical setting as aids to improve diagnostic accuracy, help determine the appropriateness of specific treatments, monitor a patient's neurologic deficits through the continuum of care, and predict and gauge outcomes. Not only are different types of scales needed for these different purposes, but no single scale is suitable for capturing all of the effects of stroke. A plethora of stroke scales have been developed for each of these purposes as discussed in the sections that follow. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 1/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Dimensions of disease The International Classification of Functioning, Disability and Health, developed by the World Health Organization, categorizes the impact of disease into three dimensions [1]: Body Dimension, referring to the structure and function of body systems Activities Dimension, referring to the complete range of activities performed by an individual Participation Dimension, classifying areas of life in which an individual is involved, has access, has societal opportunities or barriers These three general dimensions correspond to what clinicians might describe as neurologic impairments (ie, deficits such as a hemianopsia, aphasia, limb paresis, gait imbalance, or sensory loss), disabilities (ie, loss of the ability to perform daily tasks, such as eating, dressing, and bathing, resulting from physiological deficits), and handicaps (ie, the impact of deficits and disabilities on social participation such as employment) [2]. Additionally, it is becoming increasingly important to assess the effects of disease and treatment on quality of life. Measuring the impact of stroke Although the impact of stroke as reflected by these different dimensions (body, activity, participation) is generally consistent, it is important to measure each dimension, as focusing on any one alone could be misleading. As an example, consider a patient with a paralyzed hand. This deficit would be measured in the Body Dimension as a motor impairment. With compensatory strategies such as the use of the unimpaired hand or prosthetics, that same patient might have no disability (ie, able to eat, dress, bathe). If the patient was a truck driver, they might be able to return to work by driving a modified vehicle (no handicap), whereas if they were a watchmaker, they might be unable to return to their previous employment (ie, a social handicap). Thus, the impact of a neurologic impairment on quality of life can be quite different depending on individual circumstances. In addition, a stroke considered to be mild based upon a measure of one dimension may be severe when measured on a different dimension [3]. A homonymous inferior quadrantanopia might represent a minimal impairment and result in no disability, but could be an important handicap and have a large impact on quality of life because driving a motor vehicle is precluded. Therefore, when choosing a stroke scale, one must first consider why it is being used and what it is measuring. STROKE DIAGNOSIS https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 2/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Because of poor recognition and the nonspecific nature of many stroke symptoms, stroke scales and grading systems have been developed both to aid the general public, emergency responders, and emergency physicians in the identification of persons with acute stroke, and to hasten transport of stroke victims to appropriate medical facilities. These tools must be simple and rapidly applicable. Selected diagnostic scales The best-studied scales for general stroke recognition and diagnosis are the Face Arm Speech Test (FAST), the Cincinnati Prehospital Stroke Scale (CPSS), the Los Angeles Prehospital Stroke Screen (LAPSS), and the Recognition of Stroke in the Emergency Room (ROSIER). FAST and CPSS are simple and easy to use, which makes them most appropriate for the general public and nonmedical first responders [4]. Each evaluates the presence or absence of facial weakness, arm weakness, and speech difficulty. The main difference between the two is that FAST incorporates assessment of language function during normal conversation, whereas CPSS tests language by asking the patient to repeat a short sentence. Both the American Stroke Association and the United States Centers for Disease Control and Prevention promote FAST as a tool to increase public awareness of stroke signs and symptoms [5,6]. LAPSS and ROSIER are more complex and may be more appropriate for use by trained emergency responders and emergency physicians [4]. The LAPSS and ROSIER scales incorporate additional items to help exclude stroke mimics and to increase specificity with a potential disadvantage of reduced sensitivity [7]. FAST The Face Arm Speech Test (FAST; the "T" is a reminder of the importance of time and the need to reach a hospital immediately) evaluates patients with suspected stroke by assessing them for the presence of facial weakness, arm weakness, and speech impairment ( figure 1) [8]. FAST is considered positive if at least one item is abnormal. A prospective study found good agreement for the detection of the acute stroke signs between emergency medical responders using the FAST system and stroke physicians [9]. The scale is insensitive to isolated stroke-related visual or sensory impairments, vertigo, and gait disturbances. BE-FAST The BE-FAST test is a modification of FAST that accounts for imbalance or leg weakness (B for balance) and visual symptoms (E for eyes), as these potentially debilitating symptoms are not otherwise captured by either screening tool [10]. The BE-FAST test may reduce the likelihood of a stroke diagnosis missed using the FAST test but requires field validation in a prospective study. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 3/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate CPSS The CPSS focuses on the assessment facial paresis, arm drift, and abnormal speech ( table 1) [11]. In a prospective report evaluating the CPSS, the diagnostic accuracy for emergency department physicians compared with non-physician emergency medical personnel was similar with high correlation for total score between these groups [12]. The presence of an abnormality on any one of the three stroke scale items was associated with a marked increase in the likelihood of stroke [13]. It has the same limitations as FAST for certain stroke-related deficits that can occur in isolation. LAPSS The LAPSS assesses for unilateral arm drift, handgrip weakness, and facial paresis ( form 1) [14]. The criteria for an "in-the-field" stroke diagnosis are met when the patient age is >45 years, seizure/epilepsy history is absent, symptom duration is <24 hours, the patient is not a full-time wheelchair user or bedridden at baseline, the blood glucose is between 60 and 400 mg/dL, and a unilateral deficit is present in one of the three items (arm, handgrip, or face). The LAPSS was evaluated in an observer-blind prospective study of all non-comatose, non-trauma patients with neurologic complaints compatible with stroke who were transported by emergency medical technicians to a single hospital [14]. Compared with the final diagnosis, a prehospital stroke diagnosis made by paramedics with LAPSS had a sensitivity of 91 percent (95% CI 76-98 percent) and specificity of 97 percent (95% CI 93-99 percent). ROSIER The ROSIER scale was developed to facilitate rapid stroke patient identification and triage by emergency department clinicians [15]. The ROSIER scale incorporates the Glasgow Coma Scale ( table 2) and measurement of blood pressure and blood glucose along with assessment of a seven-item stroke-recognition scale. The first two items inquire about clinical history to exclude stroke mimics [15]: Loss of consciousness or syncope (yes = -1; no = 0) Seizure activity (yes = -1; no = 0) The next five items inquire about specific neurologic deficits of new acute onset (or present since awakening from sleep): Asymmetric facial weakness (yes = +1; no = 0) Asymmetric arm weakness (yes = +1; no = 0) Asymmetric leg weakness (yes = +1; no = 0) Speech disturbance (yes = +1; no = 0) Visual field defect (yes = +1; no = 0) https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 4/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate The total score range is -2 to +5. Stroke is unlikely, but not completely excluded, if total score is 0 [15]. When prospectively validated at a cut-off score of >0 in the original publication, the scale had a sensitivity of 93 percent (95% CI 89-97 percent) and specificity of 83 percent (95% CI 77-89 percent) [15]. A 2020 systematic review and meta-analysis identified 15 datasets that evaluated the ROSIER scale and found that the combined sensitivity and specificity were 88 and 66 percent, respectively [16]. Utility of stroke diagnostic scales In a 2019 systematic review of studies evaluating the accuracy of stroke recognition scales used in the prehospital setting or emergency department, the CPSS had the highest sensitivity in prehospital settings, while the ROSIER had the highest sensitivity in emergency department settings [4]. LARGE VESSEL OCCLUSION TRIAGE Selected triage scales The advent of proven therapies for the treatment of patients with large-vessel distribution ischemic stroke requires the triage of patients to centers capable of rapid endovascular clot retrieval [17]. Scales that have been evaluated as stroke triage aids to detect patients with large vessel occlusion include the Rapid Arterial oCclusion Evaluation (RACE) scale ( table 3), the Los Angeles Motor Scale (LAMS) ( table 4), the Cincinnati Stroke Triage Assessment Tool (C-STAT) ( table 5), and the Field Assessment Stroke Triage for Emergency Destination (FAST-ED) scale ( table 6). As reviewed below, none of the available scales predict stroke due to large vessel occlusion with both high sensitivity and specificity. With this limitation in mind, our EMS providers generally use RACE. (See 'Utility of stroke triage scales' below.) RACE The RACE scale is based on the items of National Institutes of Health Stroke Scale (NIHSS) that had the highest predictive value for large artery occlusion, as determined in a retrospective study of 654 patients with acute ischemic stroke of the anterior circulation [18]. The RACE scale assesses facial palsy, limb motor function, head and gaze deviation, and aphasia or agnosia, as shown in the table ( table 3). The RACE score ranges from a normal of 0 to a maximum of 9 points. For detecting large vessel occlusion, a RACE scale score 5 had sensitivity and specificity of 85 and 68 percent, respectively [18]. LAMS The LAMS ( table 4) employs a three-item motor score derived from the LAPSS and assesses facial droop, arm drift, and grip strength, with the total score ranging from 0 to 5 points [19]. In a retrospective study of 119 patients with anterior circulation ischemic stroke evaluated within 12 hours of time last known well, a LAMS score of 4 predicted a large vessel occlusion with a sensitivity and specificity of 81 and 89 percent, respectively [20]. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 5/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate C-STAT The C-STAT ( table 5) is a three-item score that assigns two points for conjugate gaze deviation, one point if the patient answers incorrectly on one of two level of consciousness questions and does not follow one of two commands from the NIHSS, and one point for arm weakness; the total score ranges from 0 to 4 points [21,22]. In a prospective study of prehospital evaluation with complete data for 58 patients who had a positive FAST score among 158 screened for suspicion for stroke or TIA, a C-STAT score 2 had a sensitivity of 71 percent (95% CI 29-96) and specificity of 70 percent (95% CI 55-83) for the diagnosis of large vessel stroke [22]. FAST-ED The FAST-ED scale ( table 6) assigns points for facial palsy, arm weakness, speech changes, eye deviation, and denial or neglect; the total score ranges from 0 to 9 [23]. In a retrospective study of 727 patients suspected of having acute stroke within 24 hours of symptom onset, large vessel occlusion was detected in 240. For prediction of large vessel occlusion, a FAST-ED score 4 had a sensitivity of 61 percent and a specificity of 89 percent [23]. Utility of stroke triage scales Although detection of ischemic stroke caused by a large artery occlusion is important to help identify patients who may benefit from mechanical thrombectomy, none of the available scales predicts this type of stroke with optimal accuracy. Triage decisions based on the use of these scales will miss some patients with large vessel occlusion who have milder stroke impairments [24]. This limitation needs to be understood if these scales are used to help triage patients for mechanical thrombectomy. (See "Approach to reperfusion therapy for acute ischemic stroke" and "Mechanical thrombectomy for acute ischemic stroke".) In a 2018 systematic review of prediction scales for large vessel occlusion, the sensitivities of these scales ranged from 47 to 73 percent, and the specificities ranged from 78 to 90 percent; no single scale could predict a large vessel occlusion with high sensitivity and specificity [24]. A prospective cohort study of 2007 patients conducted in the Netherlands comparing seven stroke prediction scales found that sensitivities for large vessel occlusion ranged from 38 to 62 percent and specificities ranged from 80 to 93 percent, with LAMS and RACE having the highest accuracy [25]. Another prospective cohort study from the Netherlands of over 1000 patients with suspected stroke found that the RACE was the best performing scale for detecting large vessel occlusion [26]. Another cohort study found similar calibrations for RACE, LAMS C-STAT, and FAST- ED [27]. None had an AUC (area under the receiver operating curve) >0.8, a threshold generally considered for clinical usefulness. STROKE IMPAIRMENT AND SEVERITY https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 6/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate The main stroke impairment scales are the National Institutes of Health Stroke Scale (NIHSS), the Pediatric National Institutes of Health Stroke Scale (pedNIHSS), the European Stroke Scale, and the Canadian Neurologic Scale (CNS). The Scandinavian Stroke Scale has also been used in clinical trials. Although these scales are useful to assess the severity of neurologic impairment due to stroke, they are not useful for making the diagnosis of stroke. Stroke severity and prognosis Stroke severity is assessed with an impairment-level scale, such as the NIHSS. Stroke prognosis is largely determined by the severity of the patient's initial impairments. The association of neurologic impairment, stroke severity, and outcome after ischemic stroke is reviewed separately. (See "Overview of ischemic stroke prognosis in adults", section on 'Neurologic severity'.) NIHSS The NIHSS is both reliable and valid, and has become a standard stroke impairment scale for use in both clinical trials and as part of clinical care in the United States in many other countries [28-32]. As examples, the NIHSS score is part of the assessment that helps determine whether a patient is a candidate for reperfusion therapy with intravenous thrombolysis and/or mechanical thrombectomy (see "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use" and "Mechanical thrombectomy for acute ischemic stroke"). In addition, the baseline NIHSS score is predictive of long-term outcome after acute stroke, as noted above. The NIHSS can also be assessed remotely and may be useful in telemedicine programs [33]. The NIHSS measures neurologic impairment using a 15 item scale ( table 7) [28]. A printable version of the NIHSS is available online at https://www.stroke.nih.gov/documents/NIH_Stroke_Scale_508C.pdf. An NIHSS calculator (calculator 1) is best used by a certified NIHSS examiner in conjunction with a copy of the full NIHSS. Both physician and nurse stroke providers can be trained to use the scale with similar levels of accuracy [34]. Reliability can be further improved through the use of standardized video training [35,36]. However, the value of routine retraining is uncertain [37]. The NIHSS has been validated for retrospective use based upon information available in the patient's medical record over a range of severities [38-41]. An important limitation of the NIHSS is that it does not capture all stroke-related impairments, particularly with infarction involving the vertebrobasilar circulation [42,43]. This is also true for modified, shortened versions of the scale [44,45]. Modified NIHSS The modified NIHSS (mNIHSS) is a shortened version of the NIHSS that omits level of consciousness (item 1a), facial weakness (item 4), limb ataxia (item 7), and dysarthria (item 10) from the original NIHSS and condenses the sensory test (item 8) choices from three to two responses ( table 8) [46]. In the original derivation study and subsequent prospective https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 7/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate validation, the validity and reliability of the mNIHSS was nearly identical to the original NIHSS [44,46]. The use of the "Cookie Theft" picture for language assessment as part of the NIHSS may be culturally biased [47]. An alternative has not yet been adopted. Pediatric NIHSS The Pediatric National Institutes of Health Stroke Scale (PedNIHSS) was developed by modifying the adult NIHSS so that examination items and testing materials are age-appropriate ( table 9 and figure 2 and figure 3 and figure 4) [48]. In a multicenter, prospective cohort study of children with acute arterial ischemic stroke, the PedNIHSS showed good interrater reliability when employed by trained pediatric neurologists. Other impairment scales European Stroke Scale The European Stroke Scale was designed to evaluate patients with stroke involving the territory of the middle cerebral artery. It is similar to the NIHSS and is also reliable and partially validated [49]. Canadian Neurological Scale The Canadian Neurological Scale (CNS) is simpler and more rapidly performed than the NIHSS, but does not capture many stroke-related impairments ( table 10) [50,51]. Like the NIHSS, the CNS has been validated for use retrospectively based on information available in the patient's medical record over a range of severities [40,52]. Scandinavian Stroke Scale The Scandinavian Stroke Scale assesses consciousness, gaze palsy, arm and leg weakness, dysphasia, orientation, facial palsy, and gait [53]. The scale has good to excellent reliability. It can be reliably scored based on data routinely recorded in the medical record and has been validated for retrospective use [54]. Specific neurologic deficits Scales to measure specific types of deficits have been developed and validated in patients with stroke: Motor impairments (eg, Fugl-Meyer Assessment [55,56], Motor Assessment Scale [57], and Motricity Index [58,59]) Balance (eg, Berg Balance Scale [60]) Arm/hand function (eg, Research Action Arm Test [61-64]) Mobility (eg, Rivermead Mobility Index [65]) Aphasia (eg, Frenchay Aphasia Screening Test [66,67] and Porch Index of Communicative Ability [68]) Cognition (eg, Montreal Cognitive Assessment [MoCA] [69,70]) https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 8/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate These scales are most useful for research studies targeting specific types of deficits. One exception is the MoCA, which is a widely used clinical screening test for cognitive impairment. The MoCA includes assessments of executive functions that are commonly affected by stroke. (See "Mental status scales to evaluate cognition", section on 'Montreal Cognitive Assessment (MoCA)'.) In addition, depression commonly complicates the recovery of stroke patients, and several instruments are available to aid in its diagnosis and measurement, including the following: Beck Depression Inventory (BDI) [71] Center for Epidemiological Studies of Depression (CES-D) [72] Hamilton Depression Scale [73] Personal Health Questionnaire (PHQ-9) [74] Of these, aphasic patients and older adults may have difficulty with the BDI, CES-D, and the PHQ- 9. The Hamilton Depression Scale is observer- rather than patient-rated, but its inter-observer reliability may be limited. These depression rating scales have been used primarily in research settings. The PHQ-9 has been validated for use as a depression screening tool in general practice settings. A simple two-question screen for depression has been used in primary care settings, but its use in stroke populations has not been assessed [75]. DISABILITY The two most frequently used stroke disability scales are the Barthel Index (BI) and the Functional Independence Measure (FIM). Both were similarly responsive to change in disability in one study [76], whereas another report found that the FIM was more sensitive to change [77]. Instrumental activities of daily living (IADL) scales attempt to bridge the gap between disability and handicap. Combining basic scales such as the BI or FIM with IADL assessments may provide more comprehensive information than can be gleaned from either type of scale alone and can be a useful strategy for both clinical and research applications in stroke patients [78]. Barthel Index The BI measures 10 basic aspects of self-care and physical dependency ( table 11) [79-81]. A normal score is 100, and lower scores indicate increasing disability; a BI >60 corresponds to assisted independence, and a BI <40 corresponds to severe dependency [80]. A systematic review and meta-analysis concluded that the interrater reliability of the BI is excellent [82]. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 9/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Although not specifically designed as a stroke scale, the BI correlates moderately well with radiologic infarct size [83-86]. In addition, the BI is frequently used as an outcome measure for stroke trials [81], and limited evidence suggests that the BI can predict outcome after stroke [83,87,88]. However, the predictive capacity of the BI for outcome is reduced in the setting of acute stroke, particularly within the first 72 hours [42,89]. In addition, the BI has significant limitations related to floor and ceiling effects, meaning that the BI is relatively insensitive to change in function at the extreme ends of the scale [3,77,81]. FIM The FIM is a proprietary instrument that assesses patient disability in 13 aspects of motor function and five aspects of cognitive function [90-92]. The FIM is widely used for monitoring functional improvement through the course of rehabilitation therapy [93,94]. It can be assessed by telephone as well as in person [95]. A systematic review concluded that the FIM may have some utility for predicting outcome after stroke, though high-quality evidence was limited [91]. IADL As noted above, IADL scales attempt to bridge the gap between disability and handicap [96]. They are intended to capture the patient's ability to live independently in the home and assess a variety of activities (cooking, home management, recreation, etc). Several IADL scales are available, but the Frenchay Activities Index was specifically developed for use with stroke patients and is reliable [97-99]. HANDICAP The main stroke handicap scales are the Rankin Scale and its derivatives, the modified Rankin Scale (mRS), the Rankin Focused Assessment, and the Oxford Handicap Scale [100-104]. Of these, the mRS is the most widely used. The Craig Handicap Assessment and Reporting Technique (CHART) was specifically designed to assess handicap [105,106], but has not been used as extensively as the mRS in the assessment of patients with stroke. Modified Rankin Scale The mRS measures functional independence on a seven grade scale ( table 12) [100,101]. The mRS has been used as a measure of stroke-related handicap in many interventional trials and is frequently used as a global measure of the functional impact of stroke [31,107,108]. In addition, the mRS score at 90 days after intravenous thrombolysis or endovascular interventions for acute ischemic stroke is a proposed "core metric" of comprehensive stroke centers in the United States [31]. A systematic review published in 2007 concluded that interrater reliability of the mRS was moderate and was improved with structured interview [109], although a subsequent study found no significant difference between standard and structured mRS [110]. A systematic review https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 10/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate published in 2009 found that the overall interrater reliability of the mRS was moderate but varied widely among included studies; the effect of structured interview was inconsistent [111]. The mRS score shows moderate correlation with the volume of cerebral infarction [85,86,112]. The mRS ( table 12) places particular emphasis on the patient's ability to walk. Because it is weighted towards physical function [107], the results of the mRS correlate closely with scores on the Barthel Index [113-115] and therefore do not fully reflect the impact of stroke on social participation. There has been some debate regarding cutoffs and the analysis of mRS data in the setting of clinical trials. Different trials have used dichotomous cutoff scores of 1, 2, or 3 to identify those with favorable compared with unfavorable outcomes. Another approach is using a so- called "shift" analysis, in which the entire range of possible scores is considered rather than dichotomous outcomes [116]. Some trials that were negative using prespecified dichotomous cutoffs might have been positive if a shift analysis had been used [117]. QUALITY OF LIFE Health-related quality of life (HRQOL) reflects the physical, emotional, and social aspects of life that can be affected by acute or chronic disease [118]. These types of assessments are generally used for research and not clinical purposes. Generic scales Several generic scales have been used for the assessment of HRQOL in patients with stroke, including the following: Sickness Impact Profile [119,120] Short Form 36 [121] Health Utilities Index [122-125] EuroQol [126-128] The use of these HRQOL scales in patients with stroke is particularly challenging because the scales are generally lengthy, and because the disease itself can affect the patient's ability to respond, often necessitating obtaining responses from proxies [129]. The physical subscore of the Sickness Impact Profile correlates with stroke-related impairments as measured with the National Institutes of Health Stroke Scale (NIHSS) and Canadian Neurologic Scale (CNS) [114]. Disability scores measured with the Barthel Index and handicap scores measured with the Rankin Scale explain only 33 percent of the variance in Sickness Impact Profile scores [130]. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 11/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Stroke-specific scales One response to the difficulty of assessing quality of life in stroke patients with generic scales has been the development of stroke-specific HRQOL instruments, such as the following: Stroke Impact Scale (SIS) [131] Stroke-Specific Quality of Life Scale [132,133] Stroke-adapted version of the Sickness Impact Profile [134] The SIS was designed to measure changes in hand function, activities of daily living, mobility, emotion, communication, memory, thinking, and participation after stroke [131]. The SIS is reliable, valid, and sensitive to change [131,135]. A briefer version focused on physical functioning has also been developed [136]. In addition, the SIS has been evaluated for postal administration [137]. As with other HRQOL scales, a major limitation of the SIS is that assessment is made by self-report of the patient, posing an obstacle to its use in patients with aphasia or other cognitive impairments [42]. This limitation can be partially addressed by use of a proxy [138]. ADDITIONAL STROKE SCALES A number of stroke scales specific to transient ischemic attack (TIA), intracerebral hemorrhage (ICH), and subarachnoid hemorrhage are discussed in separate topic reviews. These include: 2 TIA The ABCD score ( table 13) is intended to estimate the risk of ischemic stroke in the first days after a TIA. Intracerebral hemorrhage The ICH score is intended to predict mortality after intracerebral hemorrhage. Subarachnoid hemorrhage Grading systems used to classify patients with subarachnoid hemorrhage include the Glasgow Coma Scale, the Hunt and Hess grading system, the World Federation of Neurological Surgeons scale, the Fisher scale, the modified Fisher scale, and the Ogilvy and Carter grading system. (See "Subarachnoid hemorrhage grading scales".) SUMMARY AND RECOMMENDATIONS Stroke scales are useful for clinical and research purposes as aids to improve diagnostic accuracy, determine the suitability of specific treatments, monitor change in neurologic https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 12/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate impairments, and measure outcome. No single stroke scale is available or appropriate for all purposes, and each available scale has its own inherent limitations. (See 'Role of scales in stroke assessment' above.) The Cincinnati Prehospital Stroke Scale (CPSS) or the Face Arm Speech Test (FAST) have been suggested for use by prehospital personnel because they are easy to learn and rapidly administered. BE-FAST offers the advantage of also capturing vertebrobasilar symptoms and is being used more widely, but it has not been fully validated in the prehospital setting. (See 'Stroke diagnosis' above.) Scales to detect ischemic stroke caused by large artery occlusion, such as the Rapid Arterial oCclusion Evaluation (RACE) scale, have limited utility; none of the available scales has both high sensitivity and specificity. (See 'Large vessel occlusion triage' above.) The National Institutes of Health Stroke Scale (NIHSS) is a measure of general stroke impairment and is useful for both clinical and research purposes. (See 'NIHSS' above.) Despite their shortcomings, the Barthel Index and Rankin Scales are the most widely used measures of stroke-related disability and handicap, respectively. (See 'Barthel Index' above and 'Modified Rankin Scale' above.) Health-Related Quality of Life (HRQOL) in patients with stroke may be best measured with a stroke-specific instrument such as the Stroke Impact Scale (SIS). Use of UpToDate is subject to the Terms of Use. REFERENCES 1. World Health Organization. International Classification of Functioning, Disability and Health (ICF). http://www.who.int/classifications/icf/en/ (Accessed on April 21, 2011). 2. Orgogozo JM. The concepts of impairment, disability, and handicap. Cerebrovasc Dis 1994; 4 (Suppl 2):2. 3. Duncan PW, Samsa GP, Weinberger M, et al. Health status of individuals with mild stroke. Stroke 1997; 28:740. 4. Zhelev Z, Walker G, Henschke N, et al. Prehospital stroke scales as screening tools for early identification of stroke and transient ischemic attack. Cochrane Database Syst Rev 2019; 4:CD011427. 5. American Stroke Association. Stroke symptoms. Available at: https://www.stroke.org/en/abo ut-stroke/stroke-symptoms (Accessed on March 05, 2021). https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 13/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate 6. Centers for Disease Control and Prevention. Stroke signs and symptoms. Available at: http s://www.cdc.gov/stroke/signs_symptoms.htm (Accessed on March 05, 2021). 7. Rudd M, Buck D, Ford GA, Price CI. A systematic review of stroke recognition instruments in hospital and prehospital settings. Emerg Med J 2016; 33:818. 8. Harbison J, Hossain O, Jenkinson D, et al. Diagnostic accuracy of stroke referrals from primary care, emergency room physicians, and ambulance staff using the face arm speech test. Stroke 2003; 34:71. 9. Nor AM, McAllister C, Louw SJ, et al. Agreement between ambulance paramedic- and physician-recorded neurological signs with Face Arm Speech Test (FAST) in acute stroke patients. Stroke 2004; 35:1355. 10. Aroor S, Singh R, Goldstein LB. BE-FAST (Balance, Eyes, Face, Arm, Speech, Time): Reducing the Proportion of Strokes Missed Using the FAST Mnemonic. Stroke 2017; 48:479. 11. Kothari R, Hall K, Brott T, Broderick J. Early stroke recognition: developing an out-of-hospital NIH Stroke Scale. Acad Emerg Med 1997; 4:986. 12. Kothari RU, Pancioli A, Liu T, et al. Cincinnati Prehospital Stroke Scale: reproducibility and validity. Ann Emerg Med 1999; 33:373. 13. Goldstein LB, Simel DL. Is this patient having a stroke? JAMA 2005; 293:2391. 14. Kidwell CS, Starkman S, Eckstein M, et al. Identifying stroke in the field. Prospective validation of the Los Angeles prehospital stroke screen (LAPSS). Stroke 2000; 31:71. 15. Nor AM, Davis J, Sen B, et al. The Recognition of Stroke in the Emergency Room (ROSIER) scale: development and validation of a stroke recognition instrument. Lancet Neurol 2005; 4:727. 16. Han F, Zuo C, Zheng G. A systematic review and meta-analysis to evaluate the diagnostic accuracy of recognition of stroke in the emergency department (ROSIER) scale. BMC Neurol 2020; 20:304. 17. Schlemm L, Ebinger M, Nolte CH, Endres M. Impact of Prehospital Triage Scales to Detect Large Vessel Occlusion on Resource Utilization and Time to Treatment. Stroke 2018; 49:439. 18. P rez de la Ossa N, Carrera D, Gorchs M, et al. Design and validation of a prehospital stroke scale to predict large arterial occlusion: the rapid arterial occlusion evaluation scale. Stroke 2014; 45:87. 19. Llanes JN, Kidwell CS, Starkman S, et al. The Los Angeles Motor Scale (LAMS): a new measure to characterize stroke severity in the field. Prehosp Emerg Care 2004; 8:46. 20. Nazliel B, Starkman S, Liebeskind DS, et al. A brief prehospital stroke severity scale identifies ischemic stroke patients harboring persisting large arterial occlusions. Stroke 2008; https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 14/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate 39:2264. 21. Katz BS, McMullan JT, Sucharew H, et al. Design and validation of a prehospital scale to predict stroke severity: Cincinnati Prehospital Stroke Severity Scale. Stroke 2015; 46:1508. 22. McMullan JT, Katz B, Broderick J, et al. Prospective Prehospital Evaluation of the Cincinnati Stroke Triage Assessment Tool. Prehosp Emerg Care 2017; 21:481. 23. Lima FO, Silva GS, Furie KL, et al. Field Assessment Stroke Triage for Emergency Destination: A Simple and Accurate Prehospital Scale to Detect Large Vessel Occlusion Strokes. Stroke 2016; 47:1997. 24. Smith EE, Kent DM, Bulsara KR, et al. Accuracy of Prediction Instruments for Diagnosing Large Vessel Occlusion in Individuals With Suspected Stroke: A Systematic Review for the 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke. Stroke 2018; 49:e111. 25. Nguyen TTM, van den Wijngaard IR, Bosch J, et al. Comparison of Prehospital Scales for Predicting Large Anterior Vessel Occlusion in the Ambulance Setting. JAMA Neurol 2021; 78:157. 26. Duvekot MHC, Venema E, Rozeman AD, et al. Comparison of eight prehospital stroke scales to detect intracranial large-vessel occlusion in suspected stroke (PRESTO): a prospective observational study. Lancet Neurol 2021; 20:213. 27. Grewal P, Lahoti S, Aroor S, et al. Effect of Known Atrial Fibrillation and Anticoagulation Status on the Prehospital Identification of Large Vessel Occlusion. J Stroke Cerebrovasc Dis 2019; 28:104404. 28. Brott T, Adams HP Jr, Olinger CP, et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke 1989; 20:864. 29. Goldstein LB, Bertels C, Davis JN. Interrater reliability of the NIH stroke scale. Arch Neurol 1989; 46:660. 30. Wityk RJ, Pessin MS, Kaplan RF, Caplan LR. Serial assessment of acute stroke using the NIH Stroke Scale. Stroke 1994; 25:362. 31. Leifer D, Bravata DM, Connors JJ 3rd, et al. Metrics for measuring quality of care in comprehensive stroke centers: detailed follow-up to Brain Attack Coalition comprehensive stroke center recommendations: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011; 42:849. 32. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 15/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344.

impairments, and measure outcome. No single stroke scale is available or appropriate for all purposes, and each available scale has its own inherent limitations. (See 'Role of scales in stroke assessment' above.) The Cincinnati Prehospital Stroke Scale (CPSS) or the Face Arm Speech Test (FAST) have been suggested for use by prehospital personnel because they are easy to learn and rapidly administered. BE-FAST offers the advantage of also capturing vertebrobasilar symptoms and is being used more widely, but it has not been fully validated in the prehospital setting. (See 'Stroke diagnosis' above.) Scales to detect ischemic stroke caused by large artery occlusion, such as the Rapid Arterial oCclusion Evaluation (RACE) scale, have limited utility; none of the available scales has both high sensitivity and specificity. (See 'Large vessel occlusion triage' above.) The National Institutes of Health Stroke Scale (NIHSS) is a measure of general stroke impairment and is useful for both clinical and research purposes. (See 'NIHSS' above.) Despite their shortcomings, the Barthel Index and Rankin Scales are the most widely used measures of stroke-related disability and handicap, respectively. (See 'Barthel Index' above and 'Modified Rankin Scale' above.) Health-Related Quality of Life (HRQOL) in patients with stroke may be best measured with a stroke-specific instrument such as the Stroke Impact Scale (SIS). Use of UpToDate is subject to the Terms of Use. REFERENCES 1. World Health Organization. International Classification of Functioning, Disability and Health (ICF). http://www.who.int/classifications/icf/en/ (Accessed on April 21, 2011). 2. Orgogozo JM. The concepts of impairment, disability, and handicap. Cerebrovasc Dis 1994; 4 (Suppl 2):2. 3. Duncan PW, Samsa GP, Weinberger M, et al. Health status of individuals with mild stroke. Stroke 1997; 28:740. 4. Zhelev Z, Walker G, Henschke N, et al. Prehospital stroke scales as screening tools for early identification of stroke and transient ischemic attack. Cochrane Database Syst Rev 2019; 4:CD011427. 5. American Stroke Association. Stroke symptoms. Available at: https://www.stroke.org/en/abo ut-stroke/stroke-symptoms (Accessed on March 05, 2021). https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 13/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate 6. Centers for Disease Control and Prevention. Stroke signs and symptoms. Available at: http s://www.cdc.gov/stroke/signs_symptoms.htm (Accessed on March 05, 2021). 7. Rudd M, Buck D, Ford GA, Price CI. A systematic review of stroke recognition instruments in hospital and prehospital settings. Emerg Med J 2016; 33:818. 8. Harbison J, Hossain O, Jenkinson D, et al. Diagnostic accuracy of stroke referrals from primary care, emergency room physicians, and ambulance staff using the face arm speech test. Stroke 2003; 34:71. 9. Nor AM, McAllister C, Louw SJ, et al. Agreement between ambulance paramedic- and physician-recorded neurological signs with Face Arm Speech Test (FAST) in acute stroke patients. Stroke 2004; 35:1355. 10. Aroor S, Singh R, Goldstein LB. BE-FAST (Balance, Eyes, Face, Arm, Speech, Time): Reducing the Proportion of Strokes Missed Using the FAST Mnemonic. Stroke 2017; 48:479. 11. Kothari R, Hall K, Brott T, Broderick J. Early stroke recognition: developing an out-of-hospital NIH Stroke Scale. Acad Emerg Med 1997; 4:986. 12. Kothari RU, Pancioli A, Liu T, et al. Cincinnati Prehospital Stroke Scale: reproducibility and validity. Ann Emerg Med 1999; 33:373. 13. Goldstein LB, Simel DL. Is this patient having a stroke? JAMA 2005; 293:2391. 14. Kidwell CS, Starkman S, Eckstein M, et al. Identifying stroke in the field. Prospective validation of the Los Angeles prehospital stroke screen (LAPSS). Stroke 2000; 31:71. 15. Nor AM, Davis J, Sen B, et al. The Recognition of Stroke in the Emergency Room (ROSIER) scale: development and validation of a stroke recognition instrument. Lancet Neurol 2005; 4:727. 16. Han F, Zuo C, Zheng G. A systematic review and meta-analysis to evaluate the diagnostic accuracy of recognition of stroke in the emergency department (ROSIER) scale. BMC Neurol 2020; 20:304. 17. Schlemm L, Ebinger M, Nolte CH, Endres M. Impact of Prehospital Triage Scales to Detect Large Vessel Occlusion on Resource Utilization and Time to Treatment. Stroke 2018; 49:439. 18. P rez de la Ossa N, Carrera D, Gorchs M, et al. Design and validation of a prehospital stroke scale to predict large arterial occlusion: the rapid arterial occlusion evaluation scale. Stroke 2014; 45:87. 19. Llanes JN, Kidwell CS, Starkman S, et al. The Los Angeles Motor Scale (LAMS): a new measure to characterize stroke severity in the field. Prehosp Emerg Care 2004; 8:46. 20. Nazliel B, Starkman S, Liebeskind DS, et al. A brief prehospital stroke severity scale identifies ischemic stroke patients harboring persisting large arterial occlusions. Stroke 2008; https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 14/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate 39:2264. 21. Katz BS, McMullan JT, Sucharew H, et al. Design and validation of a prehospital scale to predict stroke severity: Cincinnati Prehospital Stroke Severity Scale. Stroke 2015; 46:1508. 22. McMullan JT, Katz B, Broderick J, et al. Prospective Prehospital Evaluation of the Cincinnati Stroke Triage Assessment Tool. Prehosp Emerg Care 2017; 21:481. 23. Lima FO, Silva GS, Furie KL, et al. Field Assessment Stroke Triage for Emergency Destination: A Simple and Accurate Prehospital Scale to Detect Large Vessel Occlusion Strokes. Stroke 2016; 47:1997. 24. Smith EE, Kent DM, Bulsara KR, et al. Accuracy of Prediction Instruments for Diagnosing Large Vessel Occlusion in Individuals With Suspected Stroke: A Systematic Review for the 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke. Stroke 2018; 49:e111. 25. Nguyen TTM, van den Wijngaard IR, Bosch J, et al. Comparison of Prehospital Scales for Predicting Large Anterior Vessel Occlusion in the Ambulance Setting. JAMA Neurol 2021; 78:157. 26. Duvekot MHC, Venema E, Rozeman AD, et al. Comparison of eight prehospital stroke scales to detect intracranial large-vessel occlusion in suspected stroke (PRESTO): a prospective observational study. Lancet Neurol 2021; 20:213. 27. Grewal P, Lahoti S, Aroor S, et al. Effect of Known Atrial Fibrillation and Anticoagulation Status on the Prehospital Identification of Large Vessel Occlusion. J Stroke Cerebrovasc Dis 2019; 28:104404. 28. Brott T, Adams HP Jr, Olinger CP, et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke 1989; 20:864. 29. Goldstein LB, Bertels C, Davis JN. Interrater reliability of the NIH stroke scale. Arch Neurol 1989; 46:660. 30. Wityk RJ, Pessin MS, Kaplan RF, Caplan LR. Serial assessment of acute stroke using the NIH Stroke Scale. Stroke 1994; 25:362. 31. Leifer D, Bravata DM, Connors JJ 3rd, et al. Metrics for measuring quality of care in comprehensive stroke centers: detailed follow-up to Brain Attack Coalition comprehensive stroke center recommendations: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011; 42:849. 32. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 15/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. 33. Wang S, Lee SB, Pardue C, et al. Remote evaluation of acute ischemic stroke: reliability of National Institutes of Health Stroke Scale via telestroke. Stroke 2003; 34:e188. 34. Goldstein LB, Samsa GP. Reliability of the National Institutes of Health Stroke Scale. Extension to non-neurologists in the context of a clinical trial. Stroke 1997; 28:307. 35. Lyden P, Brott T, Tilley B, et al. Improved reliability of the NIH Stroke Scale using video training. NINDS TPA Stroke Study Group. Stroke 1994; 25:2220. 36. 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Stroke 2002; 33:2593. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 22/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Topic 14084 Version 16.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 23/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate GRAPHICS Face Arm Speech Test Reproduced with permission from: Harbison J, Hossain O, Jenkinson D, et al. Diagnostic accuracy of stroke referrals from primary care, emergency room physicians, and ambulance sta using the face arm speech test. Stroke 2003; 34:71. Copyright 2003 Lippincott Williams & Wilkins. Graphic 54134 Version 7.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 24/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Cincinnati Prehospital Stroke Scale (CPSS) The CPSS evaluates for facial palsy, arm weakness, and speech abnormalities. Items are scored as either normal or abnormal. Facial droop The patient shows teeth or smiles Normal: Both sides of face move equally. Abnormal: One side of face does not move as well as the other. Arm drift The patient closes their eyes and extends both arms straight out for 10 seconds Normal: Both arms move the same, or both arms do not move at all. Abnormal: One arm either does not move, or one arm drifts down compared to the other. Speech The patient repeats "The sky is blue in Cincinnati" Normal: The patient says correct words with no slurring of words. Abnormal: The patient slurs words, says the wrong words, or is unable to speak. Reproduced from: Kothari RU, Pancioli A, Liu T, et al. Cincinnati Prehospital Stroke Scale: reproducibility and validity. Ann Emerg Med 1999; 33:373. Illustration used with the permission of Elsevier Inc. All rights reserved. Graphic 62856 Version 3.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 25/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Los Angeles Prehospital Stroke Screen Reproduced with permission from: Kidwell CS, Starkman S, Eckstein M, et al. Identifying stroke in the eld. Prospective validation of the Los Angeles prehospital stroke screen (LAPSS). Stroke 2000; 31:71. Copyright 2000 Lippincott Williams & Wilkins. Graphic 78128 Version 10.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 26/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Glasgow Coma Scale (GCS) Score Eye opening Spontaneous 4 Response to verbal command 3 Response to pain 2 No eye opening 1 Best verbal response Oriented 5 Confused 4 Inappropriate words 3 Incomprehensible sounds 2 No verbal response 1 Best motor response Obeys commands 6 Localizing response to pain 5 Withdrawal response to pain 4 Flexion to pain 3 Extension to pain 2 No motor response 1 Total The GCS is scored between 3 and 15, 3 being the worst and 15 the best. It is composed of three parameters: best eye response (E), best verbal response (V), and best motor response (M). The components of the GCS should be recorded individually; for example, E2V3M4 results in a GCS score of 9. A score of 13 or higher correlates with mild brain injury, a score of 9 to 12 correlates with moderate injury, and a score of 8 or less represents severe brain injury. Graphic 81854 Version 9.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 27/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Rapid Arterial oCclusion Evaluation (RACE) scale RACE NIHSS score Item score equivalence Facial palsy Absent 0 0 Mild 1 1 Moderate to severe 2 2 to 3 Arm motor function Normal to mild 0 0 to 1 Moderate 1 2 Severe 2 3 to 4 Leg motor function Normal to mild 0 0 to 1 Moderate 1 2 Severe 2 3 to 4 Head and gaze deviation Absent 0 0 Present 1 1 to 2 Aphasia* (if right hemiparesis) Performs both tasks correctly 0 0 Performs 1 task correctly 1 1 Performs neither tasks 2 2 Agnosia (if left hemiparesis) Patient recognizes their arm and the impairment 0 0 Does not recognize their arm or the impairment 1 1 Does not recognize their arm nor the impairment 2 2 Score total 0 to 9 Aphasia: Ask the patient to (1) "close your eyes"; (2) "make a fist" and evaluate if the patient obeys. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 28/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Agnosia: Ask the patient: (1) while showing their the paretic arm: "Whose arm is this" and evaluate if the patient recognizes their own arm. (2) "Can you lift both arms and clap" and evaluate if the patient recognizes their functional impairment. From: P rez de la Ossa N, Carrera D, Gorchs M, et al. Design and validation of a prehospital stroke scale to predict large arterial occlusion: the rapid arterial occlusion evaluation scale. Stroke 2014; 45:87. DOI: 10.1161/STROKEAHA.113.003071. Copyright American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 130953 Version 2.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 29/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate The Los Angeles Motor Scale (LAMS) Facial droop Absent 0 Present 1 Arm drift Absent 0 Drifts down 1 Falls rapidly 2 Grip strength Normal 0 Weak grip 1 No grip 2 From: Nazliel B, Starkman S, Liebeskind DS, et al. A brief prehospital stroke severity scale identi es ischemic stroke patients harboring persisting large arterial occlusions. Stroke 2008; 39:2264. DOI: 10.1161/STROKEAHA.107.508127. Copyright 2008 American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 130951 Version 1.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 30/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Cincinnati Stroke Triage Assessment Tool (C-STAT) Score Symptom NIHSS equivalent 1 on NIHSS item for Gaze 2 points Conjugate gaze deviation 1 on NIHSS item for Level of consciousness 1b and 1c 1 point Incorrectly answers at least one of two level of consciousness questions on NIHSS (age or current month) and does not follow at least one of two commands (close eyes, open and close hand) 2 on the NIHSS item for Motor arm 1 point Cannot hold arm (either right, left, or both) up to 10 seconds before arm(s) falls to bed NIHSS: National Institutes of Health Stroke Scale. From: Katz BS, McMullan JT, Sucharew H, et al. Design and validation of a prehospital scale to predict stroke severity: Cincinnati Prehospital Stroke Severity Scale. Stroke 2015; 46:1508. DOI: 10.1161/STROKEAHA.115.008804. Copyright American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 130949 Version 1.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 31/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate The FAST-ED scale and its correspondence to the NIHSS NIHSS FAST-ED Item score source score Facial palsy Normal or minor paralysis 0 0 to 1 Partial or complete paralysis 1 2 to 3 Arm weakness No drift 0 0 Drift or some effort against gravity 1 1 to 2 No effort against gravity or no movement 2 3 to 4 Speech changes Absent 0 0 Mild to moderate 1 1 Severe, global aphasia, or mute 2 2 to 3 Eye deviation Absent 0 0 Partial 1 1 Forced deviation 2 2 Denial/neglect Absent 0 0 Extinction to bilateral simultaneous stimulation in only 1 sensory modality 1 1 Does not recognize own hand or orients only to one side of the 2 2 body FAST-ED: Field Assessment Stroke Triage for Emergency Destination; NIHSS: National Institutes of Health Stroke Scale. From: Lima FO, Silva GS, Furie KL, et al. Field Assessment Stroke Triage for Emergency Destination: A Simple and Accurate Prehospital Scale to Detect Large Vessel Occlusion Strokes. Stroke 2016; 47:1997. DOI: 10.1161/STROKEAHA.116.013301. Copyright 2016 American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 32/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Graphic 130950 Version 1.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 33/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate National Institutes of Health Stroke Scale (NIHSS) Administer stroke scale items in the order listed. Record performance in each category after each subscale exam. Do not go back and change scores. Follow directions provided for each exam technique. Scores should reflect what the patient does, not what the clinician thinks the patient can do. The clinician should record answers while administering the exam and work quickly. Except where indicated, the patient should not be coached (ie, repeated requests to patient to make a special effort). Instructions Scale definition Score 1a. Level of consciousness: The investigator must choose a response if a full 0 = Alert; keenly responsive. 1 = Not alert; but arousable by minor stimulation to obey, answer, or respond. evaluation is prevented by such obstacles as an endotracheal tube, language barrier, 2 = Not alert; requires repeated stimulation orotracheal trauma/bandages. A 3 is scored to attend, or is obtunded and requires only if the patient makes no movement (other than reflexive posturing) in response _____ strong or painful stimulation to make movements (not stereotyped). to noxious stimulation. 3 = Responds only with reflex motor or autonomic effects or totally unresponsive, flaccid, and areflexic. 1b. Level of consciousness questions: The 0 = Answers both questions correctly. patient is asked the month and his/her age. The answer must be correct - there is no 1 = Answers one question correctly. 2 = Answers neither question correctly. partial credit for being close. Aphasic and stuporous patients who do not comprehend the questions will score 2. Patients unable to speak because of endotracheal intubation, orotracheal trauma, severe dysarthria from _____ any cause, language barrier, or any other problem not secondary to aphasia are given a 1. It is important that only the initial answer be graded and that the examiner not "help" the patient with verbal or non-verbal cues. 1c. Level of consciousness commands: The patient is asked to open and close the eyes 0 = Performs both tasks correctly. _____ 1 = Performs one task correctly. and then to grip and release the non-paretic hand. Substitute another one step 2 = Performs neither task correctly. command if the hands cannot be used. Credit is given if an unequivocal attempt is made but not completed due to weakness. If the patient does not respond to command, the task should be demonstrated to him or her (pantomime), and the result scored (ie, https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 34/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate follows none, one or two commands). Patients with trauma, amputation, or other physical impediments should be given suitable one-step commands. Only the first attempt is scored. 2. Best gaze: Only horizontal eye movements will be tested. Voluntary or 0 = Normal. 1 = Partial gaze palsy; gaze is abnormal in one or both eyes, but forced deviation or reflexive (oculocephalic) eye movements will be scored, but caloric testing is not done. If the patient has a conjugate deviation of the total gaze paresis is not present. 2 = Forced deviation, or total gaze paresis eyes that can be overcome by voluntary or reflexive activity, the score will be 1. If a not overcome by the oculocephalic maneuver. patient has an isolated peripheral nerve paresis (cranial nerves III, IV or VI), score a 1. _____ Gaze is testable in all aphasic patients. Patients with ocular trauma, bandages, pre- existing blindness, or other disorder of visual acuity or fields should be tested with reflexive movements, and a choice made by the investigator. Establishing eye contact and then moving about the patient from side to side will occasionally clarify the presence of a partial gaze palsy. 3. Visual: Visual fields (upper and lower quadrants) are tested by confrontation, 0 = No visual loss. 1 = Partial hemianopia. using finger counting or visual threat, as appropriate. Patients may be encouraged, 2 = Complete hemianopia. but if they look at the side of the moving fingers appropriately, this can be scored as 3 = Bilateral hemianopia (blind including cortical blindness). normal. If there is unilateral blindness or

29/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate The Los Angeles Motor Scale (LAMS) Facial droop Absent 0 Present 1 Arm drift Absent 0 Drifts down 1 Falls rapidly 2 Grip strength Normal 0 Weak grip 1 No grip 2 From: Nazliel B, Starkman S, Liebeskind DS, et al. A brief prehospital stroke severity scale identi es ischemic stroke patients harboring persisting large arterial occlusions. Stroke 2008; 39:2264. DOI: 10.1161/STROKEAHA.107.508127. Copyright 2008 American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 130951 Version 1.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 30/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Cincinnati Stroke Triage Assessment Tool (C-STAT) Score Symptom NIHSS equivalent 1 on NIHSS item for Gaze 2 points Conjugate gaze deviation 1 on NIHSS item for Level of consciousness 1b and 1c 1 point Incorrectly answers at least one of two level of consciousness questions on NIHSS (age or current month) and does not follow at least one of two commands (close eyes, open and close hand) 2 on the NIHSS item for Motor arm 1 point Cannot hold arm (either right, left, or both) up to 10 seconds before arm(s) falls to bed NIHSS: National Institutes of Health Stroke Scale. From: Katz BS, McMullan JT, Sucharew H, et al. Design and validation of a prehospital scale to predict stroke severity: Cincinnati Prehospital Stroke Severity Scale. Stroke 2015; 46:1508. DOI: 10.1161/STROKEAHA.115.008804. Copyright American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 130949 Version 1.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 31/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate The FAST-ED scale and its correspondence to the NIHSS NIHSS FAST-ED Item score source score Facial palsy Normal or minor paralysis 0 0 to 1 Partial or complete paralysis 1 2 to 3 Arm weakness No drift 0 0 Drift or some effort against gravity 1 1 to 2 No effort against gravity or no movement 2 3 to 4 Speech changes Absent 0 0 Mild to moderate 1 1 Severe, global aphasia, or mute 2 2 to 3 Eye deviation Absent 0 0 Partial 1 1 Forced deviation 2 2 Denial/neglect Absent 0 0 Extinction to bilateral simultaneous stimulation in only 1 sensory modality 1 1 Does not recognize own hand or orients only to one side of the 2 2 body FAST-ED: Field Assessment Stroke Triage for Emergency Destination; NIHSS: National Institutes of Health Stroke Scale. From: Lima FO, Silva GS, Furie KL, et al. Field Assessment Stroke Triage for Emergency Destination: A Simple and Accurate Prehospital Scale to Detect Large Vessel Occlusion Strokes. Stroke 2016; 47:1997. DOI: 10.1161/STROKEAHA.116.013301. Copyright 2016 American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 32/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Graphic 130950 Version 1.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 33/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate National Institutes of Health Stroke Scale (NIHSS) Administer stroke scale items in the order listed. Record performance in each category after each subscale exam. Do not go back and change scores. Follow directions provided for each exam technique. Scores should reflect what the patient does, not what the clinician thinks the patient can do. The clinician should record answers while administering the exam and work quickly. Except where indicated, the patient should not be coached (ie, repeated requests to patient to make a special effort). Instructions Scale definition Score 1a. Level of consciousness: The investigator must choose a response if a full 0 = Alert; keenly responsive. 1 = Not alert; but arousable by minor stimulation to obey, answer, or respond. evaluation is prevented by such obstacles as an endotracheal tube, language barrier, 2 = Not alert; requires repeated stimulation orotracheal trauma/bandages. A 3 is scored to attend, or is obtunded and requires only if the patient makes no movement (other than reflexive posturing) in response _____ strong or painful stimulation to make movements (not stereotyped). to noxious stimulation. 3 = Responds only with reflex motor or autonomic effects or totally unresponsive, flaccid, and areflexic. 1b. Level of consciousness questions: The 0 = Answers both questions correctly. patient is asked the month and his/her age. The answer must be correct - there is no 1 = Answers one question correctly. 2 = Answers neither question correctly. partial credit for being close. Aphasic and stuporous patients who do not comprehend the questions will score 2. Patients unable to speak because of endotracheal intubation, orotracheal trauma, severe dysarthria from _____ any cause, language barrier, or any other problem not secondary to aphasia are given a 1. It is important that only the initial answer be graded and that the examiner not "help" the patient with verbal or non-verbal cues. 1c. Level of consciousness commands: The patient is asked to open and close the eyes 0 = Performs both tasks correctly. _____ 1 = Performs one task correctly. and then to grip and release the non-paretic hand. Substitute another one step 2 = Performs neither task correctly. command if the hands cannot be used. Credit is given if an unequivocal attempt is made but not completed due to weakness. If the patient does not respond to command, the task should be demonstrated to him or her (pantomime), and the result scored (ie, https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 34/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate follows none, one or two commands). Patients with trauma, amputation, or other physical impediments should be given suitable one-step commands. Only the first attempt is scored. 2. Best gaze: Only horizontal eye movements will be tested. Voluntary or 0 = Normal. 1 = Partial gaze palsy; gaze is abnormal in one or both eyes, but forced deviation or reflexive (oculocephalic) eye movements will be scored, but caloric testing is not done. If the patient has a conjugate deviation of the total gaze paresis is not present. 2 = Forced deviation, or total gaze paresis eyes that can be overcome by voluntary or reflexive activity, the score will be 1. If a not overcome by the oculocephalic maneuver. patient has an isolated peripheral nerve paresis (cranial nerves III, IV or VI), score a 1. _____ Gaze is testable in all aphasic patients. Patients with ocular trauma, bandages, pre- existing blindness, or other disorder of visual acuity or fields should be tested with reflexive movements, and a choice made by the investigator. Establishing eye contact and then moving about the patient from side to side will occasionally clarify the presence of a partial gaze palsy. 3. Visual: Visual fields (upper and lower quadrants) are tested by confrontation, 0 = No visual loss. 1 = Partial hemianopia. using finger counting or visual threat, as appropriate. Patients may be encouraged, 2 = Complete hemianopia. but if they look at the side of the moving fingers appropriately, this can be scored as 3 = Bilateral hemianopia (blind including cortical blindness). normal. If there is unilateral blindness or enucleation, visual fields in the remaining eye are scored. Score 1 only if a clear-cut _____ asymmetry, including quadrantanopia, is found. If patient is blind from any cause, score 3. Double simultaneous stimulation is performed at this point. If there is extinction, patient receives a 1, and the results are used to respond to item 11. 4. Facial palsy: Ask - or use pantomime to encourage - the patient to show teeth or 0 = Normal symmetrical movements. _____ 1 = Minor paralysis (flattened nasolabial fold, asymmetry on smiling). raise eyebrows and close eyes. Score symmetry of grimace in response to noxious 2 = Partial paralysis (total or near-total stimuli in the poorly responsive or non- paralysis of lower face). comprehending patient. If facial trauma/bandages, orotracheal tube, tape or https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 35/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate other physical barriers obscure the face, these should be removed to the extent 3 = Complete paralysis of one or both sides (absence of facial movement in the upper possible. and lower face). 5. Motor arm: The limb is placed in the 0 = No drift; limb holds 90 (or 45) degrees appropriate position: extend the arms (palms down) 90 degrees (if sitting) or 45 for full 10 seconds. 1 = Drift; limb holds 90 (or 45) degrees, but drifts down before full 10 seconds; does not degrees (if supine). Drift is scored if the arm falls before 10 seconds. The aphasic patient hit bed or other support. is encouraged using urgency in the voice and pantomime, but not noxious 2 = Some effort against gravity; limb cannot get to or maintain (if cued) 90 (or 45) stimulation. Each limb is tested in turn, degrees, drifts down to bed, but has some effort against gravity. beginning with the non-paretic arm. Only in the case of amputation or joint fusion at the _____ shoulder, the examiner should record the score as untestable (UN), and clearly write 3 = No effort against gravity; limb falls. 4 = No movement. the explanation for this choice. UN = Amputation or joint fusion, explain:________________ 5a. Left arm 5b. Right arm 6. Motor leg: The limb is placed in the 0 = No drift; leg holds 30-degree position appropriate position: hold the leg at 30 degrees (always tested supine). Drift is for full 5 seconds. 1 = Drift; leg falls by the end of the 5-second period but does not hit bed. scored if the leg falls before 5 seconds. The aphasic patient is encouraged using urgency in the voice and pantomime, but not 2 = Some effort against gravity; leg falls to bed by 5 seconds, but has some effort noxious stimulation. Each limb is tested in turn, beginning with the non-paretic leg. against gravity. _____ Only in the case of amputation or joint fusion at the hip, the examiner should 3 = No effort against gravity; leg falls to bed immediately. record the score as untestable (UN), and 4 = No movement. clearly write the explanation for this choice. UN = Amputation or joint fusion, explain:________________ 6a. Left leg 6b. Right leg 7. Limb ataxia: This item is aimed at finding evidence of a unilateral cerebellar lesion. 0 = Absent. _____ 1 = Present in one limb. Test with eyes open. In case of visual defect, 2 = Present in two limbs. ensure testing is done in intact visual field. The finger-nose-finger and heel-shin tests UN = Amputation or joint fusion, are performed on both sides, and ataxia is scored only if present out of proportion to explain:________________ weakness. Ataxia is absent in the patient https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 36/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate who cannot understand or is paralyzed. Only in the case of amputation or joint fusion, the examiner should record the score as untestable (UN), and clearly write the explanation for this choice. In case of blindness, test by having the patient touch nose from extended arm position. 8. Sensory: Sensation or grimace to pinprick when tested, or withdrawal from noxious 0 = Normal; no sensory loss. 1 = Mild-to-moderate sensory loss; patient feels pinprick is less sharp or is dull on the stimulus in the obtunded or aphasic patient. Only sensory loss attributed to stroke is affected side; or there is a loss of superficial pain with pinprick, but patient is aware of scored as abnormal and the examiner should test as many body areas (arms [not being touched. hands], legs, trunk, face) as needed to 2 = Severe to total sensory loss; patient is accurately check for hemisensory loss. A score of 2, "severe or total sensory loss," not aware of being touched in the face, arm, and leg. should only be given when a severe or total loss of sensation can be clearly _____ demonstrated. Stuporous and aphasic patients will, therefore, probably score 1 or 0. The patient with brainstem stroke who has bilateral loss of sensation is scored 2. If the patient does not respond and is quadriplegic, score 2. Patients in a coma (item 1a=3) are automatically given a 2 on this item. 9. Best language: A great deal of information about comprehension will be 0 = No aphasia; normal. _____ 1 = Mild-to-moderate aphasia; some obtained during the preceding sections of obvious loss of fluency or facility of comprehension, without significant the examination. For this scale item, the patient is asked to describe what is limitation on ideas expressed or form of expression. Reduction of speech and/or happening in the attached picture, to name the items on the attached naming sheet and comprehension, however, makes conversation about provided materials to read from the attached list of sentences. Comprehension is judged from responses here, as well as to all of the commands in difficult or impossible. For example, in conversation about provided materials, examiner can identify picture or naming the preceding general neurological exam. If visual loss interferes with the tests, ask the card content from patient's response. patient to identify objects placed in the hand, repeat, and produce speech. The 2 = Severe aphasia; all communication is through fragmentary expression; great need intubated patient should be asked to write. for inference, questioning, and guessing by The patient in a coma (item 1a=3) will automatically score 3 on this item. The the listener. Range of information that can be exchanged is limited; listener carries examiner must choose a score for the patient with stupor or limited cooperation, burden of communication. Examiner cannot but a score of 3 should be used only if the https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 37/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate patient is mute and follows no one-step identify materials provided from patient commands. response. 3 = Mute, global aphasia; no usable speech or auditory comprehension. 10. Dysarthria: If patient is thought to be normal, an adequate sample of speech must 0 = Normal. 1 = Mild-to-moderate dysarthria; patient slurs at least some words and, at worst, can be obtained by asking patient to read or repeat words from the attached list. If the be understood with some difficulty. patient has severe aphasia, the clarity of articulation of spontaneous speech can be 2 = Severe dysarthria; patient's speech is so slurred as to be unintelligible in the absence _____ rated. Only if the patient is intubated or has of or out of proportion to any dysphasia, or other physical barriers to producing speech, the examiner should record the score as is mute/anarthric. untestable (UN), and clearly write an explanation for this choice. Do not tell the UN = Intubated or other physical barrier, explain:________________ patient why he or she is being tested. 11. Extinction and inattention (formerly neglect): Sufficient information to identify 0 = No abnormality. 1 = Visual, tactile, auditory, spatial, or personal inattention or extinction to neglect may be obtained during the prior testing. If the patient has a severe visual loss preventing visual double simultaneous bilateral simultaneous stimulation in one of the sensory modalities. stimulation, and the cutaneous stimuli are normal, the score is normal. If the patient 2 = Profound hemi-inattention or extinction to more than one modality; _____ has aphasia but does appear to attend to both sides, the score is normal. The does not recognize own hand or orients to only one side of space. presence of visual spatial neglect or anosognosia may also be taken as evidence of abnormality. Since the abnormality is scored only if present, the item is never untestable. _____ Adapted from: Goldstein LB, Samsa GP. Reliability of the National Institutes of Health Stroke Scale. Extension to non- neurologists in the context of a clinical trial. Stroke 1997; 28:307. Graphic 61698 Version 8.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 38/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate The Modified National Institutes of Health Stroke Scale (mNIHSS) scoring sheet Patient score Item number Item name Scoring guide 1b LOC questions 0 = Answers both correctly 1 = Answers one correctly _____ 2 = Answers neither correctly 1c LOC commands 0 = Performs both tasks correctly 1 = Performs one task _____ correctly 2 = Performs neither task 2 Gaze 0 = Normal 1 = Partial gaze palsy _____ 2 = Total gaze palsy 3 Visual fields 0 = No visual loss 1 = Partial hemianopsia _____ 2 = Complete hemianopsia 3 = Bilateral hemianopsia 5a Left arm motor 0 = No drift 1 = Drift before 10 seconds 2 = Falls before 10 seconds _____ 3 = No effort against gravity 4 = No movement https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 39/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate 5b Right arm motor 0 = No drift 1 = Drift before 10 seconds 2 = Falls before 10 seconds _____ 3 = No effort against gravity 4 = No movement 6a Left leg motor 0 = No drift 1 = Drift before 5 seconds 2 = Falls before 5 seconds _____ 3 = No effort against gravity 4 = No movement 6b Right leg motor 0 = No drift 1 = Drift before 5 seconds 2 = Falls before 5 seconds _____ 3 = No effort against gravity 4 = No movement 8 Sensory 0 = Normal _____ 1 = Abnormal 9 Language 0 = Normal 1 = Mild aphasia _____ 2 = Severe aphasia 3 = Mute or global aphasia 11 Neglect 0 = Normal 1 = Mild _____ 2 = Severe Score (out of 31): _____ The item numbers correspond to the NIHSS scale. The scale is shorter, having only 11 total items (versus 15 items on the NIHSS). LOC: level of consciousness. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 40/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate From: Meyer BC, Hemmen TM, Jackson CM, Lyden PD. Modi ed National Institutes of Health Stroke Scale for use in stroke clinical trials: prospective reliability and validity. Stroke 2002; 33:1261. DOI: 10.1161/01.str.0000015625.87603.a7. Copyright 2002 American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 130998 Version 1.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 41/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Pediatric National Institutes of Health Stroke Scale (PedNIHSS) PedNIHSS INSTRUCTIONS: Administer stroke scale items in the order listed. Follow directions provided for each exam item. Scores should reflect what the patient does, not what the clinician thinks the patient can do. MODIFICATIONS FOR CHILDREN: Modi cations to testing instructions from the adult version for use in children are shown in bold italic with each item where appropriate. Items with no modi cations should be administered and scored with children in the same manner as for adults. Scale definition and Item# and instructions scoring guide 1a. Level of consciousness: The investigator must choose a response, even if a full evaluation 0 = Alert; keenly responsive. is prevented by such obstacles as an endotracheal tube, language barrier, orotracheal trauma/bandages. A 3 is scored only if the 1 = Not alert, but arousable by minor stimulation to obey, answer, or respond. patient makes no movement (other than reflexive posturing) in response to noxious stimulation. 2 = Not alert, requires repeated stimulation to attend, or is obtunded and requires strong or painful stimulation to make movements (not stereotyped). 3 = Responds only with reflex motor or autonomic effects or totally unresponsive, flaccid, areflexic. 1b. LOC questions: The patient is asked the month and his/her age. The answer must 0 = Answers both questions be correct - there is no partial credit for being close. Aphasic and stuporous patients who do not comprehend the questions will correctly. 1 = Answers one question correctly. score 2. Patients unable to speak because of endotracheal intubation, orotracheal trauma, severe dysarthria from any cause, 2 = Answers neither question language barrier or any other problem not secondary to aphasia correctly. are given a 1. It is important that only the initial answer be graded and that the examiner not "help" the patient with verbal or non- verbal cues. Modi ed for children, age 2 years and up. A familiar Family Member must be present for this item: Ask the child "how old are you?" Or "How many years old are you?" for question number one. Give credit if the child states the correct age, or shows the correct number of ngers for his/her age. For the second question, ask the child "where is XX?", XX referring to the name of the parent or other familiar family member present. Use the name for that person which the child typically uses, eg, https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 42/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate "mommy". Give credit if the child correctly points to or gazes purposefully in the direction of the family member. 1c. LOC commands: The patient is asked to open and close the eyes and then to grip 0 = Performs both tasks and release the non-paretic hand. For children one may substitute the command to grip the hand with the command "show me your correctly. 1 = Performs one task correctly. nose" or "touch your nose". Substitute another one step command if the hands cannot be used. Credit is given if an 2 = Performs neither task unequivocal attempt is made but not completed due to weakness. correctly. If the patient does not respond to command, the task should be demonstrated to them (pantomime) and score the result (ie, follows none, one or two commands). Patients with trauma, amputation, or other physical impediments should be given suitable one-step commands. Only the first attempt is scored. 2. Best gaze: Only horizontal eye movements will be tested. Voluntary or reflexive (oculocephalic) eye movements will be scored but caloric 0 = Normal. 1 = Partial gaze palsy. This score is given when gaze is testing is not done. If the patient has a conjugate deviation of the eyes that can be overcome by voluntary or reflexive activity, the abnormal in one or both eyes, but where forced deviation or score will be 1. If a patient has an isolated peripheral nerve paresis (cranial nerves III, IV or VI) score a 1. Gaze is testable in all aphasic total gaze paresis are not present. patients. Patients with ocular trauma, bandages, pre-existing blindness or other disorder of visual acuity or fields should be tested with reflexive movements and a choice made by the 2 = Forced deviation, or total gaze paresis not overcome by investigator. Establishing eye contact and then moving about the patient from side to side will occasionally clarify the presence of a the oculocephalic maneuver. partial gaze palsy. 3. Visual: Visual fields (upper and lower quadrants) are tested by confrontation, using finger counting (for children >6 years) or 0 = No visual loss. 1 = Partial hemianopia. visual threat (for children age 2 to 6 years) as appropriate. Patient must be encouraged, but if they look at the side of the moving 2 = Complete hemianopia. fingers appropriately, this can be scored as normal. If there is unilateral blindness or enucleation, visual fields in the remaining 3 = Bilateral hemianopia (blind including cortical blindness). eye are scored. Score 1 only if a clear-cut asymmetry, including quadrantanopia is found. If patient is blind from any cause score 3. Double simultaneous stimulation is performed at this point. If there is extinction patient receives a 1 and the results are used to answer question 11. 4. Facial palsy: Ask, or use pantomime to encourage the patient to show teeth or 0 = Normal symmetrical raise eyebrows and close eyes. Score symmetry of grimace in movement. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 43/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate response to noxious stimuli in the poorly responsive or non- 1 = Minor paralysis (flattened comprehending patient. If facial trauma/bandages, orotracheal tube, tape or other physical barrier obscures the face, these nasolabial fold, asymmetry on smiling). should be removed to the extent possible. 2 = Partial paralysis (total or near total paralysis of lower face). 3 = Complete paralysis of one or both sides (absence of facial movement in the upper and lower face). 5 & 6. Motor arm and leg: https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 44/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate The limb is placed in the appropriate position: extend the arms 5a. Left arm (palms down) 90 degrees (if sitting) or 45 degrees (if supine) and the leg 30 degrees (always tested supine). Drift is scored if the arm 5b. Right arm 0 = No drift, limb holds 90 (or 45) degrees for full 10 falls before 10 seconds or the leg before 5 seconds. For children too immature to follow precise directions or uncooperative for seconds. any reason, power in each limb should be graded by observation of spontaneous or elicited movement according to the same 1 = Drift, limb holds 90 (or 45) degrees, but drifts down grading scheme, excluding the time limits. The aphasic patient is before full 10 seconds; does encouraged using urgency in the voice and pantomime but not noxious stimulation. Each limb is tested in turn, beginning with not hit bed or other support. the non-paretic arm. Only in the case of amputation or joint fusion at the shoulder or hip, or immobilization by an IV board, may the 2 = Some effort against gravity, limb cannot get to or score be "9" and the examiner must clearly write the explanation maintain (if cued) 90 (or 45) degrees, drifts down to bed, for scoring as a "9". Score each limb separately. but has some effort against gravity. 3 = No effort against gravity, limb falls. 4 = No movement. 9 = Amputation, joint fusion explain. 6a. Left leg 6b. Right leg 0 = No drift, leg holds 30 degrees position for full 5 seconds. 1 = Drift, leg falls by the end of the 5 second period but does not hit bed. 2 = Some effort against gravity; leg falls to bed by 5 seconds, but has some effort against gravity. 3 = No effort against gravity, leg falls to bed immediately. 4 = No movement. 9 = Amputation, joint fusion explain. 7. Limb ataxia: https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 45/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate This item is aimed at finding evidence of a unilateral cerebellar 0 = Absent. lesion. Test with eyes open. In case of visual defect, insure testing 1 = Present in one limb. is done in intact visual field. The finger-nose-finger and heel-shin 2 = Present in two limbs. tests are performed on both sides, and ataxia is scored only if present out of proportion to weakness. In children, substitute this task with reaching for a toy for the upper extremity, and kicking a toy or the examiner's hand, in children too young (<5 years) or otherwise uncooperative for the standard exam item. Ataxia is absent in the patient who cannot understand or is paralyzed. Only in the case of amputation or joint fusion may the item be scored "9", and the examiner must clearly write the explanation for not scoring. In case of blindness test by touching nose from extended arm position. 8. Sensory: Sensation or grimace to pin prick when tested, or withdrawal from 0 = Normal; no sensory loss. noxious stimulus in the obtunded or aphasic patient. For children 1 = Mild to moderate sensory too young or otherwise uncooperative for reporting gradations of loss; patient feels pinprick is sensory loss, observe for any behavioral response to pin prick, less sharp or is dull on the affected side; or there is a loss and score it according to the same scoring scheme as a "normal" response, "mildly diminished" or "severely diminished" response. of superficial pain with Only sensory loss attributed to stroke is scored as abnormal and pinprick but patient is aware the examiner should test as many body areas [arms (not hands), he/she is being touched. legs, trunk, face] as needed to accurately check for hemisensory 2 = Severe to total sensory loss. A score of 2, "severe or total," should only be given when a severe or total loss of sensation can be clearly demonstrated. loss; patient is not aware of being touched in the face, Stuporous and aphasic patients will therefore probably score 1 or arm, and leg. 0. 9. Best language: A great deal of information about comprehension will be obtained 0 = No aphasia, normal. during the preceding sections of the examination. For children age 6 years and up with normal language development before 1 = Mild to moderate aphasia; some obvious loss of fluency onset of stroke: The patient is asked to describe what is or facility of comprehension, happening in the attached picture, to name the items on the without significant limitation on ideas expressed or form of attached naming sheet, to repeat words from the attached list, and to read from the attached list of sentences (see Table expression. Reduction of S1 "Language testing items" below, and see separate gures speech and/or for Cookie theft picture, Picture naming for PedNIHSS, and comprehension, however, Reading for PedNIHSS). Comprehension is judged from responses makes conversation about provided material difficult or here as well as to all of the commands in the preceding general neurological exam. If visual loss interferes with the tests, ask the impossible. For example in patient to identify objects placed in the hand, repeat, and produce conversation about provided speech. The intubated patient should be asked to write. The materials examiner can patient in coma (question 1a = 3) will arbitrarily score 3 on this identify picture or naming card from patient's response. item. The examiner must choose a score in the patient with stupor https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 46/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate or limited cooperation but a score of 3 should be used only if the 2 = Severe aphasia; all patient is mute and follows no one step commands. For children communication is through age 2 years to 6 years (or older children with premorbid language skills <6 year level), score this item based on observations of fragmentary expression; great need for inference, language comprehension and speech during the examination. questioning, and guessing by The patient with brain stem stroke who has bilateral loss of the listener. Range of sensation is scored 2. If the patient does not respond and is quadriplegic score 2. Patients in coma (item 1a = 3) are arbitrarily information that can be exchanged is limited; listener given a 2 on this item. carries burden of communication. Examiner cannot identify materials provided from patient response. 3 = Mute, global aphasia; no usable speech or auditory comprehension. 10. Dysarthria: If patient is thought to be normal an adequate sample of speech 0 = Normal. must be obtained by asking patient to read or repeat words from 1 = Mild to moderate; patient the attached list. If the patient has severe aphasia, the clarity of articulation of spontaneous speech can be rated. Only if the slurs at least some words and, at worst, can be understood patient is intubated or has other physical barrier to producing with some difficulty. speech, may the item be scored "9", and the examiner must 2 = Severe; patient's speech is clearly write an explanation for not scoring. Do not tell the patient why he/she is being tested. so slurred as to be unintelligible in the absence of or out of proportion to any dysphasia, or is mute/anarthric. 9 = Intubated or other physical barrier, explain. 11. Extinction and inattention (formerly neglect): Sufficient information to identify neglect may be obtained during 0 = No abnormality. the prior testing. If the patient has a severe visual loss preventing 1 = Visual, tactile, auditory, visual double simultaneous stimulation, and the cutaneous stimuli spatial, or personal inattention or extinction to are normal, the score is normal. If the patient has aphasia but does appear to attend to both sides, the score is normal. The bilateral simultaneous presence of visual spatial neglect or anosognosia may also be stimulation in one of the taken as evidence of abnormality. Since the abnormality is scored sensory modalities. only if present, the item is never untestable. 2 = Profound hemi-inattention or hemi-inattention to more than one modality. Does not https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 47/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate recognize own hand or orients to only one side of space. Table S1. Language testing items for PedNIHSS: Repetition Each of 4 word-repetition tasks is presented: a. Stop b. Stop and go c. If it rains we play inside d. The President lives in Washington Reading Each of 3 items is presented for the child to read (see separate "Reading items figure for PedNIHSS"). Adjust expectations according to child's age/school level. Name Pictures are presented of a clock, pencil, skateboard, shirt, baseball, and bicycle (see separate "Picture naming figure for PedNIHSS"). Fluency and word finding The Cookie theft picture is presented and the child is asked to describe what he/she sees (see separate "Cookie theft picture for NIHSS and PedNIHSS"). NIHSS: National Institutes of Health Stroke Scale; PedNIHSS: Pediatric National Institutes of Health Stroke Scale. Reproduced with permission from: Ichord RN, Bastian R, Abraham L, et al. Interrater reliability of the Pediatric National Institutes of Health Stroke Scale (PedNIHSS) in a multicenter study. Stroke 2011; 42:613. Copyright 2011 Lippincott Williams & Wilkins. Graphic 76120 Version 2.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 48/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Reading items figure for PedNIHSS Words to test reading for Item 9 (Best language) of PedNIHSS. Reproduced with permission from: Ichord RN, Bastian R, Abraham L, et al. Interrater reliability of the Pediatric National Institutes of Health Stroke Scale (PedNIHSS) in a multicenter study. Stroke 2011; 42:613. Copyright 2011 Lippincott Williams & Wilkins. Graphic 83404 Version 4.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 49/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Picture naming figure for PedNIHSS Pictures to test naming for Item 9 (Best language) of PedNIHSS. Reproduced with permission from: Ichord RN, Bastian R, Abraham L, et al. Interrater reliability of the Pediatric National Institutes of Health Stroke Scale (PedNIHSS) in a multicenter study. Stroke 2011; 42:613. Copyright 2011 Lippincott Williams & Wilkins. Graphic 83405 Version 4.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 50/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Cookie theft picture for NIHSS and PedNIHSS Cookie theft picture to test story-telling for Item 9 Best language of NIHSS and PedNIHSS. Reproduced with permission from: Ichord RN, Bastian R, Abraham L, et al. Interrater reliability of the Pediatric National Institutes of Health Stroke Scale (PedNIHSS) in a multicenter study. Stroke 2011; 42:613. Copyright 2011 Lippincott Williams & Wilkins. Graphic 83406 Version 4.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 51/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Canadian Neurological Scale Patient Name: Rater Name: Date: Time: Mentation Score Level consciousness Alert 3.0 Drowsy 1.5 Orientation Oriented 1.0 Disoriented/NA 0.0 Speech Normal 1.0 Expressive deficit 0.5 Receptive deficit 0.0 TOTAL: Motor functions (no comprehension deficit) Weakness Score Face None 0.5 Present 0.0 Arm: proximal None 1.5 Mild 1.0 Significant 0.5 Total 0 Arm: distal None 1.5 Mild 1.0 Significant 0.5 Total 0 Leg None 1.5 Mild 1.0 Significant 0.5 Total 0 TOTAL: Motor response (comprehension deficit) Score https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 52/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Face Symmetrical .5 Asymmetrical 0 Arms Equal 1.5 Unequal 0 Legs Equal 1.5 Unequal 0 TOTAL: Reproduced with permission from: C t R, Hachinski VC, Shurvell BL, et al. The Canadian Neurological Scale: a preliminary study in acute stroke. Stroke 1986; 17:731. Copyright 1986 Lippincott Williams & Wilkins. Graphic 55644 Version 9.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 53/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Barthel Index Activity Score Feeding 0 = Unable 5 = Needs help cutting, spreading butter, etc, or requires modified diet 10 = Independent Bathing 0 = Dependent 5 = Independent (or in shower) Grooming 0 = Needs to help with personal care 5 = Independent face/hair/teeth/shaving (implements provided) Dressing 0 = Dependent 5 = Needs help but can do about half unaided 10 = Independent (including buttons, zips, laces, etc) Bowels 0 = Incontinent (or needs to be given enemas) 5 = Occasional accident 10 = Continent Bladder 0 = Incontinent, or catheterized and unable to manage alone 5 = Occasional accident 10 = Continent Toilet use 0 = Dependent 5 = Needs some help, but can do something alone 10 = Independent (on and off, dressing, wiping) Transfers (bed to chair and back)

or limited cooperation but a score of 3 should be used only if the 2 = Severe aphasia; all patient is mute and follows no one step commands. For children communication is through age 2 years to 6 years (or older children with premorbid language skills <6 year level), score this item based on observations of fragmentary expression; great need for inference, language comprehension and speech during the examination. questioning, and guessing by The patient with brain stem stroke who has bilateral loss of the listener. Range of sensation is scored 2. If the patient does not respond and is quadriplegic score 2. Patients in coma (item 1a = 3) are arbitrarily information that can be exchanged is limited; listener given a 2 on this item. carries burden of communication. Examiner cannot identify materials provided from patient response. 3 = Mute, global aphasia; no usable speech or auditory comprehension. 10. Dysarthria: If patient is thought to be normal an adequate sample of speech 0 = Normal. must be obtained by asking patient to read or repeat words from 1 = Mild to moderate; patient the attached list. If the patient has severe aphasia, the clarity of articulation of spontaneous speech can be rated. Only if the slurs at least some words and, at worst, can be understood patient is intubated or has other physical barrier to producing with some difficulty. speech, may the item be scored "9", and the examiner must 2 = Severe; patient's speech is clearly write an explanation for not scoring. Do not tell the patient why he/she is being tested. so slurred as to be unintelligible in the absence of or out of proportion to any dysphasia, or is mute/anarthric. 9 = Intubated or other physical barrier, explain. 11. Extinction and inattention (formerly neglect): Sufficient information to identify neglect may be obtained during 0 = No abnormality. the prior testing. If the patient has a severe visual loss preventing 1 = Visual, tactile, auditory, visual double simultaneous stimulation, and the cutaneous stimuli spatial, or personal inattention or extinction to are normal, the score is normal. If the patient has aphasia but does appear to attend to both sides, the score is normal. The bilateral simultaneous presence of visual spatial neglect or anosognosia may also be stimulation in one of the taken as evidence of abnormality. Since the abnormality is scored sensory modalities. only if present, the item is never untestable. 2 = Profound hemi-inattention or hemi-inattention to more than one modality. Does not https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 47/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate recognize own hand or orients to only one side of space. Table S1. Language testing items for PedNIHSS: Repetition Each of 4 word-repetition tasks is presented: a. Stop b. Stop and go c. If it rains we play inside d. The President lives in Washington Reading Each of 3 items is presented for the child to read (see separate "Reading items figure for PedNIHSS"). Adjust expectations according to child's age/school level. Name Pictures are presented of a clock, pencil, skateboard, shirt, baseball, and bicycle (see separate "Picture naming figure for PedNIHSS"). Fluency and word finding The Cookie theft picture is presented and the child is asked to describe what he/she sees (see separate "Cookie theft picture for NIHSS and PedNIHSS"). NIHSS: National Institutes of Health Stroke Scale; PedNIHSS: Pediatric National Institutes of Health Stroke Scale. Reproduced with permission from: Ichord RN, Bastian R, Abraham L, et al. Interrater reliability of the Pediatric National Institutes of Health Stroke Scale (PedNIHSS) in a multicenter study. Stroke 2011; 42:613. Copyright 2011 Lippincott Williams & Wilkins. Graphic 76120 Version 2.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 48/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Reading items figure for PedNIHSS Words to test reading for Item 9 (Best language) of PedNIHSS. Reproduced with permission from: Ichord RN, Bastian R, Abraham L, et al. Interrater reliability of the Pediatric National Institutes of Health Stroke Scale (PedNIHSS) in a multicenter study. Stroke 2011; 42:613. Copyright 2011 Lippincott Williams & Wilkins. Graphic 83404 Version 4.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 49/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Picture naming figure for PedNIHSS Pictures to test naming for Item 9 (Best language) of PedNIHSS. Reproduced with permission from: Ichord RN, Bastian R, Abraham L, et al. Interrater reliability of the Pediatric National Institutes of Health Stroke Scale (PedNIHSS) in a multicenter study. Stroke 2011; 42:613. Copyright 2011 Lippincott Williams & Wilkins. Graphic 83405 Version 4.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 50/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Cookie theft picture for NIHSS and PedNIHSS Cookie theft picture to test story-telling for Item 9 Best language of NIHSS and PedNIHSS. Reproduced with permission from: Ichord RN, Bastian R, Abraham L, et al. Interrater reliability of the Pediatric National Institutes of Health Stroke Scale (PedNIHSS) in a multicenter study. Stroke 2011; 42:613. Copyright 2011 Lippincott Williams & Wilkins. Graphic 83406 Version 4.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 51/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Canadian Neurological Scale Patient Name: Rater Name: Date: Time: Mentation Score Level consciousness Alert 3.0 Drowsy 1.5 Orientation Oriented 1.0 Disoriented/NA 0.0 Speech Normal 1.0 Expressive deficit 0.5 Receptive deficit 0.0 TOTAL: Motor functions (no comprehension deficit) Weakness Score Face None 0.5 Present 0.0 Arm: proximal None 1.5 Mild 1.0 Significant 0.5 Total 0 Arm: distal None 1.5 Mild 1.0 Significant 0.5 Total 0 Leg None 1.5 Mild 1.0 Significant 0.5 Total 0 TOTAL: Motor response (comprehension deficit) Score https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 52/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Face Symmetrical .5 Asymmetrical 0 Arms Equal 1.5 Unequal 0 Legs Equal 1.5 Unequal 0 TOTAL: Reproduced with permission from: C t R, Hachinski VC, Shurvell BL, et al. The Canadian Neurological Scale: a preliminary study in acute stroke. Stroke 1986; 17:731. Copyright 1986 Lippincott Williams & Wilkins. Graphic 55644 Version 9.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 53/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Barthel Index Activity Score Feeding 0 = Unable 5 = Needs help cutting, spreading butter, etc, or requires modified diet 10 = Independent Bathing 0 = Dependent 5 = Independent (or in shower) Grooming 0 = Needs to help with personal care 5 = Independent face/hair/teeth/shaving (implements provided) Dressing 0 = Dependent 5 = Needs help but can do about half unaided 10 = Independent (including buttons, zips, laces, etc) Bowels 0 = Incontinent (or needs to be given enemas) 5 = Occasional accident 10 = Continent Bladder 0 = Incontinent, or catheterized and unable to manage alone 5 = Occasional accident 10 = Continent Toilet use 0 = Dependent 5 = Needs some help, but can do something alone 10 = Independent (on and off, dressing, wiping) Transfers (bed to chair and back) https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 54/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate 0 = Unable, no sitting balance 5 = Major help (one or two people, physical), can sit 10 = Minor help (verbal or physical) 15 = Independent Mobility (on level surfaces) 0 = Immobile or <50 yards 5 = Wheelchair independent, including corners, >50 yards 10 = Walks with help of one person (verbal or physical) >50 yards 15 = Independent (but may use any aid; for example, stick) >50 yards Stairs 0 = Unable 5 = Needs help (verbal, physical, carrying aid) 10 = Independent Total (0-100): The Barthel ADL Index: Guidelines The index should be used as a record of what a patient does, not as a record of what a patient could do The main aim is to establish degree of independence from any help, physical or verbal, however minor and for whatever reason The need for supervision renders the patient not independent Patient performance should be established using the best available evidence provided by the patient, family, friends and caregivers; direct observation and common sense are also important, but direct testing is not needed Usually the patient's performance over the preceding 24 to 48 hours is important, but occasionally longer periods will be relevant Middle categories imply that the patient supplies over 50 percent of the effort Use of aids to be independent is allowed ADL: activities of daily living. References: 1. Mahoney FI, Barthel D. Functional evaluation: The Barthel Index. Maryland State Medical Journal 1965; 14:56. Used with permission. 2. Loewen SC, Anderson BA. Predictors of stroke outcome using objective measurement scales. Stroke 1990; 21:78. 3. Gresham GE, Phillips TF, Labi ML. ADL status in stroke: Relative merits of three standard indexes. Arch Phys Med Rehabil 1980; 61:355. 4. Collin C, Wade DT, Davies S, Horne V. The Barthel ADL Index: A reliability study. Int Disability Study 1988; 10:61. https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 55/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Graphic 77371 Version 3.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 56/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Modified Rankin Scale Score Description 0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties and activities 2 Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent, and requiring constant nursing care and attention 6 Dead Reproduced with permission from: Van Swieten JC, Koudstaa PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988; 19:604. Copyright 1988 Lippincott Williams & Wilkins. Graphic 75411 Version 13.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 57/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate 2 ABCD score 2 The ABCD score can be used to estimate the risk of ischemic stroke in the first two days after TIA. The score is tallied as follows: Age: 60 years 1 point <60 years 0 points Blood pressure elevation when first assessed after TIA: Systolic 140 mmHg or diastolic 90 mmHg 1 point Systolic <140 mmHg and diastolic <90 mmHg 0 points Clinical features: Unilateral weakness 2 points Isolated speech disturbance 1 point Other 0 points Duration of TIA symptoms: 60 minutes 2 points 10 to 59 minutes 1 point <10 minutes 0 points Diabetes: Present 1 point Absent 0 points Data from: Johnston SC, Rothwell PM, Nguyen-Huynh MN, et al. Validation and re nement of scores to predict very early stroke risk after transient ischaemic attack. Lancet 2007; 369:283. Graphic 62381 Version 3.0 https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 58/59 7/5/23, 12:03 PM Use and utility of stroke scales and grading systems - UpToDate Contributor Disclosures Larry B Goldstein, MD, FAAN, FANA, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/use-and-utility-of-stroke-scales-and-grading-systems/print 59/59

7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Cerebrovascular disorders complicating pregnancy : Susan Hickenbottom, MD, MS, Men-Jean Lee, MD : Jos Biller, MD, FACP, FAAN, FAHA, Charles J Lockwood, MD, MHCM : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Sep 14, 2022. INTRODUCTION Cerebrovascular disease during pregnancy can be distilled into two major categories: thrombosis/ischemia (including arterial and venous infarction) and hemorrhage (including intracerebral and subarachnoid hemorrhage). Normal physiologic changes associated with pregnancy, combined with pathophysiologic processes unique to pregnancy, predispose women to develop stroke during pregnancy and the puerperium. This topic review will focus on the relationship between pregnancy and cerebrovascular disorders. Other neurologic disorders complicating pregnancy are discussed separately. (See "Neurologic disorders complicating pregnancy".) EPIDEMIOLOGY Incidence Pregnant or recently pregnant women develop stroke (incidence 30 per 100,000 pregnancies) more frequently than their nonpregnant counterparts (annual incidence, 10.7 per 100,000 women of reproductive age) [1]. Data from a population-based registry in Finland suggest that the incidence of stroke during pregnancy or puerperium has increased over time; in the study, the incidence rose by more than two-fold from the initial five-year period (1987 to 1991) compared with the last five-year period (2012 to 2016) [2]. Highest risk periods The third trimester of pregnancy and the postpartum period are associated with a marked increase in the relative risk and a small increase in the absolute risk of ischemic stroke and intracerebral hemorrhage; the highest risk is during the puerperium [3-8]. https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 1/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate Approximately 10 percent of strokes occur in the antepartum period, 40 percent occur proximate to delivery, and 50 percent occur postpartum and after discharge [3]. Although data are inconsistent, the incidence of stroke during the antenatal period alone, excluding stroke during the puerperium, may be similar to the incidence in nonpregnant women of childbearing age [9]. The increased relative risk of stroke in the postpartum period was illustrated in a review of female hospital discharges from central Maryland and Washington, DC for the years 1988 and 1991 that determined the magnitude of the effect of pregnancy (including spontaneous and induced abortions) on stroke risk [4]. For cerebral infarction, the relative risk was 0.7 during pregnancy (a nonsignificant difference) but increased to 8.7 in the postpartum period (within six weeks of a live birth or stillbirth). For intracerebral hemorrhage, the adjusted relative risk was 2.5 during pregnancy but increased to 28.3 in the postpartum period. For both types of stroke, which occurred with equal frequency, the excess risk during the postpartum period was 8.1 strokes per 100,000 pregnancies. Similar findings were reported in a large study from France [5] and in an analysis from the Nationwide Inpatient Sample of all pregnancy-related discharges in the United States from 2000 to 2001 [3]. Major risk factors and mechanisms Important physiologic and pathophysiologic alterations are associated with an increased risk for ischemic and hemorrhagic strokes during pregnancy. These include changes in cardiovascular hemodynamics, coagulation factors, and hemoconcentration, accompanied by endothelial dysfunction, inflammation, and impaired cerebrovascular tone [10]. A number of complications of pregnancy can present as either a stroke or a stroke-like event, including the following: Preeclampsia/eclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets) (see 'Preeclampsia, eclampsia, and HELLP' below) Reversible cerebral vasoconstriction syndrome/postpartum cerebral angiopathy (see 'RCVS/postpartum angiopathy' below) Cerebral venous thrombosis (see 'Cerebral venous thrombosis' below) Hypercoagulable state (see 'Hypercoagulable state' below) Peripartum cardiomyopathy (see 'Peripartum cardiomyopathy' below) Amniotic fluid embolism (see "Amniotic fluid embolism") Gestational trophoblastic disease (see 'Gestational trophoblastic disease' below) https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 2/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate Other risk factors for stroke related to pregnancy include cesarean delivery, gestational hypertension [7], and peripartum infection [3,11,12]. The risk factors for stroke in pregnancy also include the risk factors for nonpregnant patients, such as hypertension, smoking, antiphospholipid antibody syndrome, inherited thrombophilia, arterial disease, certain types of heart disease, hyperlipidemia, paradoxical emboli, arterial dissection, substance abuse, age over 35 years, migraine with aura, and being from a Black population [3,13]. Women with essential thrombocythemia (primary thrombocytosis) are also at increased risk for thromboembolic events during pregnancy [14]. Risk factors and causes of cerebral venous thrombosis and intracranial hemorrhage in pregnancy are reviewed in greater detail below. (See 'Epidemiology of CVT' below and 'Causes of intracranial hemorrhage' below.) Stroke subtypes All types of stroke can be seen in pregnancy and the puerperium ( table 1). The major causes in this setting are the following [15-17]: Hemorrhagic stroke from hypertensive disorders of pregnancy (preeclampsia/eclampsia, HELLP), reversible cerebral vasoconstriction syndrome (RCVS), arteriovenous malformations, and aneurysms Ischemic stroke from cerebral venous sinus thrombosis, preeclampsia/eclampsia, and cardiogenic embolism OVERVIEW OF DIAGNOSTIC EVALUATION The diagnostic evaluation and treatment of stroke in pregnant women is similar to that in nonpregnant individuals [18]. (See "Initial assessment and management of acute stroke".) Rapid evaluation In pregnant patients, ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, and cerebral venous thrombosis have clinical features similar to those occurring in nonpregnant patients. All patients with suspected acute stroke require an urgent evaluation; important aspects include: Assessing vital signs and ensuring stabilization of airway, breathing, and circulation. Checking serum glucose with finger stick or rapid point of care test. Low serum glucose (<60 mg/dL [3.3 mmol/L]) should be corrected rapidly. It is reasonable to treat https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 3/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate hyperglycemia if the glucose level is >180 mg/dL (>10 mmol/L) with a goal of keeping serum glucose levels within a range of 140 to 180 mg/dL (7.8 to 10 mmol/L). Obtaining a rapid but accurate history (including the time last known well) and examination to help distinguish stroke mimics and other disorders in the differential diagnosis ( table 2) of acute stroke. Obtaining urgent brain imaging with computed tomography (CT) or magnetic resonance imaging (MRI), neurovascular imaging with CT angiography (CTA) or magnetic resonance angiography (MRA) and other important laboratory studies including cardiac monitoring. Managing volume depletion and electrolyte disturbances. Assessing swallowing and preventing aspiration. Neuroimaging An imaging study of the brain is an essential component of the evaluation, regardless of cause. CT versus MRI Noncontrast head CT is often the first diagnostic study in patients with suspected stroke. The main advantages of CT are widespread access and speed of acquisition. However, MRI is safe during all trimesters of pregnancy (see "Diagnostic imaging in pregnant and lactating patients", section on 'Magnetic resonance imaging'). In addition, MRI is more sensitive than CT for the detection of early infarction, small infarcts, cerebral venous thrombosis, and structural lesions (eg, cavernous malformations) [19]. (See "Neuroimaging of acute stroke", section on 'CT or MRI for initial imaging?'.) The neuroradiographic abnormalities of reversible posterior leukoencephalopathy syndrome are often apparent on head CT but are best depicted by MRI using fluid- attenuated inversion recovery (FLAIR) sequences. (See "Reversible posterior leukoencephalopathy syndrome", section on 'Neuroimaging'.) Note that a small subarachnoid hemorrhage (SAH) can be missed by both CT and MRI, especially as the time from SAH onset to imaging study increases. Lumbar puncture may be needed to make the diagnosis of SAH in such patients. This issue is discussed in detail elsewhere. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Evaluation and diagnosis'.) Use of contrast agents Iodine and gadolinium-based contrast agents are avoided in pregnancy, if possible. (See "Diagnostic imaging in pregnant and lactating patients".) https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 4/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate Radiation exposure Radiation exposure to the fetus with head CT, cerebral angiography, and chest radiography is approximately 50, 10, and 1 milliradians, respectively. These levels are considered safe, as there is no evidence of an increased risk of fetal anomalies, intellectual disability, growth restriction, or pregnancy loss from ionizing radiation at doses less than 5000 milliradians. The abdomen should be shielded from radiation. (See "Diagnostic imaging in pregnant and lactating patients", section on 'Fetal risks'.) Cardiac studies Cardiac monitoring and echocardiography should be obtained in patients with embolic infarctions. Echocardiography should include a bubble contrast study with agitated saline to look for evidence of a right-to-left shunt via a patent foramen ovale as a pathway for paradoxical embolism from a venous source [10]. Laboratory studies The laboratory evaluation includes a complete blood count, metabolic profile, lipid panel, and toxicology screen [10]. Additional studies may be useful in select patients. Sickle cell disease Testing for sickle cell disease is warranted if there is suspicion for the diagnosis. Despite newborn screening, some adults with sickle cell disease may be undiagnosed. The diagnosis of sickle cell disease is reviewed in detail elsewhere. (See "Diagnosis of sickle cell disorders".) Hypercoagulable testing We obtain a laboratory evaluation for an inherited or acquired thrombophilia for women presenting with a cryptogenic ischemic stroke or transient ischemic attack during pregnancy. Molecular genetic testing for inherited thrombophilias (antithrombin deficiency, prothrombin G20210A, factor V Leiden, protein S deficiency, protein C deficiency) can be done anytime. For patients who are pregnant or were recently pregnant, nonmolecular laboratory testing (eg, activated protein C resistance ratio, functional assay for protein C, free protein S antigen assay, antithrombin-heparin cofactor assay) ideally should be delayed until three months or more following delivery. Details are reviewed separately. (See "Inherited thrombophilias in pregnancy".) Evaluation for the antiphospholipid syndrome includes antibody testing for antiphospholipid antibodies, as reviewed in detail elsewhere. (See "Diagnosis of antiphospholipid syndrome".) Although data are limited, the potential value of this approach was illustrated in a report of 12 previously healthy women who had a first transient ischemic neurologic event during pregnancy https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 5/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate [20]. Ten (83 percent) had an inherited thrombophilia, much higher than the 17 percent rate seen in 24 controls. (See 'Hypercoagulable state' below.) ACUTE ISCHEMIC STROKE In pregnant patients, ischemic stroke has clinical features similar to those occurring in nonpregnant patients. Evaluation The evaluation and treatment of acute ischemic stroke in pregnancy is mostly guided by the same principles as in the general population. These are discussed separately. (See "Initial assessment and management of acute stroke" and "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack" and "Initial evaluation and management of transient ischemic attack and minor ischemic stroke".) Acute reperfusion therapy Intravenous thrombolysis and endovascular mechanical thrombectomy are effective reperfusion therapies for acute ischemic stroke. The immediate goal of reperfusion therapy is to restore blood flow to the regions of brain that are ischemic but not yet infarcted. (See "Approach to reperfusion therapy for acute ischemic stroke".) Intravenous thrombolysis Intravenous thrombolytic therapy with alteplase is indicated for patients with acute ischemic stroke who meet eligibility criteria outlined in the table ( table 3), provided that treatment is initiated within 4.5 hours of clearly defined symptom onset. We agree with the 2019 American Heart Association/American Stroke Association guidelines, which state that intravenous alteplase administration may be considered in pregnancy when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding [21]. Eligible patients should be treated as quickly as possible within the appropriate 3- or 4.5-hour time limit after careful discussion of the potential risks and benefit [22-24]. (See "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use".) The prescribing label for alteplase does not list pregnancy as a contraindication but states that the risk of therapy may be increased in pregnancy [25]. Potential risks include the maternal hemorrhage with thrombolysis, possibly resulting in premature labor, placental abruption, and/or fetal demise [10,26]. Hemorrhage during parturition or cesarean delivery is a particular risk with thrombolytic therapy if the patient goes into labor or operative delivery is required [26]. Based on its molecular weight, alteplase is not expected to cross the placenta; it is unknown if alteplase is present in breast milk. There are no data regarding teratogenicity in humans, but no such risk was found in animal studies [27]. https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 6/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate Mechanical thrombectomy Mechanical thrombectomy is indicated for selected patients with acute ischemic stroke caused by an intracranial large artery occlusion in the proximal anterior circulation who can be treated within 24 hours of the time last known to be well. (See "Mechanical thrombectomy for acute ischemic stroke".) Endovascular treatment options, particularly mechanical thrombectomy, may be preferred over intravenous thrombolytic therapy for women considered to have a high risk of hemorrhage, such as those with placenta previa or a history of obstetric hemorrhage [28]. These interventions should be attempted only at centers with appropriate expertise. (See "Approach to reperfusion therapy for acute ischemic stroke" and "Mechanical thrombectomy for acute ischemic stroke".) Efficacy and safety in pregnancy The efficacy and safety of reperfusion therapies for acute ischemic stroke in pregnancy are not firmly established, as pregnant women were excluded from the randomized controlled trials testing intravenous thrombolysis and mechanical thrombectomy. However, observational data suggest these therapies are reasonably safe and effective [28,29]. One report evaluating stroke registry data found that the use of acute reperfusion therapy in pregnant or postpartum women was associated with outcomes that were similar to those in nonpregnant women [28]. The study included 338 pregnant or postpartum women and over 24,000 nonpregnant women ages 18 to 44 years with ischemic stroke. Acute reperfusion therapy was defined as intravenous tissue plasminogen activator (tPA), catheter-based thrombolysis or thrombectomy, or any combination of these interventions. Rates of acute stroke reperfusion therapy were similar in pregnant or postpartum women compared with nonpregnant women (11.8 versus 10.5 percent), although treatment with intravenous tPA monotherapy was less frequent in pregnant or postpartum women compared with nonpregnant women (4.4 versus 7.9 percent). Among those treated with acute reperfusion therapy, there was no difference between pregnant or postpartum women and nonpregnant women for rates of in-hospital death (2.1 versus 2.7 percent), discharge to home (75 versus 73 percent), or independent ambulation at home (74 versus 71 percent). There was a higher rate of symptomatic intracranial hemorrhage in pregnant or postpartum women (7.5 percent) compared with nonpregnant women (2.6 percent); the difference did not achieve statistical significance, although it was limited by small numbers of patients. Another analysis of female patients with acute ischemic stroke from the National Inpatient Sample identified 180 pregnant or postpartum women treated with mechanical thrombectomy [29]. Compared with over 48,000 nonpregnant female patients treated with https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 7/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate mechanical thrombectomy, pregnant and postpartum patients had lower rates of both intracranial hemorrhage (11 versus 24 percent) and poor functional outcome (50 versus 72 percent). Blood pressure control Treatment of hypertension for patients with acute ischemic stroke is reviewed separately. (See "Initial assessment and management of acute stroke", section on 'Blood pressure management'.) Patients with ischemic stroke attributed to preeclampsia or eclampsia require treatment of severe hypertension and prompt delivery. (See 'Preeclampsia, eclampsia, and HELLP' below.) Acute antiplatelet therapy Early aspirin therapy is recommended for patients with acute ischemic stroke who are not receiving full-dose anticoagulation. This recommendation is in accord with national guidelines [21,30]. Aspirin should be given as soon as possible within 48 hours of stroke onset, except that aspirin should be withheld for 24 hours following intravenous thrombolytic therapy. Aspirin may also be used in combination with subcutaneous heparin for deep vein thrombosis prophylaxis. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Efficacy of aspirin'.) We do not routinely use clopidogrel or any regimen of dual antiplatelet therapy (DAPT) to treat ischemic stroke or transient ischemic attack (TIA) during pregnancy, given the risk of bleeding in pregnancy. However, the short-term use of DAPT (eg, aspirin with clopidogrel) during pregnancy for the treatment of minor ischemic stroke or high-risk TIA may be considered using shared decision-making and based upon individual patient circumstances and risk factors. Secondary prevention An antiplatelet agent for secondary prevention is recommended for patients with a history of noncardioembolic stroke or TIA of atherothrombotic, lacunar (small vessel occlusive type), or cryptogenic type. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) Aspirin, clopidogrel, and the combination of aspirin-extended-release dipyridamole are all acceptable options for preventing recurrent noncardioembolic ischemic stroke after pregnancy. An aspirin dose of 60 to 81 mg/day is considered safe in pregnancy [31,32]. Clopidogrel and the combination of aspirin-extended-release dipyridamole have not been evaluated in large numbers of patients or over prolonged periods of time. Ischemic stroke associated with a hypercoagulable state Rare cases of ischemic stroke in pregnancy may be associated with a documented hypercoagulable state; management is reviewed separately. (See 'Hypercoagulable state' below and "Inherited thrombophilias in https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 8/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate pregnancy" and "Antiphospholipid syndrome: Obstetric implications and management in pregnancy".) CEREBRAL VENOUS THROMBOSIS Epidemiology of CVT Cerebral venous thrombosis (CVT), also known as cerebral venous sinus thrombosis, is rare in the general population but occurs more commonly in association with pregnancy [33,34]. It presents most often in the third trimester of pregnancy and the puerperium. In hospital discharge data from the United States covering 2850 pregnancies that included a diagnosis of stroke for the years 2000 and 2001, CVT was the cause of 2 percent of pregnancy-related stroke [3]. Smaller retrospective studies have reported that CVT accounts for 3 to 57 percent of pregnancy-related stroke [4,33,35-38]. Some cases have been linked to inherited and acquired thrombophilias [33,36]. Other risk factors include cesarean delivery, hypertension, and infection. (See "Inherited thrombophilias in pregnancy".) Clinical manifestations Clinical manifestations of CVT consist of headache, vomiting, focal or generalized seizure, confusion, blurred vision, focal neurologic deficits, and/or altered consciousness. The headache frequently precedes other symptoms, is diffuse, and is often severe. The severity of symptoms correlates with the degree of thrombosis and the vessel involved. Isolated intracranial hypertension syndrome (ie, headache associated with papilledema or visual obscurations) accounts for a significant proportion of CVT cases. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis", section on 'Clinical aspects'.) Diagnosis Urgent neuroimaging is necessary as the first step in the diagnostic evaluation of suspected CVT. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis", section on 'Diagnosis'.) Anticoagulation The mainstay for the treatment of symptomatic CVT, with or without hemorrhagic venous infarction, is anticoagulation therapy with intravenous heparin or subcutaneous low molecular weight heparin. For women with CVT during pregnancy, guidelines from the American Heart Association/American Stroke Association conclude that low molecular weight heparin in full anticoagulant doses should be continued throughout pregnancy, and low molecular weight heparin or a vitamin K antagonist with a target international normalized ratio (INR) of 2 to 3 should be continued for at least six weeks postpartum for a total minimum duration of therapy of six months [39,40]. Symptomatic management issues include control of seizures and intracranial hypertension. (See "Cerebral venous thrombosis: Treatment and prognosis".) https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 9/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate INTRACRANIAL HEMORRHAGE Causes of intracranial hemorrhage Subarachnoid and/or intracerebral hemorrhage during pregnancy or the postpartum period may be caused by hypertensive disorders of pregnancy (preeclampsia, eclampsia, and HELLP [hemolysis, elevated liver enzymes, and low platelets]), reversible cerebral vasoconstriction syndrome (RCVS), and bleeding from a vascular malformation [16,41]. Hemodynamic, angiogenic, and endocrine changes associated with pregnancy may affect the growth and rupture of aneurysms in the gravid patient [42]. Data are conflicting regarding the occurrence of aneurysmal subarachnoid hemorrhage (SAH) during pregnancy, delivery, and the postpartum period. Some studies have reported an increased risk [43,44], while others concluded that aneurysmal rupture is not more frequent [45]. Most data suggest that the risk of hemorrhage from a cerebral arteriovenous malformation is not increased during pregnancy, but the issue is controversial, and no definitive data exist [46- 49]. One of the better studies was a retrospective analysis of 451 women with a brain arteriovenous malformation [46]. The hemorrhage rate in pregnant women in this population was not significantly different compared with the rate for nonpregnant women (3.5 versus 3.1 percent per person-year). In a study that examined a 10-year representative sample of the entire United States obstetrical population, involving nearly seven million deliveries, 423 women had pregnancy-related intracerebral hemorrhage [6]. Independent risk factors for intracerebral hemorrhage in this population were advanced maternal age, preexisting and gestational hypertension, preeclampsia/eclampsia, preexisting hypertension superimposed on preeclampsia/eclampsia, coagulopathy, tobacco abuse, and being from a Black population. One retrospective study reported 154 women with intracranial hemorrhage during pregnancy or the puerperium who had an identified vascular lesion [50]. The cause of the hemorrhage was cerebral aneurysm or arteriovenous malformation in 77 and 23 percent, respectively. Aneurysm rupture during pregnancy occurred most frequently in the third trimester (55 percent) and less so in the second trimester (31 percent), first trimester (6 percent), or postpartum period (8 percent). One old retrospective study found that among 37 pregnant women in good condition after SAH from a verified intracranial aneurysm, recurrent bleeding during the same pregnancy from surgically untreated aneurysms occurred in 13 (35 percent) [51]. The overall incidence of rebleeding after initial SAH in the modern era is uncertain. Limited data from older literature https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 10/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate suggest that the maternal case fatality rate of aneurysmal SAH is approximately 50 percent [50], which is similar to that of the general population (see "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Complications'). The fetal case fatality rate is approximately 17 percent [50]. Management by cause of hemorrhage Preeclampsia/eclampsia/HELLP Retrospective data suggest that severe preeclampsia/eclampsia/HELLP (hemolysis, elevated liver enzymes, and low platelets) is the cause of 14 to 55 percent of hemorrhagic strokes in pregnancy. In such cases, management goals are to stabilize the mother, prevent recurrent convulsions, treat severe hypertension to reduce or prevent cerebral edema and hemorrhage, and initiate delivery of the fetus. (See 'Preeclampsia, eclampsia, and HELLP' below.) Vascular malformations Intracerebral aneurysms and arteriovenous malformations (AVMs) can be managed by surgical (ie, clipping) or endovascular (eg, embolization) treatment of the causative lesion [52]. Treatment In general, ruptured intracranial aneurysms in pregnant women are treated as they would be in patients who are not pregnant. Endovascular coiling is preferred to surgical clipping for appropriately shaped aneurysms. Several reports have described successful endovascular coiling of intracranial aneurysms associated with term or near-term births [53-56]. However, aneurysms with broad necks, a low neck-to- fundus ratio, distal segment lesions, and a number of giant aneurysms are not amenable to endovascular therapy. Stable, unruptured asymptomatic aneurysms can usually be observed without intervention during pregnancy, whereas symptomatic or enlarging unruptured aneurysms can be treated [57,58]. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis" and "Unruptured intracranial aneurysms".) Symptomatic AVMs in pregnant women are treated as they would be in patients who are not pregnant. There are a few case reports of successful embolization of hemorrhagic AVMs during pregnancy via the endovascular approach, followed by surgical resection of the AVM [59,60]. Computed tomography (CT) angiography with shielding of the abdomen during pregnancy can be performed prior to the embolization procedure to delineate any prenidal or intranidal aneurysms that might be the source of the bleed. (See "Brain arteriovenous malformations" and "Vascular malformations of the central nervous system".) https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 11/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate Labor and delivery Women who have had the cause of their cerebral hemorrhage treated (eg, clipping or embolization of a cerebral aneurysm or AVM) may undergo labor and delivery. However, there is controversy regarding management of labor and delivery with ruptured aneurysms or AVMs that have not been definitively treated. The two major alternatives are (1) prophylactic cesarean delivery and (2) regional anesthesia with instrumental delivery to eliminate cerebral hemodynamic fluctuations associated with pain and the Valsalva maneuver. There are no data from large series or randomized trials, but it appears that maternal and fetal mortality rates are the same with both methods. As a result, cesarean delivery should be reserved for the usual obstetrical indications [50]. Aneurysm rupture has occurred during elective cesarean birth; thus, it is not completely protective. Therefore, regardless of the mode of delivery, it is important to control hypertension and minimize fluctuations in blood pressure. Some experts believe that selected patients who are stable after intracranial hemorrhage can be managed supportively until the pregnancy is taken to term [52]. The lesion can then be treated by surgical or endovascular means after delivery. However, emergency surgery is indicated if there is neurologic deterioration caused by recurrent bleeding. RCVS The evaluation and management of RCVS/postpartum angiopathy is reviewed below. (See 'RCVS/postpartum angiopathy' below.) PREECLAMPSIA, ECLAMPSIA, AND HELLP The syndromes of severe preeclampsia, eclampsia, and HELLP (hemolysis, elevated liver enzymes, and low platelets) are among the most common causes of both ischemic and hemorrhagic stroke in pregnancy [4,5,35,61,62]. However, the most frequent cerebrovascular disturbance associated with preeclampsia and eclampsia is posterior reversible encephalopathy syndrome (PRES), which is also known as reversible posterior leukoencephalopathy syndrome. The presumed mechanism is impairment of cerebrovascular autoregulation. (See "Reversible posterior leukoencephalopathy syndrome".) Preeclampsia, eclampsia, and HELLP syndrome are discussed in detail elsewhere. (See "Preeclampsia: Clinical features and diagnosis" and "Eclampsia" and "HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets)".) https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 12/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate Manifestations Neurologic manifestations of the reversible encephalopathy associated with severe preeclampsia, eclampsia, and HELLP syndrome may include headache, blurred vision, scotomata, cortical blindness, and/or generalized tonic-clonic seizures. Untreated cases may progress to coma. Neuroimaging often shows vasogenic edema in subcortical white matter, predominantly in the parietal and occipital lobes. (See "Preeclampsia: Clinical features and diagnosis" and "Eclampsia" and "HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets)".) The available data regarding ischemic and hemorrhagic stroke associated with severe preeclampsia/eclampsia/HELLP are limited to retrospective studies. In a report from Mexico of 240 women with pregnancy-related cerebrovascular complications, preeclampsia/eclampsia was commonly associated with both ischemic stroke of arterial origin (36 percent) and intracerebral hemorrhage (55 percent) but less frequently with cerebral venous thrombosis (10 percent) [35]. In a review from Maryland of 31 pregnancy-related strokes, 17 patients had cerebral infarction and 14 had intracerebral hemorrhage [4]. Severe preeclampsia/eclampsia accounted for 24 percent of infarctions and 14 percent of hemorrhages. In a study from France of 31 pregnancy-related strokes, eclampsia accounted for 47 percent of infarctions and 44 percent of hemorrhages [5]. The clinical characteristics of patients with stroke in association with severe preeclampsia/eclampsia/HELLP were illustrated in a review of 28 such patients with a mean age of 30 years (range 14 to 42 years) who were otherwise free of risk factors for stroke [61]. Seven of the patients were ascertained from hospital medical records, while the other 21 were derived from forensic sources. In the 27 patients who had intracranial imaging, the type of stroke was hemorrhagic-arterial in 25 (93 percent) and thrombotic-arterial in 2 (7 percent). There were more strokes in the postpartum than antepartum period (57 versus 43 percent). Since most of the cases reported were derived from forensic sources, these findings may not be representative of the risks to the overall population of pregnant women with severe preeclampsia/eclampsia/HELLP [61]. Management The goals of management of severe preeclampsia and eclampsia and HELLP are to stabilize the mother, prevent recurrent convulsions, treat severe hypertension promptly to reduce or prevent cerebral edema and hemorrhage, and initiate prompt delivery. Indications for antihypertensive therapy and drug choices are discussed in detail separately. (See "Treatment of hypertension in pregnant and postpartum patients".) https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 13/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate Magnesium sulfate is the drug of choice for seizure prophylaxis. Platelet transfusion is indicated in HELLP syndrome if there is significant maternal bleeding or if the platelet count is <20,000 cells/microL. (See "Preeclampsia: Antepartum management and timing of delivery" and "Eclampsia", section on 'Management' and "HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets)", section on 'Management of patients presenting before delivery'.) RCVS/POSTPARTUM ANGIOPATHY Postpartum angiopathy is one member of a group of reversible cerebral vasoconstriction syndromes (RCVS) with similar clinical and radiologic features that are characterized by thunderclap headache and diffuse, segmental, reversible cerebral vasospasm [63]. Other entities encompassed by RCVS include idiopathic thunderclap headache with vasospasm, benign angiopathy of the central nervous system, migrainous vasospasm, Call-Fleming syndrome, and drug-induced cerebral vasoconstriction. (See "Reversible cerebral vasoconstriction syndrome".) The available retrospective studies are inconsistent regarding the frequency of pregnancy complications (eg, eclampsia or gestational diabetes) preceding RCVS [64,65]. However, the clinical, laboratory, and neuroimaging features of RCVS/postpartum angiopathy and eclampsia are not strictly separated, suggesting these entities may represent different clinical expressions of the same underlying pregnancy-related disorder [66,67]. In one retrospective series that reported 18 patients with postpartum angiopathy from three tertiary care centers, pregnancy was complicated by preeclampsia or eclampsia in 7 (39 percent) [65]. It is important to determine if any drugs capable of causing vascular spasm have been used. Some reports suggest that sympathomimetic drugs may increase the risk of postpartum angiopathy [64]. Clinical features Headache remains the only symptom in many patients with RCVS; others develop focal deficits neurologic findings that can include visual disturbance, hemiplegia, dysarthria, aphasia, numbness, ataxia, seizure, and encephalopathy, often in combination [65]. Vasogenic brain edema, intraparenchymal hemorrhage, subarachnoid hemorrhage, ischemic stroke ( image 1), and even death have been reported [65,68]. Blood pressure may be normal or elevated. Imaging and laboratory studies Smooth narrowing of multiple segments of intracranial arteries is seen on cerebral angiography and can be seen on magnetic resonance angiography or computed tomographic angiography ( image 2), although these noninvasive studies may not be able to adequately image smaller arterioles that are https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 14/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate typically involved. In addition, cerebral angiography may be normal early in the clinical course [65]. The angiographic changes are reversible but may persist for days to months. Laboratory testing is usually normal. Cerebrospinal fluid findings are typically without abnormalities, but minor abnormalities can result from ischemic or hemorrhagic strokes. Differential diagnosis The differential diagnosis of postpartum angiopathy and RCVS includes primary angiitis of the central nervous system (PACNS). Findings that favor PACNS rather than postpartum angiopathy associated with pregnancy include an insidious onset of dull headache, stepwise progression of symptoms, spinal fluid abnormalities, and more distal intracranial blood vessels affected on angiography. (See "Primary angiitis of the central nervous system in adults".) Treatment of postpartum angiopathy As with all central nervous system vasculopathy syndromes, there is no proof that any therapeutic intervention is effective for postpartum angiopathy. The syndrome is usually self-limiting. Some patients have received glucocorticoids (especially those with findings that suggest primary angiitis of the central nervous system), calcium channel blockers, and/or magnesium [65]. Progressive deterioration is usually a relatively early finding (within the first few weeks) and may be due to increasing brain edema. Prognosis The prognosis of postpartum angiopathy was thought to be good, but in one of the largest series (n = 18), a complete recovery was achieved by nine patients (50 percent), while a fulminant course followed by death affected four patients (22 percent) [65]. There is no evidence of a high risk of recurrence in future pregnancies [69], although at least one recurrent case has been reported [70], or of an increased risk of eclampsia/preeclampsia in future pregnancies. HYPERCOAGULABLE STATE Pregnancy is a hypercoagulable state that is due, in part, to the progressive increase in resistance to activated protein C in the second and third trimesters, as well as decreased protein

12/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate Manifestations Neurologic manifestations of the reversible encephalopathy associated with severe preeclampsia, eclampsia, and HELLP syndrome may include headache, blurred vision, scotomata, cortical blindness, and/or generalized tonic-clonic seizures. Untreated cases may progress to coma. Neuroimaging often shows vasogenic edema in subcortical white matter, predominantly in the parietal and occipital lobes. (See "Preeclampsia: Clinical features and diagnosis" and "Eclampsia" and "HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets)".) The available data regarding ischemic and hemorrhagic stroke associated with severe preeclampsia/eclampsia/HELLP are limited to retrospective studies. In a report from Mexico of 240 women with pregnancy-related cerebrovascular complications, preeclampsia/eclampsia was commonly associated with both ischemic stroke of arterial origin (36 percent) and intracerebral hemorrhage (55 percent) but less frequently with cerebral venous thrombosis (10 percent) [35]. In a review from Maryland of 31 pregnancy-related strokes, 17 patients had cerebral infarction and 14 had intracerebral hemorrhage [4]. Severe preeclampsia/eclampsia accounted for 24 percent of infarctions and 14 percent of hemorrhages. In a study from France of 31 pregnancy-related strokes, eclampsia accounted for 47 percent of infarctions and 44 percent of hemorrhages [5]. The clinical characteristics of patients with stroke in association with severe preeclampsia/eclampsia/HELLP were illustrated in a review of 28 such patients with a mean age of 30 years (range 14 to 42 years) who were otherwise free of risk factors for stroke [61]. Seven of the patients were ascertained from hospital medical records, while the other 21 were derived from forensic sources. In the 27 patients who had intracranial imaging, the type of stroke was hemorrhagic-arterial in 25 (93 percent) and thrombotic-arterial in 2 (7 percent). There were more strokes in the postpartum than antepartum period (57 versus 43 percent). Since most of the cases reported were derived from forensic sources, these findings may not be representative of the risks to the overall population of pregnant women with severe preeclampsia/eclampsia/HELLP [61]. Management The goals of management of severe preeclampsia and eclampsia and HELLP are to stabilize the mother, prevent recurrent convulsions, treat severe hypertension promptly to reduce or prevent cerebral edema and hemorrhage, and initiate prompt delivery. Indications for antihypertensive therapy and drug choices are discussed in detail separately. (See "Treatment of hypertension in pregnant and postpartum patients".) https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 13/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate Magnesium sulfate is the drug of choice for seizure prophylaxis. Platelet transfusion is indicated in HELLP syndrome if there is significant maternal bleeding or if the platelet count is <20,000 cells/microL. (See "Preeclampsia: Antepartum management and timing of delivery" and "Eclampsia", section on 'Management' and "HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets)", section on 'Management of patients presenting before delivery'.) RCVS/POSTPARTUM ANGIOPATHY Postpartum angiopathy is one member of a group of reversible cerebral vasoconstriction syndromes (RCVS) with similar clinical and radiologic features that are characterized by thunderclap headache and diffuse, segmental, reversible cerebral vasospasm [63]. Other entities encompassed by RCVS include idiopathic thunderclap headache with vasospasm, benign angiopathy of the central nervous system, migrainous vasospasm, Call-Fleming syndrome, and drug-induced cerebral vasoconstriction. (See "Reversible cerebral vasoconstriction syndrome".) The available retrospective studies are inconsistent regarding the frequency of pregnancy complications (eg, eclampsia or gestational diabetes) preceding RCVS [64,65]. However, the clinical, laboratory, and neuroimaging features of RCVS/postpartum angiopathy and eclampsia are not strictly separated, suggesting these entities may represent different clinical expressions of the same underlying pregnancy-related disorder [66,67]. In one retrospective series that reported 18 patients with postpartum angiopathy from three tertiary care centers, pregnancy was complicated by preeclampsia or eclampsia in 7 (39 percent) [65]. It is important to determine if any drugs capable of causing vascular spasm have been used. Some reports suggest that sympathomimetic drugs may increase the risk of postpartum angiopathy [64]. Clinical features Headache remains the only symptom in many patients with RCVS; others develop focal deficits neurologic findings that can include visual disturbance, hemiplegia, dysarthria, aphasia, numbness, ataxia, seizure, and encephalopathy, often in combination [65]. Vasogenic brain edema, intraparenchymal hemorrhage, subarachnoid hemorrhage, ischemic stroke ( image 1), and even death have been reported [65,68]. Blood pressure may be normal or elevated. Imaging and laboratory studies Smooth narrowing of multiple segments of intracranial arteries is seen on cerebral angiography and can be seen on magnetic resonance angiography or computed tomographic angiography ( image 2), although these noninvasive studies may not be able to adequately image smaller arterioles that are https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 14/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate typically involved. In addition, cerebral angiography may be normal early in the clinical course [65]. The angiographic changes are reversible but may persist for days to months. Laboratory testing is usually normal. Cerebrospinal fluid findings are typically without abnormalities, but minor abnormalities can result from ischemic or hemorrhagic strokes. Differential diagnosis The differential diagnosis of postpartum angiopathy and RCVS includes primary angiitis of the central nervous system (PACNS). Findings that favor PACNS rather than postpartum angiopathy associated with pregnancy include an insidious onset of dull headache, stepwise progression of symptoms, spinal fluid abnormalities, and more distal intracranial blood vessels affected on angiography. (See "Primary angiitis of the central nervous system in adults".) Treatment of postpartum angiopathy As with all central nervous system vasculopathy syndromes, there is no proof that any therapeutic intervention is effective for postpartum angiopathy. The syndrome is usually self-limiting. Some patients have received glucocorticoids (especially those with findings that suggest primary angiitis of the central nervous system), calcium channel blockers, and/or magnesium [65]. Progressive deterioration is usually a relatively early finding (within the first few weeks) and may be due to increasing brain edema. Prognosis The prognosis of postpartum angiopathy was thought to be good, but in one of the largest series (n = 18), a complete recovery was achieved by nine patients (50 percent), while a fulminant course followed by death affected four patients (22 percent) [65]. There is no evidence of a high risk of recurrence in future pregnancies [69], although at least one recurrent case has been reported [70], or of an increased risk of eclampsia/preeclampsia in future pregnancies. HYPERCOAGULABLE STATE Pregnancy is a hypercoagulable state that is due, in part, to the progressive increase in resistance to activated protein C in the second and third trimesters, as well as decreased protein S activity, increased fibrinogen, increased factors II, VII, VIII, X, and XII and von Willebrand factor, and increased activity of fibrinolytic inhibitors. (See "Maternal adaptations to pregnancy: Hematologic changes", section on 'Coagulation and fibrinolysis'.) The risk of thrombosis is increased in women with the antiphospholipid syndrome or an inherited thrombophilia, such as factor V Leiden, the prothrombin gene mutation, or a https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 15/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate deficiency of antithrombin, protein C, or protein S. (See "Inherited thrombophilias in pregnancy" and "Antiphospholipid syndrome: Obstetric implications and management in pregnancy".) Anticoagulants and antiplatelet agents have been employed to prevent stroke due to the antiphospholipid syndrome. Pregnant women with the antiphospholipid syndrome are at increased risk for maternal thrombosis and for late fetal loss, early and severe preeclampsia, growth restriction, and possibly recurrent early pregnancy loss. The management of these women is controversial and is discussed elsewhere. (See "Antiphospholipid syndrome: Obstetric implications and management in pregnancy".) The evaluation and management of the inherited thrombophilias is discussed in greater detail separately. (See "Inherited thrombophilias in pregnancy" and "Antithrombin deficiency" and "Protein C deficiency" and "Protein S deficiency" and "Factor V Leiden and activated protein C resistance" and "Prothrombin G20210A" and "Overview of homocysteine".) TTP AND HUS Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are acute syndromes with abnormalities in multiple organ systems that demonstrate microangiopathic hemolytic anemia and thrombocytopenia ( table 4). Clinical features Although some studies distinguish between TTP and HUS, the presenting features are similar in most patients: microangiopathic hemolytic anemia and thrombocytopenia without another apparent cause and, in many patients, neurologic and/or renal abnormalities. Neurologic manifestations can include coma, confusion, seizure, transient ischemic attack, stroke, posterior reversible encephalopathy syndrome (PRES), and headache. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".) Differential When developing during or after pregnancy, TTP and HUS must be distinguished from severe preeclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), which can be accompanied by acute thrombocytopenic disorders that are expected to resolve spontaneously within several days after delivery. The distinction between TTP, HUS, and severe preeclampsia or HELLP is important for therapeutic and prognostic reasons. However, the clinical and histologic features are so similar that establishing the correct diagnosis is often difficult; furthermore, these disorders may occur concurrently. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)" and "Thrombocytopenia in pregnancy".) https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 16/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate Treatment For the majority of patients with suspected TTP during pregnancy, urgent plasma exchange therapy is the appropriate treatment. (See "Immune TTP: Initial treatment", section on 'Immune TTP during pregnancy'.) An exception is a woman with known hereditary TTP or a strong suspicion of hereditary TTP based on hereditary TTP in a sibling. For these individuals, plasma infusion is the appropriate treatment. (See "Hereditary thrombotic thrombocytopenic purpura (hTTP)", section on 'Management of pregnancy'.) For patients with suspected complement-mediated hemolytic uremic syndrome (HUS), which often presents in the postpartum period, the risk for end-stage kidney disease is high. It may be reasonable to initiate anticomplement therapy urgently in order to limit preventable renal damage while the diagnosis is being confirmed (or excluded). (See "Complement-mediated hemolytic uremic syndrome in children", section on 'Complement blockade (eculizumab)'.) Delivery Importantly, unlike preeclampsia and HELLP syndrome, there is no evidence that delivery alters the course of TTP or HUS. If TTP or HUS is the presumptive diagnosis, delivery should only be performed for obstetric reasons. PERIPARTUM CARDIOMYOPATHY Peripartum cardiomyopathy is characterized by the development of systolic heart failure towards the end of pregnancy or in the months following pregnancy, with left ventricular ejection fraction (LVEF) generally less than 45 percent in the absence of another identifiable cause of heart failure. Risk factors include older age, multiple gestation, African descent, and a history of preeclampsia, eclampsia, or postpartum hypertension. Symptoms are similar to those in other forms of heart failure due to cardiomyopathy; left ventricular thrombus with systemic or pulmonary thromboembolism can result. Women with peripartum cardiomyopathy may be at risk for cardioembolic stroke due to the hypercoagulable state of pregnancy and poor cardiac function. (See "Peripartum cardiomyopathy: Etiology, clinical manifestations, and diagnosis".) The treatment of peripartum cardiomyopathy, including anticoagulation for patients with intracardiac thrombus or systemic embolism, is discussed elsewhere. (See "Peripartum cardiomyopathy: Treatment and prognosis".) AMNIOTIC FLUID EMBOLISM https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 17/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate Amniotic fluid embolism is a rare, often catastrophic condition that typically occurs during labor or within 30 minutes postpartum. It is caused by a breach in maternal-fetal interface with entry of amniotic fluid (which contains fetal cells and other antigenic material) into the maternal systemic circulation, which leads to abnormal activation of humoral and immunological processes and release of vasoactive and procoagulant substances. Patients classically develop cardiorespiratory compromise or sudden hypoxia and hypotension, often with noncardiogenic pulmonary edema and hemorrhage due to disseminated intravascular coagulopathy. Neurologic manifestations may include ischemic stroke, seizure, and altered mental status. Persistent neurological impairment has been reported in 6 to 61 percent of survivors [71]. Clinical aspects of amniotic fluid embolism, including management, are reviewed in detail separately. (See "Amniotic fluid embolism".) GESTATIONAL TROPHOBLASTIC DISEASE Gestational trophoblastic disease comprises a heterogeneous group of related lesions arising from abnormal proliferation of trophoblast of the placenta. The maternal lesions arise from fetal, not maternal, tissue. Metastases from gestational trophoblastic neoplasia can involve the brain; patients may be asymptomatic initially, but as the disease progresses, patients develop neurologic signs and symptoms due to increased intracranial pressure or hemorrhage. (See "Gestational trophoblastic neoplasia: Epidemiology, clinical features, diagnosis, staging, and risk stratification".) UNIQUE MANAGEMENT ISSUES Anticoagulation during pregnancy Definitive recommendations for anticoagulant therapy for stroke during pregnancy are difficult because of a lack of applicable studies. In theory, anticoagulation can be given to prevent recurrent thrombosis in hypercoagulable states and to treat cerebral venous thrombosis. (See 'Cerebral venous thrombosis' above.) While there are no randomized controlled trials or epidemiologic studies to guide the duration of anticoagulant therapy, many patients will require anticoagulation throughout the pregnancy and the postpartum period, after which re-evaluation of the need for treatment can take place. We typically reinitiate unfractionated heparin or low molecular weight heparin (LMWH) 4 to 6 hours after vaginal delivery or 6 to 12 hours after Cesarean delivery, unless there was significant intraoperative or postpartum bleeding. https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 18/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate The 2012 American College of Chest Physician (ACCP) guidelines recommend LMWH instead of unfractionated heparin for the prevention and treatment of venous thromboembolism during pregnancy and recommend LMWH instead of vitamin K antagonist treatment antenatally [72]. The ACCP guidelines further suggest that anticoagulant therapy be continued for at least six weeks postpartum, and for a minimum total duration of three months for pregnant women with acute venous thromboembolism. The ACCP guidelines recommend discontinuation of LMWH or unfractionated heparin at least 24 hours before induction of labor, cesarean delivery, or expected time of neuraxial anesthesia [72]. Other approaches to the management of anticoagulation and neuraxial analgesia are reviewed separately. (See "Adverse effects of neuraxial analgesia and anesthesia for obstetrics", section on 'Neuraxial analgesia and the anticoagulated patient'.) Concerns related to the different types of anticoagulants can be summarized as follows: Warfarin is potentially teratogenic when given between the sixth and ninth weeks of gestation. In addition, when given in the second and third trimesters, warfarin can lead to central nervous system abnormalities that are thought to be due to repeated cerebral microhemorrhages. Heparin does not cross the placenta and therefore is not teratogenic and does not anticoagulate the fetus. Concerns with heparin therapy include the relative difficulty of maintaining a stable therapeutic response, the inconvenience of parenteral administration, and the complications of heparin-induced thrombocytopenia and bone demineralization, which can lead to fractures in patients treated for more than six months. LMWH does not cross the placenta. Compared with unfractionated heparin, LMWH has the advantages of producing a more predictable anticoagulant response to fixed doses administered once or twice daily and is less likely to produce thrombocytopenia or possibly bone demineralization. Issues related to anticoagulation in pregnant women are discussed in detail elsewhere. (See "Use of anticoagulants during pregnancy and postpartum".) Stroke remote from term When stroke occurs in a pregnant woman who is <24 weeks of gestation, the stroke should be managed as dictated by the patient's clinical condition. Every effort should be made to protect the salvageable brain tissue, prevent medical complications (eg, aspiration), control maternal physiologic factors that may worsen the stroke, such as blood pressure, and facilitate long-term physical rehabilitation. Pregnancy termination is an option if thrombolytic therapy is being considered. https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 19/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate As mentioned earlier, some women with ischemic stroke or cerebral venous thrombosis will require anticoagulation throughout the pregnancy. (See 'Anticoagulation during pregnancy' above.) Stroke near term For women who have a stroke between 24 and 32 weeks gestation, antenatal glucocorticoids can be administered to accelerate fetal lung maturation. A multidisciplinary approach in consultation with neurology, neurosurgery, anesthesia, neonatology, and perinatology should take place to stabilize the mother and assess fetal status. As long as maternal and fetal well-being are not deteriorating, plans can be made to continue the pregnancy with a scheduled controlled delivery between 34 to 39 weeks gestation to optimize fetal outcome. For pregnant women diagnosed with ischemic stroke or cerebral venous sinus thrombosis, anticoagulation with unfractionated heparin, LMWH, or antiplatelet therapy with aspirin should be considered in consultation with neurologists throughout the remainder of the pregnancy. (See 'Anticoagulation during pregnancy' above.) After 36 weeks of pregnancy, LMWH can be changed over to unfractionated heparin until a scheduled labor induction at 39 weeks can take place, and LMWH can resume in the postpartum period. Aspirin should be stopped within one week of a planned delivery (ie, induction of labor or cesarean delivery). Breastfeeding A small fraction of iodinated or gadolinium contrast agents is secreted in maternal milk. Based upon these data, women who require neurovascular imaging should discontinue breastfeeding for 24 hours after receiving intravenous contrast media and discard milk expressed during that interval before resuming normal breastfeeding. There are no contraindications to breastfeeding while being treated with unfractionated heparin or LMWH. Similarly, nursing mothers can safely take warfarin because there is no convincing evidence that warfarin exerts an anticoagulant effect on the breast-fed infant. FUTURE PREGNANCY Counseling When counseling women with a prior history of stroke, it is important to obtain a detailed history of the etiology of and the circumstances surrounding the stroke to determine the stroke type (ischemic/thrombotic or hemorrhagic) and underlying mechanism. This classification will help to guide management for the impending pregnancy. Consultation with a neurologist, hematologist, or neurosurgeon may also be indicated prior to attempting conception to optimize pregnancy outcomes. https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 20/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate Risk of recurrent stroke For most women with prior stroke during pregnancy, the recurrence rate during a subsequent pregnancy and postpartum period is low ( 1 percent), particularly if any causative vascular lesions have been repaired [73-76]. However, data are sparse, and the risk in future pregnancies varies depending upon the cause of the initial stroke. Ischemic stroke The risk of recurrent ischemic stroke is low. This was illustrated in a review of 441 women with a history of ischemic stroke (373 with arterial ischemic stroke and 68 with cerebral venous thrombosis); during a mean follow-up of five years, there were 13 recurrent arterial ischemic strokes and no recurrences of cerebral venous thrombosis [74]. The overall risk of recurrence was 1 percent at one year and 2.3 percent at five years. The risk of recurrence during pregnancy or the puerperium was 1.8 percent (not significantly different from outside pregnancy), but the relative risk of recurrence was significantly higher during the postpartum period (risk ratio 9.7, 95% CI 1.2-78.9). The outcome of the 187 subsequent pregnancies was similar to that expected from the general population. The authors concluded that a previous ischemic stroke is not a contraindication to a subsequent pregnancy. Hypercoagulable states Few studies have examined recurrence after pregnancy-related stroke associated with hypercoagulable states. One report evaluated 12 women with a previous cerebrovascular event (infarction, transient ischemic attack, or amaurosis fugax) in the setting of thrombophilia [77]. In 15 subsequent pregnancies, there were four thromboembolic events, including two amaurosis fugax, one transient ischemic attack, and one cerebral infarction. None of the patients had persistent neurologic deficits. CVT There are insufficient data to assess the risk of recurrent cerebral venous sinus thrombosis (CVT), and the role of antithrombotic prophylaxis during subsequent pregnancies is unproven in women with a history of CVT. There is no consensus regarding this issue. Many experts believe that antithrombotic prophylaxis during pregnancy is probably unnecessary unless a prothrombotic condition or a previous thromboembolism (ie, a previous CVT or deep venous thrombosis before the index CVT) has been identified. However, other experts would prefer to treat with intravenous heparin or subcutaneous low molecular weight heparin starting during the late third trimester and continuing for up to eight weeks postpartum. (See "Cerebral venous thrombosis: Treatment and prognosis", section on 'Subsequent pregnancy'.) Untreated AVMs Untreated brain arteriovenous malformations (AVMs) are prone to rebleeding whether or not the patient becomes pregnant. In one study, the annual rate of recurrent hemorrhage in women with a brain AVM was estimated to be 31 percent in the first year following an initial hemorrhage and 6 percent in subsequent years [78]. https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 21/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate Therefore, brain AVMs should be definitively treated by surgical excision or endovascular embolization in women before reattempting pregnancy, if possible. (See "Vascular malformations of the central nervous system" and "Brain arteriovenous malformations", section on 'Acute management issues'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults" and "Society guideline links: Anticoagulation in pregnancy".) SUMMARY AND RECOMMENDATIONS Incidence Pregnant or recently pregnant women have a higher incidence of stroke (incidence 30 per 100,000 pregnancies) compared with their nonpregnant counterparts. The third trimester of pregnancy and the postpartum period are associated with a marked increase in the relative risk and a small increase in the absolute risk of stroke. (See 'Epidemiology' above.) Evaluation All patients with suspected acute stroke require an urgent evaluation. An imaging study of the brain is an essential component of the evaluation. A head computed tomography (CT) scan is both informative and readily available. However, brain magnetic resonance imaging (MRI) is more sensitive than CT for the detection of early infarction, small infarcts, cerebral venous thrombosis, and structural lesions (eg, cavernous malformations). Etiologies The most common causes of hemorrhagic stroke in pregnancy are preeclampsia/eclampsia, arteriovenous malformations, and aneurysms. The most common causes of ischemic stroke are cerebral venous sinus thrombosis, preeclampsia/eclampsia, and cardiogenic embolism. The main causes of stroke and stroke-like episodes in pregnancy are listed in the table ( table 1). (See 'Stroke subtypes' above.) Acute ischemic stroke For eligible patients with acute ischemic stroke, intravenous alteplase administration may be considered in pregnancy when the anticipated benefits outweigh the anticipated increased risks of uterine bleeding. Eligible patients should be treated as quickly as possible within the appropriate 3- or 4.5-hour time window from time last known well. Mechanical thrombectomy is indicated for selected patients with acute https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 22/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate ischemic stroke caused by an intracranial large artery occlusion in the proximal anterior circulation who can be treated within 24 hours of the time last known to be well. Cerebral venous thrombosis The treatment of symptomatic cerebral venous thrombosis, with or without hemorrhagic venous infarction, is anticoagulation therapy with intravenous heparin or subcutaneous low molecular weight heparin. Intracranial hemorrhage Subarachnoid and/or intracerebral hemorrhage due to aneurysmal rupture or bleeding from a vascular malformation can be managed by surgical (ie, clipping) or endovascular (eg, embolization) treatment of the causative lesion. (See 'Intracranial hemorrhage' above.) Preeclampsia/eclampsia/HELLP Preeclampsia/eclampsia and HELLP (hemolysis, elevated liver enzymes, and low platelets) are among the most common causes of both ischemic infarction and hemorrhagic stroke in pregnancy. Management goals are to stabilize the mother, prevent recurrent convulsions, treat severe hypertension to reduce or prevent cerebral edema and hemorrhage, and initiate prompt delivery. (See 'Preeclampsia, eclampsia, and HELLP' above.) RCVS/postpartum angiopathy Postpartum angiopathy is one type of a group of reversible cerebral vasoconstriction syndromes (RCVS) characterized by thunderclap headache and diffuse, segmental, reversible cerebral vasospasm. Some patients develop neurologic symptoms (eg, visual disturbance, hemiplegia, dysarthria, aphasia, ataxia, seizure, and encephalopathy). With severe cases, intraparenchymal hemorrhage, subarachnoid hemorrhage, or ischemic stroke may result. No therapeutic intervention has been proven effective. The syndrome is usually self-limiting. (See 'RCVS/postpartum angiopathy' above.) Other causes Several other causes of stroke and cerebrovascular events during pregnancy and postpartum are reviewed above: Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome (see 'TTP and HUS' above) Peripartum cardiomyopathy (see 'Peripartum cardiomyopathy' above) Amniotic fluid embolism (see 'Amniotic fluid embolism' above) Gestational trophoblastic disease (see 'Gestational trophoblastic disease' above) Recurrence risk The risk of recurrent stroke in future pregnancy is probably low, but data are sparse. (See 'Risk of recurrent stroke' above.) https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 23/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Swartz RH, Cayley ML, Foley N, et al. 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13. Wabnitz A, Bushnell C. Migraine, cardiovascular disease, and stroke during pregnancy: systematic review of the literature. Cephalalgia 2015; 35:132. 14. Skeith L, Carrier M, Robinson SE, et al. Risk of venous thromboembolism in pregnant women with essential thrombocythemia: a systematic review and meta-analysis. Blood 2017; 129:934. https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 24/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate 15. Camargo EC, Feske SK, Singhal AB. Stroke in Pregnancy: An Update. Neurol Clin 2019; 37:131. 16. Camargo EC, Singhal AB. Stroke in Pregnancy: A Multidisciplinary Approach. Obstet Gynecol Clin North Am 2021; 48:75. 17. Hung SK, Lee MS, Lin HY, et al. Impact of Hypertensive Disorders of Pregnancy on the Risk of Stroke Stratified by Subtypes and Follow-Up Time. Stroke 2022; 53:338. 18. Mas JL, Lamy C. Stroke in pregnancy and the puerperium. J Neurol 1998; 245:305. 19. Cauldwell M, Rudd A, Nelson-Piercy C. Management of stroke and pregnancy. Eur Stroke J 2018; 3:227. 20. Kupferminc MJ, Yair D, Bornstein NM, et al. Transient focal neurological deficits during pregnancy in carriers of inherited thrombophilia. Stroke 2000; 31:892. 21. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. 22. De Keyser J, Gdovinov Z, Uyttenboogaart M, et al. Intravenous alteplase for stroke: beyond the guidelines and in particular clinical situations. Stroke 2007; 38:2612. 23. Selim MH, Molina CA. The use of tissue plasminogen-activator in pregnancy: a taboo treatment or a time to think out of the box. Stroke 2013; 44:868. 24. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scientific Rationale for the Inclusion and Exclusion Criteria for Intravenous Alteplase in Acute Ischemic Stroke: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2016; 47:581. 25. Activase (alteplase) prescribing information. https://www.accessdata.fda.gov/drugsatfda_do cs/label/2018/103172s5259lbl.pdf (Accessed on October 25, 2021). 26. Murugappan A, Coplin WM, Al-Sadat AN, et al. Thrombolytic therapy of acute ischemic stroke during pregnancy. Neurology 2006; 66:768. 27. Leonhardt G, Gaul C, Nietsch HH, et al. Thrombolytic therapy in pregnancy. J Thromb Thrombolysis 2006; 21:271. 28. Leffert LR, Clancy CR, Bateman BT, et al. Treatment patterns and short-term outcomes in ischemic stroke in pregnancy or postpartum period. Am J Obstet Gynecol 2016; 214:723.e1. 29. Dicpinigaitis AJ, Sursal T, Morse CA, et al. Endovascular Thrombectomy for Treatment of Acute Ischemic Stroke During Pregnancy and the Early Postpartum Period. Stroke 2021; 52:3796. https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 25/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate 30. Lansberg MG, O'Donnell MJ, Khatri P, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e601S. 31. Sibai BM, Caritis SN, Thom E, et al. Prevention of preeclampsia with low-dose aspirin in healthy, nulliparous pregnant women. The National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med 1993; 329:1213. 32. Duley L, Henderson-Smart D, Knight M, King J. Antiplatelet drugs for prevention of pre- eclampsia and its consequences: systematic review. BMJ 2001; 322:329. 33. Jeng JS, Tang SC, Yip PK. Incidence and etiologies of stroke during pregnancy and puerperium as evidenced in Taiwanese women. Cerebrovasc Dis 2004; 18:290. 34. Silvis SM, Lindgren E, Hiltunen S, et al. Postpartum Period Is a Risk Factor for Cerebral Venous Thrombosis. Stroke 2019; 50:501. 35. Cantu-Brito C, Arauz A, Aburto Y, et al. Cerebrovascular complications during pregnancy and postpartum: clinical and prognosis observations in 240 Hispanic women. Eur J Neurol 2011; 18:819. 36. Skidmore FM, Williams LS, Fradkin KD, et al. Presentation, etiology, and outcome of stroke in pregnancy and puerperium. J Stroke Cerebrovasc Dis 2001; 10:1. 37. Witlin AG, Friedman SA, Egerman RS, et al. Cerebrovascular disorders complicating pregnancy beyond eclampsia. Am J Obstet Gynecol 1997; 176:1139. 38. Liang CC, Chang SD, Lai SL, et al. Stroke complicating pregnancy and the puerperium. Eur J Neurol 2006; 13:1256. 39. Saposnik G, Barinagarrementeria F, Brown RD Jr, et al. Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011; 42:1158. 40. Bushnell C, McCullough LD, Awad IA, et al. Guidelines for the prevention of stroke in women: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014; 45:1545. 41. Miller EC, Leffert L. Stroke in Pregnancy: A Focused Update. Anesth Analg 2020; 130:1085. 42. Marshman LA, Aspoas AR, Rai MS, Chawda SJ. The implications of ISAT and ISUIA for the management of cerebral aneurysms during pregnancy. Neurosurg Rev 2007; 30:177. 43. Fox MW, Harms RW, Davis DH. Selected neurologic complications of pregnancy. Mayo Clin Proc 1990; 65:1595. https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 26/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate 44. Salonen Ros H, Lichtenstein P, Bellocco R, et al. Increased risks of circulatory diseases in late pregnancy and puerperium. Epidemiology 2001; 12:456. 45. Tiel Groenestege AT, Rinkel GJ, van der Bom JG, et al. The risk of aneurysmal subarachnoid hemorrhage during pregnancy, delivery, and the puerperium in the Utrecht population: case-crossover study and standardized incidence ratio estimation. Stroke 2009; 40:1148. 46. Horton JC, Chambers WA, Lyons SL, et al. Pregnancy and the risk of hemorrhage from cerebral arteriovenous malformations. Neurosurgery 1990; 27:867. 47. Liu XJ, Wang S, Zhao YL, et al. Risk of cerebral arteriovenous malformation rupture during pregnancy and puerperium. Neurology 2014; 82:1798. 48. Gross BA, Du R. Hemorrhage from arteriovenous malformations during pregnancy. Neurosurgery 2012; 71:349. 49. Porras JL, Yang W, Philadelphia E, et al. Hemorrhage Risk of Brain Arteriovenous Malformations During Pregnancy and Puerperium in a North American Cohort. Stroke 2017; 48:1507. 50. Dias MS, Sekhar LN. Intracranial hemorrhage from aneurysms and arteriovenous malformations during pregnancy and the puerperium. Neurosurgery 1990; 27:855. 51. POOL JL. TREATMENT OF INTRACRANIAL ANEURYSMS DURING PREGNANCY. JAMA 1965; 192:209. 52. Qaiser R, Black P. Neurosurgery in pregnancy. Semin Neurol 2007; 27:476. 53. Tarnaris A, Haliasos N, Watkins LD. Endovascular treatment of ruptured intracranial aneurysms during pregnancy: is this the best way forward? Case report and review of the literature. Clin Neurol Neurosurg 2012; 114:703. 54. Pumar JM, Pardo MI, Carreira JM, et al. Endovascular treatment of an acutely ruptured intracranial aneurysm in pregnancy: report of eight cases. Emerg Radiol 2010; 17:205. 55. Meyers PM, Halbach VV, Malek AM, et al. Endovascular treatment of cerebral artery aneurysms during pregnancy: report of three cases. AJNR Am J Neuroradiol 2000; 21:1306. 56. Piotin M, de Souza Filho CB, Kothimbakam R, Moret J. Endovascular treatment of acutely ruptured intracranial aneurysms in pregnancy. Am J Obstet Gynecol 2001; 185:1261. 57. Davie CA, O'Brien P. Stroke and pregnancy. J Neurol Neurosurg Psychiatry 2008; 79:240. 58. Stoodley MA, Macdonald RL, Weir BK. Pregnancy and intracranial aneurysms. Neurosurg Clin N Am 1998; 9:549. 59. Dashti SR, Spalding AC, Yao TL. Multimodality treatment of a ruptured grade IV posterior fossa arteriovenous malformation in a patient pregnant with twins: case report. J Neurointerv Surg 2012; 4:e21. https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 27/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate 60. Jermakowicz WJ, Tomycz LD, Ghiassi M, Singer RJ. Use of endovascular embolization to treat a ruptured arteriovenous malformation in a pregnant woman: a case report. J Med Case Rep 2012; 6:113. 61. Martin JN Jr, Thigpen BD, Moore RC, et al. Stroke and severe preeclampsia and eclampsia: a paradigm shift focusing on systolic blood pressure. Obstet Gynecol 2005; 105:246. 62. McDermott M, Miller EC, Rundek T, et al. Preeclampsia: Association With Posterior Reversible Encephalopathy Syndrome and Stroke. Stroke 2018; 49:524. 63. Singhal AB, Bernstein RA. Postpartum angiopathy and other cerebral vasoconstriction syndromes. Neurocrit Care 2005; 3:91. 64. Bakhru A, Atlas RO. A case of postpartum cerebral angiitis and review of the literature. Arch Gynecol Obstet 2011; 283:663. 65. Fugate JE, Ameriso SF, Ortiz G, et al. Variable presentations of postpartum angiopathy. Stroke 2012; 43:670. 66. Singhal AB. Postpartum angiopathy with reversible posterior leukoencephalopathy. Arch Neurol 2004; 61:411. 67. Fletcher JJ, Kramer AH, Bleck TP, Solenski NJ. Overlapping features of eclampsia and postpartum angiopathy. Neurocrit Care 2009; 11:199. 68. Fugate JE, Wijdicks EF, Parisi JE, et al. Fulminant postpartum cerebral vasoconstriction syndrome. Arch Neurol 2012; 69:111. 69. R mi J, Pfefferkorn T, Fesl G, et al. Uncomplicated pregnancy and delivery after previous severe postpartum cerebral angiopathy. Case Rep Neurol 2011; 3:252. 70. Ursell MR, Marras CL, Farb R, et al. Recurrent intracranial hemorrhage due to postpartum cerebral angiopathy: implications for management. Stroke 1998; 29:1995. 71. Piva I, Scutiero G, Greco P. Amniotic Fluid Embolism: An Update of the Evidence. Med Toxicol Clin Forens Med 2016; 2:2. 72. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e419S. 73. Sibai BM, Coppage KH. Diagnosis and management of women with stroke during pregnancy/postpartum. Clin Perinatol 2004; 31:853. 74. Lamy C, Hamon JB, Coste J, Mas JL. Ischemic stroke in young women: risk of recurrence during subsequent pregnancies. French Study Group on Stroke in Pregnancy. Neurology 2000; 55:269. https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 28/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate 75. Coppage KH, Hinton AC, Moldenhauer J, et al. Maternal and perinatal outcome in women with a history of stroke. Am J Obstet Gynecol 2004; 190:1331. 76. Cruz-Herranz A, Ill n-Gala I, Mart nez-S nchez P, et al. Recurrence of stroke amongst women of reproductive age: impact of and on subsequent pregnancies. Eur J Neurol 2015; 22:681. 77. Soriano D, Carp H, Seidman DS, et al. Management and outcome of pregnancy in women with thrombophylic disorders and past cerebrovascular events. Acta Obstet Gynecol Scand 2002; 81:204. 78. Mast H, Young WL, Koennecke HC, et al. Risk of spontaneous haemorrhage after diagnosis of cerebral arteriovenous malformation. Lancet 1997; 350:1065. Topic 1108 Version 49.0 https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 29/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate GRAPHICS Causes of stroke or stroke-like events in pregnancy Hematologic Essential thrombocythemia Sickle cell disease Thrombophilias (inherited or acquired) Thrombotic thrombocytopenic purpura Cardiac Valvular abnormalities Arrhythmias, especially atrial fibrillation Cardiomyopathy Infective endocarditis Patent foramen ovale Atrial septal defect Vascular Aneurysms Arteriovenous malformations Vasculopathy (eg, moyamoya disease or syndrome, Takayasu arteritis) Cervical artery dissection Atherosclerotic steno-occlusive cerebrovascular disease Reversible cerebral vasoconstriction syndrome (RCVS) Posterior reversible encephalopathy syndrome (PRES) Cerebral venous thrombosis Pregnancy related disorders Preeclampsia, eclampsia, and HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome Peripartum cardiomyopathy Amniotic fluid embolism Air embolism caused by caesarean delivery, uterine manipulation, central venous catheterization, or sexual activity Gestational trophoblastic disease https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 30/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate Graphic 60303 Version 8.0 https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 31/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate Acute stroke differential diagnosis Migraine aura Seizure with postictal paresis (Todd paralysis), aphasia, or neglect Central nervous system tumor or abscess Cerebral venous thrombosis Functional deficit (conversion reaction) Hypertensive encephalopathy Head trauma Mitochondrial disorder (eg, mitochondrial encephalopathy with lactic acidosis and stroke-like episodes or MELAS) Multiple sclerosis Posterior reversible encephalopathy syndrome (PRES) Reversible cerebral vasoconstriction syndromes (RCVS) Spinal cord disorder (eg, compressive myelopathy, spinal dural arteriovenous fistula) Subdural hematoma Syncope Systemic infection Toxic-metabolic disturbance (eg, hypoglycemia, exogenous drug intoxication) Transient global amnesia Viral encephalitis (eg, herpes simplex encephalitis) Wernicke encephalopathy Graphic 69869 Version 7.0 https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 32/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate Eligibility criteria for the treatment of acute ischemic stroke with intravenous thrombolysis (recombinant tissue plasminogen activator or tPA) Inclusion criteria Clinical diagnosis of ischemic stroke causing measurable neurologic deficit Onset of symptoms <4.5 hours before beginning treatment; if the exact time of stroke onset is not known, it is defined as the last time the patient was known to be normal or at neurologic baseline Age 18 years Exclusion criteria Patient history Ischemic stroke or severe head trauma in the previous three months Previous intracranial hemorrhage Intra-axial intracranial neoplasm Gastrointestinal malignancy Gastrointestinal hemorrhage in the previous 21 days Intracranial or intraspinal surgery within the prior three months Clinical Symptoms suggestive of subarachnoid hemorrhage Persistent blood pressure elevation (systolic 185 mmHg or diastolic 110 mmHg) Active internal bleeding Presentation consistent with infective endocarditis Stroke known or suspected to be associated with aortic arch dissection Acute bleeding diathesis, including but not limited to conditions defined under 'Hematologic' Hematologic 3 Platelet count <100,000/mm * Current anticoagulant use with an INR >1.7 or PT >15 seconds or aPTT >40 seconds* Therapeutic doses of low molecular weight heparin received within 24 hours (eg, to treat VTE and ACS); this exclusion does not apply to prophylactic doses (eg, to prevent VTE) Current use (ie, last dose within 48 hours in a patient with normal renal function) of a direct thrombin inhibitor or direct factor Xa inhibitor with evidence of anticoagulant effect by laboratory tests such as aPTT, INR, ECT, TT, or appropriate factor Xa activity assays Head CT Evidence of hemorrhage https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 33/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate Extensive regions of obvious hypodensity consistent with irreversible injury Warnings Only minor and isolated neurologic signs or rapidly improving symptoms Serum glucose <50 mg/dL (<2.8 mmol/L) Serious trauma in the previous 14 days Major surgery in the previous 14 days History of gastrointestinal bleeding (remote) or genitourinary bleeding Seizure at the onset of stroke with postictal neurologic impairments Pregnancy** Arterial puncture at a noncompressible site in the previous seven days Large ( 10 mm), untreated, unruptured intracranial aneurysm Untreated intracranial vascular malformation Additional warnings for treatment from 3 to 4.5 hours from symptom onset Age >80 years Oral anticoagulant use regardless of INR Severe stroke (NIHSS score >25) Combination of both previous ischemic stroke and diabetes mellitus ACS: acute coronary syndrome; aPTT: activated partial thromboplastin time; ECT: ecarin clotting time; INR: international normalized ratio; PT: prothrombin time; NIHSS: National Institutes of Health Stroke Scale; tPA: intravenous alteplase; TT: thrombin time; VTE: venous thromboembolism. Although it is desirable to know the results of these tests, thrombolytic therapy should not be delayed while results are pending unless (1) there is clinical suspicion of a bleeding abnormality or thrombocytopenia, (2) the patient is currently on or has recently received anticoagulants (eg, heparin, warfarin, a direct thrombin inhibitor, or a direct factor Xa inhibitor), or (3) use of anticoagulants is not known. Otherwise, treatment with intravenous tPA can be started before availability of coagulation test results but should be discontinued if the INR, PT, or aPTT exceed the limits stated in the table, or 3 if platelet count is <100,000 mm . With careful consideration and weighting of risk-to-benefit, patients may receive intravenous alteplase despite one or more warnings. Patients who have a persistent neurologic deficit that is potentially disabling, despite improvement of any degree, should be treated with tPA in the absence of other contraindications. Any of the following should be considered disabling deficits: Complete hemianopia: 2 on NIHSS question 3, or Severe aphasia: 2 on NIHSS question 9, or Visual or sensory extinction: 1 on NIHSS question 11, or Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6, or Any deficits that lead to a total NIHSS >5, or https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 34/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate Any remaining deficit considered potentially disabling in the view of the patient and the treating practitioner using clinical judgment Patients may be treated with intravenous alteplase if glucose level is subsequently normalized. The potential risks of bleeding with alteplase from injuries related to the trauma should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. The increased risk of surgical site bleeding with alteplase should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. There is a low increased risk of new bleeding with alteplase in the setting of past gastrointestinal or genitourinary bleeding. However, alteplase administration within 21 days of gastrointestinal bleeding is not recommended. Alteplase is reasonable in patients with a seizure at stroke onset if evidence suggests that residual impairments are secondary to acute ischemic stroke and not to a postictal phenomenon. * Alteplase can be given in pregnancy when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding. The safety and efficacy of administering alteplase is uncertain for these relative exclusions. Although these were exclusions in the trial showing benefit in the 3 to 4.5 hour window, intravenous alteplase appears to be safe and may be beneficial for patients with these criteria, including patients taking oral anticoagulants with an INR <1.7. Adapted from: 1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359:1317. 2. Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke Association. Stroke 2009; 40:2945. 3. Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force:, Levine SR, Khatri P, et al. Review, historical context, and clari cations of the NINDS rt-PA stroke trials exclusion criteria: Part 1: rapidly improving stroke symptoms. Stroke 2013; 44:2500. 4. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scienti c rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2016; 47:581. 5. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. Graphic 71462 Version 26.0 https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 35/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate Brain MRI of a 33-year-old woman with postpartum angiopathy (reversible cerebral vasoconstriction syndrome) Head MRI axial cuts: FLAIR (A, B, E, F) and apparent diffusion coefficient map (C, D, G, H) sequences. Upper panel MRI, performed on admission, showed FLAIR hyperintensities and diffusion restriction in the right parietal lobe and in the splenium of the corpus callosum (arrows). Lower panel, done on hospital day 3 when the patient deteriorated, showed worsening bilateral lesions involving the cortex and subcortical white matter of the parietal, posterior frontal, and occipital lobes (arrows). MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery. Reproduced with permission from: Maalouf N, Harik SI. Clinical reasoning: A 33-year-old woman with severe postpartum occipital headaches. Neurology 2012; 78:366. Copyright 2012 Lippincott Williams & Wilkins. Graphic 77149 Version 7.0 https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 36/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate CTA showing segmental narrowing of intracranial vessels in a 33 year old woman with postpartum angiopathy (reversible cerebral vasoconstriction syndrome) Head CT angiography (CTA) six days after onset of postpartum occipital headache reveals segmental narrowing of the left middle cerebral artery and the A1 segment of the right anterior cerebral artery (panel A, arrows); in addition, there is segmental narrowing of the posterior cerebral and left distal vertebral arteries with broad narrowing of the basilar artery (panel B, arrows). Head magnetic resonance angiography (MRA) two months after discharge shows complete reversal of arterial pathology (panels C and D). The magnification is similar in all parts of the figure; the white vertical band denotes 5 cm. CT: computed tomography. Reproduced with permission from: Maalouf N, Harik SI. Clinical reasoning: A 33-year-old woman with severepostpartum occipital headaches. Neurology 2012; 78:366. Copyright 2012 Lippincott Williams & Wilkins. Graphic 64318 Version 7.0 https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 37/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate TMA syndromes and other systemic disorders associated with microangiopathic hemolytic anemia (MAHA) and thrombocytopenia Syndrome Clinical features Laboratory findings Primary thrombotic microangiopathy (TMA) syndromes Thrombotic thrombocytopenic May have severe neurologic abnormalities. Severe MAHA and thrombocytopenia; acute kidney injury is rare. purpura (TTP) Inherited; may present in a newborn Severe deficiency of ADAMTS13 infant, a child with thrombocytopenia, or, less (activity <10%). Acquired cases often have a detectable ADAMTS13 commonly, an adult. Among adults, a inhibitor (autoantibody). common presentation is during a first pregnancy. Inherited TTP has ADAMTS13 gene mutation. Acquired autoimmune: Uncommon in children. Complement- mediated TMA Inherited and acquired disorders may present in children or adults. Renal failure is prominent. Inherited disorders usually have a heterozygous mutation in a gene encoding a regulatory protein in the alternate complement pathway (eg, CFH, CFI, CD46/MCP, C3, CFB, CFHRs). Acquired disorder has antibodies to complement factor H or I. Shiga toxin- Abdominal pain; diarrhea (often Renal failure is prominent. Stool may mediated hemolytic uremic bloody); possible history of outbreak or exposure to livestock be positive for the organism (Escherichia coli or Shigella dysenteriae) syndrome (ST- HUS) or contaminated food, although most cases are sporadic. or Shiga toxin. Drug-induced History of exposure to quinine or Immune mediated: Severe acute TMA other implicated medication. kidney injury; drug-dependent Immune-mediated forms have an abrupt onset with fever, chills, antibodies to platelets and/or neutrophils can be demonstrated. abdominal pain, nausea, anuric acute kidney injury. Toxic, dose-related Toxic, dose related: May have gradual or sudden onset of renal failure and hypertension. etiologies may arise gradually, or onset may be sudden with an intravenous toxic agent (eg, Opana- ER). Coagulation- Inherited, typically presents in DGKE, thrombomodulin, or mediated TMA children <1 year old. plasminogen gene mutation. https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 38/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate Metabolism- Inherited, typically presents in Elevated serum homocysteine and mediated TMA children <1 year old, but may also present in adults. methylmalonic acid, and low methionine levels; increased urinary methyl-malonic acid. MMACHC gene mutation. Systemic disorders that may present with MAHA and thrombocytopenia Disseminated May be caused by infection, Thrombocytopenia, decreased intravascular coagulation (DIC) malignancy, postpartum hemorrhage with hypotension, or a vascular fibrinogen, and elevated D-dimer are typical with acute or chronic DIC. abnormality such as a giant MAHA may occur. Prolongation of the hemangioma (eg, Kasabach-Merritt syndrome). PT and aPTT are seen in acute DIC. Systemic infection May include bacterial, viral, rickettsial, or fungal organisms. High fever and shaking chills are common. Systemic May occur with occult systemic Depends on specific tumor. malignancy malignancy. Breast, prostate, lung, pancreatic, or gastrointestinal tumors are often responsible. Pregnancy-related Typically present in third trimester or Elevated hepatic transaminases. syndromes (eg, severe postpartum. Severe hypertension and liver involvement are often present. Acute kidney injury is uncommon. preeclampsia, HELLP) Abnormalities resolve with delivery. Severe Typically, systolic BP >200 mm Hg and Often associated with severe renal hypertension diastolic BP >100 mm Hg. Neurologic features including PRES may be failure. Renal biopsy demonstrates TMA identical to the primary TMA present. Hypertension may also occur syndromes. in primary TMAs with severe renal involvement, so the temporal relationship is important. Abnormalities resolve with control of the BP. Systemic rheumatic SLE may be associated with hypertension, renal insufficiency, and Serologic testing may show autoantibodies characteristic of the diseases (eg, SLE, autoimmune cytopenias. APS typically underlying condition; APS may have SSc, APS) presents with arterial and/or venous thromboembolism but can also prolonged aPTT. Renal biopsy may demonstrate TMA identical to the produce a TMA. primary TMA syndromes. Hematopoietic cell transplant May occur with autologous or allogeneic transplant. May be No specific findings. associated with exposure to cytotoxic https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 39/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate chemotherapy, radiation, systemic infection, or a calcineurin inhibitor. Solid organ May be associated with calcineurin Renal biopsy may have features of transplant inhibitor administration. May be rejection. associated with infection such as CMV in the setting of immunosuppression. In patients receiving a kidney transplant for a primary TMA syndrome, the syndrome may recur in the transplanted kidney. Therapy for primary TMAs is directed at the underlying pathophysiology; therapy for other systemic disorders associated with MAHA and thrombocytopenia is focused on the underlying disorder. Refer to UpToDate topics on evaluating patients with suspected TMA and on specific syndromes for additional information on presentation/diagnosis and management. TMA: thrombotic microangiopathy; ADAMTS13: A Disintegrin And Metalloprotease with a ThromboSpondin type 1 motif, member 13; DGKE: diacylglycerol kinase epsilon; HELLP: hemolysis, elevated liver function tests, and low platelets; BP: blood pressure; PRES: posterior reversible encephalopathy; SLE: systemic lupus erythematosus; SSc: systemic sclerosis (scleroderma); APS: antiphospholipid syndrome; CMV: cytomegalovirus; PT: prothrombin time; aPTT: activated partial thromboplastin time. Modi ed from: George JN, Nester CM. Syndromes of thrombotic microangiopathy. N Eng J Med 2014; 371:654. Graphic 100722 Version 5.0 https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 40/41 7/5/23, 12:04 PM Cerebrovascular disorders complicating pregnancy - UpToDate Contributor Disclosures Susan Hickenbottom, MD, MS No relevant financial relationship(s) with ineligible companies to disclose. Men-Jean Lee, MD No relevant financial relationship(s) with ineligible companies to disclose. Jos Biller, MD, FACP, FAAN, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Charles J Lockwood, MD, MHCM No relevant financial relationship(s) with ineligible companies to disclose. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy/print 41/41

7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Complications of stroke: An overview : Koto Ishida, MD : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 19, 2023. INTRODUCTION Complications of acute stroke are common. They increase the risk of poor clinical outcomes. Preventative strategies and treatments are available and should be used when appropriate. The prognosis of stroke is reviewed separately: (See "Overview of ischemic stroke prognosis in adults".) (See "Lacunar infarcts", section on 'Prognosis'.) (See "Intracranial large artery atherosclerosis: Treatment and prognosis", section on 'Prognosis'.) (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Prognosis'.) (See "Stroke after cardiac catheterization", section on 'Prognosis'.) (See "Ischemic stroke in children: Management and prognosis", section on 'Prognosis'.) (See "Stroke in the newborn: Management and prognosis", section on 'Prognosis'.) (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Early prognosis'.) (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Prognosis'.) MEDICAL COMPLICATIONS https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 1/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate The rates of reported medical complications of stroke are high ( table 1 and table 2) [1-5]. Serious complications include pneumonia, urinary tract infection, gastrointestinal bleeding, myocardial infarction, deep vein thrombosis, and pulmonary embolism. Incidence rates and populations vary across studies, but improving care may be reducing some complication rates. In one prospective longitudinal study, the frequency of one or more medical complications within the first week after stroke declined from 2003 to 2013 by 36 percent [6]. In an analysis from the United States of the 2007-2019 National Inpatient Sample database of over 5,750,000 adults admitted with a primary diagnosis of acute ischemic stroke, infectious complications decreased while noninfectious complications increased over the study period [7]. The presence of any in-hospital medical complication, many of which are preventable, has been associated with a significantly increased risk for 30-day readmission (adjusted hazard ratio 1.68; 95% CI 1.04-2.73) [8]. Dysphagia Dysphagia is a common complication of stroke and is a major risk factor for developing aspiration pneumonia. Dysphagia related to stroke is more precisely characterized as oropharyngeal dysphagia, defined by swallowing impairment of the upper digestive tract. This definition has been extended to capture impairments in swallowing efficiency and safety, including delays in the timing of movements, reduced range of movements, and frank aspiration [9]. Aspiration in this population is usually a sign of severe dysphagia, and refers to abnormal entry of fluid, particulate exogenous substances, or endogenous secretions into the airways. These observations are supported by a systematic review of 24 studies that evaluated oropharyngeal dysphagia and aspiration in adult patients with stroke [9]. In pooled analysis of studies with sufficient data, the risk of pneumonia was increased with dysphagia compared with no dysphagia (relative risk [RR] 3.17, 95% CI 2.07-4.87) and especially with aspiration compared with no aspiration (RR 11.56, 95% CI 3.36-39.77). The incidence of dysphagia after stroke was lowest when identified by screening methods, mainly water swallow (37 to 45 percent) [9]. The incidence was intermediate when identified by a trained swallowing clinician (51 to 55 percent), and it was highest when identified by instrumental testing, mainly videofluoroscopy (64 to 78 percent). The dysphagia rates may have been overestimated by instrumental testing, which can reveal movement patterns that reflect the normal effects of aging; these were not distinguished from pathologic dysphagia by the definitions used in the studies. Independent predictors of dysphagia on initial presentation include male sex, age greater than 70, disabling stroke, impaired pharyngeal response, incomplete oral clearance, and palatal weakness or asymmetry [10]. Dysphagia usually improves spontaneously with return of safe https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 2/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate swallowing function by two weeks in approximately 90 percent of patients [9,11,12]. However, a significant minority of patients have persistent dysphagia. Screening for dysphagia We evaluate swallowing function using a water swallow test at the time of admission for all patients with acute stroke before administering oral medications or food [13]. The water swallow test is simple and quick to perform, although the specific method of testing can vary in different stroke centers. The patient, who must be awake and alert, is positioned upright in bed as high as tolerated between 30 to 90 degrees and instructed to drink 3 ounces (90 cc) of water from a cup by mouth (use of a straw is permitted) slowly and steadily without stopping [14-16]. The test is passed if the patient is able to drink the entire volume of water without coughing or choking during or immediately (eg, within one minute) after swallowing. The test is failed if the patient develops coughing, choking, gurgling, or is unable to drink the entire volume of water in a single or sequential swallows. Videofluoroscopy with modified barium swallow can be performed once the patient is stable in order to assess the severity of oropharyngeal dysfunction and risk of aspiration. (See "Oropharyngeal dysphagia: Clinical features, diagnosis, and management", section on 'Videofluoroscopic modified barium swallow'.) In a prospective, multicenter study, use of a formal screening protocol for dysphagia (eg, water swallow test) for all patients admitted with stroke was associated with a significantly decreased risk of aspiration pneumonia compared with no formal screen (adjusted odds ratio 0.10, 95% CI 0.03-0.45) [17]. The pneumonia rates at sites with and without a formal dysphagia screen were 2.4 versus 5.4 percent, for an absolute risk reduction of 3 percent. Bedside tests to screen for swallowing dysfunction are useful but have a lower sensitivity compared with more comprehensive testing [18-20]. In a 2016 systematic review and meta- analysis of 11 studies and 770 patients with stroke, the water swallow test for aspiration had a sensitivity of 64 to 79 percent and a specificity of 61 to 81 percent [19]. One study found that the best bedside predictors of aspiration to thin liquid were spontaneous cough during test swallows and the overall sense of the presence of aspiration by the examiner [21]. A 2012 systematic review found that cough or voice change in response to bedside water swallow test had a low to moderate sensitivity and moderate to high specificity for predicting aspiration [22]. Preventing aspiration Prevention of aspiration for patients with acute stroke includes initial nil per os (NPO) status for those who may be at risk for aspiration and subsequent dietary modifications for those who have persistent dysphagia. Intravenous hydration with https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 3/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate normal saline should be administered to maintain volume status [23]. (See "Oropharyngeal dysphagia: Clinical features, diagnosis, and management".) Patients with acute stroke who cannot take food and fluids orally due to persistent dysphagia, altered mental status, and/or mechanical ventilation should receive nutrition and hydration via nasogastric, nasoduodenal, or percutaneous endoscopic gastrostomy tube feedings while undergoing efforts to restore swallowing [24]. In most cases, a nasogastric tube should be placed within 48 hours of stroke onset if enteral nutrition is likely to be needed for less than four weeks; nasogastric tube placement may be placed sooner if necessary to administer oral medications. Ideally, percutaneous gastrostomy tube placement can be deferred for two to four weeks to determine whether spontaneous recovery of swallowing will develop and to allow time to discuss the risks and benefits of gastrostomy tube insertion. However, observational data from the United States suggest that the median time to placement is closer to seven days for patients with stroke [25]. Early gastrostomy tube placement is probably driven in part by requirements for disposition, since nasogastric tube feeding is not an option at many acute rehabilitation facilities. (See "Nutrition support in critically ill patients: An overview" and "Gastrostomy tubes: Uses, patient selection, and efficacy in adults" and "Enteral feeding: Gastric versus post-pyloric".) Venous thromboembolism Venous thromboembolism (VTE) encompasses deep vein thrombosis (DVT) and pulmonary embolism, which is potentially life threatening. VTE prophylaxis is indicated for all patients with acute stroke who have restricted mobility. The approach to prevention and treatment of VTE is reviewed in detail separately. (See "Prevention and treatment of venous thromboembolism in patients with acute stroke".) Fever and infection Burden of fever Fever is a common complication of stroke, may worsen outcomes, and can sometimes lead to clinically nonindicated and potentially harmful antimicrobial use. In one retrospective report of 1361 patients hospitalized with acute ischemic stroke, one or more episodes of fever affected approximately 36 percent of patients [26]. Effect on outcomes Fever is associated with unfavorable outcomes in human studies of stroke [26-29]. In a meta-analysis of over 14,000 patients with neurologic injury, including hemorrhagic and/or ischemic stroke, fever was associated with increased mortality rates, greater disability, more dependence, worse functional outcome, greater severity, and longer intensive care unit and hospital stays [27]. These results were consistent for overall pooled data and for subgroups limited to studies of patients with hemorrhagic, ischemic, https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 4/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate or all stroke types. A subsequent meta-analysis found that fever within 24 hours of hospital admission in patients with ischemic stroke was associated with a two-fold increase in the odds of mortality at one month after stroke onset [29]. Fever may contribute to brain injury in patients with an acute stroke. This concept has been demonstrated in animal models in which ischemic injury is increased in the presence of elevated temperature. Hyperthermia may act via several mechanisms to worsen cerebral ischemia [30,31]: Enhanced release of neurotransmitters Exaggerated oxygen radical production More extensive blood-brain barrier breakdown Increased numbers of potentially damaging ischemic depolarizations in the focal ischemic penumbra Impaired recovery of energy metabolism and enhanced inhibition of protein kinases Worsening of cytoskeletal proteolysis Management Temperature reduction to achieve normothermia is the preferred strategy for the management of fever. (See "Initial assessment and management of acute stroke", section on 'Fever'.) Prophylactic antibiotics may reduce the rate of overall infection in patients with acute stroke but do not reduce mortality or improve functional outcome [32]. Pneumonia Pneumonia develops in 3 to 10 percent of patients with acute stroke [4,6,7,33,34]. Stroke-related pneumonia is associated with a higher mortality and a poorer long- term outcome [4,33,35,36]. Risk factors and causes Risk factors for in-hospital pneumonia include older age, dysarthria, dysphagia, aphasia, stroke severity, cognitive impairment, use of gastric acid suppressive medications, and an abnormal water swallow test [37-40]. Aspiration is the cause of approximately 60 percent of poststroke pneumonia [2]. Aspiration pneumonia refers to the pulmonary consequences resulting from the abnormal entry of fluid, particulate exogenous substances, or endogenous secretions into the lower airways. Most pneumonia arises following the "aspiration" of microorganisms from the oral cavity or nasopharynx. Aspiration pneumonia following stroke is usually due to stroke- related dysphagia (ie, impairment of motor and sensory mechanisms involved in deglutition) or to a decreased level of consciousness that results in compromise of the cough reflex and glottic closure. (See 'Dysphagia' above.) https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 5/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate Prevention Measures to prevent aspiration pneumonia in patients with dysphagia include initial nil per os (NPO; nothing by mouth) status and subsequent dietary modifications for those who have persistent dysphagia. (See "Oropharyngeal dysphagia: Clinical features, diagnosis, and management".) Screening on admission for swallowing difficulty is an important measure to prevent pneumonia in patients with acute stroke, as discussed above. (See 'Dysphagia' above.) Additional preventive measures include patient mobilization when neurologically stable and good pulmonary care [23]. For intubated patients, risk reduction measures include daily assessment for potential extubation, minimizing sedation, suctioning of secretions, elevating the head of the bed when possible, and maintaining ventilator circuits. (See "Risk factors and prevention of hospital-acquired and ventilator-associated pneumonia in adults".) Given the apparent increased risk of hospital-acquired pneumonia associated with the use of histamine-2 receptor antagonists and proton pump inhibitors, we avoid agents that suppress gastric acid in patients who are not at high risk of developing a stress ulcer or stress gastritis. Prophylactic antibiotics for patients with acute stroke do not reduce the incidence of poststroke pneumonia or improve functional outcomes [41,42]. A number of other interventions (eg, positioning, drugs, oral hygiene, tube feeding, influenza vaccination, pneumococcal vaccination) have been proposed to prevent aspiration in hospitalized and nonhospitalized older adult patients. However, no clinical trials have evaluated the utility of these measures specifically in patients with stroke. (See "Aspiration pneumonia in adults" and "Risk factors and prevention of hospital-acquired and ventilator- associated pneumonia in adults" and "Pneumococcal vaccination in adults" and "Seasonal influenza vaccination in adults".) Diagnosis and management The diagnosis and management of hospital acquired pneumonia is reviewed elsewhere. (See "Treatment of hospital-acquired and ventilator- associated pneumonia in adults".) Urinary tract infection Urinary tract infection occurs in 11 to 15 percent of patients followed for up to three months after acute stroke [1,4,7] and constitutes a serious complication (ie, prolonged, immediately life threatening, or resulting in hospitalization or death) in approximately 1 percent [2]. Urinary tract infection remains a common complication when patients are followed for up to 30 months [1]. Risk factors and causes In a meta-analysis, the main risk factors for urinary tract infection were female sex, older age, higher modified Rankin Scale score (a measure of https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 6/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate poststroke disability), and postvoid residual volume >100 mL [43]. It is common practice to place indwelling bladder catheters in patients with stroke due to immobility, incontinence, urinary retention, or convenience. However, placement of an indwelling bladder catheter is an important risk factor for infection, and the duration of catheterization is directly related to risk of urinary tract infection [44]. Prevention The use of indwelling urinary catheters should be avoided whenever possible [13]. The use of external catheter systems (ie, condom catheters for men, adhesive urinary pouches for women) or intermittent catheterizations are alternatives that may be associated with a lower risk of urinary tract infections compared with an indwelling urethral catheter. However, supporting data are scant. (See "Placement and management of urinary bladder catheters in adults" and "Complications of urinary bladder catheters and preventive strategies" and "Catheter-associated urinary tract infection in adults".) Diagnosis and management We test for urinary tract infection if patients have signs of infection (eg, fever, leukocytosis), unexplained altered mental status, or suggestive symptoms. Classic manifestations of urinary tract infection include dysuria, urinary frequency or urgency, suprapubic pain, or flank pain, often accompanied by fever, chills, and/or elevated peripheral white blood cell count. Urine cultures are important in diagnosing catheter-related urinary tract infection. The vast majority of patients with 5 symptomatic bacteriuria (ie, urinary tract infection) have bacterial culture growth 10 colony forming units (CFU)/mL or fungal growth in urine. (See "Catheter-associated urinary tract infection in adults", section on 'Clinical features'.) Indwelling urinary catheters and older age are associated with an increased risk of asymptomatic bacteriuria. Treatment of asymptomatic bacteriuria does not improve patient outcomes and increases the likelihood of emergence of resistant bacteria. Thus, with few exceptions, screening and treatment for asymptomatic bacteriuria in catheterized patients is not indicated. (See "Catheter-associated urinary tract infection in adults", section on 'Asymptomatic bacteriuria'.) After the diagnosis is made, treatment options should be tailored to the culture results and regional organism sensitivities. Bladder catheter management, methods to reduce the risk of infection associated with indwelling catheters, and treatment of catheter-associated urinary tract infection are reviewed elsewhere. (See "Catheter-associated urinary tract infection in adults".) Issues related to acute cystitis, recurrent urinary tract infection, and acute pyelonephritis are discussed separately. (See "Acute simple cystitis in females" and "Acute simple cystitis in https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 7/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate adult males" and "Recurrent simple cystitis in women" and "Acute complicated urinary tract infection (including pyelonephritis) in adults".) Cardiac complications Myocardial infarction, cardiac arrhythmias, and neurogenic cardiac injury are potential short- and long-term complications of acute stroke [45]. Myocardial infarction All patients with acute stroke should have electrocardiography (ECG) and troponin level on admission, and continuous cardiac monitoring for at least the first 24 hours of admission to detect arrhythmias, particularly atrial fibrillation [13,46]. Data from the modern era suggest that myocardial infarction (MI) occurs in approximately 1 to 2.5 percent of patients with acute stroke during initial hospitalization and is associated with poor outcome [2,6,7,47]. MI should be suspected in patients who have chest pain, shortness of breath, new heart failure, or sudden cardiac arrest. The diagnosis of MI is supported by the presence of ST and/or T wave changes on ECG, positive cardiac biomarkers, or hemodynamic abnormalities. (See "Diagnosis of acute myocardial infarction".) Elevated cardiac enzymes Cardiac troponin is the standard blood-based test to confirm the diagnosis of acute myocardial infarction (see "Diagnosis of acute myocardial infarction", section on 'Definitions'). However, troponin is not specific for acute thrombotic occlusion of a coronary artery, the most common precursor to acute myocardial infarction. Increased blood concentrations of cardiac troponin can also be seen in a variety of other diseases ( table 3), including acute stroke. In such cases, elevation of troponin and other cardiac enzymes after acute stroke may be related to stroke-induced autonomic dysfunction or other types of nonischemic myocardial injury. (See "Elevated cardiac troponin concentration in the absence of an acute coronary syndrome", section on 'Acute stroke'.) Limited retrospective data suggest that elevated troponin on admission for acute stroke is associated with embolic stroke of unknown source (ESUS) and cardioembolic stroke [48], but further studies are needed to confirm this finding. ECG abnormalities The ECG is an essential diagnostic test for patients with possible or established myocardial ischemia, injury, or infarction (see "Electrocardiogram in the diagnosis of myocardial ischemia and infarction"). Abnormalities are manifest in the ST- segment, T wave, and QRS complex. However, the ECG may be normal or nonspecific in a patient with either myocardial ischemia or MI. Furthermore, ECG abnormalities that appear to represent myocardial ischemia or infarction may be present for other reasons. ECG changes may occur in the setting of stroke, likely mediated by the autonomic nervous https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 8/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate system, particularly related to subarachnoid hemorrhage. These include QT prolongation, T wave abnormalities, ST segment elevation, and aberrant Q waves. These abnormalities may also represent pre-existing coronary disease [49]. Management The management of patients with suspected acute coronary syndrome (MI, unstable angina) is reviewed separately. (See "Initial evaluation and management of suspected acute coronary syndrome (myocardial infarction, unstable angina) in the emergency department" and "Overview of the acute management of ST-elevation myocardial infarction" and "Overview of the acute management of non-ST-elevation acute coronary syndromes".) Arrhythmias Cardiac arrhythmias are frequently present in the setting of acute stroke [50,51], stressing the importance of continuous cardiac monitoring in the initial phase of stroke management. In many cases, the cardiac rhythm disturbances likely were present prior to the stroke and were not directly related to the stroke [52]. Symptomatic arrhythmias generally require management in an intensive care unit setting with cardiology consultation. In a prospective study of 501 patients with acute stroke, potentially serious cardiac arrhythmia events occurred in 126 patients (25 percent) during the first 72 hours after admission to a monitored stroke unit [50]. Tachycardia occurred mainly with atrial fibrillation; other causes included focal atrial tachycardia, undetermined supraventricular tachycardia, ventricular ectopy, nonsustained ventricular tachycardia, and atrial flutter. Bradyarrhythmias were caused by atrial fibrillation, Mobitz type II atrioventricular block, asystole/sinoatrial block, and complete atrioventricular block. Neurogenic cardiac damage A wide spectrum of regional left ventricular wall motion abnormalities, typically but not always reversible, can occur with subarachnoid hemorrhage and less often with other types of stroke [53]. Some patients develop a pattern of transient apical left ventricular dysfunction that mimics myocardial infarction, but in the absence of significant coronary artery disease [54]. This condition is known as takotsubo cardiomyopathy. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis" and "Clinical manifestations and diagnosis of stress (takotsubo) cardiomyopathy".) Stroke-induced cardiac damage is uncommon but is well described [55,56]. It is unlikely that the only mechanism explaining cardiac damage after acute stroke is the presence of underlying coronary disease, particularly since signs of cardiac damage may occur in patients with subarachnoid hemorrhage, who are often young and without underlying heart disease. In addition, the rapid appearance and disappearance of the ST changes argue against macrovascular factors and in favor of neural factors [57,58]. Myocardial injury in these cases is https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 9/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate most likely the result of a centrally mediated release of catecholamines caused by stroke-related brain injury. This type of cardiac injury is similar to stress cardiomyopathy (also called takotsubo cardiomyopathy) characterized by transient regional systolic dysfunction of the left ventricle (LV), mimicking myocardial infarction, but in the absence of angiographic evidence of obstructive coronary artery disease or acute plaque rupture. (See "Clinical manifestations and diagnosis of stress (takotsubo) cardiomyopathy".) Cardiac myofibrillar degeneration has been described in patients who die from acute stroke, and is histologically identical to the cardiac lesions of catecholamine infusion, "voodoo death," hypothalamic stimulation, or reperfusion of transiently ischemic cardiac muscle [55]. The myofibrillar degeneration occurs in the vicinity of the cardiac nerves, and not in the macrovascular distribution seen in patients with coronary disease [55,59]. The lesion also differs from the necrosis seen in coronary disease because it is visible within minutes of onset, and the cells die in a hypercontracted state with contraction bands, associated mononuclear infiltration, and early calcification. Accumulating experimental and clinical evidence suggests that stroke involving the insular cortex may be associated with adverse cardiac outcomes including repolarization abnormalities, arrhythmias, neurogenic cardiac damage, heart failure, and sudden death [60-66]. The presumed biologic basis for this association is the role of the insular cortex in the autonomic control of cardiovascular function [61,65-73]. Acute kidney injury In an analysis of the 2007-2019 National Inpatient Sample of over 5,750,000 adults admitted for acute ischemic stroke in the United States, the prevalence of acute kidney injury was approximately 10 percent, making it one of the most common complications [7]. Among patients on mechanical ventilation, the prevalence of AKI was approximately 25 percent. Pulmonary complications Serious pulmonary complications of stroke include pneumonia, neurogenic pulmonary edema, and the need for intubation and mechanical ventilation [74]. Pneumonia Pneumonia is a common cause of fever within the first 48 hours of acute stroke. Aspiration is the most frequent cause of poststroke pneumonia, and it is usually due to stroke-related dysphagia or to decreased level of consciousness. (See 'Pneumonia' above and 'Dysphagia' above.) Need for mechanical ventilation Intubation and mechanical ventilation of patients with ischemic stroke is usually performed to treat pulmonary edema or for inability to protect the airway. Additional indications include partial airway obstruction, hypoventilation, and aspiration pneumonia. (See "Overview of initiating invasive mechanical ventilation in adults https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 10/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate in the intensive care unit" and "Clinical and physiologic complications of mechanical ventilation: Overview", section on 'Increased intracranial pressure'.) Neurogenic pulmonary edema Neurogenic pulmonary edema (NPE) is reviewed here briefly and discussed in detail elsewhere. (See "Neurogenic pulmonary edema".) Neurogenic pulmonary edema (NPE) is an increase in interstitial and alveolar fluid that occurs in the setting of head trauma, seizures, or stroke, particularly subarachnoid hemorrhage ( table 4). NPE most often develops abruptly and progresses quickly after the onset of the neurologic insult. The typical patient with NPE is dyspneic, tachycardic, and hypertensive, with bilateral rales. Most cases of NPE resolve spontaneously and are well tolerated, but the condition can be fatal in severe cases. Treatment of NPE is largely supportive and directed mainly towards treatment of the underlying neurologic condition. Abnormal respiratory patterns Abnormal respiratory patterns may complicate stroke; these include Cheyne-Stokes breathing, periodic breathing, apneustic breathing, central sleep apnea, ataxic breathing, and failure of automatic breathing ( figure 1). (See "Disorders of ventilatory control".) Sleep-related breathing disorders The relationship of sleep-disordered breathing (including both obstructive sleep apnea and central sleep apnea syndrome) as a possible risk factor for stroke and as a possible complication of stroke is discussed separately. (See "Sleep-related breathing disorders and stroke".) Gastrointestinal bleeding Gastrointestinal (GI) hemorrhage affects 1.1 to 3 percent of patients with acute stroke [2,7,75,76]. Patients with acute stroke and GI hemorrhage have worse outcomes, with higher rates of dependency and mortality. Overt GI bleeding may be severe or even life threatening and manifests with hematemesis, melena, or hematochezia. Occult GI bleeding (ie, no visible evidence of bleeding) is generally less serious; it is suspected in the setting of iron deficiency anemia or a positive fecal occult blood test. Risk factors Retrospective data from various studies suggest that risk factors for GI hemorrhage include older age, severe stroke, posterior circulation stroke, infection, history of hypertension, hepatic cirrhosis, prestroke dependence, and a history of peptic ulcer disease or cancer predating the incident stroke [75-78]. Prevention GI stress ulcer prophylaxis with proton pump inhibitors or H2 antagonists is effective for reducing overt GI bleeding but may increase the risk of nosocomial pneumonia. Therefore, stress ulcer prophylaxis is not used routinely for patients with acute stroke but is reserved for select patients who need intensive care unit management or are https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 11/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate otherwise at high risk. Stress ulcer prophylaxis is reasonable for patients who have risk factors such as intensive care unit stay lasting more than one week, mechanical ventilation for >48 hours, sepsis, hereditary or acquired coagulopathy, including therapeutic anticoagulation, a history of GI ulceration or bleeding within the past year, occult gastrointestinal bleeding lasting 6 days, or treatment with high-dose glucocorticoids. (See "Stress ulcers in the intensive care unit: Diagnosis, management, and prevention", section on 'High-risk patients'.) There is some evidence that enteral nutrition alone may reduce the risk of overt GI bleeding due to stress ulceration and that stress ulcer prophylaxis may be ineffective or harmful among patients who are receiving enteral nutrition, as reviewed separately. (See "Stress ulcers in the intensive care unit: Diagnosis, management, and prevention", section on 'High-risk patients'.) Management Withholding of antiplatelet or anticoagulant therapy in the setting of clinically overt GI bleeding should be individualized. The management of GI bleeding is discussed in detail elsewhere. (See "Approach to acute upper gastrointestinal bleeding in adults" and "Approach to acute lower gastrointestinal bleeding in adults" and "Evaluation of occult gastrointestinal bleeding".) Urinary incontinence Urinary incontinence is a common problem after stroke and is associated with poor functional outcome and mortality, perhaps because it is a marker of stroke severity [79-83]. Urinary incontinence is present in 32 to 79 percent of patients on admission, and 25 to 28 percent at discharge [84]. Data from prospective population-based studies suggest that in previously continent patients, new urinary incontinence is found in 35 to 40 percent of patients at 7 to 10 days after acute stroke [83]. The prevalence of poststroke incontinence decreases with time. Of a group of 95 patients with incontinence 7 to 10 days after stroke, incontinence persisted at three months, one year, and two years in 36, 24, and 13 percent, respectively [85]. The most frequent urodynamic finding is detrusor hyperreflexia [86]. The loss of inhibitory input from higher neurologic centers is thought to cause this hyperreflexia leading to urinary urgency, frequency, and urge incontinence. In addition to detrusor hyperreflexia, detrusor hyporeflexia or areflexia may also occur following stroke, leading to overflow incontinence. Detrusor-sphincter dyssynergia is an uncommon phenomenon in patients with recent stroke, unlike other neurologic disorders associated with incontinence. Risk factors Risk factors for the development of urinary incontinence in patients with stroke include hemiparesis, depression, cognitive impairment, age >75 years, dysphagia, https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 12/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate visual field defect, and large infarcts (cortical plus subcortical area involvement) [87,88]. Other factors contributing to urinary retention include the use of anticholinergic drugs, diabetic cystopathy, and bladder outlet obstruction. Prevention Indwelling bladder catheter placement should be avoided when possible to decrease the risks of nosocomial infection, which is a potential contributing factor for urinary incontinence. Evaluation and management Practitioners can easily overlook urinary incontinence if patients or nursing staff are not directly queried. Diagnosis of the type of incontinence and appropriate treatment can be coordinated with a urologist. Detrusor hyperreflexia can be treated with scheduled voiding, tailored fluid restriction, and anticholinergic drugs. There is little evidence to support specific interventions for urinary incontinence after stroke [89]. The evaluation and treatment of urinary incontinence is discussed in detail separately. (See "Urinary incontinence in men" and "Female urinary incontinence: Evaluation" and "Female urinary incontinence: Treatment".) Falls and bone fractures Falls have been cited as the one of the most common complications of acute stroke [1,90]. In a prospective multicenter study of 311 patients followed up to 30 months after stroke, falls occurred in 25 percent and were associated with serious injury in 5 percent [1]. Hip fractures represent 45 percent of poststroke fractures and are two to four times more common in the population with stroke compared with an age-matched reference population [91]. A retrospective case-control study found that the rate of falls among hospitalized patients with acute ischemic stroke was only 2.3 percent [92]. Hospitalized patients with stroke not only have skeletal "unloading" secondary to bed rest, but they also have disuse of the paretic limbs. These factors predispose patients to bone resorption. Patients who are able to ambulate early after stroke appear to lose bone density only on the paretic side (hemiosteoporosis), while those who are not ambulatory lose bone mineral density on both sides. Relearning to walk by two months has been associated with diminished bone density loss compared with remaining nonambulatory [93]. Risk factors Patients with cognitive impairment, neglect, anosognosia, and/or polypharmacy may be at especially high risk for falls [23]. Most fractures after stroke occur on the paretic side and are secondary to accidental falls [91,94]. Poststroke patients tend to fall toward the paretic side and lack ample protective responses, such as outstretching an arm, putting them at higher risk for fractures. (See "Falls in older persons: Risk factors and patient evaluation".) https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 13/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate Prevention Fall precautions should be implemented for all patients with acute stroke; specific elements include measures to reduce the risk of delirium, the use of bed and chair alarms, minimal use of mechanical restraints, and use of ceiling lifts to assist with transfers [23]. However, the evidence supporting these measures for fall prevention in patients with stroke is limited [95]. Depression Poststroke depression is common, although difficult to quantify precisely due to methodologic differences among studies. A 2013 meta-analysis, with pooled data from 43 studies and over 20,000 patients, found that the prevalence of depression observed at any time after stroke was 29 percent (95% CI 25-32 percent) [96]. There was no significant difference in prevalence rates of depression at different time points after stroke. In pooled data from 10 studies with over 16,000 patients, predictors of poststroke depression were disability, prestroke depression, cognitive impairment, stroke severity, and anxiety. In a later case-control study that compared over 135,000 patients with stroke and no diagnosis of depression at baseline with 145,000 matched controls, the incidence of depression during the first two years after hospitalization was significantly higher for the group with stroke (25 versus 8 percent) [97]. Depression after stroke is correlated with poorer functional outcomes [98], although causation cannot be inferred from this. Nonetheless, when patients are matched for initial functional outcome, remission of depression is associated with a better functional outcome at three and six months than continued depression [99]. There appears to be a relationship between depression and 12- and 24-month mortality, but confounders likely exist [100]. The theory that depression is more commonly associated with left than with right hemisphere strokes and with lesions of the left anterior brain than with other regions [101] is not supported by the data. In a systematic review of 48 studies, the relative risk of depression after a left versus right hemisphere stroke was 0.95 (95% CI 0.83-1.10) [102]. Similarly, the risk of depression after a left anterior lesion compared with all other brain lesions was 1.17 (0.87-1.62). Risk factors Possible risk factors for poststroke depression include physical disability, stroke severity, prestroke depression, cognitive impairment, and insufficient family and social support [98]. Prevention It is unclear whether interventions to prevent poststroke depression are effective. A 2020 systematic review identified 49 trials involving 3342 subjects that evaluated prevention of poststroke depression [103]. The review concluded that there was only very low certainty evidence that pharmacologic or psychologic therapies reduced the prevalence of poststroke depression.

"Stress ulcers in the intensive care unit: Diagnosis, management, and prevention", section on 'High-risk patients'.) Management Withholding of antiplatelet or anticoagulant therapy in the setting of clinically overt GI bleeding should be individualized. The management of GI bleeding is discussed in detail elsewhere. (See "Approach to acute upper gastrointestinal bleeding in adults" and "Approach to acute lower gastrointestinal bleeding in adults" and "Evaluation of occult gastrointestinal bleeding".) Urinary incontinence Urinary incontinence is a common problem after stroke and is associated with poor functional outcome and mortality, perhaps because it is a marker of stroke severity [79-83]. Urinary incontinence is present in 32 to 79 percent of patients on admission, and 25 to 28 percent at discharge [84]. Data from prospective population-based studies suggest that in previously continent patients, new urinary incontinence is found in 35 to 40 percent of patients at 7 to 10 days after acute stroke [83]. The prevalence of poststroke incontinence decreases with time. Of a group of 95 patients with incontinence 7 to 10 days after stroke, incontinence persisted at three months, one year, and two years in 36, 24, and 13 percent, respectively [85]. The most frequent urodynamic finding is detrusor hyperreflexia [86]. The loss of inhibitory input from higher neurologic centers is thought to cause this hyperreflexia leading to urinary urgency, frequency, and urge incontinence. In addition to detrusor hyperreflexia, detrusor hyporeflexia or areflexia may also occur following stroke, leading to overflow incontinence. Detrusor-sphincter dyssynergia is an uncommon phenomenon in patients with recent stroke, unlike other neurologic disorders associated with incontinence. Risk factors Risk factors for the development of urinary incontinence in patients with stroke include hemiparesis, depression, cognitive impairment, age >75 years, dysphagia, https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 12/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate visual field defect, and large infarcts (cortical plus subcortical area involvement) [87,88]. Other factors contributing to urinary retention include the use of anticholinergic drugs, diabetic cystopathy, and bladder outlet obstruction. Prevention Indwelling bladder catheter placement should be avoided when possible to decrease the risks of nosocomial infection, which is a potential contributing factor for urinary incontinence. Evaluation and management Practitioners can easily overlook urinary incontinence if patients or nursing staff are not directly queried. Diagnosis of the type of incontinence and appropriate treatment can be coordinated with a urologist. Detrusor hyperreflexia can be treated with scheduled voiding, tailored fluid restriction, and anticholinergic drugs. There is little evidence to support specific interventions for urinary incontinence after stroke [89]. The evaluation and treatment of urinary incontinence is discussed in detail separately. (See "Urinary incontinence in men" and "Female urinary incontinence: Evaluation" and "Female urinary incontinence: Treatment".) Falls and bone fractures Falls have been cited as the one of the most common complications of acute stroke [1,90]. In a prospective multicenter study of 311 patients followed up to 30 months after stroke, falls occurred in 25 percent and were associated with serious injury in 5 percent [1]. Hip fractures represent 45 percent of poststroke fractures and are two to four times more common in the population with stroke compared with an age-matched reference population [91]. A retrospective case-control study found that the rate of falls among hospitalized patients with acute ischemic stroke was only 2.3 percent [92]. Hospitalized patients with stroke not only have skeletal "unloading" secondary to bed rest, but they also have disuse of the paretic limbs. These factors predispose patients to bone resorption. Patients who are able to ambulate early after stroke appear to lose bone density only on the paretic side (hemiosteoporosis), while those who are not ambulatory lose bone mineral density on both sides. Relearning to walk by two months has been associated with diminished bone density loss compared with remaining nonambulatory [93]. Risk factors Patients with cognitive impairment, neglect, anosognosia, and/or polypharmacy may be at especially high risk for falls [23]. Most fractures after stroke occur on the paretic side and are secondary to accidental falls [91,94]. Poststroke patients tend to fall toward the paretic side and lack ample protective responses, such as outstretching an arm, putting them at higher risk for fractures. (See "Falls in older persons: Risk factors and patient evaluation".) https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 13/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate Prevention Fall precautions should be implemented for all patients with acute stroke; specific elements include measures to reduce the risk of delirium, the use of bed and chair alarms, minimal use of mechanical restraints, and use of ceiling lifts to assist with transfers [23]. However, the evidence supporting these measures for fall prevention in patients with stroke is limited [95]. Depression Poststroke depression is common, although difficult to quantify precisely due to methodologic differences among studies. A 2013 meta-analysis, with pooled data from 43 studies and over 20,000 patients, found that the prevalence of depression observed at any time after stroke was 29 percent (95% CI 25-32 percent) [96]. There was no significant difference in prevalence rates of depression at different time points after stroke. In pooled data from 10 studies with over 16,000 patients, predictors of poststroke depression were disability, prestroke depression, cognitive impairment, stroke severity, and anxiety. In a later case-control study that compared over 135,000 patients with stroke and no diagnosis of depression at baseline with 145,000 matched controls, the incidence of depression during the first two years after hospitalization was significantly higher for the group with stroke (25 versus 8 percent) [97]. Depression after stroke is correlated with poorer functional outcomes [98], although causation cannot be inferred from this. Nonetheless, when patients are matched for initial functional outcome, remission of depression is associated with a better functional outcome at three and six months than continued depression [99]. There appears to be a relationship between depression and 12- and 24-month mortality, but confounders likely exist [100]. The theory that depression is more commonly associated with left than with right hemisphere strokes and with lesions of the left anterior brain than with other regions [101] is not supported by the data. In a systematic review of 48 studies, the relative risk of depression after a left versus right hemisphere stroke was 0.95 (95% CI 0.83-1.10) [102]. Similarly, the risk of depression after a left anterior lesion compared with all other brain lesions was 1.17 (0.87-1.62). Risk factors Possible risk factors for poststroke depression include physical disability, stroke severity, prestroke depression, cognitive impairment, and insufficient family and social support [98]. Prevention It is unclear whether interventions to prevent poststroke depression are effective. A 2020 systematic review identified 49 trials involving 3342 subjects that evaluated prevention of poststroke depression [103]. The review concluded that there was only very low certainty evidence that pharmacologic or psychologic therapies reduced the prevalence of poststroke depression. https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 14/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate Further study in rigorous clinical trials is needed to determine the utility of antidepressant interventions for preventing depression after acute stroke. Assessment There are many depression scales that can be used to assess depression after stroke. The single question "Do you often feel sad or depressed?" was found to have a sensitivity and specificity of 86 and 78 percent, respectively when used against the Montgomery-Asberg depression rating in screening for poststroke depression [104]. (See "Unipolar depression in adults: Assessment and diagnosis".) Treatment Major depression is a treatable illness that responds to a variety of therapeutic interventions, and it is likely that the standard approach to the treatment of depression in adults is generalizable to patients with poststroke depression. The initial treatment of depression is discussed separately. (See "Unipolar major depression in adults: Choosing initial treatment".) There is no definitive evidence to guide the specific choice of therapy for patients with poststroke depression [98]. The effectiveness of pharmacotherapy, psychotherapy, or combined use of these modalities for poststroke depression is not established, but accumulating evidence suggests that these interventions are beneficial. For patients able to engage in physical activity, exercise may be helpful. (See "Unipolar major depression in adults: Choosing initial treatment", section on 'Exercise'.) Poststroke fatigue Poststroke fatigue lacks a consensus definition, but encompasses a subjective feeling of exhaustion and lack of physical or mental energy and/or an increased need for rest that interferes with usual activities [105,106]. It is generally distinguished from poststroke depression, although the two may exist concurrently. The pathophysiology of poststroke fatigue is unsettled; possible factors include disturbances in cortical excitability, inflammation, and genes that modulate inflammation [105,107,108]. The prevalence of poststroke fatigue ranges from 23 to 75 percent in different studies [109]; the wide range is likely due to variation in definitions, patient populations, assessment scales, and time points (most often six months after stroke onset) among different reports [105]. Some studies distinguish between early poststroke fatigue (up to two to three months after stroke onset) and late poststroke fatigue (more than three months after stroke onset) [107,108,110]. However, it is unclear whether these two phases of fatigue are distinct [107]. There is no consensus about the need to screen for poststroke fatigue, and no proven therapy is available [111]. In a randomized trial of 36 patients with poststroke fatigue more than three months after stroke, modafinil was more effective than placebo for reducing fatigue and improving quality of life [112], but definitive conclusions are precluded by the small size of the https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 15/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate trial, and further study is needed. Other suggested interventions for poststroke fatigue include promoting physical activity and exercise, identifying and treating depression, anxiety, pain, and sleep disturbances, and avoiding sedating drugs and excessive alcohol [105,106]. NEUROLOGIC COMPLICATIONS Intracranial complications Intracranial complications of acute stroke include the development of cerebral edema, symptomatic hemorrhagic transformation of ischemic stroke, elevated intracranial pressure, and hydrocephalus. Cerebral edema with space-occupying mass effect develops in a minority of ischemic stroke but can cause neurologic deterioration and life- threatening herniation. The clinical features and management of intracranial complications of stroke are reviewed separately for each major type of stroke: Ischemic stroke (see "Malignant cerebral hemispheric infarction with swelling and risk of herniation") Intracerebral hemorrhage (see "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis") Subarachnoid hemorrhage (see "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis") The general management of elevated intracranial pressure is discussed elsewhere. (See "Evaluation and management of elevated intracranial pressure in adults".) Early neurologic deterioration Early neurologic deterioration (END) after acute stroke occurs in 2 to 38 percent of patients and is associated with poor outcomes [113-116]. The wide range in the frequency of END probably reflects differences in the patient populations studied and variations in the definitions of END. The mechanisms of END are heterogeneous. Common causes include extension of the infarct into surrounding areas of hypoperfused brain tissue, hematoma expansion of intracerebral hemorrhage, delayed cerebral ischemia associated with subarachnoid hemorrhage, other intracranial complications (eg, progressive cerebral edema, hemorrhagic transformation of ischemic stroke) and toxic-metabolic encephalopathy due to medical complications (eg, concomitant infection; cardiovascular, pulmonary, and/or renal dysfunction) [113,117-119]. Interventions that address the underlying cause may help to improve outcome. However, the cause of END is often unclear [113]. https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 16/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate Seizures Early seizures after stroke are relatively uncommon but are associated with poor outcome. Risk factors include worse stroke severity and cortical involvement. Poststroke seizures are reviewed elsewhere. (See "Overview of the management of epilepsy in adults", section on 'Poststroke seizures'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Stroke (The Basics)" and "Patient education: Recovery after stroke (The Basics)") Beyond the Basics topics (see "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Medical complications after ischemic stroke are common ( table 1 and table 2) and influence outcome. Potentially serious complications include pneumonia, urinary tract infection, gastrointestinal bleeding, myocardial infarction, deep vein thrombosis, and pulmonary embolism. (See 'Medical complications' above.) https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 17/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate We evaluate swallowing function using a water swallow test at the time of admission for all patients with acute stroke before administering oral medications or food. Prevention of aspiration in patients with dysphagia includes initial nil per os (NPO; nothing by mouth) status for those who may be at risk for aspiration and subsequent dietary modifications for those who have persistent dysphagia. Patients with acute stroke who cannot take food and fluids orally should receive nutrition and hydration via nasogastric, nasoduodenal, or percutaneous endoscopic gastrostomy tube feedings while undergoing efforts to restore swallowing. (See 'Dysphagia' above.) VTE prophylaxis is indicated for all patients with acute stroke who have restricted mobility, as reviewed separately. (See "Prevention and treatment of venous thromboembolism in patients with acute stroke".) Pneumonia and urinary tract infection are the two most common infectious complications of acute stroke. Screening on admission for swallowing difficulty is an important measure to prevent pneumonia in patients with acute stroke, as discussed above. Measures to prevent aspiration pneumonia in patients with dysphagia include initial NPO status and subsequent dietary modifications for those who have persistent dysphagia. Placement of an indwelling bladder catheter is an important risk factor for urinary tract infection and should be avoided if possible. (See 'Pneumonia' above and 'Urinary tract infection' above.) Myocardial infarction, cardiac arrhythmias, and neurogenic cardiac injury are potential complications of acute stroke. All patients with acute stroke should have ECG and troponin level on admission, and continuous cardiac monitoring at least the first 24 hours of admission. (See 'Cardiac complications' above.) Besides pneumonia, serious pulmonary complications of stroke include neurogenic pulmonary edema and the need for intubation and mechanical ventilation. (See 'Pulmonary complications' above.) Gastrointestinal (GI) bleeding is one of the more common complications of acute stroke. Risk factors include older age, severe stroke, and a history of peptic ulcer disease or cancer predating the incident stroke. GI stress ulcer prophylaxis with proton pump inhibitors or histamine-2 antagonists is not used routinely for patients with acute stroke but is reserved for select patients who need intensive care unit management. (See 'Gastrointestinal bleeding' above.) Urinary incontinence after stroke is associated with poor functional outcome and mortality, perhaps because it is a marker of stroke severity. in previously continent patients, new urinary incontinence is found in 35 to 40 percent of patients at 7 to 10 days after acute https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 18/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate stroke. The prevalence of poststroke incontinence decreases with time. (See 'Urinary incontinence' above.) Falls after acute stroke and are associated with serious injury in 5 percent of patients. Fall precautions should be implemented for all patients with stroke, particularly those with hemiparesis, cognitive impairment, neglect, anosognosia, and/or polypharmacy. (See 'Falls and bone fractures' above.) The prevalence of poststroke depression is 18 to 61 percent. Stroke severity, physical disability, and cognitive impairment are likely risk factors. The effectiveness of pharmacotherapy, psychotherapy, or combined use of these modalities for poststroke depression is not established, but accumulating evidence suggests that these interventions are beneficial. Thus, the standard approach to the treatment of depression is likely to be generalizable to patients with poststroke depression. (See 'Depression' above.) Neurologic complications of acute stroke encompass intracranial morbidities (progressive cerebral edema, symptomatic hemorrhagic transformation of ischemic stroke, elevated intracranial pressure, hydrocephalus), neurologic deterioration, and (uncommonly) seizures. 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Myocardial ultrastructure and haemodynamic reactions during experimental subarachnoid haemorrhage. J Mol Cell Cardiol 1972; 4:287. 60. Tokg zoglu SL, Batur MK, Top uoglu MA, et al. Effects of stroke localization on cardiac autonomic balance and sudden death. Stroke 1999; 30:1307. 61. Sander D, Klingelh fer J. Changes of circadian blood pressure patterns after hemodynamic and thromboembolic brain infarction. Stroke 1994; 25:1730. 62. Laowattana S, Zeger SL, Lima JA, et al. Left insular stroke is associated with adverse cardiac outcome. Neurology 2006; 66:477. 63. Abboud H, Berroir S, Labreuche J, et al. Insular involvement in brain infarction increases risk for cardiac arrhythmia and death. Ann Neurol 2006; 59:691. 64. Ay H, Koroshetz WJ, Benner T, et al. Neuroanatomic correlates of stroke-related myocardial injury. Neurology 2006; 66:1325. 65. Krause T, Werner K, Fiebach JB, et al. Stroke in right dorsal anterior insular cortex Is related to myocardial injury. Ann Neurol 2017; 81:502. 66. Koppikar S, Baranchuk A, Guzm n JC, Morillo CA. Stroke and ventricular arrhythmias. Int J https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 23/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate Cardiol 2013; 168:653. 67. Meyer S, Strittmatter M, Fischer C, et al. Lateralization in autonomic dysfunction in ischemic stroke involving the insular cortex. Neuroreport 2004; 15:357. 68. Smith KE, Hachinski VC, Gibson CJ, Ciriello J. Changes in plasma catecholamine levels after insula damage in experimental stroke. Brain Res 1986; 375:182. 69. Ruggiero DA, Mraovitch S, Granata AR, et al. A role of insular cortex in cardiovascular function. J Comp Neurol 1987; 257:189. 70. Oppenheimer SM, Gelb A, Girvin JP, Hachinski VC. Cardiovascular effects of human insular cortex stimulation. Neurology 1992; 42:1727. 71. Oppenheimer SM, Kedem G, Martin WM. Left-insular cortex lesions perturb cardiac autonomic tone in humans. Clin Auton Res 1996; 6:131. 72. Zhang ZH, Rashba S, Oppenheimer SM. Insular cortex lesions alter baroreceptor sensitivity in the urethane-anesthetized rat. Brain Res 1998; 813:73. 73. S r s P, Hachinski V. Cardiovascular and neurological causes of sudden death after ischaemic stroke. Lancet Neurol 2012; 11:179. 74. Balofsky A, George J, Papadakos P. Neuropulmonology. Handb Clin Neurol 2017; 140:33. 75. Davenport RJ, Dennis MS, Warlow CP. Gastrointestinal hemorrhage after acute stroke. Stroke 1996; 27:421. 76. O'Donnell MJ, Kapral MK, Fang J, et al. Gastrointestinal bleeding after acute ischemic stroke. Neurology 2008; 71:650. 77. Fu J. Factors affecting the occurrence of gastrointestinal bleeding in acute ischemic stroke patients. Medicine (Baltimore) 2019; 98:e16312. 78. Ji R, Shen H, Pan Y, et al. Risk score to predict gastrointestinal bleeding after acute ischemic stroke. BMC Gastroenterol 2014; 14:130. 79. Taub NA, Wolfe CD, Richardson E, Burney PG. Predicting the disability of first-time stroke sufferers at 1 year. 12-month follow-up of a population-based cohort in southeast England. Stroke 1994; 25:352. 80. Nakayama H, J rgensen HS, Pedersen PM, et al. Prevalence and risk factors of incontinence after stroke. The Copenhagen Stroke Study. Stroke 1997; 28:58. 81. Hankey GJ, Jamrozik K, Broadhurst RJ, et al. Five-year survival after first-ever stroke and related prognostic factors in the Perth Community Stroke Study. Stroke 2000; 31:2080. 82. Pettersen R, Wyller TB. Prognostic significance of micturition disturbances after acute stroke. J Am Geriatr Soc 2006; 54:1878. https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 24/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate 83. Mehdi Z, Birns J, Bhalla A. Post-stroke urinary incontinence. Int J Clin Pract 2013; 67:1128. 84. Brittain KR, Peet SM, Castleden CM. Stroke and incontinence. Stroke 1998; 29:524. 85. Patel M, Coshall C, Rudd AG, Wolfe CD. Natural history and effects on 2-year outcomes of urinary incontinence after stroke. Stroke 2001; 32:122. 86. Burney TL, Senapati M, Desai S, et al. Acute cerebrovascular accident and lower urinary tract dysfunction: a prospective correlation of the site of brain injury with urodynamic findings. J Urol 1996; 156:1748. 87. Gelber DA, Good DC, Laven LJ, Verhulst SJ. Causes of urinary incontinence after acute hemispheric stroke. Stroke 1993; 24:378. 88. Linsenmeyer TA. Post-CVA voiding dysfunctions: clinical insights and literature review. NeuroRehabilitation 2012; 30:1. 89. Thomas LH, Coupe J, Cross LD, et al. Interventions for treating urinary incontinence after stroke in adults. Cochrane Database Syst Rev 2019; 2:CD004462. 90. Minet LR, Peterson E, von Koch L, Ytterberg C. Occurrence and Predictors of Falls in People With Stroke: Six-Year Prospective Study. Stroke 2015; 46:2688. 91. Ramnemark A, Nyberg L, Borss n B, et al. Fractures after stroke. Osteoporos Int 1998; 8:92. 92. Cox R, Buckholtz B, Bradas C, et al. Risk Factors for Falls Among Hospitalized Acute Post- Ischemic Stroke Patients. J Neurosci Nurs 2017; 49:355. 93. J rgensen L, Jacobsen BK, Wilsgaard T, Magnus JH. Walking after stroke: does it matter? Changes in bone mineral density within the first 12 months after stroke. A longitudinal study. Osteoporos Int 2000; 11:381. 94. Myint PK, Poole KE, Warburton EA. Hip fractures after stroke and their prevention. QJM 2007; 100:539. 95. Winstein CJ, Stein J, Arena R, et al. Guidelines for Adult Stroke Rehabilitation and Recovery: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2016; 47:e98. 96. Ayerbe L, Ayis S, Wolfe CD, Rudd AG. Natural history, predictors and outcomes of depression after stroke: systematic review and meta-analysis. Br J Psychiatry 2013; 202:14. 97. J rgensen TS, Wium-Andersen IK, Wium-Andersen MK, et al. Incidence of Depression After Stroke, and Associated Risk Factors and Mortality Outcomes, in a Large Cohort of Danish Patients. JAMA Psychiatry 2016; 73:1032. 98. Towfighi A, Ovbiagele B, El Husseini N, et al. Poststroke Depression: A Scientific Statement for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2017; 48:e30. https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 25/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate 99. Chemerinski E, Robinson RG, Kosier JT. Improved recovery in activities of daily living associated with remission of poststroke depression. Stroke 2001; 32:113. 100. House A, Knapp P, Bamford J, Vail A. Mortality at 12 and 24 months after stroke may be associated with depressive symptoms at 1 month. Stroke 2001; 32:696. 101. Robinson RG, Price TR. Post-stroke depressive disorders: a follow-up study of 103 patients. Stroke 1982; 13:635. 102. Carson AJ, MacHale S, Allen K, et al. Depression after stroke and lesion location: a systematic review. Lancet 2000; 356:122. 103. Allida S, Cox KL, Hsieh CF, et al. Pharmacological, psychological, and non-invasive brain stimulation interventions for treating depression after stroke. Cochrane Database Syst Rev 2020; 1:CD003437. 104. Watkins C, Daniels L, Jack C, et al. Accuracy of a single question in screening for depression in a cohort of patients after stroke: comparative study. BMJ 2001; 323:1159. 105. Hinkle JL, Becker KJ, Kim JS, et al. Poststroke Fatigue: Emerging Evidence and Approaches to Management: A Scientific Statement for Healthcare Professionals From the American Heart Association. Stroke 2017; 48:e159. 106. Paciaroni M, Acciarresi M. Poststroke Fatigue. Stroke 2019; 50:1927. 107. De Doncker W, Dantzer R, Ormstad H, Kuppuswamy A. Mechanisms of poststroke fatigue. J Neurol Neurosurg Psychiatry 2018; 89:287. 108. Kutlubaev MA, Duncan FH, Mead GE. Biological correlates of post-stroke fatigue: a systematic review. Acta Neurol Scand 2012; 125:219. 109. Choi-Kwon S, Kim JS. Poststroke fatigue: an emerging, critical issue in stroke medicine. Int J Stroke 2011; 6:328. 110. Wu S, Mead G, Macleod M, Chalder T. Model of understanding fatigue after stroke. Stroke 2015; 46:893. 111. Wu S, Kutlubaev MA, Chun HY, et al. Interventions for post-stroke fatigue. Cochrane Database Syst Rev 2015; :CD007030. 112. Bivard A, Lillicrap T, Krishnamurthy V, et al. MIDAS (Modafinil in Debilitating Fatigue After Stroke): A Randomized, Double-Blind, Placebo-Controlled, Cross-Over Trial. Stroke 2017; 48:1293. 113. Seners P, Turc G, Oppenheim C, Baron JC. Incidence, causes and predictors of neurological deterioration occurring within 24 h following acute ischaemic stroke: a systematic review with pathophysiological implications. J Neurol Neurosurg Psychiatry 2015; 86:87. https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 26/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate 114. Helleberg BH, Ellekjaer H, Indredavik B. Outcomes after Early Neurological Deterioration and Transitory Deterioration in Acute Ischemic Stroke Patients. Cerebrovasc Dis 2016; 42:378. 115. Siegler JE, Martin-Schild S. Early Neurological Deterioration (END) after stroke: the END depends on the definition. Int J Stroke 2011; 6:211. 116. Park TH, Lee JK, Park MS, et al. Neurologic deterioration in patients with acute ischemic stroke or transient ischemic attack. Neurology 2020; 95:e2178. 117. Alawneh JA, Moustafa RR, Baron JC. Hemodynamic factors and perfusion abnormalities in early neurological deterioration. Stroke 2009; 40:e443.

function. J Comp Neurol 1987; 257:189. 70. Oppenheimer SM, Gelb A, Girvin JP, Hachinski VC. Cardiovascular effects of human insular cortex stimulation. Neurology 1992; 42:1727. 71. Oppenheimer SM, Kedem G, Martin WM. Left-insular cortex lesions perturb cardiac autonomic tone in humans. Clin Auton Res 1996; 6:131. 72. Zhang ZH, Rashba S, Oppenheimer SM. Insular cortex lesions alter baroreceptor sensitivity in the urethane-anesthetized rat. Brain Res 1998; 813:73. 73. S r s P, Hachinski V. Cardiovascular and neurological causes of sudden death after ischaemic stroke. Lancet Neurol 2012; 11:179. 74. Balofsky A, George J, Papadakos P. Neuropulmonology. Handb Clin Neurol 2017; 140:33. 75. Davenport RJ, Dennis MS, Warlow CP. Gastrointestinal hemorrhage after acute stroke. Stroke 1996; 27:421. 76. O'Donnell MJ, Kapral MK, Fang J, et al. Gastrointestinal bleeding after acute ischemic stroke. Neurology 2008; 71:650. 77. Fu J. Factors affecting the occurrence of gastrointestinal bleeding in acute ischemic stroke patients. Medicine (Baltimore) 2019; 98:e16312. 78. Ji R, Shen H, Pan Y, et al. Risk score to predict gastrointestinal bleeding after acute ischemic stroke. BMC Gastroenterol 2014; 14:130. 79. Taub NA, Wolfe CD, Richardson E, Burney PG. Predicting the disability of first-time stroke sufferers at 1 year. 12-month follow-up of a population-based cohort in southeast England. Stroke 1994; 25:352. 80. Nakayama H, J rgensen HS, Pedersen PM, et al. Prevalence and risk factors of incontinence after stroke. The Copenhagen Stroke Study. Stroke 1997; 28:58. 81. Hankey GJ, Jamrozik K, Broadhurst RJ, et al. Five-year survival after first-ever stroke and related prognostic factors in the Perth Community Stroke Study. Stroke 2000; 31:2080. 82. Pettersen R, Wyller TB. Prognostic significance of micturition disturbances after acute stroke. J Am Geriatr Soc 2006; 54:1878. https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 24/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate 83. Mehdi Z, Birns J, Bhalla A. Post-stroke urinary incontinence. Int J Clin Pract 2013; 67:1128. 84. Brittain KR, Peet SM, Castleden CM. Stroke and incontinence. Stroke 1998; 29:524. 85. Patel M, Coshall C, Rudd AG, Wolfe CD. Natural history and effects on 2-year outcomes of urinary incontinence after stroke. Stroke 2001; 32:122. 86. Burney TL, Senapati M, Desai S, et al. Acute cerebrovascular accident and lower urinary tract dysfunction: a prospective correlation of the site of brain injury with urodynamic findings. J Urol 1996; 156:1748. 87. Gelber DA, Good DC, Laven LJ, Verhulst SJ. Causes of urinary incontinence after acute hemispheric stroke. Stroke 1993; 24:378. 88. Linsenmeyer TA. Post-CVA voiding dysfunctions: clinical insights and literature review. NeuroRehabilitation 2012; 30:1. 89. Thomas LH, Coupe J, Cross LD, et al. Interventions for treating urinary incontinence after stroke in adults. Cochrane Database Syst Rev 2019; 2:CD004462. 90. Minet LR, Peterson E, von Koch L, Ytterberg C. Occurrence and Predictors of Falls in People With Stroke: Six-Year Prospective Study. Stroke 2015; 46:2688. 91. Ramnemark A, Nyberg L, Borss n B, et al. Fractures after stroke. Osteoporos Int 1998; 8:92. 92. Cox R, Buckholtz B, Bradas C, et al. Risk Factors for Falls Among Hospitalized Acute Post- Ischemic Stroke Patients. J Neurosci Nurs 2017; 49:355. 93. J rgensen L, Jacobsen BK, Wilsgaard T, Magnus JH. Walking after stroke: does it matter? Changes in bone mineral density within the first 12 months after stroke. A longitudinal study. Osteoporos Int 2000; 11:381. 94. Myint PK, Poole KE, Warburton EA. Hip fractures after stroke and their prevention. QJM 2007; 100:539. 95. Winstein CJ, Stein J, Arena R, et al. Guidelines for Adult Stroke Rehabilitation and Recovery: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2016; 47:e98. 96. Ayerbe L, Ayis S, Wolfe CD, Rudd AG. Natural history, predictors and outcomes of depression after stroke: systematic review and meta-analysis. Br J Psychiatry 2013; 202:14. 97. J rgensen TS, Wium-Andersen IK, Wium-Andersen MK, et al. Incidence of Depression After Stroke, and Associated Risk Factors and Mortality Outcomes, in a Large Cohort of Danish Patients. JAMA Psychiatry 2016; 73:1032. 98. Towfighi A, Ovbiagele B, El Husseini N, et al. Poststroke Depression: A Scientific Statement for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2017; 48:e30. https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 25/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate 99. Chemerinski E, Robinson RG, Kosier JT. Improved recovery in activities of daily living associated with remission of poststroke depression. Stroke 2001; 32:113. 100. House A, Knapp P, Bamford J, Vail A. Mortality at 12 and 24 months after stroke may be associated with depressive symptoms at 1 month. Stroke 2001; 32:696. 101. Robinson RG, Price TR. Post-stroke depressive disorders: a follow-up study of 103 patients. Stroke 1982; 13:635. 102. Carson AJ, MacHale S, Allen K, et al. Depression after stroke and lesion location: a systematic review. Lancet 2000; 356:122. 103. Allida S, Cox KL, Hsieh CF, et al. Pharmacological, psychological, and non-invasive brain stimulation interventions for treating depression after stroke. Cochrane Database Syst Rev 2020; 1:CD003437. 104. Watkins C, Daniels L, Jack C, et al. Accuracy of a single question in screening for depression in a cohort of patients after stroke: comparative study. BMJ 2001; 323:1159. 105. Hinkle JL, Becker KJ, Kim JS, et al. Poststroke Fatigue: Emerging Evidence and Approaches to Management: A Scientific Statement for Healthcare Professionals From the American Heart Association. Stroke 2017; 48:e159. 106. Paciaroni M, Acciarresi M. Poststroke Fatigue. Stroke 2019; 50:1927. 107. De Doncker W, Dantzer R, Ormstad H, Kuppuswamy A. Mechanisms of poststroke fatigue. J Neurol Neurosurg Psychiatry 2018; 89:287. 108. Kutlubaev MA, Duncan FH, Mead GE. Biological correlates of post-stroke fatigue: a systematic review. Acta Neurol Scand 2012; 125:219. 109. Choi-Kwon S, Kim JS. Poststroke fatigue: an emerging, critical issue in stroke medicine. Int J Stroke 2011; 6:328. 110. Wu S, Mead G, Macleod M, Chalder T. Model of understanding fatigue after stroke. Stroke 2015; 46:893. 111. Wu S, Kutlubaev MA, Chun HY, et al. Interventions for post-stroke fatigue. Cochrane Database Syst Rev 2015; :CD007030. 112. Bivard A, Lillicrap T, Krishnamurthy V, et al. MIDAS (Modafinil in Debilitating Fatigue After Stroke): A Randomized, Double-Blind, Placebo-Controlled, Cross-Over Trial. Stroke 2017; 48:1293. 113. Seners P, Turc G, Oppenheim C, Baron JC. Incidence, causes and predictors of neurological deterioration occurring within 24 h following acute ischaemic stroke: a systematic review with pathophysiological implications. J Neurol Neurosurg Psychiatry 2015; 86:87. https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 26/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate 114. Helleberg BH, Ellekjaer H, Indredavik B. Outcomes after Early Neurological Deterioration and Transitory Deterioration in Acute Ischemic Stroke Patients. Cerebrovasc Dis 2016; 42:378. 115. Siegler JE, Martin-Schild S. Early Neurological Deterioration (END) after stroke: the END depends on the definition. Int J Stroke 2011; 6:211. 116. Park TH, Lee JK, Park MS, et al. Neurologic deterioration in patients with acute ischemic stroke or transient ischemic attack. Neurology 2020; 95:e2178. 117. Alawneh JA, Moustafa RR, Baron JC. Hemodynamic factors and perfusion abnormalities in early neurological deterioration. Stroke 2009; 40:e443. 118. You S, Zheng D, Delcourt C, et al. Determinants of Early Versus Delayed Neurological Deterioration in Intracerebral Hemorrhage. Stroke 2019; 50:1409. 119. Yu WM, Abdul-Rahim AH, Cameron AC, et al. The Incidence and Associated Factors of Early Neurological Deterioration After Thrombolysis: Results From SITS Registry. Stroke 2020; 51:2705. Topic 1093 Version 45.0 https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 27/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate GRAPHICS Common medical complications of stroke Complication Percent Falls 25 Urinary tract infection 24 Chest infection 22 Pressure sores 21 Depression 16 Shoulder pain 9 Deep venous thrombosis 2 Pulmonary embolism 1 Medical complications of stroke were frequent in a prospective multicenter study of 311 patients followed weekly through hospital discharge and again at 6, 18, and 30 months after stroke. Data from: Langhorne, P, Stott, DJ, Robertson, L, et al. Medical complications after stroke: a multicenter study. Stroke 2000; 31:1223. Graphic 52076 Version 2.0 https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 28/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate Serious medical complications of stroke Complication Percent All pneumonias 5 Aspiration pneumonia alone 3 Heart failure 3 Gastrointestinal bleeding 3 Cardiac arrest 2 Angina/MI/cardiac ischemia 1 Deep venous thrombosis 1 Pulmonary embolism 1 Hypoxia 1 Urinary tract infection 1 Sepsis 1 Cellulitis 1 Peripheral vascular disorder 1 Dyspnea 1 Pulmonary edema 1 Dehydration 1 In a prospective study that analyzed the placebo group of the RANTTAS database (n = 279), at least one serious medical complication (defined as prolonged, immediately life threatening, or resulting in hospitalization or death) occurred in 24 percent of patients. Data from: Johnston, KC, Li, JY, Lyden, PD, et al. Medical and neurological complications of ischemic stroke: experience from the RANTTAS trial. RANTTAS Investigators. Stroke 1998; 29:447. Graphic 68148 Version 3.0 https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 29/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate Causes of elevated troponin Myocardial ischemia Acute coronary syndrome STEMI NSTEMI Other coronary ischemia Arrhythmia: tachy- or brady- Cocaine/methamphetamine use Coronary intervention (PCI or cardiothoracic surgery) Coronary artery spasm (variant angina) Stable coronary atherosclerotic disease in setting of increased O demand (eg, tachycardia) 2 Severe hypertension Coronary embolus Aortic dissection Coronary artery vasculitis (SLE, Kawasaki) Noncoronary ischemia Shock (hypotension) Hypoxia Hypoperfusion Pulmonary embolism Global ischemia Cardiothoracic surgery Myocardial injury with no ischemia Comorbidities Renal failure Sepsis Infiltrative diseases Acute respiratory failure Stroke Subarachnoid hemorrhage https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 30/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate Specific identifiable precipitants Extreme exertion Cardiac contusion Burns >30% BSA Cardiotoxic meds: anthracyclines, herceptin Electrical shock Carbon monoxide exposure Other Stress (takotsubo) cardiomyopathy Myocarditis Myopericarditis Rhabdomyolysis involving cardiac muscle Hypertrophic cardiomyopathy Peripartum cardiomyopathy Heart failure, malignancy, stress cardiomyopathy STEMI: ST elevation myocardial infarction; NSTEMI: non-ST elevation myocardial infarction; PCI: percutaneous coronary intervention; SLE: systemic lupus erythematosus; BSA: body surface area. Graphic 54910 Version 15.0 https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 31/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate Causes of neurogenic pulmonary edema Major causes Epileptic seizures, particularly status epilepticus Intracranial hemorrhage (including intracerebral hemorrhage, intraventricular hemorrhage, epidural hemorrhage, subdural hemorrhage) Head injury Minor causes Guillain-Barr syndrome Multiple sclerosis with medullary involvement Nonhemorrhagic strokes Trigeminal nerve block Bulbar poliomyelitis Vertebral artery ligation Vertebral artery dissection Ruptured spinal arteriovenous malformation Air embolism Brain tumors Electroconvulsive therapy Induction of general anesthesia Colloid cyst Hydrocephalus Reye syndrome Bacterial meningitis Viral meningoencephalitis (including enterovirus-7) Cervical spinal cord injury Cryptococcal meningoencephalitis Hyponatremia High-voltage electrical injury Graphic 57483 Version 6.0 https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 32/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate Respiratory patterns associated with neurological injury Graphic 74371 Version 2.0 https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 33/34 7/5/23, 12:05 PM Complications of stroke: An overview - UpToDate Contributor Disclosures Koto Ishida, MD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/complications-of-stroke-an-overview/print 34/34

7/5/23, 12:06 PM Locked-in syndrome - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Locked-in syndrome : Louis R Caplan, MD : Jos Biller, MD, FACP, FAAN, FAHA, Glenn A Tung, MD, FACR : Janet L Wilterdink, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Sep 20, 2021. INTRODUCTION The locked-in syndrome is a catastrophic condition caused most often by ischemic stroke or hemorrhage, affecting the corticospinal, corticopontine, and corticobulbar tracts in the brainstem. Because consciousness and higher cortical functions are spared, patients can sometimes communicate through eye movements. Alexandre Dumas provided one of the earliest descriptions of the locked-in syndrome in "The Count of Monte Cristo" by vividly depicting a character who was "a corpse with living eyes." Following a stroke, Monsignor Noirtier de Villefort could only communicate by raising, closing, or winking his eyes [1]. Issues related to the locked-in syndrome will be reviewed here. Conditions superficially similar to the locked-in syndrome, such as coma, minimally conscious state, and persistent vegetative state, are discussed separately. (See "Stupor and coma in adults".) DEFINITION AND ANATOMY In 1966, Plum and Posner coined the term "locked-in" to describe the state of quadriplegia and anarthria (speechlessness due to severe dysarthria) with preserved consciousness [2]. Synonymous with locked-in syndrome are "de-efferented state," "pseudocoma," and "coma vigilante." There are two requisites for the diagnosis of locked-in syndrome: https://www.uptodate.com/contents/locked-in-syndrome/print 1/20 7/5/23, 12:06 PM Locked-in syndrome - UpToDate Retained alertness and cognitive abilities Paralysis of the limbs and oral structures such that the individual cannot signal with the limbs or speak The important neuronal tracts that are disrupted in patients with locked-in syndrome course from the cortex toward the bulbar motor neurons and spinal cord by traveling through the brainstem. Limb movements are mediated by the tracts to the spinal cord neurons that travel in the basal and ventral portions of the brainstem; these include the cerebral peduncles in the midbrain, the base of the pons, and the medullary pyramids. Bilateral lesions of these structures cause a loss of voluntary limb movement accompanied by exaggerated deep tendon reflexes, limb spasticity, and extensor plantar reflexes (Babinski signs). Motor function of the mouth, pharynx, and jaws is mediated by the corticobulbar fibers that travel in the dorsal portion of the midbrain and pons near the tegmental-basal junction and synapse with the motor neurons located in the ambiguous (cranial nerves IX, X, XI), trigeminal (cranial nerve V), and facial (cranial nerve VII) nuclei. Bilateral lesions involving these fibers cause a loss of voluntary mouth and tongue movement as well as loss of speech and swallow. The structures within the brainstem that control eye movements and consciousness are located in the dorsal portion of the tegmentum in the midbrain and pons near the midline. The eye movement nuclei (cranial nerves III, IV, VI) and connecting pathways that relate to eye movements (the medial longitudinal fasciculi [MLF] and the so-called pontine lateral gaze center in the paramedian pontine reticular formation [PPRF]) are symmetrically represented in the medial tegmentum on each side of the midline. Bilateral lesions that involve these structures cause a loss of horizontal eye movements. When the lesions involve only one side, some horizontal eye movement is preserved. The medial and lateral reticular formation subserves consciousness and the control of respiratory, cardiac, and vasomotor functions, respectively. The portion of the reticular activating system that relates to consciousness is located in the paramedian tegmentum, while cardiovascular and respiratory-related structures are located more laterally in the tegmentum of the pons and medulla oblongata. Lesions must involve the medial tegmentum bilaterally to cause coma. Automatic respirations and cardiovascular functions are not affected if the brainstem tegmental lesions are paramedial, and lateral tegmental structures are spared. (See "Stupor and coma in adults".) ETIOLOGY https://www.uptodate.com/contents/locked-in-syndrome/print 2/20 7/5/23, 12:06 PM Locked-in syndrome - UpToDate The most common cause of locked-in syndrome is ischemic or hemorrhagic stroke, accounting for 38 of 44 cases in a review from France [3]. Ischemic infarction of the ventral pons is usually due to basilar artery embolism or thrombosis ( picture 1) [4]. The most vulnerable territory is the paramedian base of the pons. Because the tegmentum has generous collateral supply that courses from the lateral aspect, the lateral and medial tegmentum are often spared. Midbrain infarction or traumatic injury of the bilateral cerebral peduncles causing the locked-in syndrome has also been reported [5-7]. A second cause of stroke-induced locked-in syndrome is pontine hemorrhage, which is most often related to hypertension but can also result from vascular malformations. Hypertensive pontine hemorrhages typically begin at the tegmentobasal junction and usually cause coma, loss of horizontal gaze, quadriplegia, and eventually death. A residual locked-in state is rare. Additional causes of the locked-in syndrome include trauma [3,7], pontine abscess [8], brainstem tumors [9,10], central pontine myelinolysis [11-13], toxins, heroin abuse [14], and others [15]. CLINICAL FEATURES Bilateral ventral pontine damage causes quadriplegia and inability to speak or swallow, but consciousness is preserved. Because the supranuclear ocular motor pathways lie more dorsally, patients with locked-in syndrome can move their eyes. Thus, voluntary blinking and vertical eye movements remain intact, but the patient cannot otherwise move muscles in the limbs, trunk, or face. Sparing of the reticular formation allows for normal wakefulness, but sleep-wake cycles may be abnormal depending on the extent of damage to the intricate sleep pathways in the brainstem. Various abnormalities have been identified in both rapid eye movement (REM) and non-REM sleep [15]. Tegmental lesions In some patients, the initial dysfunction (most often ischemia) also extends to the tegmentum of the pons on one or both sides. Bilateral lesions affecting the paramedian tegmentum result in coma and loss of horizontal eye movements. Vertical eye movements, which are controlled in the rostral portion of the brainstem, are preserved. Sometimes, the eyes bob downward spontaneously or when the head is rolled from side to side in the "doll's eyes" maneuver. With unilateral pontine tegmental lesions, consciousness is preserved. In such cases, the eye movement abnormality may consist of one of the following types: https://www.uptodate.com/contents/locked-in-syndrome/print 3/20 7/5/23, 12:06 PM Locked-in syndrome - UpToDate Loss of horizontal conjugate gaze to the side of the lesion. An internuclear ophthalmoplegia (INO) manifested by abnormalities of gaze to the opposite side that are due to loss of adduction of the ipsilateral eye along with nystagmus of the abducting eye. As an example, a lesion of the left medial longitudinal fasciculus (MLF) would result in loss of rightward movement of the left eye and nystagmus of the right eye during attempted gaze to the right side. (See "Internuclear ophthalmoparesis".) A combination of the lateral gaze and internuclear deficits referred to as a "one-and-a-half" syndrome. If gaze to each side is tallied as one, the only gaze remaining is abduction of one eye (ie, only one-half of the usual two movements). As an example, a lesion of the left pontine tegmentum affecting both the paramedian pontine reticular formation (PPRF) and the MLF would result in the only residual movement being abduction of the right eye on right lateral gaze. Other Many patients with the locked-in syndrome retain some other voluntary movements beside vertical eye motion such as horizontal gaze, facial expression, limb, head, or tongue movements [15]. Patients with the locked-in syndrome may have various different involuntary motor phenomena including ocular bobbing, crying, trismus, oral automatisms, groaning, facial grimacing, yawning, palatal myoclonus, sighing, coughing, bruxism, and laughing [15]. Some have involuntary limb movements that resemble seizures, especially when they first become weak [16]. These movements can be periodic limb-stiffening, shivering, and dystonic postures. Respiration is often affected in the locked-in syndrome when the lateral tegmentum of the pons or medulla is involved. Patients may require assistance in ventilation and pulmonary toilet. The lips, tongue, and soft palate are all thoroughly weakened as to prevent coordination of breathing, voluntary vocalization, or swallowing. DIAGNOSIS In order to establish the diagnosis of the locked-in syndrome, it is imperative to demonstrate preservation of consciousness, alertness, and cognitive function in a patient with paralysis of the limbs and oral structures. Observation and examination of eye movements during bedside interaction is the key to making this determination, since patients with the locked-in syndrome cannot respond to questions by speaking or moving the limbs. The diagnosis can easily be missed if voluntary vertical eye movements are not examined with great care in patients who seem unresponsive [17]. https://www.uptodate.com/contents/locked-in-syndrome/print 4/20 7/5/23, 12:06 PM Locked-in syndrome - UpToDate Vertical eye movements should be reexamined in otherwise unresponsive patients if brain magnetic resonance imaging (MRI) shows a lesion in the ventral pons [17]. In addition, eye movements should be reexamined over time, as some patients may emerge from coma into a locked-in state after a variable delay. Hearing may recover before eye-opening [18]. Some investigators have noted that patients with the locked-in syndrome tire quickly when using vertical eye movements to communicate [17]. In addition, patients with the locked-in syndrome may have a severely limited attention span in the first weeks or months after onset of the locked-in syndrome [17]. Because of the inherent difficulty in diagnosing the locked-in syndrome, the diagnosis is often delayed. In a review of 44 cases from France, the mean time to diagnosis of the locked-in syndrome was 79 days after onset [3]. The neurologic examination should begin by determining whether the patient is awake, opens eyes to voice, blinks to command, and can move the limbs. The paralyzed patient with the locked-in syndrome will be able to respond to complex linguistic requests with vertical eye movements and blinking but cannot move the limbs or speak. Neuroimaging Infarction and other structural lesions of the brainstem including tumor, abscess, and demyelination are best visualized on MRI because computed tomography (CT) of the posterior fossa may be compromised by beam-hardening artifact ( image 1). Diffusion- weighted MRI is very sensitive for acute ischemic infarction. Noncontrast CT and both T2*-weighted gradient echo and susceptibility-weighted MRI are sensitive for the detection of brainstem hemorrhage ( image 2). Both CT and magnetic resonance angiography can identify the location and severity of large- and medium-size vessel occlusions in the extracranial arteries of the neck and intracranial circulation. Steno-occlusive disease of short and long circumferential basilar artery branches that supply the pons is often too small to be detected on these examinations. Other tests Electroencephalography (EEG) reactivity is not a reliable measure of consciousness in patients with the locked-in syndrome as reactivity can be absent in some cases [19]. However, the presence of alpha coma does help to distinguish diffuse cerebral injuries such as the persistent vegetative state from the locked-in syndrome. In addition, a normal EEG in a patient who seems unresponsive suggests either the locked-in syndrome or psychogenic coma, so it can be helpful. Somatosensory evoked potentials have variable patterns and thus show no specific characteristics in the locked-in syndrome [19]. Brainstem auditory evoked potentials are normal https://www.uptodate.com/contents/locked-in-syndrome/print 5/20 7/5/23, 12:06 PM Locked-in syndrome - UpToDate when brainstem lesions do not involve auditory pathways, as can be the case in the locked-in syndrome. A lumbar puncture is warranted to consider inflammatory and infectious causes such as encephalitis if MRI does not reveal a structural cause in patients with possible locked-in syndrome. Differential diagnosis When immobile patients do not respond to queries or directions, the differential diagnosis includes the locked-in syndrome, coma, persistent vegetative state, akinetic mutism, catatonia, and psychogenic unresponsiveness ( table 1). Is the patient not responding because of paralysis with retained consciousness (the locked-in syndrome), reduced consciousness and awareness (stupor or coma), wakefulness without awareness (persistent vegetative state), or a psychiatric disorder (catatonia or psychogenic unresponsiveness)? (See "Stupor and coma in adults".) The essential criteria to make a diagnosis of the locked-in syndrome are paralysis with intact awareness and cognitive function. Comatose patients do not open or move the eyes, respond to voice or noxious stimuli, or move the limbs. The patient with the locked-in syndrome uses vertical eye movements and blinking to follow complex linguistic requests. Since control of eye movements rests in the medial tegmentum of the brainstem, examination of eye movement function is an important key to differential diagnosis. What is the position of the eyes at rest? An ocular skew may indicate damage to the brainstem. Are there spontaneous roving eye movements? This finding is often caused by bilateral cerebral hemisphere disease due to bilateral strokes or metabolic or toxic disorders. Is there bobbing of the eyes downward? This finding suggests a pontine lesion. Can the patient open the eyes and look up and down? Preserved vertical eye movements indicate intact midbrain function. Are doll's eyes movements in the horizontal and vertical positions preserved? In coma due to brainstem lesions, horizontal eye movements are lost and vertical eye movements are often spared. In akinetic mutism, patients lack drive and motivation to move and speak spontaneously. Maintenance of body posture is a distinguishing feature of catatonia. https://www.uptodate.com/contents/locked-in-syndrome/print 6/20 7/5/23, 12:06 PM Locked-in syndrome - UpToDate Amyotrophic lateral sclerosis (ALS) is another central cause of the locked-in syndrome in which oculomotor function is spared, but ALS causes gradual weakness and does not present acutely. (See "Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease".) Purely peripheral conditions that may have clinical features similar to the locked-in syndrome include severe polyneuropathy, such as acute inflammatory demyelinating polyradiculoneuropathy (AIDP; also known as Guillain-Barr syndrome); neuromuscular disorders, such as myasthenia gravis and critical illness neuropathy/myopathy; and pharmacologic neuromuscular blockade. (See "Guillain-Barr syndrome in adults: Pathogenesis, clinical features, and diagnosis" and "Clinical manifestations of myasthenia gravis" and "Neuromuscular weakness related to critical illness".) While these neuromuscular disorders may cause profound diffuse limb weakness, it is rare for any of them to cause complete bulbar and limb paralysis. Either speech or some limb motion is typically spared, permitting communication or signaling. The past history and gradual development of paralysis almost always allows identification of a peripheral neuromuscular problem. Toxic-metabolic encephalopathies and the presence of sedative, analgesic, or psychotropic drugs must all be considered and ruled out when the patient is unresponsive and imaging does not support a structural cause. (See "Diagnosis of delirium and confusional states" and "Stupor and coma in adults".) PROGNOSIS Although early literature suggested that the locked-in syndrome was an irreversible condition leading to death shortly after onset [20], accumulating evidence suggests that a substantial proportion regain some function over time, and a minority have a good functional recovery. However, most survivors of the locked-in syndrome remain chronically locked-in or severely impaired. Case studies described patients who recovered from the locked-in syndrome anywhere from 30 minutes to several weeks after onset. In these cases, the causes of the locked-in syndrome were brainstem ischemia, encephalitis, and trauma [21]. One report described four patients with the locked-in syndrome due to presumed basilar artery occlusion who made substantial functional gains over several months while receiving supportive therapy and rehabilitation [22]. These patients recovered to independence in at least some activities of daily living; they regained https://www.uptodate.com/contents/locked-in-syndrome/print 7/20 7/5/23, 12:06 PM Locked-in syndrome - UpToDate bowel and bladder control, could eat by mouth, and regained functional, although dysarthric, speech. Few large-scale studies have evaluated the extent of recovery and mortality of patients with the locked-in syndrome. In the largest published review of 139 cases, the mortality rate was 60 percent, and most of the deaths (87 percent) occurred within the first four months [15]. The most common causes of death were pneumonia, pulmonary embolism, extension of brainstem lesions, and sepsis. Patients with the locked-in syndrome due to nonvascular etiologies (eg, trauma) had lower mortalities and faster and more complete recoveries compared with patients with the locked-in syndrome due to vascular causes, mainly pontine infarction. However, functional recovery was generally good in those patients with a vascular etiology who survived beyond four months. The most extensive longitudinal evidence comes from a cohort of 27 patients with the locked-in syndrome who were locked-in for over a year; the first report from this cohort was an observational study published in 1987 [23]. Mean survival was 4.9 years and ranged from 1.2 to 12.8 years by study completion. The majority of the survivors were at home, while some lived in nursing homes or acute care hospitals. Eleven patients never moved their limbs or head, six had minor movements, and 10 could trigger a switch, point, or type. Seven patients could use an electric wheelchair. Many patients in this series achieved bowel and bladder continence [23]. All except for seven ate food by mouth. Eight patients (29 percent) could consistently answer questions appropriately but had learning difficulties. Some of those patients had extrapontine hemorrhages or traumatic injury. Sixteen patients (59 percent) recovered the ability to cry involuntarily or speak words and sentences. All except for three patients communicated with gestures, limb movements, a letter board, or electronic equipment. Almost all of the patients in this series developed typical complications of chronic assisted care including urinary tract infections, pneumonia, pressure sores, gastrointestinal bleeding, and deep venous thrombosis [23]. Many of these medical problems were attributed to indwelling urinary catheters, gastrostomy tubes, and tracheostomies, although there were insufficient patient numbers to ascertain a statistical association between medical complications and these devices. In a subsequent report published in 1992 by the same investigators, who added two further patients, survival ranged from 2 to 18 years [24]. A telephone survey published in 2003 found that from the original cohort of 29 patients, 16 had died in the interim. Overall survival rates at https://www.uptodate.com/contents/locked-in-syndrome/print 8/20 7/5/23, 12:06 PM Locked-in syndrome - UpToDate 10 and 20 years were 83 and 40 percent, respectively [25]. This is one of the few studies to date showing that some patients with the locked-in syndrome survive for a decade or more. In another study, among 11 patients with the locked-in syndrome followed anywhere from 7 months to 10 years, four (36 percent) achieved good functional outcomes [26]. All of the patients could manipulate a digital switch, and some used electric wheelchairs and computers for communication. Recovery tended to progress distally and spread proximally along the axial musculature. Quality of life There is limited information on the quality of life or emotional state of patients with the locked-in syndrome. A psychological analysis of seven long-term survivors found that their quality of life was worse than cancer patients but better than the terminally ill; all scored in the range of a depressive illness, and four had contemplated suicide. All, however, wanted life-sustaining treatments including antibiotics for pneumonia [27]. In a retrospective survey cited above involving 13 survivors with the locked-in syndrome (from an initial cohort of 29) or their caregivers, satisfaction with life was expressed by seven patients, occasional depression was reported for five patients, euthanasia was never considered by seven, euthanasia was considered but refused by six, and a wish to die was expressed by one patient [25]. None had do not resuscitate (DNR) directives. A subsequent case-control study compared 19 patients with the locked-in syndrome and 20 age-matched healthy control subjects [28]. There was no significant difference between the locked-in syndrome group and healthy controls on scores assessing overall quality of life and mental health. However, the locked-in syndrome group had significantly lower scores on measures of physical function, as might be expected. In addition, the locked-in syndrome group had a significantly higher frequency of depressive symptoms. These studies underscore the need to screen for the development of and to address possible treatment for depression and suicidal ideation in patients with the locked-in syndrome. TREATMENT While there are no proven medical therapies that promote recovery from the locked-in syndrome, care should be centralized and coordinated in a specialized rehabilitation center experienced in the locked-in syndrome. Multimodal therapy with physical and speech therapy https://www.uptodate.com/contents/locked-in-syndrome/print 9/20 7/5/23, 12:06 PM Locked-in syndrome - UpToDate and assistive devices to facilitate interaction may improve outcome. Supportive and preventive measures are of paramount importance for patients with the locked-in syndrome. Patients with the locked-in syndrome are fully conscious and should be encouraged to participate in decisions affecting their care at all stages of treatment. Immediate therapies The acute stage of treatment for the locked-in syndrome focuses on securing and maintaining an airway and ensuring adequate oxygenation. Primary attention should be paid to rapidly identifying the vascular cause of the locked-in syndrome. For patients with the locked-in syndrome due to acute ischemic stroke (within 48 hours from onset or most recent deterioration) with persistent vascular occlusion, revascularization is appropriate. This recommendation is made because of the poor functional prognosis of brainstem stroke associated with the locked-in syndrome. The utility of intravenous thrombolysis and endovascular treatments for posterior circulation stroke are discussed separately. (See "Approach to reperfusion therapy for acute ischemic stroke", section on 'Posterior circulation stroke'.) The use of antithrombotic therapy for vertebral and basilar artery dissection is reviewed separately. (See "Cerebral and cervical artery dissection: Treatment and prognosis".) Nonvascular causes should be managed according to specific etiologies (eg, antibiotics for infection, steroids for inflammatory lesions, radiation/chemotherapy for brainstem tumors). Subacute and chronic therapies Given that many patients can achieve some meaningful recovery, we suggest aggressive supportive measures; intense physical, speech, respiratory, and swallowing therapy; and assisted devices to facilitate interaction with others and the environment [17]. Although data are limited, support for aggressive rehabilitation therapy comes from a case series published in 2003 that evaluated the recovery patterns of 14 patients with the locked-in syndrome who underwent intensive, multidisciplinary rehabilitation within a mean of one month of symptom onset [29]. The following observations were made: Partial or full independence in activities of daily living within three to six months of onset was achieved by three patients (21 percent) Complete swallowing ability recovered in six (43 percent) Verbal communication recovered despite dysarthria and dysphonia in four (28 percent) Ability to use a device by hand, finger, or head movement was achieved in six (43 percent) https://www.uptodate.com/contents/locked-in-syndrome/print 10/20 7/5/23, 12:06 PM Locked-in syndrome - UpToDate Tracheostomy removal was achieved by six patients (43 percent) Finally, all but four patients returned home. Unless patients themselves express wishes not to be sustained, we discourage attitudes of medical nihilism towards the locked-in syndrome [30,31]. After hospitalization, care should be centralized and coordinated in a specialized rehabilitation center experienced in the locked-in syndrome. Care should include identifying and treating reversible medical conditions such as infections and electrolyte abnormalities, inquiring about and treating pain, and preventing immobility, contractures, corneal abrasions, and decubitus ulcers. The locked-in syndrome poses high risks for respiratory complications, and patients need to be monitored closely for difficulties handling secretions or needs for ventilatory assistance. Accordingly, we favor chest physiotherapy, deep breathing exercises [29], and chest mobilization to facilitate bronchial secretions. Vigorous medical management may allow for the formation of collateral circulation and recovery of damaged neural pathways. Modification of vascular risk factors is imperative to reduce the risk of subsequent strokes and other vascular events. (See "Overview of secondary prevention of ischemic stroke".) Planning with family and friends is necessary to design long-term care. Communication For basic communication, a combination of eyelid-blinking and vertical eye movements can be used to establish a yes/no code. A variety of electronic devices are available to facilitate communication, including computers, printers, synthetic voice machines triggered by sensitive switches, and head or eye gaze sensors [32]. Such communication devices have allowed patients to e-mail, use the internet, read daily news, write stories, compose music, and shop online [32]. Whatever form of communication is used, the method should be posted at the bedside. SUMMARY AND RECOMMENDATIONS Definition The locked-in syndrome is a rare catastrophic condition characterized by limb paralysis and loss of speech with retained consciousness, alertness, and cognition. (See 'Definition and anatomy' above.) Neuroanatomy and causes The locked-in syndrome is caused by destructive bilateral brainstem lesions affecting the corticospinal, corticopontine, and corticobulbar tracts. The https://www.uptodate.com/contents/locked-in-syndrome/print 11/20 7/5/23, 12:06 PM Locked-in syndrome - UpToDate most common cause is ischemic infarction of the ventral pons. (See 'Etiology' above.) Clinical features Quadriplegia and inability to speak or swallow with retained cognition are the hallmarks of the locked-in syndrome. Respiration is often affected. Because the supranuclear ocular motor pathways are spared, patients can move their eyes and blink. Many patients with LIS also retain some other voluntary movements such as horizontal gaze, facial expression, and limb, head, or tongue movements. In addition, patients with the locked-in syndrome may have involuntary ocular, oral, or limb movements. (See 'Clinical features' above.) Diagnosis In a patient with quadriplegia who cannot speak, demonstration of preserved consciousness requires close observation and examination of eye movements during bedside interaction. This is the key to making the diagnosis of the locked-in syndrome. (See 'Diagnosis' above.) Differential diagnosis The differential diagnosis of the locked-in syndrome includes coma, persistent vegetative state, akinetic mutism, catatonia, and psychogenic unresponsiveness. (See 'Differential diagnosis' above.) Management The acute stage of treatment for the locked-in syndrome focuses on securing and maintaining an airway, ensuring adequate oxygenation, and rapidly identifying and treating vascular causes. (See 'Immediate therapies' above.) For patients with the locked-in syndrome due to acute ischemic stroke caused by vertebral or basilar artery embolism or thrombosis with persistent vascular occlusion, reperfusion therapy is advised. Specific recommendations are provided separately. (See "Approach to reperfusion therapy for acute ischemic stroke", section on 'Posterior circulation stroke'.) Prognosis Most survivors of the locked-in syndrome remain chronically locked-in or severely impaired. However, many regain some motor function over time, and a minority have a good functional recovery. Aggressive multidisciplinary rehabilitation measures are appropriate for patients with the locked-in syndrome who indicate a desire for such therapy. Ideally, such therapy should begin within one month of onset and include intense physical, speech, and respiratory therapy. (See 'Subacute and chronic therapies' above.) Long-term supportive care Supportive care for the locked-in syndrome should include identifying and treating reversible medical conditions such as infections and electrolyte https://www.uptodate.com/contents/locked-in-syndrome/print 12/20 7/5/23, 12:06 PM Locked-in syndrome - UpToDate abnormalities, inquiring about and treating patients' pain, and preventing immobility, contractures, corneal abrasions, and decubitus ulcers. (See 'Subacute and chronic therapies' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Sean Savitz, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Dumas A. The Count of Monte Cristo, Wordworth Editions, London 1997. 2. Plum F, Posner JB. The Diagnosis of Stupor and Coma, FA Davis, Philadelphia 1966. 3. Le n-Carri n J, van Eeckhout P, Dom nguez-Morales Mdel R, P rez-Santamar a FJ. The locked-in syndrome: a syndrome looking for a therapy. Brain Inj 2002; 16:571. 4. Bruno MA, Schnakers C, Damas F, et al. Locked-in syndrome in children: report of five cases and review of the literature. Pediatr Neurol 2009; 41:237. 5. Karp JS, Hurtig HI. "Locked-in" state with bilateral midbrain infarcts. Arch Neurol 1974; 30:176. 6. Zakaria T, Flaherty ML. Locked-in syndrome resulting from bilateral cerebral peduncle infarctions. Neurology 2006; 67:1889. 7. Carrai R, Grippo A, Fossi S, et al. Transient post-traumatic locked-in syndrome: a case report and a literature review. Neurophysiol Clin 2009; 39:95. 8. Murphy MJ, Brenton DW, Aschenbrener CA, Van Gilder JC. Locked-in syndrome caused by a solitary pontine abscess. J Neurol Neurosurg Psychiatry 1979; 42:1062. 9. Cherington M, Stears J, Hodges J. Locked-in syndrome caused by a tumor. Neurology 1976; 26:180. 10. Inci S, Ozgen T. Locked-in syndrome due to metastatic pontomedullary tumor case report. Neurol Med Chir (Tokyo) 2003; 43:497. 11. Pirzada NA, Ali II. Central pontine myelinolysis. Mayo Clin Proc 2001; 76:559. 12. Heckmann JG, Dinkel HP. Recovery of locked-in syndrome in central pontine myelinolysis. Am J Case Rep 2013; 14:219. https://www.uptodate.com/contents/locked-in-syndrome/print 13/20 7/5/23, 12:06 PM Locked-in syndrome - UpToDate 13. Sohn MK, Nam JH. Locked-in Syndrome due to Central Pontine Myelinolysis: Case Report. Ann Rehabil Med 2014; 38:702. 14. Hall JH 3rd, Karp HR. Acute progressive ventral pontine disease in heroin abuse. Neurology 1973; 23:6. 15. Patterson JR, Grabois M. Locked-in syndrome: a review of 139 cases. Stroke 1986; 17:758. 16. Ropper AH. 'Convulsions' in basilar artery occlusion. Neurology 1988; 38:1500. 17. Smith E, Delargy M. Locked-in syndrome. BMJ 2005; 330:406. 18. Chisholm N, Gillett G. The patient's journey: living with locked-in syndrome. BMJ 2005; 331:94. 19. G tling E, Isenmann S, Wichmann W. Electrophysiology in the locked-in-syndrome. Neurology 1996; 46:1092. 20. Bauer G, Gerstenbrand F, Rumpl E. Varieties of the locked-in syndrome. J Neurol 1979; 221:77. 21. Khurana RK, Genut AA, Yannakakis GD. Locked-in syndrome with recovery. Ann Neurol 1980; 8:439. 22. McCusker EA, Rudick RA, Honch GW, Griggs RC. Recovery from the 'locked-in' syndrome. Arch Neurol 1982; 39:145. 23. Haig AJ, Katz RT, Sahgal V. Mortality and complications of the locked-in syndrome. Arch Phys Med Rehabil 1987; 68:24. 24. Katz RT, Haig AJ, Clark BB, DiPaola RJ. Long-term survival, prognosis, and life-care planning for 29 patients with chronic locked-in syndrome. Arch Phys Med Rehabil 1992; 73:403. 25. Doble JE, Haig AJ, Anderson C, Katz R. Impairment, activity, participation, life satisfaction, and survival in persons with locked-in syndrome for over a decade: follow-up on a previously reported cohort. J Head Trauma Rehabil 2003; 18:435. 26. Richard I, P reon Y, Guiheneu P, et al. Persistence of distal motor control in the locked in syndrome. Review of 11 patients. Paraplegia 1995; 33:640. 27. Anderson C, Dillon C, Burns R. Life-sustaining treatment and locked-in syndrome. Lancet 1993; 342:867. 28. Rousseau MC, Pietra S, Nadji M, Billette de Villemeur T. Evaluation of quality of life in complete locked-in syndrome patients. J Palliat Med 2013; 16:1455. 29. Casanova E, Lazzari RE, Lotta S, Mazzucchi A. Locked-in syndrome: improvement in the prognosis after an early intensive multidisciplinary rehabilitation. Arch Phys Med Rehabil 2003; 84:862. https://www.uptodate.com/contents/locked-in-syndrome/print 14/20 7/5/23, 12:06 PM Locked-in syndrome - UpToDate 30. Thiel A, Schmidt H, Prange H, Nau R. [Treatment of patients with thromboses of the basilar artery and locked-in syndrome. An ethical dilemma]. Nervenarzt 1997; 68:653. 31. Laureys S, Pellas F, Van Eeckhout P, et al. The locked-in syndrome : what is it like to be conscious but paralyzed and voiceless? Prog Brain Res 2005; 150:495. 32. S derholm S, Meinander M, Alaranta H. Augmentative and alternative communication methods in locked-in syndrome. J Rehabil Med 2001; 33:235. Topic 1099 Version 20.0 https://www.uptodate.com/contents/locked-in-syndrome/print 15/20 7/5/23, 12:06 PM Locked-in syndrome - UpToDate GRAPHICS Basilar artery thrombosis Postmortem photograph of the ventral surface of the brainstem showing a dilated, thrombosed basilar artery. The thrombus extends into the anterior inferior cerebellar artery on the right. The two vertebral arteries that join to form the basilar are seen at the bottom of the photograph. Graphic 56754 Version 2.0 https://www.uptodate.com/contents/locked-in-syndrome/print 16/20 7/5/23, 12:06 PM Locked-in syndrome - UpToDate Central pontine myelinolysis Fifty-year-old individual with alcohol use disorder was treated for hyponatremia and developed decreased consciousness and de-efferented state (ie, patient was not able to speak or move face or limbs) secondary to osmotic demyelination syndrome. Sagittal T1-weighted (A) and transverse axial T2-weighted (B) MRIs demonstrate abnormal signal intensity in basis pontis consistent with central pontine myelinolysis. MRI: magnetic resonance imaging. Courtesy of Glenn A Tung, MD, FACR. Graphic 132737 Version 2.0 https://www.uptodate.com/contents/locked-in-syndrome/print 17/20 7/5/23, 12:06 PM Locked-in syndrome - UpToDate Hypertensive pontine hemorrhage Thirty-six-year-old with locked-in syndrome from hypertensive pontine hemorrhage. Noncontrast CT (A), T2* weighted gradient echo (B), and magnified susceptibility-weighted MRI (C) demonstrate acute upper pontine hematoma. CT: computed tomography; MRI: magnetic resonance imaging. Courtesy of Glenn A Tung, MD, FACR. Graphic 132738 Version 2.0 https://www.uptodate.com/contents/locked-in-syndrome/print 18/20 7/5/23, 12:06 PM Locked-in syndrome - UpToDate Differential diagnosis of locked-in syndrome Distinguishing clinical features Anatomical lesion Locked-in Quadriplegia with preserved vertical Pontine base syndrome eye movements and consciousness Coma Unresponsive to stimuli, does not follow commands Bilateral cerebral or upper brain stem Akinetic mutism No spontaneity or motivation Bifrontal, deep gray matter, upper brain stem Catatonia Maintenance of body posture No CNS lesions Persistent vegetative state No higher cortical functions, does not follow commands, retained Diffuse cerebral hemisphere cardiovascular and respiratory functions CNS: central nervous system. Graphic 65484 Version 3.0 https://www.uptodate.com/contents/locked-in-syndrome/print 19/20 7/5/23, 12:06 PM Locked-in syndrome - UpToDate Contributor Disclosures Louis R Caplan, MD No relevant financial relationship(s) with ineligible companies to disclose. Jos Biller, MD, FACP, FAAN, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Glenn A Tung, MD, FACR No relevant financial relationship(s) with ineligible companies to disclose. Janet L Wilterdink, MD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/locked-in-syndrome/print 20/20

7/5/23, 12:06 PM Neurogenic pulmonary edema - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Neurogenic pulmonary edema : Matthew Wemple, MD, Matthew Hallman, MD, Andrew M Luks, MD : Polly E Parsons, MD : Geraldine Finlay, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jan 10, 2023. INTRODUCTION Neurogenic pulmonary edema (NPE) is an increase in pulmonary interstitial and alveolar fluid that is due to an acute central nervous system injury and usually develops rapidly after the injury [1]. It is sometimes classified as a form of the acute respiratory distress syndrome (ARDS), but its pathophysiology and prognosis are different. The clinical features, differential diagnosis, diagnosis, etiology, pathogenesis, and treatment of NPE are reviewed here. ARDS and noncardiogenic pulmonary edema due to other causes are discussed elsewhere. (See "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults" and "Noncardiogenic pulmonary edema".) ETIOLOGY The primary precipitants of NPE are epileptic seizures, traumatic brain injury, and various forms of intracranial hemorrhages [2,3]. NPE is also an increasingly recognized complication of pediatric encephalitis with Enterovirus-71 (Hand, foot, and mouth disease) [4]. Reported etiologies of NPE are listed in the table ( table 1) [4-15]. Epileptic seizures Among all patients with epilepsy the occurrence of NPE is rare. However, several case series reported that up to one-third of patients with fatal status epilepticus had clinical evidence of NPE, while an autopsy study found that 87 percent of patients with epilepsy and unexplained sudden death had NPE [3,16,17]. In a small retrospective study of patients presenting to an emergency department with seizures, who received thoracic computed https://www.uptodate.com/contents/neurogenic-pulmonary-edema/print 1/24 7/5/23, 12:06 PM Neurogenic pulmonary edema - UpToDate tomographic (CT) imaging, signs of NPE were seen in 5 of 26 patients with generalized tonic- clonic seizures (19 percent) [18]. It is uncertain whether NPE was the proximate cause of death in these studies, but it is clear that the NPE is more likely with increasing seizure severity. NPE due to epileptic seizures generally occurs during the postictal period and it may occur repeatedly in a given individual [2,19-21]. (See "Convulsive status epilepticus in adults: Classification, clinical features, and diagnosis".) NPE has also been reported following elective electroconvulsive therapy [22]. Traumatic brain injury Blunt or penetrating head injury and neurosurgical procedures can cause NPE [2,23,24]. The NPE is usually associated with elevated intracranial pressure (ICP), but raised ICP is not a necessary condition [25]. The incidence of NPE in traumatic brain injury has been estimated at 20 percent, and appears to increase with increasing severity of injury [26]. (See "Evaluation and management of elevated intracranial pressure in adults".) Intracranial hemorrhage NPE can result from multiple forms of intracranial hemorrhage ( table 1) [5-9]. Subarachnoid hemorrhage (SAH) NPE can complicate up to 43 percent of cases of SAH [27-32]. In a series of 78 cases of fatal subarachnoid hemorrhage, 31 percent had antemortem clinical evidence of NPE and 71 percent had pathological evidence of NPE at autopsy [29]. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) Onset is typically within minutes to hours of the hemorrhage although late onset days after hemorrhage or recurrence after apparent resolution have also been described [33]. NPE has also been reported during coil embolization of a ruptured cerebral aneurysm [34]. NPE following subarachnoid hemorrhage is associated with more severe clinical grade, younger age, and a vertebral artery source of the hemorrhage [32,35]. Electrocardiographic abnormalities, decreased heart rate variability, and laboratory abnormalities, including hyperglycemia, acidemia, hyperlactatemia, elevated troponin, and leukocytosis, are also associated with the development of NPE following nontraumatic subarachnoid hemorrhage [36-40]. Intracerebral hemorrhage (ICH) NPE can also be seen in up to 35 percent of patients with ICH, with the primary risk factors in such patients being higher Acute Physiology and Chronic Health Evaluation (APACHE) II scores and increased levels of serum inflammatory markers [41]. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis" and "Management of acute moderate and severe traumatic brain injury".) https://www.uptodate.com/contents/neurogenic-pulmonary-edema/print 2/24 7/5/23, 12:06 PM Neurogenic pulmonary edema - UpToDate Other forms of hemorrhage NPE has also been reported following various other forms of intracranial hemorrhage including intraventricular, epidural, subdural hemorrhage [12-14]. PATHOGENESIS The mechanism by which central nervous system injury leads to NPE is not completely understood. It is recognized that a central, transient sympathetic discharge is likely the primary instigator of the resulting pulmonary pathology. Neurologic structures The medulla oblongata is considered the critical anatomic structure involved in the pathogenesis of NPE. The importance of the medulla is supported by the observation that bilateral lesions in the nucleus of the solitary tract, area postrema and lesions in the A1 and A5 neuroadrenergic neurons (all of which are in the medulla) can cause systemic hypertension and NPE [42-45]. The medulla oblongata probably acts via the sympathetic component of the autonomic nervous system, as suggested by the following evidence from animal models [46-49]: Alpha adrenergic blockade (eg, with phentolamine or prazosin) can prevent the development of NPE NPE can be prevented by spinal cord transection at or above the C7 level, below which sympathetic fibers leave the lateral part of the cord to form the paraspinal sympathetic trunks NPE can be prevented by denervation via transection of the splanchnic sympathetic fibers to the lungs NPE may be produced by stimulation of the cord at the C7-C8 level, with the cord and sympathetic nerves intact In addition to the role of the medulla oblongata, theories regarding the pathogenesis of NPE have centered on the potential contributions of the hypothalamus, elevated intracranial pressure, activation of the sympathoadrenal system, and vagus nerve axonal injury [42,43,46- 48,50-60]. Among these, the role of the hypothalamus in NPE is most controversial. Experimental models have shown, for example, that inducing hypothalamic lesions precipitates NPE [61], while a case series of 22 patients with NPE found that half of them had radiographic evidence of hypothalamic injury, a finding associated with worse outcome [62]. However, in other animal models, mid-columnar decerebration does not prevent NPE, suggesting that higher CNS centers such as the hypothalamus are not involved in NPE development [63]. https://www.uptodate.com/contents/neurogenic-pulmonary-edema/print 3/24 7/5/23, 12:06 PM Neurogenic pulmonary edema - UpToDate Mechanisms of edema formation NPE requires a central nervous system injury or event (eg, seizure) that alters the Starling's forces in a way that increases the movement of fluid from the capillaries to the pulmonary interstitium, increases the permeability of the pulmonary capillaries, or both ( figure 1). Capillary hydrostatic pressure Increased capillary hydrostatic pressure likely contributes to most cases of NPE, since it is unlikely that a CNS injury or event could change capillary or interstitial oncotic pressure rapidly [2]. This is supported by the observation that alveolar fluid has a low fluid to serum protein ratio early during the course of NPE, consistent with hydrostatic pulmonary edema [64]. Experimental studies using animal models and uncontrolled observations in humans suggest several mechanisms by which pulmonary capillary hydrostatic pressure may increase acutely: Pulmonary venoconstriction may occur with intracranial hypertension or sympathetic stimulation. This increases the pulmonary capillary hydrostatic pressure, producing pulmonary edema [46,65-68]. Alpha adrenergic antagonists appear to attenuate this effect [69]. Excessive systemic venoconstriction may occur leading to a significant increase in venous return to the right heart and pulmonary circulation. Support for this concept comes from animal studies in which prophylactic phlebotomy (15 percent of blood volume) prior to CNS insult prevented development NPE [70]. Left ventricular performance may deteriorate for several reasons: direct myocardial damage or stunning secondary to brain injury, increased afterload due to systemic hypertension, and negative inotropic and chronotropic influences of excessive vagal tone [68,71,72]. This can cause passive elevation of the left atrial and pulmonary capillary pressures, leading to pulmonary edema [52,53,71,73-77]. Despite the evidence that increased pulmonary capillary hydrostatic pressure plays a role in NPE, there are likely additional contributors. This notion is based upon reports of NPE occurring with little or no elevation in the pulmonary capillary wedge pressure and in the absence of left atrial or systemic hypertension [65]. Pulmonary capillary permeability Increased pulmonary capillary permeability is likely also important to the pathogenesis of NPE. This idea is supported by the finding of protein- rich edema fluid in some animal models and patients with NPE, as well as the observation https://www.uptodate.com/contents/neurogenic-pulmonary-edema/print 4/24 7/5/23, 12:06 PM Neurogenic pulmonary edema - UpToDate that NPE can occur in the absence of the hemodynamic alterations associated with pulmonary edema [27,64,78,79]. As an example, a study used thermal green dye techniques to measure extravascular lung water in 18 patients with either head trauma or subarachnoid hemorrhage and 13 control patients (trauma patients without head injury) [27]. Nine of the 18 patients with brain injuries had pulmonary edema, defined as extravascular lung water values greater than two standard deviations above the control group mean. The pulmonary edema was independent of intracranial or pulmonary vascular pressure, suggesting increased vascular permeability. The mechanism by which neural influences produce changes in pulmonary vascular permeability remain unclear. Several hypotheses have been put forth: Neuropeptide Y, which is released by sympathetic nerves along with norepinephrine, increases pulmonary vascular permeability by acting directly on endothelial cells and has been found in alveolar macrophages and edema fluid in rats with NPE [63]. Alpha adrenergic agonists released in response to brain injury may cause the release of a second mediator, which increases vascular permeability (eg, endorphins, histamine, bradykinin) [2]. An initial rapid increase in pulmonary vascular pressure (eg, due to pulmonary vasospasm and/or increased systemic venous return) may cause pulmonary microvascular injury with a subsequent increase in permeability [80]. This theory, sometimes called the "blast theory" is supported by studies in rabbits showing that pulmonary capillaries are damaged when pressures exceed 40 mmHg [81]. It is also supported by the observation that patients with NPE frequently have mild hemoptysis or pulmonary hemorrhage [23]. The hypothesis is imperfect because the rapid development of acute pulmonary hypertension is not a necessary condition for NPE [82,83] and in animal models elevated pulmonary vascular pressures do not invariably lead to NPE [84]. Inflammatory mechanisms may also contribute to increased capillary permeability [59]. Evidence for inflammatory responses to severe brain injury include: Excess catecholamines can themselves lead to the release of inflammatory mediators [85,86]. S100B, a serum biomarker of brain injury, has been shown to induce the release of pro- inflammatory cytokines in alveolar type 1-like cells in vitro [87]. https://www.uptodate.com/contents/neurogenic-pulmonary-edema/print 5/24 7/5/23, 12:06 PM Neurogenic pulmonary edema - UpToDate Brain injury has been associated with increased intracranial production of pro- inflammatory mediators and subsequent release of these mediators into the systemic circulation [88,89]. In a case series of patients with intracerebral hemorrhage, patients who developed NPE were more likely to have elevated interleukin (IL)-6 levels [41]. A rat model of SAH documented increased expression of endothelial activation markers on pulmonary endothelial cells, and increased pulmonary TNF-alpha expression, which was attenuated by administration of the immune modulator IFN-beta [90]. Modulation of inflammation through a number of pathways has been associated with attenuation of NPE in several experimental rat models [90-93]. Two cellular level mechanisms, presumably induced by neural and inflammatory mediators, have been described that would result in increased pulmonary capillary permeability. In one study, an experimental animal model of epilepsy-induced NPE, suggested cell apoptosis contributes to the development of NPE by increasing Bax, decreasing Bcl-2, and activating caspase 3 [94]. In an autopsy series of pediatric patients with NPE in the setting of enterovirus 71 infection down-regulation of alveolar fluid clearance proteins, including aquaporin 4, was reported [95]. CLINICAL PRESENTATION NPE characteristically presents within minutes to hours of a severe central nervous system insult such as subarachnoid hemorrhage or traumatic brain injury. However, more rapid onset (immediate) and delayed onset (hours to days) have been described [2,23,27]. Resolution usually occurs within several days [96]. Dyspnea is the most common symptom, although mild hemoptysis or pink frothy sputum is present in many patients. The physical examination generally reveals tachypnea, tachycardia, and basilar crackles. Chest radiographs typically show a normal size heart with bilateral alveolar opacities, often with air bronchograms; unilateral opacities have also been described [28,97,98]. Hemodynamic measurements are usually normal by the time NPE is diagnosed, including the blood pressure, cardiac output, and pulmonary capillary wedge pressure. There is a broad range of severities of NPE and mild cases may never be detected. While NPE can be fulminant and contribute to death, mortality is more commonly due to the neurologic insult that precipitated the onset of NPE. https://www.uptodate.com/contents/neurogenic-pulmonary-edema/print 6/24 7/5/23, 12:06 PM Neurogenic pulmonary edema - UpToDate EVALUATION Evaluation of patients with suspected NPE is similar to that of patients with acute respiratory distress syndrome (ARDS) and should be focused on ruling out potential mimicking etiologies. (See "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults", section on 'Initial diagnostic evaluation'.) DIFFERENTIAL DIAGNOSIS Several conditions may mimic NPE. Aspiration pneumonitis The clinical findings of NPE may be confused with aspiration pneumonitis. Reliable differentiation between these syndromes is difficult because they are both common in settings of altered consciousness, such as postictal states or traumatic brain injury. NPE tends to develop more rapidly than aspiration pneumonia, while fever and focal opacities, particularly in the lower lung zones, favor aspiration. In addition, NPE tends to resolve more rapidly than lung injury related to aspiration, particularly if aspiration pneumonia develops. (See "Aspiration pneumonia in adults".) Pulmonary edema Other causes of pulmonary edema should also be considered, such as acute respiratory distress syndrome or heart failure ( table 2). The latter can sometimes be seen following severe neurologic injury as a result of neurogenic stunned myocardium [99] or, more generally, stress-induced cardiomyopathy, often referred to as Takotsubo cardiomyopathy. (See "Heart failure: Clinical manifestations and diagnosis in adults" and "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults", section on 'Differential diagnosis'.) DIAGNOSIS Definitive diagnosis of NPE is difficult because the clinical signs and routine diagnostic tests are nonspecific. Thus, NPE is a clinical diagnosis based upon the occurrence of pulmonary edema in the appropriate setting and in the absence of a more likely alternative cause. The following criteria for the diagnosis and classification of NPE have been proposed [100]: Bilateral opacities PaO /FiO ratio <200 mmHg 2 2 No evidence of left atrial hypertension https://www.uptodate.com/contents/neurogenic-pulmonary-edema/print 7/24 7/5/23, 12:06 PM Neurogenic pulmonary edema - UpToDate Presence of central nervous system (CNS) injury Absence of other common causes of acute respiratory failure or acute respiratory distress syndrome (ARDS; eg, aspiration, massive blood transfusion, sepsis) TREATMENT Treat the underlying disorder The outcome of patients with NPE is usually determined by the course of the neurologic insult and not the NPE. Thus, treatment should focus on the neurological disorder while NPE is managed in a supportive fashion. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis" and "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis" and "Management of acute moderate and severe traumatic brain injury" and "Convulsive status epilepticus in adults: Management".) Many episodes of NPE are well tolerated and resolve within 48 to 72 hours. Supportive care, oxygenation, mechanical ventilation Most patients with NPE are hypoxemic and require supplemental oxygen. Some patients may require mechanical ventilation. While most patients with NPE are hypoxemic and require supplemental oxygen, there is insufficient evidence to support specific oxygenation goals. Maintenance of an oxyhemoglobin saturation 88 percent or PaO 55 mmHg is generally acceptable in undifferentiated lung 2 injury, but specific targets in NPE should also take into consideration the effect that relative hypoxemia may have on the underlying neurological injury and the risk of secondary injury. Oxygenation goals may be achieved in some patients with noninvasive measures such as oxygen by nasal cannula, simple facemask, non-rebreather mask, or high-flow delivery systems, but mechanical ventilation may be necessary in other circumstances. Mechanical ventilation and the decision to intubate a patient are discussed separately. (See "Overview of initiating invasive mechanical ventilation in adults in the intensive care unit" and "Noninvasive ventilation in adults with acute respiratory failure: Benefits and contraindications" and "The decision to intubate".) Mechanical ventilation in patients with NPE is similar to that in patients with other causes of respiratory failure, although there are some important differences: High levels of positive end expiratory pressure (PEEP) can reduce cerebral venous return and worsen intracranial hypertension [101,102]. (See "Positive end-expiratory pressure (PEEP)", section on 'Intracranial disease'.) https://www.uptodate.com/contents/neurogenic-pulmonary-edema/print 8/24 7/5/23, 12:06 PM Neurogenic pulmonary edema - UpToDate Hypercapnia, which is often tolerated in patients with ARDS, can cause cerebral vasodilation, thereby increasing cerebral blood flow and potentially increasing ICP [1]. (See "Permissive hypercapnia during mechanical ventilation in adults", section on 'Contraindications'.) Noninvasive positive pressure ventilation or continuous positive airway pressure can be challenging to apply in patients with altered mental status. If ICP elevation is a clinical concern, ICP monitoring may be considered to guide mechanical ventilation. If ICP monitoring is available, PEEP can safely be increased to higher levels, provided PEEP is maintained at a level less than ICP, and MAP and cerebral perfusion pressure are preserved [103]. Single case reports document the use of prone ventilation, inhaled nitric oxide, and extra corporeal membranous oxygenation (ECMO) in patients with NPE and severe hypoxemia, but there is no systematic evidence supporting a benefit from these practices in such circumstances [104-106]. Because ECMO carries the risk of intracranial hemorrhage, extreme care must be taken with its application in patients with central nervous system (CNS) injury, particularly in patients following large cerebrovascular accidents who are at risk for hemorrhagic conversion. (See "Prone ventilation for adult patients with acute respiratory distress syndrome" and "Extracorporeal life support in adults in the intensive care unit: Overview".) Maintenance of low cardiac filling pressures with diuretics and limitation of intravenous fluids may decrease pulmonary edema. However, care must be taken to avoid compromising cardiac output and cerebral perfusion, which can worsen the original neurologic injury. Pulmonary artery catheterization was historically thought to be helpful in guiding therapy, but has since fallen out of favor as part of routine fluid management [96]. (See "Pulmonary artery catheterization: Indications, contraindications, and complications in adults".) The utility of less invasive methods of assessing cardiac function and pulmonary edema to guide treatment in NPE has been suggested in case reports and uncontrolled case series, but high quality, well-controlled studies are lacking [107,108]. Simultaneous assessment of cardiac output, extravascular lung water, global end diastolic volume, and pulmonary vascular permeability using less invasive hemodynamic monitors has been proposed as a method to guide management decisions, but the data are insufficient to support specific recommendations [107]. Small, limited studies have also evaluated the utility of lung ultrasound exams in NPE [109]. Investigational medications A variety of medications have been used to treat patients with NPE, but their effectiveness is not definitively proven. These include: https://www.uptodate.com/contents/neurogenic-pulmonary-edema/print 9/24 7/5/23, 12:06 PM Neurogenic pulmonary edema - UpToDate Beta adrenergic antagonists are thought to increase lymph flow, decrease edema, and reduce histamine-induced augmentation of pulmonary vascular permeability [2]. They are generally well-tolerated, but may precipitate bradyarrhythmias. Dobutamine increases cardiac output, decreases pulmonary capillary wedge pressure, and promotes diuresis [110,111]. Concerns for systemic hypotension and tachyarrhythmias preclude routine use. Our practice is to reserve it for cases of severe hypoxemia due to NPE where there is severe concomitantly reduced cardiac ejection fraction or bradycardia. Milrinone has both inotropic and lusitropic effects as well as anti-inflammatory properties that may target both the hydrostatic and capillary permeability related mechanisms of NPE. Small, open-label studies, primarily in the pediatric population have found improved short- term outcomes in those treated with both milrinone and dobutamine or milrinone and dopamine compared to either dobutamine or dopamine alone [112]. Our practice is to reserve this for cases of severe hypoxemia due to NPE where there is both severely reduced cardiac ejection fraction and pulmonary hypertension. As with dobutamine, systemic hypotension limits routine use. Chlorpromazine may block alpha adrenergic receptors to reduce edema [113]. Care must be taken as it can cause somnolence and interfere with monitoring of the underlying neurological insult. Levosimendin, an inotropic and vasodilating agent has been suggested as a useful adjunct for reducing pulmonary arterial pressure and augmenting cardiac output. However, controlled studies of this intervention are lacking and we cannot recommend it [108]. Phentolamine, an alpha adrenergic antagonist has been shown to prevent NPE or hasten its resolution in animal models, while one report demonstrated rapid improvements in oxygenation following administration of phentolamine in a single patient with NPE due to a ruptured arteriovenous malformation [69]. However, unopposed alpha adrenergic antagonists may precipitate systemic hypotension and cerebral hypoperfusion, and in the absence of data from controlled trials, routine use of these agents cannot be recommended at this time. (See "Antihypertensive therapy for secondary stroke prevention" and "Evaluation and management of elevated intracranial pressure in adults".) Naloxone, an opioid receptor antagonist, has been shown to block increases in lung permeability and NPE formation in an ovine model of herniation. However, in a placebo- controlled, randomized blinded trial of 199 lung-eligible brain-dead organ donors with hypoxemia, administration of naloxone did not improve time to reversal of hypoxemia https://www.uptodate.com/contents/neurogenic-pulmonary-edema/print 10/24 7/5/23, 12:06 PM Neurogenic pulmonary edema - UpToDate compared to placebo [114,115]. As a result, naloxone should not be used for treatment of NPE at this time. PROGNOSIS Although many episodes of NPE are well tolerated and most cases resolve within 48 to 72 hours, the development of NPE is associated with worse long-term outcomes. As an example, an observational study of 108 patients with non-traumatic intracranial hemorrhage, found that compared to those without NPE, those who developed NPE had a higher one-year mortality (37 versus 14 percent) [41]. SUMMARY AND RECOMMENDATIONS Neurogenic pulmonary edema (NPE) is an increase in pulmonary interstitial and alveolar fluid that is due to an acute central nervous system (CNS) injury. It usually develops rapidly following the injury. (See 'Introduction' above.) The primary precipitants of NPE are epileptic seizures, traumatic brain injury, and intracranial hemorrhages ( table 1). (See 'Etiology' above.) NPE is thought to occur when a neurologic insult affects the medulla oblongata, leading to a massive sympathetic discharge. This sympathetic discharge causes abrupt alterations in cardio-pulmonary hemodynamics and subsequent increased capillary hydrostatic pressure and pulmonary vascular permeability. (See 'Pathogenesis' above.) NPE characteristically presents within minutes to hours of a severe CNS insult. Dyspnea is the most common symptom, although mild hemoptysis is present in many patients. The physical examination generally reveals tachypnea, tachycardia, and basilar rales. Chest radiographs typically show a normal size heart with bilateral alveolar filling, while hemodynamic measurements are usually normal. (See 'Clinical presentation' above.) NPE is a clinical diagnosis based upon the occurrence of pulmonary edema in the appropriate setting and in the absence of a more likely alternative cause. (See 'Differential diagnosis' above and 'Diagnosis' above.) The treatment of NPE should focus on treating the neurological disorder while NPE is managed in a supportive fashion. Most patients with NPE are hypoxemic and require supplemental oxygen. Some patients may require mechanical ventilation, which differs from that for other causes of respiratory failure such that permissive hypercapnia and high https://www.uptodate.com/contents/neurogenic-pulmonary-edema/print 11/24 7/5/23, 12:06 PM Neurogenic pulmonary edema - UpToDate levels of positive end-expiratory pressure (PEEP) should be used cautiously, and use of noninvasive ventilation may be limited by altered mental status. A variety of medications have been used to treat patients with NPE, but their efficacy in this setting has not been established (See 'Treatment' above.) Many episodes of NPE are well tolerated and most resolve within 48 to 72 hours. However, the development of NPE is associated with worse long term outcomes. (See 'Prognosis' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Frank Drislane, MD, and Jess Mandel, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. 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Heart Rate Variability Predicts Neurogenic Pulmonary Edema in Patients with Subarachnoid Hemorrhage. Neurocrit Care 2016; 25:71. 40. Nastasovic T, Milakovic B, Marinkovic JE, et al. Could cardiac biomarkers predict neurogenic pulmonary edema in aneurysmal subarachnoid hemorrhage? Acta Neurochir (Wien) 2017; 159:705. https://www.uptodate.com/contents/neurogenic-pulmonary-edema/print 14/24 7/5/23, 12:06 PM Neurogenic pulmonary edema - UpToDate 41. Junttila E, Ala-Kokko T, Ohtonen P, et al. Neurogenic pulmonary edema in patients with nontraumatic intracerebral hemorrhage: predictors and association with outcome. Anesth Analg 2013; 116:855. 42. Chen HI, Sun SC, Chai CY. Pulmonary edema and hemorrhage resulting from cerebral compression. Am J Physiol 1973; 224:223. 43. Chen HI, Chai CY. Integration of the cardiovagal mechanism in the medulla oblongata of the cat. Am J Physiol 1976; 231:454. 44. Nathan MA, Reis DJ. Fulminating arterial hypertension with pulmonary edema from release of adrenomedullary catecholamines after lesions of the anterior hypothalamus in the rat. Circ Res 1975; 37:226. 45. Blessing WW, West MJ, Chalmers J. Hypertension, bradycardia, and pulmonary edema in the conscious rabbit after brainstem lesions coinciding with the A1 group of catecholamine neurons. Circ Res 1981; 49:949. 46. Maron MB, Dawson CA. Pulmonary venoconstriction caused by elevated cerebrospinal fluid pressure in the dog. J Appl Physiol Respir Environ Exerc Physiol 1980; 49:73. 47. Malik AB. Mechanisms of neurogenic pulmonary edema. Circ Res 1985; 57:1. 48. Hakim TS, van der Zee H, Malik AB. Effects of sympathetic nerve stimulation on lung fluid and protein exchange. J Appl Physiol Respir Environ Exerc Physiol 1979; 47:1025. 49. Lu WH, Hsieh KS, Lu PJ, et al. Different impacts of - and -blockers in neurogenic hypertension produced by brainstem lesions in rat. Anesthesiology 2014; 120:1192. 50. GAMBLE JE, PATTON HD. Pulmonary edema and hemorrhage from preoptic lesions in rats. Am J Physiol 1953; 172:623. 51. REYNOLDS RW. PULMONARY EDEMA AS A CONSEQUENCE OF HYPOTHALAMIC LESIONS IN RATS. Science 1963; 141:930. 52. MAIRE FW, PATTON HD. Neural structures involved in the genesis of preoptic pulmonary edema, gastric erosions and behavior changes. Am J Physiol 1956; 184:345. 53. MAIRE FW, PATTON HD. Role of the splanchnic nerve and the adrenal medulla in the genesis of preoptic pulmonary edema. Am J Physiol 1956; 184:351. 54. Garcia-Uria J, Hoff JT, Miranda S, Nishimura M. Experimental neurogenic pulmonary edema Part 2: The role of cardiopulmonary pressure change. J Neurosurg 1981; 54:632. 55. Darragh TM, Simon RP. Nucleus tractus solitarius lesions elevate pulmonary arterial pressure and lymph flow. Ann Neurol 1985; 17:565. 56. Graf CJ, Rossi NP. Catecholamine response to intracranial hypertension. J Neurosurg 1978; 49:862. https://www.uptodate.com/contents/neurogenic-pulmonary-edema/print 15/24 7/5/23, 12:06 PM Neurogenic pulmonary edema - UpToDate 57. Inobe JJ, Mori T, Ueyama H, et al. Neurogenic pulmonary edema induced by primary medullary hemorrhage: a case report. J Neurol Sci 2000; 172:73. 58. Keegan MT, Lanier WL. Pulmonary edema after resection of a fourth ventricle tumor: possible evidence for a medulla-mediated mechanism. Mayo Clin Proc 1999; 74:264. 59. Sed J, Zicha J, Kunes J, et al. Mechanisms of neurogenic pulmonary edema development. Physiol Res 2008; 57:499. 60. Atalay C, Gundogdu B, Aydin MD. Vagal Ischemia Induced Lung Immune Component Infarct Following Subarachnoid Hemorrhage: An Experimental Study. Turk Neurosurg 2017; 27:509. 61. Brown RH Jr, Beyerl BD, Iseke R, Lavyne MH. Medulla oblongata edema associated with neurogenic pulmonary edema. Case report. J Neurosurg 1986; 64:494. 62. Imai K. Radiographical investigations of organic lesions of the hypothalamus in patients suffering from neurogenic pulmonary edema due to serious intracranial diseases: relationship between radiographical findings and outcome of patients suffering from neurogenic pulmonary edema. No Shinkei Geka 2003; 31:757. 63. ed J, Kune J, Zicha J. Pathogenetic Mechanisms of Neurogenic Pulmonary Edema. J Neurotrauma 2015; 32:1135. 64. Smith WS, Matthay MA. Evidence for a hydrostatic mechanism in human neurogenic pulmonary edema. Chest 1997; 111:1326. 65. Hoff JT, Nishimura M, Garcia-Uria J, Miranda S. Experimental neurogenic pulmonary edema. Part 1: The role of systemic hypertension. J Neurosurg 1981; 54:627. 66. Kadowitz PJ, Joiner PD, Hyman AL. Influence of sympathetic stimulation and vasoactive substances on the canine pulmonary veins. J Clin Invest 1975; 56:354. 67. El-Bermani AW. Innervation of the microcirculation. Ann N Y Acad Sci 1982; 384:21. 68. Macmillan CS, Grant IS, Andrews PJ. Pulmonary and cardiac sequelae of subarachnoid haemorrhage: time for active management? Intensive Care Med 2002; 28:1012. 69. Schraufnagel DE, Thakkar MB. Pulmonary venous sphincter constriction is attenuated by alpha-adrenergic antagonism. Am Rev Respir Dis 1993; 148:477. 70. Sed J, Zicha J, Nedv dkov J, Kunes J. The role of sympathetic nervous system in the

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Acta Neurochir (Wien) 2017; 159:705. https://www.uptodate.com/contents/neurogenic-pulmonary-edema/print 14/24 7/5/23, 12:06 PM Neurogenic pulmonary edema - UpToDate 41. Junttila E, Ala-Kokko T, Ohtonen P, et al. Neurogenic pulmonary edema in patients with nontraumatic intracerebral hemorrhage: predictors and association with outcome. Anesth Analg 2013; 116:855. 42. Chen HI, Sun SC, Chai CY. Pulmonary edema and hemorrhage resulting from cerebral compression. Am J Physiol 1973; 224:223. 43. Chen HI, Chai CY. Integration of the cardiovagal mechanism in the medulla oblongata of the cat. Am J Physiol 1976; 231:454. 44. Nathan MA, Reis DJ. Fulminating arterial hypertension with pulmonary edema from release of adrenomedullary catecholamines after lesions of the anterior hypothalamus in the rat. Circ Res 1975; 37:226. 45. Blessing WW, West MJ, Chalmers J. Hypertension, bradycardia, and pulmonary edema in the conscious rabbit after brainstem lesions coinciding with the A1 group of catecholamine neurons. Circ Res 1981; 49:949. 46. Maron MB, Dawson CA. Pulmonary venoconstriction caused by elevated cerebrospinal fluid pressure in the dog. J Appl Physiol Respir Environ Exerc Physiol 1980; 49:73. 47. Malik AB. Mechanisms of neurogenic pulmonary edema. Circ Res 1985; 57:1. 48. Hakim TS, van der Zee H, Malik AB. Effects of sympathetic nerve stimulation on lung fluid and protein exchange. J Appl Physiol Respir Environ Exerc Physiol 1979; 47:1025. 49. Lu WH, Hsieh KS, Lu PJ, et al. Different impacts of - and -blockers in neurogenic hypertension produced by brainstem lesions in rat. Anesthesiology 2014; 120:1192. 50. GAMBLE JE, PATTON HD. Pulmonary edema and hemorrhage from preoptic lesions in rats. Am J Physiol 1953; 172:623. 51. REYNOLDS RW. PULMONARY EDEMA AS A CONSEQUENCE OF HYPOTHALAMIC LESIONS IN RATS. Science 1963; 141:930. 52. MAIRE FW, PATTON HD. Neural structures involved in the genesis of preoptic pulmonary edema, gastric erosions and behavior changes. Am J Physiol 1956; 184:345. 53. MAIRE FW, PATTON HD. Role of the splanchnic nerve and the adrenal medulla in the genesis of preoptic pulmonary edema. Am J Physiol 1956; 184:351. 54. Garcia-Uria J, Hoff JT, Miranda S, Nishimura M. Experimental neurogenic pulmonary edema Part 2: The role of cardiopulmonary pressure change. J Neurosurg 1981; 54:632. 55. Darragh TM, Simon RP. Nucleus tractus solitarius lesions elevate pulmonary arterial pressure and lymph flow. Ann Neurol 1985; 17:565. 56. Graf CJ, Rossi NP. Catecholamine response to intracranial hypertension. J Neurosurg 1978; 49:862. https://www.uptodate.com/contents/neurogenic-pulmonary-edema/print 15/24 7/5/23, 12:06 PM Neurogenic pulmonary edema - UpToDate 57. Inobe JJ, Mori T, Ueyama H, et al. Neurogenic pulmonary edema induced by primary medullary hemorrhage: a case report. 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Pathogenetic Mechanisms of Neurogenic Pulmonary Edema. J Neurotrauma 2015; 32:1135. 64. Smith WS, Matthay MA. Evidence for a hydrostatic mechanism in human neurogenic pulmonary edema. Chest 1997; 111:1326. 65. Hoff JT, Nishimura M, Garcia-Uria J, Miranda S. Experimental neurogenic pulmonary edema. Part 1: The role of systemic hypertension. J Neurosurg 1981; 54:627. 66. Kadowitz PJ, Joiner PD, Hyman AL. Influence of sympathetic stimulation and vasoactive substances on the canine pulmonary veins. J Clin Invest 1975; 56:354. 67. El-Bermani AW. Innervation of the microcirculation. Ann N Y Acad Sci 1982; 384:21. 68. Macmillan CS, Grant IS, Andrews PJ. Pulmonary and cardiac sequelae of subarachnoid haemorrhage: time for active management? Intensive Care Med 2002; 28:1012. 69. Schraufnagel DE, Thakkar MB. Pulmonary venous sphincter constriction is attenuated by alpha-adrenergic antagonism. Am Rev Respir Dis 1993; 148:477. 70. Sed J, Zicha J, Nedv dkov J, Kunes J. 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Topic 1610 Version 19.0 https://www.uptodate.com/contents/neurogenic-pulmonary-edema/print 19/24 7/5/23, 12:06 PM Neurogenic pulmonary edema - UpToDate GRAPHICS Causes of neurogenic pulmonary edema Major causes Epileptic seizures, particularly status epilepticus Intracranial hemorrhage (including intracerebral hemorrhage, intraventricular hemorrhage, epidural hemorrhage, subdural hemorrhage) Head injury Minor causes Guillain-Barr syndrome Multiple sclerosis with medullary involvement Nonhemorrhagic strokes Trigeminal nerve block Bulbar poliomyelitis Vertebral artery ligation Vertebral artery dissection Ruptured spinal arteriovenous malformation Air embolism Brain tumors Electroconvulsive therapy Induction of general anesthesia Colloid cyst Hydrocephalus Reye syndrome Bacterial meningitis Viral meningoencephalitis (including enterovirus-7) Cervical spinal cord injury Cryptococcal meningoencephalitis Hyponatremia High-voltage electrical injury Graphic 57483 Version 6.0 https://www.uptodate.com/contents/neurogenic-pulmonary-edema/print 20/24 7/5/23, 12:06 PM Neurogenic pulmonary edema - UpToDate Capillary hemodynamic forces Schematic representation of the capillary and interstitial fluid hydraulic and oncotic pressures controlling fluid movement across the capillary wall between the plasma and the interstitial fluid. The arrows point in the direction of fluid movement induced by each of the forces. : hydraulic pressure of the capillary; : oncotic pressure of P plasma; P : hydraulic pressure of the interstitial fluid; : oncotic pressure of interstitial fluid. cap p if if Graphic 55674 Version 2.0 https://www.uptodate.com/contents/neurogenic-pulmonary-edema/print 21/24 7/5/23, 12:06 PM Neurogenic pulmonary edema - UpToDate Etiology of acute respiratory distress syndrome* Etiology Clinical features Diagnostic tests Sepsis Fever, hypotension, leukocytosis, lactic acidosis, infectious source Appropriate clinical context and positive cultures Aspiration pneumonitis Witnessed or risk for aspiration, food, lipid laden macrophages, Presumptive diagnosis with negative cultures airway erythema on bronchoscopy Infectious pneumonia (including mycobacterial, viral, fungal, parasitic) Productive cough, pleuritic pain, fever, leukocytosis, lobar consolidation or bilateral infiltrates in an immunosuppressed patient Appropriate clinical context and positive respiratory cultures Severe trauma and/or multiple fractures History of trauma or fractures within the last week Diagnosis is apparent Pulmonary contusion History of chest trauma (blunt or penetrating), chest pain Presumptive diagnosis in the correct clinical context, negative cultures Burns and smoke inhalation Exposure to fire or smoke, cough, dyspnea, DIC, particulate matter on bronchoscopy, surface burns Presumptive diagnosis in the correct clinical context, negative cultures Transfusion related acute lung injury and massive transfusions History of transfusion, dyspnea during or shortly after transfusion Diagnosis of exclusion HSCT History of HSCT Diagnosis of exclusion Pancreatitis Abdominal pain, vomiting, risk actors (eg, gallstones, alcohol, viral infection) Elevated amylase and lipase, with or without abnormal imaging Inhalation injures other than smoke (eg, near drowning, History of inhalation exposure (eg, chlorine gas) Diagnosis of exclusion gases) Thoracic surgery (eg, post- History of surgery, Diagnosis of exclusion cardiopulmonary bypass) or other major surgery intraoperative ventilation, intraoperative transfusion Drugs (chemotherapeutic agents, amiodarone, radiation) New drugs or radiation exposure on history, lymphocytosis on lavage, lavage Diagnosis of exclusion, lung biopsy occasionally helpful https://www.uptodate.com/contents/neurogenic-pulmonary-edema/print 22/24 7/5/23, 12:06 PM Neurogenic pulmonary edema - UpToDate may have suggestive features of amiodarone toxicity ("foamy macrophages") but is nonspecific ARDS has over 60 etiologies. This is an abbreviated list of the common causes of ARDS. ARDS: acute respiratory distress syndrome; DIC: disseminated intravascular coagulation; HSCT: hematopoietic stem cell transplant; AEP: acute eosinophilic pneumonia; COP: cryptogenic organizing pneumonia; DAD: diffuse alveolar damage. Use of the term ARDS to describe conditions such as AEP or COP is somewhat controversial. However, some experts consider these a "subtype" of ARDS since they present in a similar fashion to ARDS, although the pathology of such entities is different from DAD, which is the classic pathology associated with ARDS. Similarly, while neurogenic pulmonary edema meets the definition of ARDS, since it causes hypoxemia and bilateral infiltrates in the absence of pulmonary edema due to heart failure, the pathology and clinical course is likely different. Similarly, embolism of fat, air, and amniotic fluid may mimic ARDS but it is uncertain as to whether they cause ARDS. Many patients with HSCT may develop a form of lung injury after transplant but the distinction between this and ARDS due to complications of HSCT (eg, pneumonia) is often unclear. Graphic 58759 Version 4.0 https://www.uptodate.com/contents/neurogenic-pulmonary-edema/print 23/24 7/5/23, 12:06 PM Neurogenic pulmonary edema - UpToDate Contributor Disclosures Matthew Wemple, MD No relevant financial relationship(s) with ineligible companies to disclose. Matthew Hallman, MD No relevant financial relationship(s) with ineligible companies to disclose. Andrew M Luks, MD Other Financial Interest: Springer (royalties) [Cardiopulmonary exercise testing]; Taylor and Francis (royalties) [High-altitude medicine and physiology]; Wolters Kluwer (book royalties) [Respiratory physiology and pulmonary pathophysiology]. All of the relevant financial relationships listed have been mitigated. Polly E Parsons, MD Employment: Alliance for Academic Internal Medicine [President and CEO]. All of the relevant financial relationships listed have been mitigated. Geraldine Finlay, MD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/neurogenic-pulmonary-edema/print 24/24

7/5/23, 12:06 PM Neurologic complications of cardiac surgery - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Neurologic complications of cardiac surgery : Michael L McGarvey, MD, Albert T Cheung, MD, Mark M Stecker, MD, PhD, FAAN, FACNS, FASNM : Michael J Aminoff, MD, DSc, Gabriel S Aldea, MD : Janet L Wilterdink, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Sep 15, 2021. INTRODUCTION Neurologic complications are second only to heart failure as a cause of morbidity and mortality following cardiac surgery, and the presence of neurologic sequelae significantly increases the likelihood of requiring long-term care [1-4]. The neurologic complications of cardiac surgery in adults will be reviewed here. Methods to prevent these complications, issues related to coronary artery bypass grafting (CABG) in patients with known carotid artery disease, and an overview of all early complications following CABG are discussed separately. (See "Coronary artery bypass grafting in patients with cerebrovascular disease" and "Early noncardiac complications of coronary artery bypass graft surgery".) Most neurologic problems following cardiac surgery can be divided into three categories ( table 1) [2,5]: Stroke Neuropsychiatric abnormalities or encephalopathy Peripheral neuropathies A retrospective report from the Society of Thoracic Surgeons (STS) National Cardiac Database of over 400,000 cardiac surgeries between 1996 and 1997 reported an overall incidence of a new neurologic event (stroke, transient ischemic attack, or unexplained coma lasting more than 24 hours) of 3.3 percent [6]. A prospective study evaluated 2108 patients undergoing coronary artery bypass graft surgery (CABG) at 24 hospitals in the United States between 1991 and 1993 [2]. Overall, 6.1 percent suffered a cerebral complication, roughly equally divided between stroke https://www.uptodate.com/contents/neurologic-complications-of-cardiac-surgery/print 1/27 7/5/23, 12:06 PM Neurologic complications of cardiac surgery - UpToDate and encephalopathy. Increased age was a dominant risk factor, and adverse events were associated with increased mortality, longer hospitalization, and a higher rate of discharge to chronic care facilities compared with those without neurologic sequelae ( figure 1). CEREBROVASCULAR DISEASE Incidence The incidence of stroke related to cardiac operations ranges from 0.4 to 14 percent in different series, depending upon patient populations and specific procedures [1,2,7-14]. The type and number of procedures that are performed during cardiac surgery may have an impact on stroke incidence: Coronary artery bypass graft surgery (CABG) Reported perioperative stroke rates most commonly fall between 0.8 and 5.2 percent [11,12,14-26]. In a review of a Society of Thoracic Surgeons (STS) database of patients in 2017, 160,160 patients underwent isolated CABG with a reported permanent stroke incidence of 1.4 percent [14]. Valve repair Based on the STS database in the calendar year 2017, isolated open aortic valve repairs (AVR) of 25,940 patients and open mitral valve repairs (MVR) of 12,388 patients had permanent stroke risk of 1.3 and 2.3 percent, respectively [14]. Combined open AVR and CABG procedures In the same STS database, 15,971 patients underwent combined procedures, which were associated with a 1.9 percent permanent stroke incidence; combined open MVR and CABG procedures were associated with a 3.1 percent stroke incidence [14]. Regardless of the cardiac procedure, the permanent stroke incidence appears to be declining over time in large national databases [14,23-26]. The process for assessing stroke incidence may be a critical factor. In trials, where stroke is diagnosed by neurologists, stroke rates are substantially higher than those reported in surgeon- reported databases like the STS. In the Determining Neurologic Outcomes from Valve Operations (DeNOVO) trial, which included patients undergoing open aortic valve surgeries where neurologists performed neurologic examinations before and after surgery, the stroke incidence was double that of those identified in the same cohort in the STS database [27]. Of the 196 patients in the study, the clinical stroke incidence was 17 percent, whereas only 7 percent of these patients were reported as having a clinical stroke in the STS database. In addition, the burden of cerebral ischemic injury may be underestimated if only the incidence of clinical stroke is considered. Neuroimaging studies suggest that there is an even higher https://www.uptodate.com/contents/neurologic-complications-of-cardiac-surgery/print 2/27 7/5/23, 12:06 PM Neurologic complications of cardiac surgery - UpToDate incidence of so-called silent cerebral ischemia after cardiac surgery [27-29]. In the aforementioned DeNOVO trial, of the 109 patients who did not have a clinical stroke, magnetic resonance imaging (MRI) detected 59 additional silent infarctions [27]. The timing of most perioperative strokes is variously reported. Approximately 30 to 40 percent of strokes occur intraoperatively, according to large prospective reviews [7,23]. Most strokes occur in the first one to two days after surgery and are relatively uncommon after the first week [7,18,23,30]. However, the increased risk of stroke persists for up to two years after cardiac surgery [31]. Risk factors Patient-specific risk factors for perioperative stroke that have been identified in some studies include [1,2,4,6-12,15-17,23,31-45]: Prior stroke or transient ischemic attack Significant atherosclerosis of the proximal or ascending aorta, carotid, and/or intracranial cerebral arteries Advanced age Diabetes Renal failure Low cardiac output syndrome Peripheral artery disease Hypertension Pre- or postoperative atrial fibrillation Female sex Recent myocardial infarction or unstable angina Moderate or severe left ventricular dysfunction The history of a clinical stroke is a consistent risk factor for perioperative stroke among studies, with an associated increased odds ratio of 3.2 to 4.5 [2,42]. One study also found that the presence of asymptomatic stroke detected by MRI preoperatively was also a risk factor for perioperative stroke [46]. The time interval between the prior stroke and surgery did not influence perioperative stroke risk, according to one study [44]. Aortic atherosclerosis is also an important risk factor, with an associated odds ratio of 4.5 [2]. In a review of 921 consecutive patients who underwent cardiac surgery, the incidence of stroke was 8.7 percent in those with aortic atherosclerosis, compared with 1.8 percent in those without this abnormality [37]. Among patients with aortic atherosclerosis, the risk of stroke is greatest in those with aortic arch atheromas that are mobile or protrude 5 mm into the aortic lumen [38,47]. Large atheromas are more likely to occur at the site of new aortic injury during surgical https://www.uptodate.com/contents/neurologic-complications-of-cardiac-surgery/print 3/27 7/5/23, 12:06 PM Neurologic complications of cardiac surgery - UpToDate clamping and cannulation [39]. Large or mobile atheromas are also risk factors for stroke in patients not undergoing surgery. (See "Thromboembolism from aortic plaque".) The data associating carotid disease with perioperative stroke in patients are more limited. This is discussed in detail separately. (See "Coronary artery bypass grafting in patients with cerebrovascular disease".) The presence of any one risk factor for stroke is not considered a contraindication for cardiac surgery [42]. A number of risk models have been developed to predict stroke after cardiac surgery (usually CABG) using preoperative risk factors. While these models vary substantively, they emphasize the additive effect that individual risk factors have on perioperative stroke risk [15-18]. Operative factors are also important [2,4]. Closed chamber procedures, such as CABG, have a lower risk than open chamber procedures, such as valve replacement [48,49]. This difference was demonstrated in a multicenter prospective trial of 273 patients in which the rate of cerebral complications (predominantly stroke) was 6 percent in patients undergoing CABG compared with 16 percent in patients undergoing intracardiac surgery [49]. Combined or complex surgical procedures, including those that are prolonged and involve manipulation of the ascending aorta, increase the risk of neurologic complications [4,6]. Increasing the temperature of cardiopulmonary bypass (CPB) may also augment the risk of stroke [9]. Mechanisms of cerebral infarction Different mechanisms are thought to be responsible for early onset or intraoperative ischemic stroke versus delayed ischemic stroke [30,50]. Intraoperative stroke Cerebral hypoperfusion and atheroembolization are understood to be the major mechanisms underlying intraoperative stroke: Cerebral hypoperfusion can result from intraoperative hypotension and/or diminished cardiac output. Furthermore, it is hypothesized that decreased blood flow during surgery results in diminished washout of embolic material from blood vessels in the brain, particularly in borderzone (watershed) areas along the boundaries of major vascular territories, predisposing to ischemia in these regions [51]. These mechanisms may combine to increase the cumulative risk of injury in cardiac surgery and explain the presence of postoperative strokes identified as having multiple mechanisms [18]. While mean arterial pressures of 50 to 70 mmHg are common and typically well tolerated by patients during CPB, higher mean arterial blood pressure may decrease both cardiac and neurologic complications [52]. This and other techniques to avoid intraoperative cerebral hypoperfusion are discussed in detail separately. (See "Management of https://www.uptodate.com/contents/neurologic-complications-of-cardiac-surgery/print 4/27 7/5/23, 12:06 PM Neurologic complications of cardiac surgery - UpToDate cardiopulmonary bypass", section on 'Mean arterial pressure' and "Management of special populations during cardiac surgery with cardiopulmonary bypass", section on 'Cerebrovascular disease'.) Arterial emboli can cause transient or permanent occlusion of cerebral vessels and produce cerebral ischemia. This appears to be the predominant cause of intraoperative stroke, as is supported by the finding that most patients with stroke have multiple cerebral infarcts in different arterial territories on neuroimaging studies [30,50]. Three major types of emboli occur during cardiac operations: thromboemboli, atheroemboli, and air emboli [53]. Thrombi or atheromatous debris can be released from complex aortic plaques during clamping and unclamping of the ascending aorta, during the construction of the proximal CABG anastomoses in the ascending aorta, while excising severely calcified and diseased cardiac valves, or by turbulent high-velocity blood flow from the aortic cannula within a diseased aorta. Transcranial Doppler (TCD) monitoring of the middle cerebral artery blood flow detects arterial microemboli entering the cerebral circulation during cardiac surgery; these are most frequent during placement and removal of the aortic cross-clamp and the aortic cannula [54,55]. (See "Initiation of cardiopulmonary bypass", section on 'Aortic cannulation'.) Gaseous emboli enter the arterial circulation via open cardiac chambers, vascular cannulation sites, or arterial anastomoses. These may be the most common type of embolic material seen during CPB; however, the impact that these have on neurologic injury and outcome is unclear [56]. The size of the gaseous emboli may be important, with larger emboli-causing strokes and smaller emboli resulting in endothelial injury in the brain's vasculature. (See "Thromboembolism from aortic plaque", section on 'Cardiovascular procedures' and "Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism)" and "Air embolism".) Postoperative stroke Stroke that is noted after an initial uneventful neurologic recovery from surgery is most likely to be due to cardiogenic embolism [50]. Atrial fibrillation, a common postoperative complication, is believed to contribute to a significant proportion of delayed postoperative strokes [18,57]. Underlying heart disease also likely plays an important role. As in other clinical settings, the CHADS score helps stratify the risk for postoperative stroke [31]. (See 2 "Atrial fibrillation in adults: Use of oral anticoagulants".) Intracranial hemorrhage Primary intracranial hemorrhage in patients is a rare complication of cardiac surgery; most intracranial hemorrhage in this setting occurs as a complication of ischemic infarction. https://www.uptodate.com/contents/neurologic-complications-of-cardiac-surgery/print 5/27 7/5/23, 12:06 PM Neurologic complications of cardiac surgery - UpToDate Although 5 percent of patients with perioperative ischemic strokes have some hemorrhagic transformation [58], the incidence of sizable hemorrhages with mass effect is much smaller. The risk factors for significant hemorrhage include large infarcts, anticoagulation, or the presence of an infarct that is already hemorrhagic [59]. In any patient with prior intracranial hemorrhage undergoing a cardiac operation, it is imperative to perform a neurologic examination as soon as possible postoperatively to determine whether there is clinical evidence of increasing hemorrhage that might require neurosurgical intervention. Patients with endocarditis often have ongoing neurologic injury, which puts them at greater risk of intracranial hemorrhage during anticoagulation for CPB [60]. This risk may be reduced by delaying the operation for two to three weeks while antibiotic therapy is initiated; however, hemodynamic instability may preclude delay [60]. Another method to reduce bleeding risk is to perform cardiac surgery with a heparin-bonded CPB circuit, which permits reduced systemic heparinization [61,62]. Ophthalmologic complications Arterial emboli can cause symptomatic ophthalmologic complications. Intraoperative fluorescein angiography demonstrated transient microvascular occlusion in all 21 patients studied in one report [63]. In a larger series of 312 patients undergoing CABG, 26 percent experienced neuroophthalmologic sequelae, including 17 percent with retinal infarctions [64]. Visual loss due to ischemic optic neuropathy is uncommon, occurring in approximately 0.1 percent of patients undergoing CPB [65,66]. A supranuclear gaze palsy is another described complication of cardiac surgery, particularly aortic valve replacement and repair of an ascending aortic dissection [67-70]. This is probably under-recognized as the patient's complaints are often somewhat vague, and demonstration of the neurologic deficit requires specific examination of vertical and horizontal saccades. Spastic dysarthria, emotional lability, and gait disorder are frequent accompanying abnormalities. The presumed mechanism is ischemic injury to the midbrain, or elsewhere in the brainstem, but this has not been specifically documented. Diagnosis and treatment In patients stable enough to undergo brain MRI, diffusion- weighted imaging (DWI) is very sensitive and accurate for the diagnosis of acute ischemic events [18]. In addition to confirming the presence of a cerebral infarction, it is useful to identify additional, otherwise unsuspected areas of infarction and may hint at the underlying mechanism, that is, embolism versus watershed. (See "Neuroimaging of acute stroke".) It is also important to confirm the timing of the stroke. A stroke that occurs postoperatively suggests the potential for recurrent events due to ongoing risk factors, such as atrial fibrillation, https://www.uptodate.com/contents/neurologic-complications-of-cardiac-surgery/print 6/27 7/5/23, 12:06 PM Neurologic complications of cardiac surgery - UpToDate cerebrovascular disease, intramural thrombus in the heart, or inadequate anticoagulation for a mechanical valve prosthesis. An intraoperative stroke is less likely to recur. Potential interventions for the treatment of stroke after cardiac surgery are discussed in detail separately but include: The management of blood pressure in acute stroke has not been well studied. In other settings (not postoperative), blood pressure lowering is not recommended unless in excess of 220 mmHg systolic or 120 mmHg diastolic [71], or unless the patient is suffering from, or at risk of, aortic dissection, acute myocardial infarction, heart failure, or other adverse effects. However, after cardiac surgery, surgeons may recommend somewhat tighter blood pressure control. Hypotension should be avoided and treated if it occurs using supine posture and an intravenous fluid bolus. If these measures are insufficient, a pressor such as phenylephrine at low dose may be useful. Although there is no support in the literature for blood pressure augmentation in normotensive patients, it is our general practice to treat these patients with judicious use of volume expansion to improve brain perfusion. (See "Initial assessment and management of acute stroke", section on 'Blood pressure management'.) Patients with hypoxia should receive supplemental oxygen to bring saturations to levels 92 percent [71]. (See "Initial assessment and management of acute stroke", section on 'Airway, breathing and circulation'.) Hyperglycemia after stroke has been associated with worse outcomes; treatment may improve outcome. (See "Initial assessment and management of acute stroke", section on 'Hyperglycemia'.) Fever has also been associated with worse outcomes in the acute stroke setting; antipyretics are generally recommended to lower fever in patients after stroke. (See "Initial assessment and management of acute stroke", section on 'Fever'.) Use of intravenous tissue plasminogen activator is associated with significant risk of bleeding in the postoperative period and is contraindicated in patients after cardiac surgery. Other reperfusion techniques may be considered in centers with requisite expertise and for specific cases where therapy is instituted within a 24-hour time window [72]. This may be particularly relevant for patients who have undergone cardiac surgery and have suffered a perioperative stroke [73]. (See "Approach to reperfusion therapy for acute ischemic stroke".) https://www.uptodate.com/contents/neurologic-complications-of-cardiac-surgery/print 7/27 7/5/23, 12:06 PM Neurologic complications of cardiac surgery - UpToDate Anticoagulation has not been shown to be effective in acute stroke treatment, regardless of etiology. In patients with acute stroke following cardiac surgery, it carries the additional risks of systemic complications such as hemopericardium. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Limited role of early anticoagulation'.) The use of antiplatelet therapy following CABG has been shown to be safe and effective in decreasing neurologic complications [74], and has also been shown to improve outcomes following acute stroke [75]. Aspirin or clopidogrel is recommended for all patients following cardiac surgery except those with absolute contraindications. (See "Coronary artery bypass surgery: Perioperative medical management", section on 'Aspirin' and "Coronary artery bypass surgery: Perioperative medical management", section on 'Platelet P2Y12 receptor blocker therapy'.) Statin therapy is usually recommended in patients following CABG for secondary prevention of cardiovascular as well as cerebrovascular events. (See "Coronary artery bypass surgery: Perioperative medical management", section on 'Statins'.) Other therapies, such as cerebral protection or hyperbaric oxygen, may be of value in the appropriate circumstances [76,77]. Hyperbaric oxygenation is of special value in otherwise stable patients with suspected air emboli. (See "Hyperbaric oxygen therapy".) Outcome after stroke Patients who have a perioperative stroke have a poorer outcome compared with those without a stroke [12,18]. As an example, 35,733 consecutive patients were followed after CABG; 1.6 percent had a perioperative stroke. Patients with stroke had 1-, 5-, and 10-year survival rates of 83, 59, and 27 percent, respectively, representing a threefold increased risk of death compared with patients without stroke [78]. Similar findings were noted in other reports [10,18,79]. The biggest differences in mortality are seen early and stabilize over time [11,78]. In-hospital mortality rates for stroke after CABG range from 14 to 30 percent [11,12,16] and appear to be higher in patients with intraoperative versus postoperative stroke (41 versus 13 percent) [7]. Patients who have had a stroke are also likely to have functional deficits limiting independence and to be discharged to locations other than home [18]. ENCEPHALOPATHY https://www.uptodate.com/contents/neurologic-complications-of-cardiac-surgery/print 8/27 7/5/23, 12:06 PM Neurologic complications of cardiac surgery - UpToDate The major neuropsychiatric abnormalities associated with cardiac surgery are neurocognitive dysfunction, seizures, and delirium. At times, coma is seen. Rather than distinct entities, these represent a spectrum of neurologic dysfunction with overlapping clinical features and pathogeneses. Premorbid or perioperative stroke and other vascular mechanisms may also play a role in some patients with postoperative encephalopathy. Delirium Delirium after cardiac surgery occurs in 3 to 32 percent of patients, particularly those with preexisting organic mental disorders (eg, stroke, dementia), significant prior alcohol consumption, advanced age, or intracranial cerebral artery disease [2,36,80-83]. The wide incidence range indicates the difficulty of attributing delirium specifically to the surgical procedure, rather than to opiates, anesthetics, and sedative agents administered during and immediately following surgery. Other causes of postoperative delirium in the cardiac surgery patient include renal failure, hepatic failure, and thyroid abnormalities. Strokes, particularly right parietal lesions, can also present as delirium. Treatment of postoperative delirium requires a search for, and correction of, potentially reversible causes. The electroencephalography (EEG) is usually abnormal in postoperative delirium, but not in a primary psychiatric illness. (See "Acute toxic-metabolic encephalopathy in adults" and "Diagnosis of delirium and confusional states" and "Delirium and acute confusional states: Prevention, treatment, and prognosis".) Delirium may persist for more than one week and overlaps with more persistent postoperative neurocognitive dysfunction (see 'Cognitive impairment' below). In one prospective series of 225 patients after cardiac surgery, those who experienced postoperative delirium were more likely than those who did not to have persistent cognitive decline over baseline (40 versus 24 percent, p = 0.001 at six months; and 31 versus 21 percent, p = 0.055 at 12 months) [84]. Another prospective study found that delirium after CABG was a risk factor for late mortality, particularly in younger patients (<65 years old), in whom the associated hazard ratio was 2.4 [85]. (See "Delirium and acute confusional states: Prevention, treatment, and prognosis", section on 'Outcomes'.) Seizures Approximately 0.5 to 3.5 percent of patients experience seizures after coronary artery bypass graft surgery (CABG) [2,36]. Causes include hypoxemia, metabolic disturbances (eg, hyponatremia, hypoglycemia), drug toxicity (eg, lidocaine, procainamide), and structural brain injury such as stroke. EEG should be considered in patients who are unresponsive 18 to 24 hours after surgery to detect possible nonconvulsive seizure activity. (See "Convulsive status epilepticus in adults: Classification, clinical features, and diagnosis".) https://www.uptodate.com/contents/neurologic-complications-of-cardiac-surgery/print 9/27 7/5/23, 12:06 PM Neurologic complications of cardiac surgery - UpToDate Coma Coma infrequently complicates cardiac surgery and results from diffuse global anoxic injury, strokes (large hemispheric, brainstem, or multifocal infarcts), intracerebral hemorrhages, seizures, or severe metabolic derangements. Coma as a result of anoxic or structural injury carries an extremely poor prognosis. Patients with severe anoxic injury and coma may also exhibit postanoxic myoclonus and seizures. Cognitive impairment Disturbances in memory, executive function, motor speed, attention, and other cognitive functions can be detected in 3 to 79 percent of patients in the first several weeks after CABG when formal neuropsychiatric testing is performed [2,4,86-91]. The severity can range from subtle deficits detectable only by sophisticated neuropsychiatric testing to clinically overt delirium as described above. The wide variation in the reported incidence of postoperative cognitive problems is probably related to several factors, including variability in CABG procedures, constraints reducing participation in cognitive studies, different methodologies used to assess neurocognitive dysfunction, variations in the follow-up time interval, and a paucity of studies with control groups [4,18,91,92]. The importance of control groups has been illustrated in two studies. One compared neurocognitive function at baseline, 3 months, and 12 months after CABG using two different control groups: those with coronary disease but no surgery and those who were heart healthy [93]. At baseline, patients with heart disease had lower cognitive scores than the heart-healthy patients. At baseline and at follow-up, the cognitive test performance of CABG patients did not differ from control groups with heart disease. Mechanisms and risk factors While this syndrome has been called "postperfusion syndrome," "postpump syndrome," and "pump-head," these terms imply a mechanism of action that is speculative and that may not be a factor in some patients with neurocognitive dysfunction after cardiac surgery. The incidence of neuropsychiatric deficits in patients undergoing cardiac operations exceeds that of corresponding patients undergoing operations for peripheral vascular disease, suggesting that some specific features of cardiac operations, such as cerebral microemboli, may cause neuropsychiatric disturbances [55,83,86]. Microemboli appear to be generated by manipulation of the heart and aorta, particularly during aortic cannulation and clamping and cardiotomy suctioning. Clinical investigations provide mixed support for a role of microemboli in post-CABG encephalopathy. Transcranial Doppler (TCD) monitoring studies and neuropathologic studies find that platelet microemboli and ischemic lesions are common during and after cardiac surgery [94]. In one series of 40 patients undergoing intracardiac surgery, comparison of preoperative and postoperative magnetic https://www.uptodate.com/contents/neurologic-complications-of-cardiac-surgery/print 10/27 7/5/23, 12:06 PM Neurologic complications of cardiac surgery - UpToDate resonance imaging (MRI) scans and neuropsychologic testing found that postoperative decline in cognitive function was associated with the presence and severity of new ischemic lesions [95]. However, other studies have not confirmed this association [29]. Similarly, studies have not shown a causal association between the presence or number of microemboli detected during surgery and the postoperative cognitive impairment or pathologic change [83,96]. Intraoperative hypotension and prolonged oxygen desaturations may also contribute to cerebral injury and subsequent neurocognitive decline [83]. In one small study a drop in mean arterial blood pressure of 27 mmHg or greater (compared with preoperative baseline) was associated with a decrease in the Mini-Mental State Examination score of 1.4 points [97]. Other identified risk factors for cognitive impairment after cardiac surgery may be identified preoperatively and overlap with those for stroke, further implicating an underlying vascular mechanism [2,4,16,18,46]: Hypertension Carotid disease Advanced age Previous stroke (clinical event or detected on MRI) Underlying pulmonary disease Temperature is a modulator of experimental cerebral injury, and postoperative hyperthermia may be related to the development of cognitive dysfunction. In one study of 300 patients, the maximum postoperative temperature was associated with a greater amount of dysfunction at six weeks [98]. This suggests that interventions to avoid postoperative hyperthermia may be beneficial for improving cerebral outcome after CABG. Other mechanisms implicated in post-CABG cognitive decline are more speculative and include systemic inflammation and exposure to general anesthesia [83]. On-pump CABG does not appear to be associated with a higher risk for cognitive or neuropsychologic impairment compared with off-pump CABG according to a meta-analysis and subsequently performed clinical trial. (See "Off-pump and minimally invasive direct coronary artery bypass graft surgery: Clinical use", section on 'Neurologic dysfunction'.) Clinical course Neurocognitive deficits usually resolve gradually. Most patients return to their preoperative baseline by 3 to 12 months after surgery [93]. In one study, long-term recovery was more likely in patients with less severe impairments after surgery, as well as in those with more education and greater activities of daily living at six weeks [99]. https://www.uptodate.com/contents/neurologic-complications-of-cardiac-surgery/print 11/27 7/5/23, 12:06 PM Neurologic complications of cardiac surgery - UpToDate However, postoperative encephalopathy is associated with poor short-term outcomes. In one series, the length of stay was 14 days for those with encephalopathy, versus an average of eight days for patients without this complication [55]. These patients also had a three times greater in- hospital mortality rate and were less likely to be discharged to home. Late cognitive decline Some believe that post-CABG patients are at higher risk for long- term cognitive decline. In one study, serial neurocognitive testing was performed in 261 patients after CABG [89]. A decline in neurocognitive function was defined as a drop of 1 standard deviation (SD), representing a decline of approximately 20 percent. The incidence of neurocognitive decline at discharge, six weeks, six months, and five years was 53, 36, 24, and 42 percent, respectively. The main predictor of cognitive decline at five years was neurocognitive deficits at discharge. However, accumulating evidence suggests that the cause of late decline in cognitive function occurring one to five years after CABG is progression of underlying cerebrovascular disease or vascular dementia rather than CABG or cardiopulmonary bypass (CPB) [4,91]. A number of longitudinal studies have compared cognitive changes among post-CABG patients with a control group of patients with coronary disease with no surgery, revealing similar rates of cognitive decline [93,100-103]. A case-control study comparing 557 patients with incident dementia with nondemented controls found similar rates of CABG history in both groups [104]. Some studies suggest that cardiac disease (particularly low cardiac output and left ventricular diastolic dysfunction) in the absence of cardiac surgery is associated with cognitive impairments [105]. PERIPHERAL NEUROPATHY Upper extremity Upper extremity peripheral nerve injury follows cardiac operations in 2 to 15 percent of patients [8,48,106-108]. Putative mechanisms of injury include brachial plexus traction, brachial plexus compression between the clavicle and the first rib during sternal retraction, and nerve injury during internal mammary artery dissection, hypothermia, and hemodynamic changes during cardiopulmonary bypass (CPB). In one case series, hypertension, tobacco use, and diabetes were risk factors for nerve injuries [108]. Peripheral neuropathy typically presents with numbness, weakness, pain, diminished reflexes, and discoordination of one upper extremity. The presence of pain suggests a peripheral rather than central injury, while confusion, cranial nerve involvement, or hemiparesis suggests a central injury. Sensory symptoms are most frequent in the fourth and fifth fingers. Although this distribution is expected with ulnar nerve injury at the elbow, similar symptoms are associated with injury to the https://www.uptodate.com/contents/neurologic-complications-of-cardiac-surgery/print 12/27 7/5/23, 12:06 PM Neurologic complications of cardiac surgery - UpToDate lower (medial) brachial plexus elements. Overall, brachial plexus injury is more common than isolated ulnar nerve deficits after cardiac surgery. Weakness in muscles supplied by the lower cervical nerve roots but not the ulnar nerve, such as the extensor indicis and abductor pollicis brevis, indicates a plexopathy. Following intraaortic balloon pump insertion, femoral nerve injury may occur due to local trauma, vascular occlusion, pseudoaneurysm formation, or emboli. In most neuropathies related to cardiac surgery, symptoms improve or resolve within three weeks, suggesting a neurapraxic injury caused by disruption of the myelin sheath. Given this good prognosis, conservative treatment, consisting of physical therapy to improve strength and flexibility in the affected muscles, is indicated. Axonal injury is much less common and is associated with neurologic symptoms lasting for an extended period. Thus, failure to improve within three weeks following cardiac surgery should prompt electromyography and nerve conduction studies to confirm the diagnosis, delineate the site of injury and the extent of nerve disruption, and provide an accurate prognosis for recovery. Phrenic nerve Phrenic nerve injury occurs with cooling of the heart by iced slush. The reported frequency with which it occurs has varied widely from 1 to 30 percent, depending in part upon whether it is diagnosed by radiographic evidence of diaphragmatic dysfunction, which is not always due to phrenic nerve dysfunction [109], or phrenic nerve conduction studies [107,109-111]. Most patients have unilateral phrenic nerve injury, typically on the same side as the internal mammary graft with coronary artery bypass graft surgery (CABG) [110,111]. Patients with bilateral phrenic nerve dysfunction generally require prolonged mechanical ventilation [111]. Most affected patients recover fully within one year, but recovery may be delayed for two years or more [110,112]. The frequency of phrenic nerve injury has declined dramatically with changes in surgical technique. These include a reduction in the use of iced slush and an increase in the use of foam insulation [111]. Intercostal nerve Harvesting of the internal thoracic artery may be associated with injury to the anterior intercostal nerves. This nerve injury can present with numbness, tenderness, light- touch evoked pain, or constant burning pain over the sternum and left anterolateral chest wall. In one study of 37 patients, for example, 81 percent reported protracted postoperative symptoms; although this usually subsided by four months, 15 percent had symptoms that persisted for 5 to 28 months after surgery [113]. https://www.uptodate.com/contents/neurologic-complications-of-cardiac-surgery/print 13/27 7/5/23, 12:06 PM Neurologic complications of cardiac surgery - UpToDate OTHERS A dyskinetic movement disorder, so-called post-pump chorea may complicate cardiac surgery in a small number of children with congenital heart disease. This has also been described in a single case series of five adult patients who underwent pulmonary endarterectomy with coronary artery bypass graft surgery (CABG) and hypothermic circulatory arrest [114]. Symptoms presented between one and three days postoperatively and subsequently remitted over several weeks to months. Two patients had persistent mild symptoms. (See "Hyperkinetic movement disorders in children", section on 'Post-pump chorea'.) SUMMARY AND RECOMMENDATIONS Neurologic complications of cardiac surgery are not rare; there is an estimated 6 percent incidence of combined central nervous system complications (stroke, encephalopathy). Cerebrovascular disease Most strokes that occur in the setting of cardiac surgery are clinically apparent within 24 to 48 hours. The incidence is uncertain; surgical databases may substantially underestimate the incidence of stroke when compared with data collected in rigorous clinical or imaging-based studies. (See 'Incidence' above.) Valvular repairs and combined coronary artery bypass graft surgery (CABG) and valvular repairs, particularly those involving the mitral valve, appear to have a significantly higher risk of stroke than CABG alone. Mechanisms of intraoperative and postoperative ischemic stroke include cerebral hypoperfusion, artery-to-artery embolism, and cardiogenic embolism. (See 'Mechanisms of cerebral infarction' above.) Traditional atherosclerosis risk factors, prior cerebrovascular disease, and atherosclerotic disease affecting the coronary or peripheral arteries are among the risk factors for perioperative ischemic stroke. (See 'Risk factors' above.) Management of perioperative ischemic stroke in the setting of cardiac surgery is similar to that in other settings except that use of intravenous tissue plasminogen activator is contraindicated in patients after cardiac surgery. (See 'Diagnosis and treatment' above and "Initial assessment and management of acute stroke".) Encephalopathy More diffuse cerebral involvement after cardiac surgery may manifest as a delirium, seizures, and sometimes even coma. The mechanisms underlying this https://www.uptodate.com/contents/neurologic-complications-of-cardiac-surgery/print 14/27 7/5/23, 12:06 PM Neurologic complications of cardiac surgery - UpToDate complication are likely multifactorial. A minority of patients will have persistent neurocognitive dysfunction. Evaluation in these patients focuses on excluding a cerebrovascular event and reversible toxic and metabolic conditions. (See 'Encephalopathy' above.) Peripheral nerve complications Peripheral nerve injury is an uncommon complication. Specific syndromes include: Brachial plexopathy with motor-sensory deficits in the upper extremity Phrenic neuropathy with prolonged ventilator dependence Intercostal neuropathy with pain and dysesthesia in a localized distribution in the lateral chest wall Most patients improve, although recovery can sometimes take months to occur. (See 'Peripheral neuropathy' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Gardner TJ, Horneffer PJ, Manolio TA, et al. Stroke following coronary artery bypass grafting: a ten-year study. Ann Thorac Surg 1985; 40:574. 2. Roach GW, Kanchuger M, Mangano CM, et al. Adverse cerebral outcomes after coronary bypass surgery. Multicenter Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation Investigators. N Engl J Med 1996; 335:1857.

suggest that cardiac disease (particularly low cardiac output and left ventricular diastolic dysfunction) in the absence of cardiac surgery is associated with cognitive impairments [105]. PERIPHERAL NEUROPATHY Upper extremity Upper extremity peripheral nerve injury follows cardiac operations in 2 to 15 percent of patients [8,48,106-108]. Putative mechanisms of injury include brachial plexus traction, brachial plexus compression between the clavicle and the first rib during sternal retraction, and nerve injury during internal mammary artery dissection, hypothermia, and hemodynamic changes during cardiopulmonary bypass (CPB). In one case series, hypertension, tobacco use, and diabetes were risk factors for nerve injuries [108]. Peripheral neuropathy typically presents with numbness, weakness, pain, diminished reflexes, and discoordination of one upper extremity. The presence of pain suggests a peripheral rather than central injury, while confusion, cranial nerve involvement, or hemiparesis suggests a central injury. Sensory symptoms are most frequent in the fourth and fifth fingers. Although this distribution is expected with ulnar nerve injury at the elbow, similar symptoms are associated with injury to the https://www.uptodate.com/contents/neurologic-complications-of-cardiac-surgery/print 12/27 7/5/23, 12:06 PM Neurologic complications of cardiac surgery - UpToDate lower (medial) brachial plexus elements. Overall, brachial plexus injury is more common than isolated ulnar nerve deficits after cardiac surgery. Weakness in muscles supplied by the lower cervical nerve roots but not the ulnar nerve, such as the extensor indicis and abductor pollicis brevis, indicates a plexopathy. Following intraaortic balloon pump insertion, femoral nerve injury may occur due to local trauma, vascular occlusion, pseudoaneurysm formation, or emboli. In most neuropathies related to cardiac surgery, symptoms improve or resolve within three weeks, suggesting a neurapraxic injury caused by disruption of the myelin sheath. Given this good prognosis, conservative treatment, consisting of physical therapy to improve strength and flexibility in the affected muscles, is indicated. Axonal injury is much less common and is associated with neurologic symptoms lasting for an extended period. Thus, failure to improve within three weeks following cardiac surgery should prompt electromyography and nerve conduction studies to confirm the diagnosis, delineate the site of injury and the extent of nerve disruption, and provide an accurate prognosis for recovery. Phrenic nerve Phrenic nerve injury occurs with cooling of the heart by iced slush. The reported frequency with which it occurs has varied widely from 1 to 30 percent, depending in part upon whether it is diagnosed by radiographic evidence of diaphragmatic dysfunction, which is not always due to phrenic nerve dysfunction [109], or phrenic nerve conduction studies [107,109-111]. Most patients have unilateral phrenic nerve injury, typically on the same side as the internal mammary graft with coronary artery bypass graft surgery (CABG) [110,111]. Patients with bilateral phrenic nerve dysfunction generally require prolonged mechanical ventilation [111]. Most affected patients recover fully within one year, but recovery may be delayed for two years or more [110,112]. The frequency of phrenic nerve injury has declined dramatically with changes in surgical technique. These include a reduction in the use of iced slush and an increase in the use of foam insulation [111]. Intercostal nerve Harvesting of the internal thoracic artery may be associated with injury to the anterior intercostal nerves. This nerve injury can present with numbness, tenderness, light- touch evoked pain, or constant burning pain over the sternum and left anterolateral chest wall. In one study of 37 patients, for example, 81 percent reported protracted postoperative symptoms; although this usually subsided by four months, 15 percent had symptoms that persisted for 5 to 28 months after surgery [113]. https://www.uptodate.com/contents/neurologic-complications-of-cardiac-surgery/print 13/27 7/5/23, 12:06 PM Neurologic complications of cardiac surgery - UpToDate OTHERS A dyskinetic movement disorder, so-called post-pump chorea may complicate cardiac surgery in a small number of children with congenital heart disease. This has also been described in a single case series of five adult patients who underwent pulmonary endarterectomy with coronary artery bypass graft surgery (CABG) and hypothermic circulatory arrest [114]. Symptoms presented between one and three days postoperatively and subsequently remitted over several weeks to months. Two patients had persistent mild symptoms. (See "Hyperkinetic movement disorders in children", section on 'Post-pump chorea'.) SUMMARY AND RECOMMENDATIONS Neurologic complications of cardiac surgery are not rare; there is an estimated 6 percent incidence of combined central nervous system complications (stroke, encephalopathy). Cerebrovascular disease Most strokes that occur in the setting of cardiac surgery are clinically apparent within 24 to 48 hours. The incidence is uncertain; surgical databases may substantially underestimate the incidence of stroke when compared with data collected in rigorous clinical or imaging-based studies. (See 'Incidence' above.) Valvular repairs and combined coronary artery bypass graft surgery (CABG) and valvular repairs, particularly those involving the mitral valve, appear to have a significantly higher risk of stroke than CABG alone. Mechanisms of intraoperative and postoperative ischemic stroke include cerebral hypoperfusion, artery-to-artery embolism, and cardiogenic embolism. (See 'Mechanisms of cerebral infarction' above.) Traditional atherosclerosis risk factors, prior cerebrovascular disease, and atherosclerotic disease affecting the coronary or peripheral arteries are among the risk factors for perioperative ischemic stroke. (See 'Risk factors' above.) Management of perioperative ischemic stroke in the setting of cardiac surgery is similar to that in other settings except that use of intravenous tissue plasminogen activator is contraindicated in patients after cardiac surgery. (See 'Diagnosis and treatment' above and "Initial assessment and management of acute stroke".) Encephalopathy More diffuse cerebral involvement after cardiac surgery may manifest as a delirium, seizures, and sometimes even coma. The mechanisms underlying this https://www.uptodate.com/contents/neurologic-complications-of-cardiac-surgery/print 14/27 7/5/23, 12:06 PM Neurologic complications of cardiac surgery - UpToDate complication are likely multifactorial. A minority of patients will have persistent neurocognitive dysfunction. Evaluation in these patients focuses on excluding a cerebrovascular event and reversible toxic and metabolic conditions. (See 'Encephalopathy' above.) Peripheral nerve complications Peripheral nerve injury is an uncommon complication. 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Topic 1660 Version 14.0 https://www.uptodate.com/contents/neurologic-complications-of-cardiac-surgery/print 23/27 7/5/23, 12:06 PM Neurologic complications of cardiac surgery - UpToDate GRAPHICS Neurologic complications of cardiac operations Complication Incidence Preventive measures Brachial plexus 2-15 percent Minimize sternal retraction injury Attention to patient position Padding arms Stroke 0.4-6 percent Conduct of cardiopulmonary bypass Minimize duration Hypothermia Alpha-stat pH management (?) Minimally invasive procedures (?) Avoid perioperative hypotension Preoperative screening If significant carotid stenosis consider: Preoperative stent Combined CEA/CABG Avoidance of emboli De-airing maneuvers Minimize aortic trauma in patients with severely calcified aortas Monitoring TEE EEG/EP (?) TCD (?) Ophthalmologic Clinical 0.1-25 Same as stroke percent Angiography 100 percent https://www.uptodate.com/contents/neurologic-complications-of-cardiac-surgery/print 24/27 7/5/23, 12:06 PM Neurologic complications of cardiac surgery - UpToDate Delirium 3-32 percent Minimize: Sensory deprivation Benzodiazepine/narcotic use postoperatively Disruption of sleep-wake cycles Watch for metabolic encephalopathies Electrolytes Renal dysfunction Hepatic dysfunction Watch for withdrawal syndromes Subtle neuropsychological 10-79 percent Same as stroke Intracranial <0.1 percent Wait 2-4 weeks after new stroke before surgery if possible hemorrhage Seizures 0.6 percent Avoid: Hyponatremia Hypocalcemia Hypomagnesemia Avoid withdrawal of: Benzodiazepines Barbiturates Avoid toxic doses of: Lidocaine CEA: carotid endarterectomy; EEG: electroencephalography; CABG: coronary artery bypass grafting; EP: evoked potentials; TEE: transesophageal echocardiography; TCD: transcranial Doppler. Graphic 68206 Version 3.0 https://www.uptodate.com/contents/neurologic-complications-of-cardiac-surgery/print 25/27 7/5/23, 12:06 PM Neurologic complications of cardiac surgery - UpToDate Impact of age on adverse cerebral outcomes after coronary bypass surgery The incidence of adverse cerebral events after coronary artery bypass surgery is 6.1 percent, of which half are type I (focal injury, coma, or stupor at discharge) and half are type II (deterioration in intellectual function, memory defect, or seizures). The incidence of both type I and II events increase with age. Data from Roach GW, Kanchuger M, Mangano M, et al, and the Ischemia Research and Education Foundation Investigators. N Engl J Med 1996; 335:1857. Graphic 68686 Version 4.0 https://www.uptodate.com/contents/neurologic-complications-of-cardiac-surgery/print 26/27 7/5/23, 12:06 PM Neurologic complications of cardiac surgery - UpToDate Contributor Disclosures Michael L McGarvey, MD No relevant financial relationship(s) with ineligible companies to disclose. Albert T Cheung, MD No relevant financial relationship(s) with ineligible companies to disclose. Mark M Stecker, MD, PhD, FAAN, FACNS, FASNM Employment: Fresno Institute of Neuroscience [Neuroscience]. Equity Ownership/Stock Options: Fresno Institute of Neuroscience [Neuroscience]. Consultant/Advisory Boards: Legal case reviews [Intraoperative monitoring]. All of the relevant financial relationships listed have been mitigated. Michael J Aminoff, MD, DSc Consultant/Advisory Boards: Brain Neurotherapy Bio [Parkinson disease]. All of the relevant financial relationships listed have been mitigated. Gabriel S Aldea, MD No relevant financial relationship(s) with ineligible companies to disclose. Janet L Wilterdink, MD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/neurologic-complications-of-cardiac-surgery/print 27/27

7/5/23, 12:07 PM Prevention and treatment of venous thromboembolism in patients with acute stroke - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Prevention and treatment of venous thromboembolism in patients with acute stroke : Koto Ishida, MD : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Oct 04, 2021. INTRODUCTION Venous thromboembolism (VTE) encompasses deep vein thrombosis (DVT) and pulmonary embolism, which is potentially life-threatening. This topic will review the prevention and treatment of VTE in patients with acute ischemic and hemorrhagic stroke. Other aspects of acute stroke care are reviewed separately: Initial assessment and management of acute stroke Neuroimaging of acute stroke Approach to reperfusion therapy for acute ischemic stroke Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use Mechanical thrombectomy for acute ischemic stroke Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis Spontaneous intracerebral hemorrhage: Acute treatment and prognosis Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis Aneurysmal subarachnoid hemorrhage: Treatment and prognosis Complications of stroke: An overview RISK AND PREVALENCE https://www.uptodate.com/contents/prevention-and-treatment-of-venous-thromboembolism-in-patients-with-acute-stroke/print 1/20 7/5/23, 12:07 PM Prevention and treatment of venous thromboembolism in patients with acute stroke - UpToDate The risk of venous thromboembolism (VTE) is elevated in the first one to three months after stroke, due in part to stroke-related immobility [1,2]. Deep venous thrombosis Proximal deep vein thrombosis (DVT) is a serious problem because it may lead to life-threatening pulmonary embolism. The overall prevalence of clinically evident DVT after acute stroke is 1 to 10 percent [3-7]. The prevalence of asymptomatic DVT is even higher. In the largest observational report, which evaluated 5632 immobile patients with acute stroke using duplex ultrasound, DVT was detected within 10 days of enrollment in 11 percent, and within 30 days in 15 percent [6]. DVT development may occur as early as the second day after stroke onset and has a peak incidence between two to seven days [1]. Patients with hemiparesis are predisposed to DVT development, and the degree of paresis confers a graded risk of DVT [8]. In a report that included 542 patients with DVT and a weak leg, the DVT was ipsilateral to the weak leg in 73 percent, contralateral in 11 percent, and bilateral in 16 percent [6]. In addition, the presence of a DVT on the nonparetic side suggests the presence of DVT on the paretic side [8,9]. Additional important risk factors for DVT include advanced age, high stroke severity, and immobility [5,9]. Pulmonary embolism Pulmonary embolism, often unassociated with clinically recognized DVT, accounts for 13 to 25 percent of early deaths after stroke and is the most common cause of death at its peak occurrence about two to four weeks after stroke onset [1]. The incidence of pulmonary embolism in the first few months after stroke ranges from 1 to 3 percent [4,10-12]. The diagnosis of acute pulmonary embolism is reviewed elsewhere. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism".) APPROACH TO VTE PREVENTION Indications Venous thromboembolism (VTE) prophylaxis is indicated for all patients with acute stroke and restricted mobility. The approach to VTE prevention differs according to the type of stroke. Approach in acute ischemic stroke Based upon the evidence presented below, we recommend VTE prophylaxis with thigh-length intermittent pneumatic compression (IPC), starting at admission, for patients within 72 hours of acute ischemic stroke onset who have restricted mobility. (See 'Intermittent pneumatic compression' below.) In addition to IPC, we suggest pharmacologic VTE prophylaxis for select patients within 48 hours of acute ischemic stroke onset who have restricted mobility. Exceptions include patients with https://www.uptodate.com/contents/prevention-and-treatment-of-venous-thromboembolism-in-patients-with-acute-stroke/print 2/20 7/5/23, 12:07 PM Prevention and treatment of venous thromboembolism in patients with acute stroke - UpToDate transient ischemic attack (TIA) or minor stroke who are being treated with dual antiplatelet therapy (DAPT) and patients receiving full-dose heparin or oral anticoagulation for another indication. Options for pharmacologic VTE prophylaxis include subcutaneous low molecular weight (LMW) heparin (eg, enoxaparin 40 mg daily, dalteparin 5000 units once daily, tinzaparin 4500 units once daily, or nadroparin 3800 units once daily if weight 70 kg, or 5700 units once daily if >70 kg), or subcutaneous low-dose unfractionated heparin (5000 units two to three times daily). This recommendation applies only to patients for whom the assessed benefit of anticoagulation is thought to outweigh the risk of bleeding. (See 'Low-dose heparin anticoagulation' below.) The approach to VTE prevention is modified according to individual circumstances; common situations include the following: After intravenous thrombolysis For patients who are treated with intravenous thrombolysis for acute ischemic stroke, IPC should be started on admission, while anticoagulation should be delayed until 24 hours after intravenous thrombolysis. (See "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use", section on 'Monitoring'.) No intravenous thrombolysis For patients who are not treated with intravenous thrombolysis, IPC should be started on admission, and low-dose heparin (LMW or unfractionated) can be added for patients who are not being treated with DAPT for minor stroke. On dual antiplatelet therapy For patients with a TIA or minor stroke (ie, a National Institutes of Health Stroke Scale [NIHSS] score 3) who are receiving short-term DAPT with aspirin plus clopidogrel, it is reasonable to use IPC alone and avoid anticoagulation for pharmacologic VTE prophylaxis. The indications for DAPT in acute ischemic stroke are discussed separately. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Efficacy of DAPT'.) Already on anticoagulation For patients who are receiving oral anticoagulant therapy at the time of acute ischemic stroke, IPC is started on admission. Low-dose heparin (LMW or unfractionated) can be used for VTE prophylaxis (after 24 hours following intravenous thrombolysis) during the interval when full-dose oral anticoagulation is stopped, which is often done to reduce the risk of hemorrhagic transformation of the ischemic infarct during the acute phase stroke. There is no need for concomitant low-dose heparin for VTE prophylaxis if oral anticoagulation is continued, and no need for VTE prophylaxis once oral anticoagulation is restarted and has achieved a therapeutic level. (See "Early https://www.uptodate.com/contents/prevention-and-treatment-of-venous-thromboembolism-in-patients-with-acute-stroke/print 3/20 7/5/23, 12:07 PM Prevention and treatment of venous thromboembolism in patients with acute stroke - UpToDate antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Limited role of early anticoagulation'.) Contraindication to anticoagulation For patients with a contraindication to any anticoagulation (eg, gastrointestinal or other major systemic bleeding, or symptomatic hemorrhagic transformation of ischemic infarction), IPC is used alone for VTE prophylaxis. Approach in intracerebral hemorrhage IPC is the mainstay for prevention of venous thromboembolism in patients with acute intracerebral hemorrhage (ICH) and should be started on admission [13-15]. (See 'Intermittent pneumatic compression' below.) Once intracranial bleeding has stopped, some experts add low-dose LMW or unfractionated heparin after one to four days from ICH onset for patients with lack of mobility [15]. The risk of hematoma expansion may be increased in certain settings (eg, contrast extravasation ["spot sign"] on initial CT angiography, poor control of hypertension, large hematoma volume), which may weigh against the use of anticoagulation. (See 'Low-dose heparin anticoagulation' below.) Approach in subarachnoid hemorrhage For patients with subarachnoid hemorrhage and decreased mobility, IPC is started on admission and prior to aneurysm treatment. Heparin (LMW or unfractionated) can be added once the aneurysm is secured for patients who continue to have restricted mobility. (See 'Intermittent pneumatic compression' below and 'Low-dose heparin anticoagulation' below.) Duration of therapy In most cases, we continue VTE prophylaxis for acute stroke (ischemic or hemorrhagic) for the duration of the acute and rehabilitation hospital stay, or until the patient becomes fully ambulatory [16,17]. Once patients become fully ambulatory, mechanical and pharmacologic interventions of VTE prevention are generally stopped. However, the definition of ambulatory is subjective; patients who have prolonged periods of immobility in between ambulatory periods should probably continue VTE prophylaxis. The optimal duration of VTE prophylaxis is uncertain, as the clinical trials have generally employed prophylaxis for two weeks, and longer periods of treatment are not well studied in patients with stroke. A subgroup analysis of one randomized trial suggested that longer-term prophylaxis (eg, up to six weeks) with enoxaparin reduced the risk of VTE and increased the risk of major bleeding [18]. INTERVENTIONS FOR VTE PREVENTION https://www.uptodate.com/contents/prevention-and-treatment-of-venous-thromboembolism-in-patients-with-acute-stroke/print 4/20 7/5/23, 12:07 PM Prevention and treatment of venous thromboembolism in patients with acute stroke - UpToDate Effective options for the prevention of venous thromboembolism (VTE) in patients with acute stroke and limited mobility include intermittent pneumatic compression devices and low-dose anticoagulation with heparin or low molecular weight (LMW) heparin. For patients with acute stroke capable of walking, early and frequent ambulation may be encouraged in addition to mechanical and pharmacologic interventions, although there is no direct evidence that this approach is effective for preventing VTE. Intermittent pneumatic compression We suggest VTE prophylaxis with thigh-length intermittent pneumatic compression (IPC), starting at admission, for most patients with acute ischemic or hemorrhagic stroke. (See 'Approach to VTE prevention' above.) IPC is effective for deep vein thrombosis (DVT) prevention in immobilized patients with acute stroke and has few clinically important side effects. Supporting evidence comes from the open- label multicenter CLOTS 3 trial, which randomly assigned over 2800 immobile patients within the first three days of admission for acute stroke (ischemic or hemorrhagic) to treatment with thigh- length IPC or no IPC [13]. Treatment was continued for at least 30 days or until the patient regained mobility, was discharged from the hospital, or could not tolerate continuation; the median duration was 9 days. At 30 days, there was a significant reduction in the rate of DVT in the femoral or popliteal veins (ie, proximal DVT) for the IPC compared with the no IPC group (8.5 versus 12.1 percent, absolute risk reduction 3.6 percent, 95% CI 1.4-5.8; adjusted odds ratio [OR] 0.65, 95% CI 0.51-0.84). In addition, the IPC group had significantly lower rates of symptomatic DVT (proximal or calf veins) and any DVT (symptomatic or asymptomatic, proximal or calf). In the subgroup of 322 patients with hemorrhagic stroke, IPC was associated with reduced risk of proximal DVT at 30 days (6.7 versus 17 percent; OR = 0.36, 95% CI 0.17-0.75). No major adverse events were associated with IPC treatment, but the IPC group had a significantly higher rate of skin breaks (3.1 versus 1.4 percent). Approximately one-third of patients in both groups received either anticoagulant prophylaxis or therapeutic anticoagulation. The effectiveness of IPC for VTE prevention in patients on anticoagulation is not firmly established, but a 2016 meta-analysis found moderate quality evidence that combining IPC and pharmacologic prophylaxis decreased the incidence of VTE in hospitalized patients when compared with IPC alone or pharmacologic prophylaxis alone [19]. In addition, a 2013 meta- analysis of randomized controlled trials evaluating hospitalized patients found that IPC plus pharmacologic prophylaxis provided an additive benefit for DVT prevention compared with IPC alone (relative risk reduction 0.54, 95% CI 0.32-0.91) [20]. The 2012 American College of Chest Physicians (ACCP) guidelines, which were published prior to the CLOTS 3 trial, had found only indirect evidence from other populations, mainly postoperative https://www.uptodate.com/contents/prevention-and-treatment-of-venous-thromboembolism-in-patients-with-acute-stroke/print 5/20 7/5/23, 12:07 PM Prevention and treatment of venous thromboembolism in patients with acute stroke - UpToDate patients, showing that IPC was associated with reduction in DVT of approximately 50 percent compared with no treatment [16,21]. Administration There are several types of intermittent pneumatic compression devices (eg, multichamber versus monochamber, pressure applied sequentially or uniformly, whole leg versus calf only). It is not known what type is optimal for VTE prevention in stroke patients. The CLOTS trial cited above used a multichamber device that applied sequential pressure to the entire leg [13]. Less than total compliance by patients and caregivers can limit the effectiveness of IPC, so strict adherence should be encouraged for patients with limited mobility. Contraindications IPC is contraindicated in those with overt evidence of leg ischemia caused by peripheral vascular disease, and in those with leg ulcerations, dermatitis, severe leg edema, or confirmed DVT. It should not be started in patients who have already been at bed rest or immobilized without VTE prophylaxis for more than 72 hours since stroke onset, since IPC may cause a newly formed clot to dislodge. (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients", section on 'Intermittent pneumatic compression and venous foot pump'.) Low-dose heparin anticoagulation We suggest low-dose LMW heparin or unfractionated heparin for most patients with acute ischemic stroke onset who have restricted mobility. Exceptions include patients with transient ischemic attack (TIA) or minor stroke who are being treated with dual antiplatelet therapy (DAPT) and patients receiving full-dose heparin or oral anticoagulation for another indication. (See 'Approach in acute ischemic stroke' above.) The use of low-dose anticoagulation with LMH heparin or unfractionated heparin has a more restricted role for patients with acute intracerebral hemorrhage or subarachnoid hemorrhage. (See 'Approach in intracerebral hemorrhage' above and 'Approach in subarachnoid hemorrhage' above.) Efficacy Efficacy in ischemic stroke Prospective studies have established that both unfractionated heparin and LMW heparin are effective in reducing DVT and pulmonary embolism in patients with stroke [22,23]. In a 2007 systematic review of randomized controlled trials comparing early (typically within 48 hours) administration of either LMW heparin or unfractionated heparin with control (placebo or no treatment) for VTE prevention in patients with acute ischemic stroke, low-dose LMW heparin offered the best benefit-to-risk ratio for VTE prophylaxis [22]. Low- https://www.uptodate.com/contents/prevention-and-treatment-of-venous-thromboembolism-in-patients-with-acute-stroke/print 6/20 7/5/23, 12:07 PM Prevention and treatment of venous thromboembolism in patients with acute stroke - UpToDate dose LMW heparin reduced the risk of both DVT (OR 0.34, 95% CI 0.19-0.59) and pulmonary embolism (OR 0.36, 95% CI 0.15-0.87), with no increased risk of major intracranial or extracranial hemorrhage. The numbers needed to treat with low-dose LMW heparin to prevent DVT and pulmonary embolism were 7 and 38, respectively. Low-dose unfractionated heparin ( 15,000 units/day) decreased the risk of DVT but had no significant effect on the risk of pulmonary embolism and no significant effect on the risk of major intracranial or extracranial hemorrhage. In a meta-analysis of three randomized trials with over 2000 patients who had ischemic stroke, LMW heparins (enoxaparin in two trials and certoparin in one trial) were superior to unfractionated heparin for the prevention of any VTE (OR 0.54, 95% CI 0.41-0.70) [24]. In addition, LMW heparin use resulted in a reduction of pulmonary embolism (OR 0.26, 95% CI 0.07-0.95), though the number of events was small. There was no significant difference between groups for rates of intracerebral hemorrhage, overall bleeding, or mortality. Efficacy in hemorrhagic stroke There are limited data regarding the risks and benefits of anticoagulation for VTE prevention after acute intracerebral hemorrhage; data for subarachnoid hemorrhage are virtually nonexistent. A 2011 meta-analysis of four studies, two randomized, that compared anticoagulation therapy (unfractionated heparin, LMW heparin, heparinoids) with other treatments in patients with acute ICH found that anticoagulation therapy was associated with a significant reduction in pulmonary embolism (1.7 versus 2.9 percent); rates of DVT and mortality were nonsignificantly decreased, and rates of hematoma expansion were nonsignificantly increased [25]. A 2020 meta-analysis identified only two randomized controlled trials (with a total of 194 patients) evaluating anticoagulation for VTE prevention in the setting of acute ICH [26]. Compared with other treatments, low-dose enoxaparin (40 mg daily) was associated with a trend towards a lower rate of PE (OR 0.38, 95% CI 0.14 1.05) and similar rates of VTE (OR 0.77; 95% CI 0.38 1.57), hematoma enlargement (OR 0.63, 95% CI 0.03 12.51), and mortality OR 1.17, 95% CI 0.47 2.94). The trial designs in these meta-analyses varied in quality and few pulmonary emboli occurred. Therefore, these results should be interpreted cautiously. Comparison of LMW heparins with unfractionated heparin LMW heparins have a number of advantages over unfractionated heparin, including a longer duration of anticoagulant effect (permitting administration only once daily), better correlation between dose and anticoagulant response (permitting administration of a fixed dose without laboratory monitoring), and a lower risk of heparin-induced thrombocytopenia. (See "Clinical presentation and diagnosis of heparin- induced thrombocytopenia", section on 'Incidence and risk factors'.) https://www.uptodate.com/contents/prevention-and-treatment-of-venous-thromboembolism-in-patients-with-acute-stroke/print 7/20 7/5/23, 12:07 PM Prevention and treatment of venous thromboembolism in patients with acute stroke - UpToDate Potential disadvantages of LMW heparin compared with unfractionated heparin include the longer duration of action (making it more difficult to rapidly stop therapy), less effective reversal with protamine sulfate, and a prolonged half-life in patients with renal failure, especially with enoxaparin. These issues are discussed in greater detail separately. (See "Heparin and LMW heparin: Dosing and adverse effects".) Dosing of LMW heparin For VTE prevention with LMW heparin, the suggested doses for most patients with creatinine clearance >30 mL/minute and no extremes in body weight are the following: Enoxaparin 40 mg subcutaneously once daily Dalteparin 5000 units subcutaneously once daily Tinzaparin (not available in the United States) 4500 units subcutaneously once daily Nadroparin (not available in the United States) 3800 units subcutaneously once daily for patients 70 kg body weight, or 5700 units subcutaneously once daily for patients >70 kg body weight) A dose reduction of enoxaparin is needed for those with severe renal insufficiency ( table 1). For those who develop severe renal insufficiency during hospitalization, it is prudent that selected LMW heparins be discontinued and replaced with unfractionated heparin. (See "Heparin and LMW heparin: Dosing and adverse effects".) Dosing of unfractionated heparin For VTE prevention with unfractionated heparin, the suggested dose is 5000 units subcutaneously two to three times daily. There is no consensus regarding the optimal frequency of dosing (two versus three times daily), as discussed separately. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults", section on 'Low-dose unfractionated heparin'.) The dose of unfractionated heparin does not need to be adjusted for patients with renal failure. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults", section on 'Low-dose unfractionated heparin' and "Heparin and LMW heparin: Dosing and adverse effects".) Adverse effects Immune-mediated heparin-induced thrombocytopenia (HIT) is a potentially life-threatening complication that occurs in a small percentage of patients exposed to unfractionated heparin or LMW heparin, regardless of the dose, schedule, or route of administration. Thrombosis occurs in up to 50 percent of patients who develop HIT, with venous being more common than arterial thrombi. Thrombosis can lead to skin necrosis, limb https://www.uptodate.com/contents/prevention-and-treatment-of-venous-thromboembolism-in-patients-with-acute-stroke/print 8/20 7/5/23, 12:07 PM Prevention and treatment of venous thromboembolism in patients with acute stroke - UpToDate gangrene, and organ infarction. The risk of HIT is somewhat greater with unfractionated heparin compared with LMW heparin. Individuals with a presumptive diagnosis of HIT should have immediate discontinuation of all heparin exposure. The evaluation and treatment of suspected HIT is discussed in detail elsewhere. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia".) Non-immune thrombocytopenia, often of no clinical importance, occurs in a minority of patients treated with heparin or LMH heparin. It is characterized by a mild, transient drop in platelet count that typically occurs within the first two days of heparin exposure. The platelet count usually returns to normal with continued heparin administration. The mechanism appears to be a direct effect of heparin on platelets, causing non-immune platelet aggregation. The typical platelet count nadir is approximately 100,000/microL. Ineffective or unproven treatments Fondaparinux Fondaparinux has not been well-studied for VTE prevention in patients with acute stroke. One retrospective study found no difference in symptomatic VTE or hemorrhagic complications for patients with acute stroke who were treated with fondaparinux or unfractionated heparin, but the study design does not permit definitive conclusions [27]. Fondaparinux is superior to placebo and likely as effective as LMW heparin for VTE prevention among patients who are not critically ill. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults", section on 'Fondaparinux'.) Graduated compression stockings We recommend not using graduated compression stockings for VTE prophylaxis in acute stroke of any type. Graduated compression stockings are not beneficial and may be harmful in the setting of acute stroke [28]. In the randomized controlled CLOTS 1 trial that evaluated 2158 patients within one week of acute stroke, thigh-length graduated compression stockings did not reduce occurrence of symptomatic or asymptomatic proximal DVT (the primary outcome) or VTE [29]. However, skin lesions (breaks, ulcers, blisters and necrosis) were more common in patients assigned to graduated compression stockings. Direct oral anticoagulants Most direct oral anticoagulants (dabigatran, apixaban, rivaroxaban, and edoxaban) have not been evaluated for VTE prophylaxis in patients hospitalized with acute stroke, and further study is needed to determine their utility for VTE prophylaxis in this setting. Aspirin As a separate indication, early aspirin therapy is recommended for most patients with acute ischemic stroke or transient ischemic attack (TIA) who are not receiving oral https://www.uptodate.com/contents/prevention-and-treatment-of-venous-thromboembolism-in-patients-with-acute-stroke/print 9/20 7/5/23, 12:07 PM Prevention and treatment of venous thromboembolism in patients with acute stroke - UpToDate anticoagulants because it reduces the risk of early recurrent stroke or death. This is discussed in detail elsewhere. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Efficacy of aspirin'.) However, aspirin alone is not considered effective for VTE prevention in hospitalized medical patients. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults", section on 'Aspirin'.) APPROACH TO VTE Suspicion for VTE Deep vein thrombosis (DVT) should be suspected in patients who present with leg swelling, pain, warmth, and erythema. Symptoms are usually unilateral but can be bilateral. Symptoms are confined to the calf in patients with isolated distal DVT, while patients with proximal DVT may have calf or whole leg symptoms. The clinical presentation and evaluation for DVT is reviewed in detail separately. (See "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity".) Pulmonary embolism has a wide variety of presenting features, ranging from no symptoms to shock or sudden death. The most common presenting symptom is dyspnea followed by chest pain and cough. However, many patients, including some with large pulmonary emboli, have mild or nonspecific symptoms or are asymptomatic. The clinical presentation and evaluation of suspected pulmonary embolism is discussed in detail elsewhere. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism".) Treatment for VTE When acute pulmonary embolism is suspected, initial care should focus on stabilizing the patient. This may require respiratory and hemodynamic support in the intensive care unit. (See "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults", section on 'Initial approach and resuscitation'.) In other settings, venous thromboembolism (VTE) is often treated with full-dose anticoagulation. However, anticoagulation increases the risk of symptomatic hemorrhagic transformation in patients with acute ischemic stroke, and increases the risk of hematoma expansion and rebleeding in patients with intracranial hemorrhage. Full-dose anticoagulation may be appropriate for select patients with acute ischemic stroke who have small to moderate sized infarcts, but is generally avoided for the first one to two weeks after stroke onset for patients with large ischemic infarctions, which are associated with an increased risk of hemorrhagic transformation. Full-dose anticoagulation is generally contraindicated for patients with acute intracerebral hemorrhage and patients with aneurysmal subarachnoid hemorrhage prior to https://www.uptodate.com/contents/prevention-and-treatment-of-venous-thromboembolism-in-patients-with-acute-stroke/print 10/20 7/5/23, 12:07 PM Prevention and treatment of venous thromboembolism in patients with acute stroke - UpToDate aneurysm repair. In all patients, the decision to use anticoagulation for VTE treatment should be individualized and the benefits weighed against the risk of bleeding. (See "Venous thromboembolism: Initiation of anticoagulation".) For patients with acute proximal DVT, symptomatic distal DVT, or hemodynamically stable patients with pulmonary embolism, an inferior vena cava filter should be placed promptly if the bleeding risk associated with full-dose anticoagulant therapy is excessive. (See "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults", section on 'Inferior vena cava filter' and "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)", section on 'Anticoagulant therapy'.) For patients with severe acute pulmonary embolism who have contraindications to anticoagulation and thrombolysis, catheter or surgical thrombectomy (embolectomy) can be used if the necessary resources and expertise are available. (See "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults", section on 'Embolectomy'.) Systemic thrombolytic therapy is seldom if ever appropriate for pulmonary embolism when treating patients with acute ischemic stroke (beyond 4.5 hours from stroke onset) or hemorrhagic stroke ( table 2). (See "Approach to thrombolytic (fibrinolytic) therapy in acute pulmonary embolism: Patient selection and administration", section on 'Assessing risk of bleeding and contraindications'.) Definitive pulmonary embolism treatment is discussed in detail separately. (See "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults", section on 'Definitive therapy'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anticoagulation" and "Society guideline links: Stroke in adults" and "Society guideline links: Superficial vein thrombosis, deep vein thrombosis, and pulmonary embolism".) SUMMARY AND RECOMMENDATIONS Proximal deep venous thrombosis is a serious complication of stroke because it may lead to life-threatening pulmonary embolism. Patients with hemiparesis, immobility, severe https://www.uptodate.com/contents/prevention-and-treatment-of-venous-thromboembolism-in-patients-with-acute-stroke/print 11/20 7/5/23, 12:07 PM Prevention and treatment of venous thromboembolism in patients with acute stroke - UpToDate stroke, and advanced age are predisposed to the development of deep vein thrombosis. (See 'Risk and prevalence' above.) Venous thromboembolism (VTE) prophylaxis is indicated for all patients with acute stroke and restricted mobility. The approach to VTE prevention differs according to the type of stroke. (See 'Indications' above.) For most patients with acute ischemic stroke who have restricted mobility and no contraindications, we suggest combined treatment, starting at admission, with thigh- length intermittent pneumatic compression (IPC) plus low molecular weight (LMW) heparin (Grade 2C). Low-dose unfractionated heparin is an alternative to LMW heparin. We prefer LMW heparin in this setting because of ease of use and lower risk of heparin- associated thrombocytopenia compared with unfractionated heparin. (See 'Approach in acute ischemic stroke' above and 'Low-dose heparin anticoagulation' above.): Certain modifications and exceptions apply (see 'Approach in acute ischemic stroke' above): For patients treated with intravenous thrombolysis, IPC should be started on admission and pharmacologic VTE prophylaxis should be delayed until 24 hours after intravenous thrombolysis. It is reasonable to withhold pharmacologic VTE prophylaxis for patients with transient ischemic attack or minor stroke who are being treated with dual antiplatelet therapy (DAPT). Additional pharmacologic VTE prophylaxis is not needed for patients receiving full- dose heparin or oral anticoagulation for another indication. For patients with acute intracerebral hemorrhage, we suggest treatment, starting at admission, with thigh-length IPC alone rather than IPC combined with low-dose anticoagulation or low-dose anticoagulation alone (Grade 2C). Once intracranial bleeding has stopped, it may be reasonable to add low-dose LMW or unfractionated heparin after one to four days from intracerebral hemorrhage onset for selected patients with lack of mobility. (See 'Approach in intracerebral hemorrhage' above and 'Intermittent pneumatic compression' above.) For patients with acute subarachnoid hemorrhage and decreased mobility we suggest treatment, starting at admission, with thigh-length IPC alone rather than treatment with low-dose anticoagulation combined with IPC or low-dose anticoagulation alone (Grade 2C). Heparin (LMW or unfractionated) can be added once the aneurysm is secured for https://www.uptodate.com/contents/prevention-and-treatment-of-venous-thromboembolism-in-patients-with-acute-stroke/print 12/20 7/5/23, 12:07 PM Prevention and treatment of venous thromboembolism in patients with acute stroke - UpToDate patients who continue to have restricted mobility. (See 'Approach in subarachnoid hemorrhage' above.) We recommend not using graduated compression stockings for VTE prophylaxis in acute stroke of any type (Grade 1B). (See 'Ineffective or unproven treatments' above.) In most cases, we continue VTE prophylaxis for acute ischemic or hemorrhagic stroke for the duration of the acute and rehabilitation hospital stay, or until the patient becomes fully ambulatory. (See 'Duration of therapy' above.) Deep vein thrombosis should be suspected in patients who present with leg swelling, pain, warmth, and erythema. Pulmonary embolism has a wide variety of presenting features, ranging from no symptoms to shock or sudden death. The most common presenting symptom is dyspnea followed by chest pain and cough. However, many patients, including some with large pulmonary emboli, have mild or nonspecific symptoms or are asymptomatic. (See 'Suspicion for VTE' above and "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity" and "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism".) The treatment of proximal deep vein thrombosis, symptomatic distal deep vein thrombosis, and/or pulmonary embolism in patients with acute stroke may require placement of an inferior vena cava filter. Full-dose anticoagulation may be appropriate for patients with acute ischemic stroke who have small to moderate sized infarcts, but is generally avoided for the first one to two weeks after stroke onset for patients with large infarcts, and is contraindicated for patients with acute intracerebral hemorrhage and patients with aneurysmal subarachnoid hemorrhage prior to aneurysm repair. For patients with severe acute pulmonary embolism who have contraindications to anticoagulation and thrombolysis, catheter or surgical embolectomy can be used if the necessary resources and expertise are available. (See 'Treatment for VTE' above and "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)" and "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults".) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Kelly J, Rudd A, Lewis R, Hunt BJ. Venous thromboembolism after acute stroke. Stroke 2001; 32:262. https://www.uptodate.com/contents/prevention-and-treatment-of-venous-thromboembolism-in-patients-with-acute-stroke/print 13/20 7/5/23, 12:07 PM Prevention and treatment of venous thromboembolism in patients with acute stroke - UpToDate 2. Rinde LB, Sm brekke B, Mathiesen EB, et al. Ischemic Stroke and Risk of Venous Thromboembolism in the General Population: The Troms Study. J Am Heart Assoc 2016; 5. 3. Kamran SI, Downey D, Ruff RL. Pneumatic sequential compression reduces the risk of deep vein thrombosis in stroke patients. Neurology 1998; 50:1683. 4. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group. Lancet 1997; 349:1569. 5. Kelly J, Rudd A, Lewis RR, et al. Venous thromboembolism after acute ischemic stroke: a prospective study using magnetic resonance direct thrombus imaging. Stroke 2004; 35:2320. 6. Dennis M, Mordi N, Graham C, et al. The timing, extent, progression and regression of deep vein thrombosis in immobile stroke patients: observational data from the CLOTS multicenter randomized trials. J Thromb Haemost 2011; 9:2193. 7. Amin AN, Lin J, Thompson S, Wiederkehr D. Rate of deep-vein thrombosis and pulmonary embolism during the care continuum in patients with acute ischemic stroke in the United States. BMC Neurol 2013; 13:17. 8. Landi G, D'Angelo A, Boccardi E, et al. Venous thromboembolism in acute stroke. Prognostic importance of hypercoagulability. Arch Neurol 1992; 49:279. 9. Warlow C, Ogston D, Douglas AS. Deep venous thrombosis of the legs after strokes. Part I incidence and predisposing factors. Br Med J 1976; 1:1178. 10. Langhorne P, Stott DJ, Robertson L, et al. Medical complications after stroke: a multicenter study. Stroke 2000; 31:1223. 11. Johnston KC, Li JY, Lyden PD, et al. Medical and neurological complications of ischemic stroke: experience from the RANTTAS trial. RANTTAS Investigators. Stroke 1998; 29:447. 12. Pongmoragot J, Rabinstein AA, Nilanont Y, et al. Pulmonary embolism in ischemic stroke: clinical presentation, risk factors, and outcome. J Am Heart Assoc 2013; 2:e000372. 13. CLOTS (Clots in Legs Or sTockings after Stroke) Trials Collaboration, Dennis M, Sandercock P, et al. Effectiveness of intermittent pneumatic compression in reduction of risk of deep vein thrombosis in patients who have had a stroke (CLOTS 3): a multicentre randomised controlled trial. Lancet 2013; 382:516. 14. Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e195S. https://www.uptodate.com/contents/prevention-and-treatment-of-venous-thromboembolism-in-patients-with-acute-stroke/print 14/20 7/5/23, 12:07 PM Prevention and treatment of venous thromboembolism in patients with acute stroke - UpToDate 15. Hemphill JC 3rd, Greenberg SM, Anderson CS, et al. Guidelines for the Management of Spontaneous Intracerebral Hemorrhage: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2015; 46:2032. 16. Lansberg MG, O'Donnell MJ, Khatri P, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e601S. 17. Winstein CJ, Stein J, Arena R, et al. Guidelines for Adult Stroke Rehabilitation and Recovery: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2016; 47:e98. 18. Turpie AG, Hull RD, Schellong SM, et al. Venous thromboembolism risk in ischemic stroke

above): For patients treated with intravenous thrombolysis, IPC should be started on admission and pharmacologic VTE prophylaxis should be delayed until 24 hours after intravenous thrombolysis. It is reasonable to withhold pharmacologic VTE prophylaxis for patients with transient ischemic attack or minor stroke who are being treated with dual antiplatelet therapy (DAPT). Additional pharmacologic VTE prophylaxis is not needed for patients receiving full- dose heparin or oral anticoagulation for another indication. For patients with acute intracerebral hemorrhage, we suggest treatment, starting at admission, with thigh-length IPC alone rather than IPC combined with low-dose anticoagulation or low-dose anticoagulation alone (Grade 2C). Once intracranial bleeding has stopped, it may be reasonable to add low-dose LMW or unfractionated heparin after one to four days from intracerebral hemorrhage onset for selected patients with lack of mobility. (See 'Approach in intracerebral hemorrhage' above and 'Intermittent pneumatic compression' above.) For patients with acute subarachnoid hemorrhage and decreased mobility we suggest treatment, starting at admission, with thigh-length IPC alone rather than treatment with low-dose anticoagulation combined with IPC or low-dose anticoagulation alone (Grade 2C). Heparin (LMW or unfractionated) can be added once the aneurysm is secured for https://www.uptodate.com/contents/prevention-and-treatment-of-venous-thromboembolism-in-patients-with-acute-stroke/print 12/20 7/5/23, 12:07 PM Prevention and treatment of venous thromboembolism in patients with acute stroke - UpToDate patients who continue to have restricted mobility. (See 'Approach in subarachnoid hemorrhage' above.) We recommend not using graduated compression stockings for VTE prophylaxis in acute stroke of any type (Grade 1B). (See 'Ineffective or unproven treatments' above.) In most cases, we continue VTE prophylaxis for acute ischemic or hemorrhagic stroke for the duration of the acute and rehabilitation hospital stay, or until the patient becomes fully ambulatory. (See 'Duration of therapy' above.) Deep vein thrombosis should be suspected in patients who present with leg swelling, pain, warmth, and erythema. Pulmonary embolism has a wide variety of presenting features, ranging from no symptoms to shock or sudden death. The most common presenting symptom is dyspnea followed by chest pain and cough. However, many patients, including some with large pulmonary emboli, have mild or nonspecific symptoms or are asymptomatic. (See 'Suspicion for VTE' above and "Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity" and "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism".) The treatment of proximal deep vein thrombosis, symptomatic distal deep vein thrombosis, and/or pulmonary embolism in patients with acute stroke may require placement of an inferior vena cava filter. Full-dose anticoagulation may be appropriate for patients with acute ischemic stroke who have small to moderate sized infarcts, but is generally avoided for the first one to two weeks after stroke onset for patients with large infarcts, and is contraindicated for patients with acute intracerebral hemorrhage and patients with aneurysmal subarachnoid hemorrhage prior to aneurysm repair. For patients with severe acute pulmonary embolism who have contraindications to anticoagulation and thrombolysis, catheter or surgical embolectomy can be used if the necessary resources and expertise are available. (See 'Treatment for VTE' above and "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)" and "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults".) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Kelly J, Rudd A, Lewis R, Hunt BJ. Venous thromboembolism after acute stroke. Stroke 2001; 32:262. https://www.uptodate.com/contents/prevention-and-treatment-of-venous-thromboembolism-in-patients-with-acute-stroke/print 13/20 7/5/23, 12:07 PM Prevention and treatment of venous thromboembolism in patients with acute stroke - UpToDate 2. Rinde LB, Sm brekke B, Mathiesen EB, et al. Ischemic Stroke and Risk of Venous Thromboembolism in the General Population: The Troms Study. J Am Heart Assoc 2016; 5. 3. Kamran SI, Downey D, Ruff RL. Pneumatic sequential compression reduces the risk of deep vein thrombosis in stroke patients. Neurology 1998; 50:1683. 4. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group. Lancet 1997; 349:1569. 5. Kelly J, Rudd A, Lewis RR, et al. Venous thromboembolism after acute ischemic stroke: a prospective study using magnetic resonance direct thrombus imaging. Stroke 2004; 35:2320. 6. Dennis M, Mordi N, Graham C, et al. The timing, extent, progression and regression of deep vein thrombosis in immobile stroke patients: observational data from the CLOTS multicenter randomized trials. J Thromb Haemost 2011; 9:2193. 7. Amin AN, Lin J, Thompson S, Wiederkehr D. Rate of deep-vein thrombosis and pulmonary embolism during the care continuum in patients with acute ischemic stroke in the United States. BMC Neurol 2013; 13:17. 8. Landi G, D'Angelo A, Boccardi E, et al. Venous thromboembolism in acute stroke. Prognostic importance of hypercoagulability. Arch Neurol 1992; 49:279. 9. Warlow C, Ogston D, Douglas AS. Deep venous thrombosis of the legs after strokes. Part I incidence and predisposing factors. Br Med J 1976; 1:1178. 10. Langhorne P, Stott DJ, Robertson L, et al. Medical complications after stroke: a multicenter study. Stroke 2000; 31:1223. 11. Johnston KC, Li JY, Lyden PD, et al. Medical and neurological complications of ischemic stroke: experience from the RANTTAS trial. RANTTAS Investigators. Stroke 1998; 29:447. 12. Pongmoragot J, Rabinstein AA, Nilanont Y, et al. Pulmonary embolism in ischemic stroke: clinical presentation, risk factors, and outcome. J Am Heart Assoc 2013; 2:e000372. 13. CLOTS (Clots in Legs Or sTockings after Stroke) Trials Collaboration, Dennis M, Sandercock P, et al. Effectiveness of intermittent pneumatic compression in reduction of risk of deep vein thrombosis in patients who have had a stroke (CLOTS 3): a multicentre randomised controlled trial. Lancet 2013; 382:516. 14. Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e195S. https://www.uptodate.com/contents/prevention-and-treatment-of-venous-thromboembolism-in-patients-with-acute-stroke/print 14/20 7/5/23, 12:07 PM Prevention and treatment of venous thromboembolism in patients with acute stroke - UpToDate 15. Hemphill JC 3rd, Greenberg SM, Anderson CS, et al. Guidelines for the Management of Spontaneous Intracerebral Hemorrhage: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2015; 46:2032. 16. Lansberg MG, O'Donnell MJ, Khatri P, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e601S. 17. Winstein CJ, Stein J, Arena R, et al. Guidelines for Adult Stroke Rehabilitation and Recovery: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2016; 47:e98. 18. Turpie AG, Hull RD, Schellong SM, et al. Venous thromboembolism risk in ischemic stroke patients receiving extended-duration enoxaparin prophylaxis: results from the EXCLAIM study. Stroke 2013; 44:249. 19. Kakkos SK, Caprini JA, Geroulakos G, et al. Combined intermittent pneumatic leg compression and pharmacological prophylaxis for prevention of venous thromboembolism. Cochrane Database Syst Rev 2016; 9:CD005258. 20. Ho KM, Tan JA. Stratified meta-analysis of intermittent pneumatic compression of the lower limbs to prevent venous thromboembolism in hospitalized patients. Circulation 2013; 128:1003. 21. Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e227S. 22. Kamphuisen PW, Agnelli G. What is the optimal pharmacological prophylaxis for the prevention of deep-vein thrombosis and pulmonary embolism in patients with acute ischemic stroke? Thromb Res 2007; 119:265. 23. Sandercock PA, Leong TS. Low-molecular-weight heparins or heparinoids versus standard unfractionated heparin for acute ischaemic stroke. Cochrane Database Syst Rev 2017; 4:CD000119. 24. Shorr AF, Jackson WL, Sherner JH, Moores LK. Differences between low-molecular-weight and unfractionated heparin for venous thromboembolism prevention following ischemic stroke: a metaanalysis. Chest 2008; 133:149. 25. Paciaroni M, Agnelli G, Venti M, et al. Efficacy and safety of anticoagulants in the prevention of venous thromboembolism in patients with acute cerebral hemorrhage: a meta-analysis of controlled studies. J Thromb Haemost 2011; 9:893. https://www.uptodate.com/contents/prevention-and-treatment-of-venous-thromboembolism-in-patients-with-acute-stroke/print 15/20 7/5/23, 12:07 PM Prevention and treatment of venous thromboembolism in patients with acute stroke - UpToDate 26. Paciaroni M, Agnelli G, Alberti A, et al. PREvention of VENous Thromboembolism in Hemorrhagic Stroke Patients - PREVENTIHS Study: A Randomized Controlled Trial and a Systematic Review and Meta-Analysis. Eur Neurol 2020; 83:566. 27. Hackett CT, Ramanathan RS, Malhotra K, et al. Safety of venous thromboembolism prophylaxis with fondaparinux in ischemic stroke. Thromb Res 2015; 135:249. 28. Lederle FA, Zylla D, MacDonald R, Wilt TJ. Venous thromboembolism prophylaxis in hospitalized medical patients and those with stroke: a background review for an American College of Physicians Clinical Practice Guideline. Ann Intern Med 2011; 155:602. 29. CLOTS Trials Collaboration, Dennis M, Sandercock PA, et al. Effectiveness of thigh-length graduated compression stockings to reduce the risk of deep vein thrombosis after stroke (CLOTS trial 1): a multicentre, randomised controlled trial. Lancet 2009; 373:1958. Topic 121857 Version 7.0 https://www.uptodate.com/contents/prevention-and-treatment-of-venous-thromboembolism-in-patients-with-acute-stroke/print 16/20 7/5/23, 12:07 PM Prevention and treatment of venous thromboembolism in patients with acute stroke - UpToDate GRAPHICS Suggested dose adjustments of low molecular weight (LMW) heparins in adults with renal insufficiency VTE treatment VTE prophylaxis* CrCl 30 mL/min: No adjustment CrCl 30 mL/min: No adjustment Enoxaparin CrCl <30 mL/min: Reduce to 1 mg/kg once daily CrCl <30 mL/min: Reduce to 30 mg once daily (medical or surgical patients) CrCl 30 mL/min: No adjustment CrCl 30 mL/min: No adjustment Dalteparin CrCl <30 mL/min: Use an anticoagulant with less dependence on renal clearance CrCl 50 mL/min: No adjustment CrCl 50 mL/min: No adjustment Nadroparin (not available in the US) CrCl 30 to 50 mL/min: Reduce dose by 25 to 33% if clinically warranted CrCl 30 to 50 mL/min: Reduce dose by 25 to 33% if clinically warranted CrCl <30 mL/min: Contraindicated CrCl <30 mL/min: Reduce dose by 25 to 33% CrCl 30 mL/min: No adjustment CrCl 30 mL/min: No adjustment Tinzaparin (not available in CrCl <30 mL/min: Use with caution, CrCl <30 mL/min: Use with caution, the US) although evidence suggests no accumulation with CrCl as low as 20 mL/min although evidence suggests no accumulation with CrCl as low as 20 mL/min Suggested dose adjustment of LMW heparins for reduced renal function (subcutaneous dosing). Caution should be used in all patients with renal insufficiency, and all patients should be observed for signs of bleeding. Accumulation may occur with repeated doses. An alternative anticoagulant such as unfractionated heparin may be preferred, especially for individuals with CrCl <30 mL/min, with renal failure, or receiving dialysis. Examples of alternatives include: [1] Unfractionated heparin An LMW heparin with lower renal clearance A DOAC with low renal clearance (apixaban, renal clearance approximately 25%) Use of LMW heparin in patients with renal insufficiency has been associated with hyperkalemia. Refer to the UpToDate topics on the use of heparin and LMW heparin in specific clinical conditions, for infants and children, and for acute coronary syndromes and myocardial infarction (for which there are separate tables). VTE: venous thromboembolism; CrCl: creatinine clearance as determined by Cockcroft-Gault equation (a calculator is available in UpToDate); US: United States; LMW heparin: low molecular weight heparin; DOAC: direct oral anticoagulant. https://www.uptodate.com/contents/prevention-and-treatment-of-venous-thromboembolism-in-patients-with-acute-stroke/print 17/20 7/5/23, 12:07 PM Prevention and treatment of venous thromboembolism in patients with acute stroke - UpToDate Applies to short-term VTE prophylaxis (up to 10 days). For long-term use, periodic anti-factor Xa activity testing may be useful to rule out drug accumulation. [2-4] May consider checking anti-factor Xa activity, consistent with some authorities; ranges have not been established from clinical trials and no dose adjustment nomograms have been clinically validated. Other experts and a 2018 guideline from the American Society of Hematology recommend against checking anti-factor Xa activity and suggest dose adjustments based on information in the product labeling or switching to an alternative anticoagulant such as those listed above. If monitored, levels should be measured 4 to 6 hours after dosing, following at least the third however, or fourth dose. The following represent peak (4 hours after the dose) expected on-therapy values for therapeutic dosing (for VTE) for anti-factor Xa activity, although these have not been clinically validated: [1,2] [5] Enoxaparin twice daily: 0.6 to 1.0 anti-factor Xa units/mL (range, 0.5 to 1.5 Enoxaparin once daily: >1.0 anti-factor Xa units/mL Dalteparin once daily: 1.05 anti-factor Xa units/mL (range, 0.5 to 1.5 ) [6] ) [7] Nadroparin once daily: 1.3 anti-factor Xa units/mL Tinzaparin once daily: 0.85 anti-factor Xa units/mL [8] Data from: 1. Witt DM, Nieuwlaat R, Clark NP, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Advances 2018; 3257. 2. Garcia DA, Baglin TP, Weitz JI, Samama MM. Parenteral anticoagulants: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e24S. 3. Nutescu EA, Spinler SA, Wittkowsky A, Dager WE. Low-molecular-weight heparins in renal impairment and obesity: Available evidence and clinical practice recommendations across medical and surgical settings. Ann Pharmacother 2009; 43:1064. 4. Lexicomp Online. Copyright 1978-2023 Lexicomp, Inc. 5. Enoxaparin sodium injection. US FDA approved prescribing information (revised October, 2013). Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020164s102lbl.pdf. 6. Dalteparin sodium injection. US FDA approved prescribing information (revised May, 2019). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020287s072lbl.pdf. 7. Nadroparin calcium injection. Canada product monograph (revised January 2019). Available at: https://pdf.hres.ca/dpd_pm/00049107.PDF. 8. Tinzaparin sodium injection. Canada product monograph (May 26, 2017). Available at: https://pdf.hres.ca/dpd_pm/00040736.PDF. Graphic 90258 Version 15.0 https://www.uptodate.com/contents/prevention-and-treatment-of-venous-thromboembolism-in-patients-with-acute-stroke/print 18/20 7/5/23, 12:07 PM Prevention and treatment of venous thromboembolism in patients with acute stroke - UpToDate Contraindications to fibrinolytic therapy for deep venous thrombosis or acute pulmonary embolism Absolute contraindications Prior intracranial hemorrhage Known structural cerebral vascular lesion Known malignant intracranial neoplasm Ischemic stroke within 3 months (excluding stroke within 3 hours*) Suspected aortic dissection Active bleeding or bleeding diathesis (excluding menses) Significant closed-head trauma or facial trauma within 3 months Relative contraindications History of chronic, severe, poorly controlled hypertension Severe uncontrolled hypertension on presentation (SBP >180 mmHg or DBP >110 mmHg) History of ischemic stroke >3 months prior Traumatic or prolonged (>10 minutes) CPR or major surgery <3 weeks Recent (within 2 to 4 weeks) internal bleeding Noncompressible vascular punctures Recent invasive procedure For streptokinase/anistreplase Prior exposure (>5 days ago) or prior allergic reaction to these agents Pregnancy Active peptic ulcer Pericarditis or pericardial fluid Current use of anticoagulant (eg, warfarin sodium) that has produced an elevated INR >1.7 or PT >15 seconds Age >75 years Diabetic retinopathy SBP: systolic blood pressure; DBP: diastolic blood pressure; CPR: cardiopulmonary resuscitation; INR: international normalized ratio; PT: prothrombin time. The American College of Cardiology suggests that select patients with stroke may benefit from thrombolytic therapy within 4.5 hours of the onset of symptoms. Reproduced with permission from the American College of Chest Physicians. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e419S. Copyright 2012. Graphic 95035 Version 5.0 https://www.uptodate.com/contents/prevention-and-treatment-of-venous-thromboembolism-in-patients-with-acute-stroke/print 19/20 7/5/23, 12:07 PM Prevention and treatment of venous thromboembolism in patients with acute stroke - UpToDate Contributor Disclosures Koto Ishida, MD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/prevention-and-treatment-of-venous-thromboembolism-in-patients-with-acute-stroke/print 20/20

7/5/23, 12:07 PM Stroke after cardiac catheterization - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Stroke after cardiac catheterization : Robert A Taylor, MD, Pooja Khatri, MD, MSc : Scott E Kasner, MD, Donald Cutlip, MD : John F Dashe, MD, PhD, Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Oct 06, 2021. INTRODUCTION Stroke resulting from cardiac catheterization is relatively common due to the high volume of cardiac procedures performed worldwide. This topic will review periprocedural stroke in the setting of cardiac catheterization, which includes diagnostic and interventional procedures. Other aspects of acute stroke are discussed elsewhere. (See "Initial assessment and management of acute stroke" and "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use".) MECHANISMS Patients may experience either ischemic or hemorrhagic stroke in the setting of cardiac catheterization. Ischemic stroke In most cases, the mechanism of ischemic stroke is directly related to cardiac catheterization itself, which initially involves advancing catheters over wires into the aorta, generally using either transfemoral or transradial access. Catheter or wire manipulation may dislodge debris made up of thrombus, calcific material, or cholesterol particles from atherosclerotic plaques within the aortic arch and the proximal carotid and vertebral arteries [1- 4]. In addition, fresh thrombus material may form at the catheter and guidewire tips. Most cases of ischemic stroke related to cardiac catheterization are caused by such thromboemboli. (See "Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism)".) https://www.uptodate.com/contents/stroke-after-cardiac-catheterization/print 1/28 7/5/23, 12:07 PM Stroke after cardiac catheterization - UpToDate The mechanism of ischemic stroke is similar between diagnostic and interventional procedures. However, interventional catheters are on average larger than diagnostic catheters and the procedures are often longer and thus there may be a theoretical increase in risk. Ultimately, one or more catheters end up in one of the cardiac chambers or in the coronary arteries. Catheterization across a degenerated aortic valve may lead to thromboembolism and the risk of stroke may be particularly high in patients with significant valvular aortic stenosis (AS) who undergo retrograde catheterization of the aortic valve [5,6]. This was demonstrated in a study of 152 patients with AS (mean age 71 years) who were randomly assigned to cardiac catheterization with or without catheter passage through the valve [5]. The following findings were noted: Brain magnetic resonance imaging obtained before and after the catheterization demonstrated focal lesions consistent with cerebral emboli in 22 percent of those who underwent retrograde catheterization of the aortic valve, but in none of the patients who did not. Detailed neurologic examination done before and after the catheterization demonstrated clinically apparent deficits in 3 percent of those who underwent retrograde catheterization, but in none of the other patients. As a result, catheterization across a degenerated aortic valve should be performed with caution in patients with severe calcific AS and only when the information sought cannot be reliably obtained noninvasively [6]. Less common causes of ischemic stroke related to cardiac catheterization include air embolism, thromboembolism from clot in the left ventricle, periprocedural hypotension, arterial dissection, and fractured guidewire [7,8]. Hemorrhagic stroke Patients having cardiac catheterization are at increased risk for hemorrhagic stroke because of acquired hemostatic abnormalities induced by thrombolytic, anticoagulant, and/or antiplatelet regimens used in the periprocedural time period [9]. INCIDENCE Mainly retrospective data suggest that stroke (within 36 hours) occurs at a rate of 0.1 to 0.6 percent in patients undergoing diagnostic cardiac catheterization [10-13]. The higher estimate (0.6 percent) comes from a meta-analysis of studies that performed systematic neurologic evaluation and brain magnetic resonance imaging (MRI) [13]. Among those undergoing https://www.uptodate.com/contents/stroke-after-cardiac-catheterization/print 2/28 7/5/23, 12:07 PM Stroke after cardiac catheterization - UpToDate percutaneous coronary (artery) intervention (PCI), the rate ranges from 0.07 to 0.96 percent [12,14-20]. Hemorrhagic stroke, most often intracerebral hemorrhage, has accounted for 8 to 46 percent of stroke related to cardiac catheterization in the few registries that distinguish between ischemic and hemorrhagic stroke types [9,12,15,18,19,21]. Subarachnoid hemorrhage following cardiac catheterization is probably uncommon if not rare, with only a few cases reported in the literature [9,22]. However, most studies of invasive cardiac procedures reporting the incidence of intracranial hemorrhage do not distinguish intracerebral hemorrhage from subarachnoid hemorrhage. The risk of hemorrhagic stroke is probably increased for patients undergoing acute coronary interventions because of the intense antithrombotic regimens that are used [9,23]. Compared with procedures on the coronary arteries, the incidence of periprocedural stroke is somewhat higher after aortic valvuloplasty or radiofrequency catheter ablation for atrial fibrillation. (See "Atrial fibrillation: Catheter ablation", section on 'Periprocedural embolic events' and "Transcatheter aortic valve implantation: Complications", section on 'Stroke and subclinical brain injury'.) Asymptomatic embolism Asymptomatic cerebral embolism is much more common than clinically manifest stroke, as illustrated by the findings of a 2017 systematic review and meta- analysis of studies reporting brain infarcts on diffusion-weighted MRI in patients undergoing cardiac procedures [13]. All included studies performed neurologic examinations and brain MRI both pre-and post-procedure. Among 833 patients who had diagnostic cardiac catheterization, the incidence of asymptomatic radiographic brain infarcts was 8 percent (95% CI 4.1-12), while the incidence of clinically symptomatic events (ischemic stroke and transient ischemic attack) was 0.6 percent (95% CI 0.1-1.1). Transcranial Doppler ultrasonography studies reveal an even higher prevalence (up to 100 percent) of microemboli during cardiac catheterization procedures [24-27]. The majority of these microemboli occur during contrast injection, while a smaller number are observed with movement of the catheter/guide wire. Most of the signals that are seen with injection of solutions have profiles consistent with gaseous origin (eg, air bubbles) and are thought to be of no clinical consequence, whereas the microembolic signals that occur during catheter and guide wire manipulation have signal profiles consistent with particulate origin (eg, atheromatous debris), and could result in transient or persistent ischemic brain injury. Nevertheless, most patients are asymptomatic. These observations suggest that catheter manipulation in the diseased aortic root releases small pieces of atherosclerotic debris more commonly than suspected, based upon the low incidence of clinically apparent stroke. (See 'Mechanisms' above.) https://www.uptodate.com/contents/stroke-after-cardiac-catheterization/print 3/28 7/5/23, 12:07 PM Stroke after cardiac catheterization - UpToDate In a report of 47 unselected patients in whom transcranial Doppler was used to detect microemboli and MRI to detect new lesions, the median number of solid (ie, not gaseous) microemboli was significantly higher with a transradial compared with a transfemoral access (57 versus 36). New MRI lesions occurred in 5 of 33 patients (15 percent) after transradial catheterization, compared with 0 of 9 after transfemoral catheterization. Most of the patients with new lesions remained asymptomatic [24]. RISK FACTORS Clinical risk factors for stroke with cardiac catheterization and PCI include the following [3,9,10,12,15,17,18,20,21,28-30]: Older age (eg, >75 to 80 years) Hypertension Diabetes mellitus History of stroke Renal failure Heart failure Severity of coronary artery disease, including the presence of triple vessel disease Carotid artery disease Procedural risk factors for stroke include the following [5,9,10,12,15,17,18,20,21,29-31]: Emergent catheterization, including acute coronary syndrome Longer procedure time Greater contrast use Retrograde catheterization of the left ventricle in patients with aortic stenosis Interventions at bypass grafts Use of an intra-aortic balloon pump Presence of coronary artery thrombus The risk of intracerebral hemorrhage is increased in those receiving anticoagulation or thrombolytic therapy for acute myocardial infarction as well as in those with any of the following: age 75 years; female sex; systolic blood pressure 160 mmHg; being from a Black population; and low body weight ( table 1) [32]. PREVENTION https://www.uptodate.com/contents/stroke-after-cardiac-catheterization/print 4/28 7/5/23, 12:07 PM Stroke after cardiac catheterization - UpToDate Meticulous attention to technical factors such as wire and catheter exchanges is mandatory in all patients, regardless of risk. Transient neurologic deficits may also result from the injection of high osmolar contrast agents into the carotid or vertebral arteries. For patients undergoing percutaneous coronary intervention, there is some evidence that radial artery catheterization is associated with a lower risk of stroke compared with femoral artery catheterization.This evidence is reviewed elsewhere. (See "Periprocedural complications of percutaneous coronary intervention", section on 'Radial artery access'.) CLINICAL PRESENTATION Most strokes related to cardiac catheterization present during the procedure or within the first 24 hours after the procedure [21,33]. Frequent manifestations of ischemic stroke and intracerebral hemorrhage include visual disturbance, aphasia, dysarthria, hemiparesis, and altered mental status. In contrast, subarachnoid hemorrhage usually presents with headache and global neurologic deficits, mainly altered level of consciousness. A maximal deficit at onset or a fluctuating course suggest ischemic stroke, while gradual worsening of neurologic deficits over minutes to hours and signs of elevated intracranial pressure suggest hemorrhage. However, clinical features alone do not reliably distinguish brain ischemia from hemorrhage, necessitating neuroimaging. The symptoms and signs of acute ischemic stroke often correspond to recognized stroke syndromes with focal neurologic deficits attributable to ischemia within a vascular territory affecting the cerebral cortex (eg, aphasia and left hemiparesis related to embolic occlusion within the left middle cerebral artery territory), brainstem, or cerebellum. (See "Clinical diagnosis of stroke subtypes".) Monocular visual loss may be caused by retinal embolism [34,35]. Some data suggest that a disproportionate number of ischemic strokes related to cardiac catheterization affect the vertebrobasilar circulation [29,36,37], but other reports suggest that the rate of posterior circulation ischemic stroke is close to 20 percent [15], as might be expected given the percentage of blood that the posterior circulation supplies to the brain. In addition to focal deficits, a nonfocal presentation of ischemic stroke with reduced alertness and encephalopathy can occur as a result of diffuse bilateral cerebral embolization. EVALUATION AND DIAGNOSIS The evaluation of the patient who is undergoing or who has recently undergone cardiac catheterization and who is suspected of an acute stroke is presented briefly here. Acute stroke https://www.uptodate.com/contents/stroke-after-cardiac-catheterization/print 5/28 7/5/23, 12:07 PM Stroke after cardiac catheterization - UpToDate evaluation is discussed in detail separately. (See "Initial assessment and management of acute stroke".) Important aspects of the evaluation of any patient with periprocedural neurologic deterioration suggestive of stroke include: Rapid activation of the stroke team. Stabilization of airway, breathing, and circulation. Checking serum glucose, as symptoms of hypoglycemia may mimic stroke; low serum glucose (<60 mg/dL [<3.3 mmol/L]) should be corrected rapidly. Platelet count and coagulation studies if there is suspicion for thrombocytopenia or coagulopathy. Determining symptom onset time or the last time the patient was known to be neurologically normal. (In a sedated patient, this time would be when the patient was last alert enough to be assessed). A focused history and examination will help in the development of a differential diagnosis. Emergent brain imaging with noncontrast computed tomography (CT) or magnetic resonance imaging (MRI), and concurrent neurovascular imaging with CT angiogram or magnetic resonance (MR) angiogram. CT or MR perfusion imaging, if the clinical diagnosis of stroke is uncertain (eg, high suspicion for a seizure with a postictal state). However, caution should be taken not to delay stroke treatment (if indicated) in order to obtain additional tests. Perfusion studies or MRI may also be useful in patients with unknown time of onset or more than 4.5 hours from last known well. We recommend brain imaging with CT or MRI to rule out hemorrhage as a standard approach. In contrast, some experts have advocated immediate angiography followed by intra-arterial thrombolysis rather than obtaining a head CT or MRI after an acute stroke from cardiac catheterization, because the time needed for brain imaging may significantly delay treatment of a vessel occlusion [38]. However, this approach would require a high level of confidence that intracranial hemorrhage is not causing the stroke symptoms, that any identified vessel occlusion is acute and responsible for the symptoms, and that the risk of hemorrhagic transformation of the acute ischemic stroke is low (eg, the diagnostic procedure was done without the use of full- dose anticoagulation and/or glycoprotein IIb/IIIa inhibitors). https://www.uptodate.com/contents/stroke-after-cardiac-catheterization/print 6/28 7/5/23, 12:07 PM Stroke after cardiac catheterization - UpToDate DIFFERENTIAL DIAGNOSIS The differential diagnosis of acute stroke in this setting includes transient ischemic attack, seizure, migraine, encephalopathy, and toxic-metabolic disturbances such as hypoglycemia. In some cases, the recognition of stroke deficits can be confounded by altered mentation caused by sedative medications used for the procedure or by comorbid medical or neurologic conditions. An additional but rare consideration in the periprocedural period is that of contrast-induced transient cortical blindness [39-41], which can occur with ionic and nonionic contrast media. Onset is seen within minutes to hours after the procedure, typically beginning with blurred vision that rapidly progresses to complete blindness, usually associated with headache. Additional symptoms may include vomiting, confusion, aphasia, memory impairment, and limb weakness or ataxia. On head computed tomography (CT) performed without additional contrast, there is often enhancement from contrast administered during cardiac catheterization affecting the cortex, particularly the parieto-occipital lobes, as well as the deep gray structures, brainstem, and/or cerebellum. Symmetrical white matter edema in the posterior cerebral hemispheres is another frequent finding. In one affected patient evaluated with brain magnetic resonance imaging, hyperintense signal on T2-weighted sequences was seen in the occipital lobes, thalami, and cerebellum [41]. In nearly all cases, the neurologic impairments and neuroimaging abnormalities gradually resolve over days. Although the mechanism is uncertain, a transient vasculopathy with disruption of the blood-brain barrier is postulated, suggesting that this is a form of posterior reversible encephalopathy syndrome (PRES), also called reversible posterior leukoencephalopathy syndrome [40,42,43]. (See "Reversible posterior leukoencephalopathy syndrome".) In addition to being associated with the signs and symptoms described above, extravasation of contrast after coronary angiography can sometimes mimic the appearance of subarachnoid hemorrhage [44] and intracerebral hemorrhage [45] on noncontrast head CT scan. Although visual loss after cardiac catheterization has usually been related to contrast, and therefore reversible, bilateral occipital lobe infarction in this setting may present in a similar manner and must be considered [46]. TREATMENT Treatment of ischemic stroke is dependent on the time elapsed from stroke onset. As discussed below, we suggest intravenous thrombolytic therapy for eligible patients ( table 2) with https://www.uptodate.com/contents/stroke-after-cardiac-catheterization/print 7/28 7/5/23, 12:07 PM Stroke after cardiac catheterization - UpToDate ischemic stroke in the setting of cardiac catheterization who are within 4.5 hours of last known well and otherwise eligible, and consideration in some patients beyond 4.5 hours with favorable advanced imaging. However, despite the evidence of benefit in many patients, the risk of bleeding is relatively high in these patients compared with the broad population of patients with ischemic stroke due to the recent use of aggressive antithrombotic therapy as well as the potential for significant procedure site and device related (eg, retroperitoneal) bleeding. The benefits and risks of intravenous thrombolytic therapy need to be weighed carefully in potential candidates. An option for patients who are ineligible for intravenous thrombolysis consists of mechanical thrombectomy (within 6 hours of onset of onset in most patients, and in 6 to 24 hours of onset in selected patients with favorable perfusion imaging). For ischemic stroke, the goal should be to initiate reperfusion therapy within one hour and preferably sooner from the time that symptoms are first noted. For patients with hemorrhagic stroke (ie, intracerebral hemorrhage or subarachnoid hemorrhage), urgent management issues involve reversal of anticoagulation when feasible, blood pressure control, and treatment of elevated intracranial pressure. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis".) Ischemic stroke Stroke caused by embolization of fresh thrombus forming on the catheter or guidewire would seem to be ideally suited to thrombolytic treatment. However, theoretical concerns about the utility of thrombolytic therapy for ischemic stroke after cardiac catheterization are based upon the possible composition of some other types of thrombi causing stroke in this setting [47]. For example, dislodged debris from aortic atherosclerotic plaque might be made up primarily of calcific material and therefore not responsive to thrombolysis, or calcific thrombus might undergo partial lysis leading to distal migration of calcific fragments [48]. In addition, air embolism and metallic fragments would be impervious to thrombolytic agents. Despite these concerns, data from a retrospective, multicenter, observational study evaluating ischemic stroke after cardiac catheterization suggest that tissue plasminogen activator (tPA; alteplase) is safe and efficacious in this setting [47]. Among 66 consecutive cases of ischemic stroke after cardiac catheterization, 12 patients were treated acutely with thrombolysis (7 with intravenous tPA and 5 with intra-arterial tPA), while 54 received no thrombolysis. Patient demographics (age, medical comorbidities, and cardiac procedure characteristics) were similar between the thrombolysis and no thrombolysis groups. Eleven of these 12 treated patients had received periprocedural heparin, and two of the seven who received intravenous tPA had prolonged partial thromboplastin time (PTT). The following observations were made [47]: https://www.uptodate.com/contents/stroke-after-cardiac-catheterization/print 8/28 7/5/23, 12:07 PM Stroke after cardiac catheterization - UpToDate There was a statistically significant improvement in stroke symptoms by predefined end points in patients who received tPA compared with those who did not, including change in the National Institutes of Health Stroke Scale (NIHSS) score from baseline to 24 hours (-6 versus 0) and change in NIHSS score from baseline to seven days (-6.5 versus -1.5). There were no significant differences in mortality or bleeding events, including symptomatic intracranial hemorrhage, hemopericardium, and other systemic bleeding causing hemodynamic instability or requiring transfusions. Additional case reports and case series, while potentially limited by publication bias, also suggest reasonable safety and efficacy of thrombolysis for patients with acute ischemic stroke related to cardiac catheterization [36,49-55]. Therefore, patients should be evaluated for reperfusion therapy based on the time of stroke onset if no hemorrhage is seen on head computed tomography (CT) scan. For eligible patients ( table 2) with acute ischemic stroke related to cardiac catheterization, we suggest intravenous tPA (alteplase) therapy, provided that treatment is initiated within 4.5 hours of clearly defined symptom onset, and consider treatment beyond 4.5 hours in selected patients based on advanced imaging (ie, those with an ischemic brain lesion on magnetic resonance imaging (MRI) diffusion-weighted imaging but no corresponding hyperintensity on fluid-attenuated inversion recovery (FLAIR), an imaging mismatch that correlates with a stroke onset time of 4.5 hours or less). (See "Approach to reperfusion therapy for acute ischemic stroke", section on 'Benefit with imaging selection of patients'.) Furthermore, patients with acute ischemic stroke caused by a large vessel occlusion may be eligible for mechanical thrombectomy if they can be treated within 24 hours of the time they were last known to be at their neurologic baseline ( algorithm 1). The use of intravenous thrombolysis is discussed in greater detail elsewhere, including the management of blood pressure before and during alteplase administration ( table 3). (See "Approach to reperfusion therapy for acute ischemic stroke" and "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use".) Similarly, mechanical thrombectomy for acute ischemic stroke is reviewed separately. (See "Mechanical thrombectomy for acute ischemic stroke".) Regardless of reperfusion therapy modality, it is imperative to minimize the time to treatment. It is well established that longer times to reperfusion translate to lower likelihoods of good clinical outcome. https://www.uptodate.com/contents/stroke-after-cardiac-catheterization/print 9/28 7/5/23, 12:07 PM Stroke after cardiac catheterization - UpToDate Another issue of particular importance to the treatment of patients in the peri- or post- catheterization setting is the use of anticoagulants and antithrombotics: A normal PTT should be documented prior to administration of intravenous tPA for ischemic stroke, if heparin was administered within 48 hours. Protamine can be used to reverse the effect of heparin in the setting of hemorrhagic stroke. (See 'Hemorrhagic stroke' below.) For patients with a prolonged PTT, mechanical embolectomy is the preferred treatment option [56]. The degree to which glycoprotein IIb/IIIa inhibitor therapy may increase the risk of hemorrhagic complications with intravenous tPA for ischemic stroke is unknown, although preliminary data suggest safety [57-59]. Endovascular interventions are the preferred treatment option in this setting as well. Single or dual antiplatelet therapy is not a contraindication to intravenous tPA. The standard management of acute ischemic stroke is discussed in greater detail separately. (See "Initial assessment and management of acute stroke".) Hemorrhagic stroke The management of hemorrhagic stroke following cardiac catheterization follows the same principles as the management of hemorrhagic stroke in other settings. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis" and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis" and "Nonaneurysmal subarachnoid hemorrhage", section on 'Management and prognosis'.) All anticoagulant and antiplatelet drugs should be discontinued acutely, and should not be used until cessation of bleeding is documented by neuroimaging (and possibly longer depending on risk-benefit profile). Anticoagulant effect should be reversed immediately with appropriate agents. For patients with unfractionated heparin-associated intracerebral hemorrhage, protamine sulfate is recommended for urgent treatment. Protamine sulfate can be administered by slow intravenous infusion (not greater than 20 mg/min and no more than 50 mg over any 10-minute period). The appropriate dose of protamine sulfate is dependent upon the dose of heparin given and the time elapsed since that dose. For patients with low-molecular weight heparin-associated intracranial bleeding, andexanet alfa or protamine sulfate can be used for anticoagulant reversal. (See "Reversal of anticoagulation in intracranial hemorrhage", section on 'Unfractionated heparin' and "Reversal of anticoagulation in https://www.uptodate.com/contents/stroke-after-cardiac-catheterization/print 10/28 7/5/23, 12:07 PM Stroke after cardiac catheterization - UpToDate intracranial hemorrhage", section on 'LMW heparin' and "Heparin and LMW heparin: Dosing and adverse effects", section on 'Reversal'.) For patients taking warfarin, aggressive and rapid use of intravenous vitamin K, unactivated prothrombin complex concentrate (also called factor IX complex), and other factors may be necessary. Antidotes to oral factor Xa and direct thrombin inhibitors are discussed elsewhere. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Dabigatran reversal' and "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Factor Xa inhibitors' and "Reversal of anticoagulation in intracranial hemorrhage", section on 'Reversal strategy for specific anticoagulants'.) Severe elevations in blood pressure may worsen intracerebral hemorrhage by representing a continued force for bleeding. Labetalol, nicardipine, esmolol, enalapril, hydralazine, nitroprusside, and nitroglycerin are useful intravenous agents for controlling blood pressure. Specific recommendations for managing elevated blood pressure in patients with acute intracerebral hemorrhage are reviewed in detail separately. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Blood pressure management'.) Initial management of elevated intracranial pressure (ICP) includes elevating the head of the bed to 30 degrees and use of analgesia and sedation. Suggested intravenous agents for sedation are propofol, etomidate, or midazolam. Suggested agents for analgesia and antitussive effect are morphine or alfentanil. More aggressive therapies for reducing elevated ICP include osmotic diuretics (eg, mannitol), ventricular catheter drainage of cerebrospinal fluid, neuromuscular blockade, and hyperventilation. We suggest continuous monitoring of ICP and arterial blood pressure when using these aggressive therapies, with the goal of maintaining cerebral perfusion pressure above 70 mmHg. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Intracranial pressure management'.) For patients with a cerebellar hemorrhage >3 cm in diameter who are deteriorating or who have brainstem compression and/or hydrocephalus due to ventricular obstruction, we recommend surgical removal of hemorrhage. Surgery for supratentorial intracerebral hemorrhage (ICH) is controversial; standard craniotomy might be considered only for those who have lobar clots within 1 cm of the surface. The routine evacuation of supratentorial ICH in the first 96 hours is not recommended. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis".) Supportive care Important acute stroke management issues, some already mentioned above, include the following: https://www.uptodate.com/contents/stroke-after-cardiac-catheterization/print 11/28 7/5/23, 12:07 PM Stroke after cardiac catheterization - UpToDate Assessing swallowing and preventing aspiration. (See "Initial assessment and management of acute stroke", section on 'Swallowing assessment' and "Complications of stroke: An overview", section on 'Dysphagia'.) Optimizing head of bed position; for patients in the acute phase of stroke who are at risk for elevated intracranial pressure, aspiration, cardiopulmonary decompensation, or oxygen desaturation, we suggest keeping the head in neutral alignment with the body and elevating the head of the bed to 30 degrees; for patients in the acute phase of stroke who are not at risk for elevated intracranial pressure, aspiration, or worsening cardiopulmonary status, we suggest keeping the head of bed flat (0 to 15 degree head-of-bed position). (See "Initial assessment and management of acute stroke", section on 'Head and body position'.) Managing blood pressure: For patients with acute ischemic stroke who will receive thrombolytic therapy or mechanical thrombectomy, antihypertensive treatment is recommended so that systolic blood pressure is 180 mmHg and diastolic blood pressure is 105 mmHg during and after treatment ( table 3). This issue is discussed in detail separately. (See "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use", section on 'Management of blood pressure'.) For patients with acute ischemic stroke who are not treated with thrombolytic therapy, we suggest treating high blood pressure only if the hypertension is extreme (systolic blood pressure >220 mmHg or diastolic blood pressure >120 mmHg), or if the patient has another clear indication (active ischemic coronary disease, heart failure, aortic dissection, hypertensive encephalopathy, acute renal failure, or pre- eclampsia/eclampsia). When treatment is indicated, we suggest cautious lowering of blood pressure by approximately 15 percent during the first 24 hours after stroke onset. (See "Initial assessment and management of acute stroke", section on 'Blood pressure goals in ischemic stroke'.) In both intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH), the approach to blood pressure lowering must account for the potential benefits (eg, reducing further bleeding) and risks (eg, reducing cerebral perfusion). Recommendations for blood pressure management in acute ICH and SAH are discussed in detail separately. (See "Initial assessment and management of acute stroke", section on 'Blood pressure in acute hemorrhagic stroke' and "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Blood pressure management' https://www.uptodate.com/contents/stroke-after-cardiac-catheterization/print 12/28 7/5/23, 12:07 PM Stroke after cardiac catheterization - UpToDate and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Blood pressure control'.) Treating hypoglycemia and hyperglycemia. (See "Initial assessment and management of acute stroke", section on 'Hypoglycemia' and "Initial assessment and management of acute stroke", section on 'Hyperglycemia'.) Evaluating and treating the source of any fever; for patients with acute stroke, we suggest maintaining normothermia for at least the first several days after an acute stroke. (See "Initial assessment and management of acute stroke", section on 'Fever'.) Preventing deep venous thrombosis and pulmonary embolism. (See "Prevention and treatment of venous thromboembolism in patients with acute stroke", section on 'Approach to VTE prevention'.) PROGNOSIS Stroke after cardiac catheterization is associated with a high in-hospital and 30-day mortality rate [10,15,17-19,21]. In the largest of these studies, the 30-day mortality rate after percutaneous coronary interventions was 19 percent for patients who experienced an ischemic stroke and 50 percent for those who had a hemorrhagic stroke, versus 2 percent in those without stroke [19]. Few data are available for long-term outcomes among survivors, but among 69 patients with stroke or transient ischemic attack who survived hospitalization in one report, transfers to inpatient rehabilitation, nursing home, or assisted living made up 31 percent of discharges [21]. The high morbidity and mortality associated with these strokes justifies aggressive treatment strategies. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) SUMMARY AND RECOMMENDATIONS Diagnostic and interventional cardiac catheterization may lead to either ischemic or hemorrhagic stroke. The overall incidence of clinically apparent stroke during or after cardiac catheterization is well under 1 percent in most studies, but may be higher with certain interventional procedures, particularly with aortic valvuloplasty. Stroke in this https://www.uptodate.com/contents/stroke-after-cardiac-catheterization/print 13/28 7/5/23, 12:07 PM Stroke after cardiac catheterization - UpToDate setting is associated with a high morbidity and mortality rate. (See 'Mechanisms' above and 'Incidence' above and 'Prognosis' above.) Most strokes related to cardiac catheterization present during the procedure or within the first 24 hours after the procedure. Frequent manifestations of ischemic stroke and intracerebral hemorrhage include visual disturbance, aphasia, dysarthria, hemiparesis, and altered mental status. (See 'Clinical presentation' above.) Important aspects of the management of any patient with periprocedural neurologic deterioration suggestive of stroke include stabilization of airway; breathing and circulation; stroke team activation; emergent brain imaging; determination of symptom onset time; and laboratory tests such as serum glucose and measures of hemostasis. (See 'Evaluation and diagnosis' above.) The differential diagnosis of acute stroke includes transient ischemic attack, seizure, migraine, encephalopathy, and other conditions such as hypoglycemia. An additional consideration in the periprocedural period is that of contrast-induced transient cortical blindness. (See 'Differential diagnosis' above.) For eligible patients with ischemic stroke who can be treated within 4.5 hours of stroke onset, and selected patients with unknown time of onset and favorable imaging, we suggest intravenous thrombolytic therapy ( table 2) (Grade 2C), followed by mechanical thrombectomy for select patients with large vessel occlusions. (See 'Treatment' above and 'Ischemic stroke' above.) Patients with acute ischemic stroke caused by a large artery occlusion who can be treated within 24 hours of the time they were last known to be at their neurologic baseline should be evaluated for mechanical thrombectomy ( algorithm 1). (See 'Ischemic stroke' above and "Mechanical thrombectomy for acute ischemic stroke".) For patients with hemorrhagic stroke (ie, intracerebral hemorrhage or subarachnoid hemorrhage), urgent management issues involve reversal of anticoagulation, blood pressure control, and treatment of elevated intracranial pressure. (See 'Hemorrhagic stroke' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES https://www.uptodate.com/contents/stroke-after-cardiac-catheterization/print 14/28 7/5/23, 12:07 PM Stroke after cardiac catheterization - UpToDate 1. Keeley EC, Grines CL. Scraping of aortic debris by coronary guiding catheters: a prospective evaluation of 1,000 cases. J Am Coll Cardiol 1998; 32:1861. 2. Qureshi AI, Luft AR, Sharma M, et al. Prevention and treatment of thromboembolic and ischemic complications associated with endovascular procedures: Part I Pathophysiological and pharmacological features. Neurosurgery 2000; 46:1344. 3. Werner N, Zahn R, Zeymer U. Stroke in patients undergoing coronary angiography and percutaneous coronary intervention: incidence, predictors, outcome and therapeutic options. Expert Rev Cardiovasc Ther 2012; 10:1297. 4. Eggebrecht H, Oldenburg O, Dirsch O, et al. Potential embolization by atherosclerotic debris dislodged from aortic wall during cardiac catheterization:: histological and clinical findings in 7,621 patients. Catheter Cardiovasc Interv 2000; 49:389. 5. Omran H, Schmidt H, Hackenbroch M, et al. Silent and apparent cerebral embolism after retrograde catheterisation of the aortic valve in valvular stenosis: a prospective, randomised study. Lancet 2003; 361:1241. 6. Chambers J, Bach D, Dumesnil J, et al. Crossing the aortic valve in severe aortic stenosis: no longer acceptable? J Heart Valve Dis 2004; 13:344. 7. Wijman CA, Kase CS, Jacobs AK, Whitehead RE. Cerebral air embolism as a cause of stroke during cardiac catheterization. Neurology 1998; 51:318. 8. Jassal DS, Fast MD, McGinn G. Multifocal brain MRI hypointensities secondary to cardiac catheterization. Neurology 2000; 54:2023. 9. Brown DL, Topol EJ. Stroke complicating percutaneous coronary revascularization. Am J Cardiol 1993; 72:1207. 10. Segal AZ, Abernethy WB, Palacios IF, et al. Stroke as a complication of cardiac catheterization: risk factors and clinical features. Neurology 2001; 56:975. 11. Ammann P, Brunner-La Rocca HP, Angehrn W, et al. Procedural complications following diagnostic coronary angiography are related to the operator's experience and the catheter size. Catheter Cardiovasc Interv 2003; 59:13. 12. Korn-Lubetzki I, Farkash R, Pachino RM, et al. Incidence and risk factors of cerebrovascular events following cardiac catheterization. J Am Heart Assoc 2013; 2:e000413. 13. Cho SM, Deshpande A, Pasupuleti V, et al. Radiographic and Clinical Brain Infarcts in Cardiac and Diagnostic Procedures: A Systematic Review and Meta-Analysis. Stroke 2017; 48:2753. 14. Dukkipati S, O'Neill WW, Harjai KJ, et al. Characteristics of cerebrovascular accidents after percutaneous coronary interventions. J Am Coll Cardiol 2004; 43:1161. https://www.uptodate.com/contents/stroke-after-cardiac-catheterization/print 15/28 7/5/23, 12:07 PM Stroke after cardiac catheterization - UpToDate 15. Fuchs S, Stabile E, Kinnaird TD, et al. Stroke complicating percutaneous coronary interventions: incidence, predictors, and prognostic implications. Circulation 2002; 106:86. 16. Palmerini T, Biondi-Zoccai G, Reggiani LB, et al. Risk of stroke with coronary artery bypass graft surgery compared with percutaneous coronary intervention. J Am Coll Cardiol 2012; 60:798. 17. Werner N, Bauer T, Hochadel M, et al. Incidence and clinical impact of stroke complicating percutaneous coronary intervention: results of the Euro heart survey percutaneous coronary interventions registry. Circ Cardiovasc Interv 2013; 6:362. 18. Kwok CS, Kontopantelis E, Myint PK, et al. Stroke following percutaneous coronary

Treating hypoglycemia and hyperglycemia. (See "Initial assessment and management of acute stroke", section on 'Hypoglycemia' and "Initial assessment and management of acute stroke", section on 'Hyperglycemia'.) Evaluating and treating the source of any fever; for patients with acute stroke, we suggest maintaining normothermia for at least the first several days after an acute stroke. (See "Initial assessment and management of acute stroke", section on 'Fever'.) Preventing deep venous thrombosis and pulmonary embolism. (See "Prevention and treatment of venous thromboembolism in patients with acute stroke", section on 'Approach to VTE prevention'.) PROGNOSIS Stroke after cardiac catheterization is associated with a high in-hospital and 30-day mortality rate [10,15,17-19,21]. In the largest of these studies, the 30-day mortality rate after percutaneous coronary interventions was 19 percent for patients who experienced an ischemic stroke and 50 percent for those who had a hemorrhagic stroke, versus 2 percent in those without stroke [19]. Few data are available for long-term outcomes among survivors, but among 69 patients with stroke or transient ischemic attack who survived hospitalization in one report, transfers to inpatient rehabilitation, nursing home, or assisted living made up 31 percent of discharges [21]. The high morbidity and mortality associated with these strokes justifies aggressive treatment strategies. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) SUMMARY AND RECOMMENDATIONS Diagnostic and interventional cardiac catheterization may lead to either ischemic or hemorrhagic stroke. The overall incidence of clinically apparent stroke during or after cardiac catheterization is well under 1 percent in most studies, but may be higher with certain interventional procedures, particularly with aortic valvuloplasty. Stroke in this https://www.uptodate.com/contents/stroke-after-cardiac-catheterization/print 13/28 7/5/23, 12:07 PM Stroke after cardiac catheterization - UpToDate setting is associated with a high morbidity and mortality rate. (See 'Mechanisms' above and 'Incidence' above and 'Prognosis' above.) Most strokes related to cardiac catheterization present during the procedure or within the first 24 hours after the procedure. Frequent manifestations of ischemic stroke and intracerebral hemorrhage include visual disturbance, aphasia, dysarthria, hemiparesis, and altered mental status. (See 'Clinical presentation' above.) Important aspects of the management of any patient with periprocedural neurologic deterioration suggestive of stroke include stabilization of airway; breathing and circulation; stroke team activation; emergent brain imaging; determination of symptom onset time; and laboratory tests such as serum glucose and measures of hemostasis. (See 'Evaluation and diagnosis' above.) The differential diagnosis of acute stroke includes transient ischemic attack, seizure, migraine, encephalopathy, and other conditions such as hypoglycemia. An additional consideration in the periprocedural period is that of contrast-induced transient cortical blindness. (See 'Differential diagnosis' above.) For eligible patients with ischemic stroke who can be treated within 4.5 hours of stroke onset, and selected patients with unknown time of onset and favorable imaging, we suggest intravenous thrombolytic therapy ( table 2) (Grade 2C), followed by mechanical thrombectomy for select patients with large vessel occlusions. (See 'Treatment' above and 'Ischemic stroke' above.) Patients with acute ischemic stroke caused by a large artery occlusion who can be treated within 24 hours of the time they were last known to be at their neurologic baseline should be evaluated for mechanical thrombectomy ( algorithm 1). (See 'Ischemic stroke' above and "Mechanical thrombectomy for acute ischemic stroke".) For patients with hemorrhagic stroke (ie, intracerebral hemorrhage or subarachnoid hemorrhage), urgent management issues involve reversal of anticoagulation, blood pressure control, and treatment of elevated intracranial pressure. (See 'Hemorrhagic stroke' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES https://www.uptodate.com/contents/stroke-after-cardiac-catheterization/print 14/28 7/5/23, 12:07 PM Stroke after cardiac catheterization - UpToDate 1. Keeley EC, Grines CL. Scraping of aortic debris by coronary guiding catheters: a prospective evaluation of 1,000 cases. J Am Coll Cardiol 1998; 32:1861. 2. Qureshi AI, Luft AR, Sharma M, et al. Prevention and treatment of thromboembolic and ischemic complications associated with endovascular procedures: Part I Pathophysiological and pharmacological features. Neurosurgery 2000; 46:1344. 3. Werner N, Zahn R, Zeymer U. Stroke in patients undergoing coronary angiography and percutaneous coronary intervention: incidence, predictors, outcome and therapeutic options. Expert Rev Cardiovasc Ther 2012; 10:1297. 4. Eggebrecht H, Oldenburg O, Dirsch O, et al. Potential embolization by atherosclerotic debris dislodged from aortic wall during cardiac catheterization:: histological and clinical findings in 7,621 patients. Catheter Cardiovasc Interv 2000; 49:389. 5. Omran H, Schmidt H, Hackenbroch M, et al. Silent and apparent cerebral embolism after retrograde catheterisation of the aortic valve in valvular stenosis: a prospective, randomised study. Lancet 2003; 361:1241. 6. Chambers J, Bach D, Dumesnil J, et al. Crossing the aortic valve in severe aortic stenosis: no longer acceptable? J Heart Valve Dis 2004; 13:344. 7. Wijman CA, Kase CS, Jacobs AK, Whitehead RE. Cerebral air embolism as a cause of stroke during cardiac catheterization. Neurology 1998; 51:318. 8. Jassal DS, Fast MD, McGinn G. Multifocal brain MRI hypointensities secondary to cardiac catheterization. Neurology 2000; 54:2023. 9. Brown DL, Topol EJ. Stroke complicating percutaneous coronary revascularization. Am J Cardiol 1993; 72:1207. 10. 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Risk of stroke associated with abciximab among patients undergoing percutaneous coronary intervention. JAMA 2001; 286:78. 24. Lund C, Nes RB, Ugelstad TP, et al. Cerebral emboli during left heart catheterization may cause acute brain injury. Eur Heart J 2005; 26:1269. 25. Bladin CF, Bingham L, Grigg L, et al. Transcranial Doppler detection of microemboli during percutaneous transluminal coronary angioplasty. Stroke 1998; 29:2367. 26. Leclercq F, Kassnasrallah S, Cesari JB, et al. Transcranial Doppler detection of cerebral microemboli during left heart catheterization. Cerebrovasc Dis 2001; 12:59. 27. Dittrich R, Ringelstein EB. Occurrence and clinical impact of microembolic signals during or after cardiosurgical procedures. Stroke 2008; 39:503. 28. Hamon M, Baron JC, Viader F, Hamon M. Periprocedural stroke and cardiac catheterization. Circulation 2008; 118:678. 29. Lazar JM, Uretsky BF, Denys BG, et al. Predisposing risk factors and natural history of acute neurologic complications of left-sided cardiac catheterization. Am J Cardiol 1995; 75:1056. https://www.uptodate.com/contents/stroke-after-cardiac-catheterization/print 16/28 7/5/23, 12:07 PM Stroke after cardiac catheterization - UpToDate 30. Batchelor WB, Anstrom KJ, Muhlbaier LH, et al. Contemporary outcome trends in the elderly undergoing percutaneous coronary interventions: results in 7,472 octogenarians. National Cardiovascular Network Collaboration. J Am Coll Cardiol 2000; 36:723. 31. Meine TJ, Harrison JK. Should we cross the valve: the risk of retrograde catheterization of the left ventricle in patients with aortic stenosis. Am Heart J 2004; 148:41. 32. Brass LM, Lichtman JH, Wang Y, et al. Intracranial hemorrhage associated with thrombolytic therapy for elderly patients with acute myocardial infarction: results from the Cooperative Cardiovascular Project. Stroke 2000; 31:1802. 33. B sing KA, Schulte-Sasse C, Fl chter S, et al. Cerebral infarction: incidence and risk factors after diagnostic and interventional cardiac catheterization prospective evaluation at diffusion-weighted MR imaging. Radiology 2005; 235:177. 34. Daly MJ, Boyle AJ, Morrison L, Hunter EK. Visual disturbance following cardiac catheterization. J Am Coll Cardiol 2013; 61:e5. 35. Kymionis GD, Tsilimbaris MK, Christodoulakis EB, Pallikaris IG. Late onset branch retinal artery occlusion following coronary angiography. Acta Ophthalmol Scand 2005; 83:122. 36. Serry R, Tsimikas S, Imbesi SG, Mahmud E. Treatment of ischemic stroke complicating cardiac catheterization with systemic thrombolytic therapy. Catheter Cardiovasc Interv 2005; 66:364. 37. Dawson DM, Fischer EG. Neurologic complications of cardiac catheterization. Neurology 1977; 27:496. 38. De Marco F, Antonio Fernandez-Diaz J, Lef vre T, et al. Management of cerebrovascular accidents during cardiac catheterization: immediate cerebral angiography versus early neuroimaging strategy. Catheter Cardiovasc Interv 2007; 70:560. 39. Horwitz NH, Wener L. Temporary cortical blindness following angiography. J Neurosurg 1974; 40:583. 40. Zwicker JC, Sila CA. MRI findings in a case of transient cortical blindness after cardiac catheterization. Catheter Cardiovasc Interv 2002; 57:47. 41. Vranckx P, Ysewijn T, Wilms G, et al. Acute posterior cerebral circulation syndrome accompanied by serious cardiac rhythm disturbances: a rare but reversible complication following bypass graft angiography. Catheter Cardiovasc Interv 1999; 48:397. 42. Saigal G, Bhatia R, Bhatia S, Wakhloo AK. MR findings of cortical blindness following cerebral angiography: is this entity related to posterior reversible leukoencephalopathy? AJNR Am J Neuroradiol 2004; 25:252. https://www.uptodate.com/contents/stroke-after-cardiac-catheterization/print 17/28 7/5/23, 12:07 PM Stroke after cardiac catheterization - UpToDate 43. Borghi C, Saia F, Marzocchi A, Branzi A. The conundrum of transient cortical blindness following coronary angiography. J Cardiovasc Med (Hagerstown) 2008; 9:1063. 44. Velden J, Milz P, Winkler F, et al. Nonionic contrast neurotoxicity after coronary angiography mimicking subarachnoid hemorrhage. Eur Neurol 2003; 49:249. 45. Korn-Lubetzki I, Rosenmann D, Steiner-Birmanns B. Reaction to intravenous contrast media mimicking intracerebral hemorrhage after percutaneous coronary intervention. Med Sci Monit 2008; 14:CS142. 46. Papaconstantinou D, Georgalas I, Diagourtas A, et al. Cortical blindness due to bilateral embolism: a rare complication of cardiac catheterisation. Clin Exp Optom 2010; 93:366. 47. Khatri P, Taylor RA, Palumbo V, et al. The safety and efficacy of thrombolysis for strokes after cardiac catheterization. J Am Coll Cardiol 2008; 51:906. 48. Kissela BM, Kothari RU, Tomsick TA, et al. Embolization of calcific thrombi after tissue plasminogen activator treatment. J Stroke Cerebrovasc Dis 2001; 10:135. 49. Khatri P, Kasner SE. Ischemic strokes after cardiac catheterization: opportune thrombolysis candidates? Arch Neurol 2006; 63:817. 50. Chan AW, Henderson MA. Immediate catheter-directed reperfusion for acute stroke occurring during diagnostic cardiac catheterization. Catheter Cardiovasc Interv 2006; 67:314. 51. Horowitz M, Jovin T, Levy E, Anderson W. Emergent basilar artery and bilateral posterior cerebral artery angioplasty, urokinase thrombolysis, and stenting for acute basilar artery occlusion secondary to diagnostic cardiac catheterization: case presentation. J Neuroimaging 2005; 15:315. 52. Presbitero P, Gasparini GL, Pagnotta P. Images in cardiovascular medicine. Intra-arterial thrombolysis for left middle cerebral artery embolic stroke during coronary angiography. Circulation 2006; 113:e64. 53. Zaidat OO, Slivka AP, Mohammad Y, et al. Intra-arterial thrombolytic therapy in peri- coronary angiography ischemic stroke. Stroke 2005; 36:1089. 54. Arnold M, Fischer U, Schroth G, et al. Intra-arterial thrombolysis of acute iatrogenic intracranial arterial occlusion attributable to neuroendovascular procedures or coronary angiography. Stroke 2008; 39:1491. 55. Harb SC, Thomas G, Saliba WI, et al. Characteristics, treatment, and outcomes of periprocedural cerebrovascular accidents during electrophysiologic procedures. J Interv Card Electrophysiol 2013; 37:41. https://www.uptodate.com/contents/stroke-after-cardiac-catheterization/print 18/28 7/5/23, 12:07 PM Stroke after cardiac catheterization - UpToDate 56. Nogueira RG, Smith WS, MERCI and Multi MERCI Writing Committee. Safety and efficacy of endovascular thrombectomy in patients with abnormal hemostasis: pooled analysis of the MERCI and multi MERCI trials. Stroke 2009; 40:516. 57. Deshmukh VR, Fiorella DJ, Albuquerque FC, et al. Intra-arterial thrombolysis for acute ischemic stroke: preliminary experience with platelet glycoprotein IIb/IIIa inhibitors as adjunctive therapy. Neurosurgery 2005; 56:46. 58. Straub S, Junghans U, Jovanovic V, et al. Systemic thrombolysis with recombinant tissue plasminogen activator and tirofiban in acute middle cerebral artery occlusion. Stroke 2004; 35:705. 59. Pancioli AM, Adeoye O, Schmit PA, et al. Combined approach to lysis utilizing eptifibatide and recombinant tissue plasminogen activator in acute ischemic stroke-enhanced regimen stroke trial. Stroke 2013; 44:2381. Topic 14083 Version 20.0 https://www.uptodate.com/contents/stroke-after-cardiac-catheterization/print 19/28 7/5/23, 12:07 PM Stroke after cardiac catheterization - UpToDate GRAPHICS Cooperative cardiovascular project risk model for intracranial hemorrhage with thrombolytic therapy Risk Factors* Age 75 years Black race Female sex Prior history of stroke Systolic blood pressure 160 mmHg Weight 65 kg for women or 80 kg for men INR >4 or PT >24 Use of alteplase (versus other thrombolytic agent) Rate of intracranial hemorrhage, percent Risk score 0 or 1 0.69 2 1.02 3 1.63 4 2.49 5 4.11 Each risk factor is worth 1 point if present, 0 points if absent. Points are added to determine the risk score. INR: international normalized ratio; PT: prothrombin time. Data from Brass LM, Lichtman JH, Wang Y, et al. Intracranial hemorrhage associated with thrombolytic therapy for elderly patients with acute myocardial infarction: results from the cooperative cardiovascular project. Stroke 2000; 31:1802. Graphic 62946 Version 6.0 https://www.uptodate.com/contents/stroke-after-cardiac-catheterization/print 20/28 7/5/23, 12:07 PM Stroke after cardiac catheterization - UpToDate Eligibility criteria for the treatment of acute ischemic stroke with intravenous thrombolysis (recombinant tissue plasminogen activator or tPA) Inclusion criteria Clinical diagnosis of ischemic stroke causing measurable neurologic deficit Onset of symptoms <4.5 hours before beginning treatment; if the exact time of stroke onset is not known, it is defined as the last time the patient was known to be normal or at neurologic baseline Age 18 years Exclusion criteria Patient history Ischemic stroke or severe head trauma in the previous three months Previous intracranial hemorrhage Intra-axial intracranial neoplasm Gastrointestinal malignancy Gastrointestinal hemorrhage in the previous 21 days Intracranial or intraspinal surgery within the prior three months Clinical Symptoms suggestive of subarachnoid hemorrhage Persistent blood pressure elevation (systolic 185 mmHg or diastolic 110 mmHg) Active internal bleeding Presentation consistent with infective endocarditis Stroke known or suspected to be associated with aortic arch dissection Acute bleeding diathesis, including but not limited to conditions defined under 'Hematologic' Hematologic 3 Platelet count <100,000/mm * Current anticoagulant use with an INR >1.7 or PT >15 seconds or aPTT >40 seconds* Therapeutic doses of low molecular weight heparin received within 24 hours (eg, to treat VTE and ACS); this exclusion does not apply to prophylactic doses (eg, to prevent VTE) Current use (ie, last dose within 48 hours in a patient with normal renal function) of a direct thrombin inhibitor or direct factor Xa inhibitor with evidence of anticoagulant effect by laboratory tests such as aPTT, INR, ECT, TT, or appropriate factor Xa activity assays Head CT Evidence of hemorrhage https://www.uptodate.com/contents/stroke-after-cardiac-catheterization/print 21/28 7/5/23, 12:07 PM Stroke after cardiac catheterization - UpToDate Extensive regions of obvious hypodensity consistent with irreversible injury Warnings Only minor and isolated neurologic signs or rapidly improving symptoms Serum glucose <50 mg/dL (<2.8 mmol/L) Serious trauma in the previous 14 days Major surgery in the previous 14 days History of gastrointestinal bleeding (remote) or genitourinary bleeding Seizure at the onset of stroke with postictal neurologic impairments Pregnancy** Arterial puncture at a noncompressible site in the previous seven days Large ( 10 mm), untreated, unruptured intracranial aneurysm Untreated intracranial vascular malformation Additional warnings for treatment from 3 to 4.5 hours from symptom onset Age >80 years Oral anticoagulant use regardless of INR Severe stroke (NIHSS score >25) Combination of both previous ischemic stroke and diabetes mellitus ACS: acute coronary syndrome; aPTT: activated partial thromboplastin time; ECT: ecarin clotting time; INR: international normalized ratio; PT: prothrombin time; NIHSS: National Institutes of Health Stroke Scale; tPA: intravenous alteplase; TT: thrombin time; VTE: venous thromboembolism. Although it is desirable to know the results of these tests, thrombolytic therapy should not be delayed while results are pending unless (1) there is clinical suspicion of a bleeding abnormality or thrombocytopenia, (2) the patient is currently on or has recently received anticoagulants (eg, heparin, warfarin, a direct thrombin inhibitor, or a direct factor Xa inhibitor), or (3) use of anticoagulants is not known. Otherwise, treatment with intravenous tPA can be started before availability of coagulation test results but should be discontinued if the INR, PT, or aPTT exceed the limits stated in the table, or 3 if platelet count is <100,000 mm . With careful consideration and weighting of risk-to-benefit, patients may receive intravenous alteplase despite one or more warnings. Patients who have a persistent neurologic deficit that is potentially disabling, despite improvement of any degree, should be treated with tPA in the absence of other contraindications. Any of the following should be considered disabling deficits: Complete hemianopia: 2 on NIHSS question 3, or Severe aphasia: 2 on NIHSS question 9, or Visual or sensory extinction: 1 on NIHSS question 11, or Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6, or Any deficits that lead to a total NIHSS >5, or https://www.uptodate.com/contents/stroke-after-cardiac-catheterization/print 22/28 7/5/23, 12:07 PM Stroke after cardiac catheterization - UpToDate Any remaining deficit considered potentially disabling in the view of the patient and the treating practitioner using clinical judgment Patients may be treated with intravenous alteplase if glucose level is subsequently normalized. The potential risks of bleeding with alteplase from injuries related to the trauma should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. The increased risk of surgical site bleeding with alteplase should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. There is a low increased risk of new bleeding with alteplase in the setting of past gastrointestinal or genitourinary bleeding. However, alteplase administration within 21 days of gastrointestinal bleeding is not recommended. Alteplase is reasonable in patients with a seizure at stroke onset if evidence suggests that residual impairments are secondary to acute ischemic stroke and not to a postictal phenomenon. * Alteplase can be given in pregnancy when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding. The safety and efficacy of administering alteplase is uncertain for these relative exclusions. Although these were exclusions in the trial showing benefit in the 3 to 4.5 hour window, intravenous alteplase appears to be safe and may be beneficial for patients with these criteria, including patients taking oral anticoagulants with an INR <1.7. Adapted from: 1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359:1317. 2. Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke Association. Stroke 2009; 40:2945. 3. Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force:, Levine SR, Khatri P, et al. Review, historical context, and clari cations of the NINDS rt-PA stroke trials exclusion criteria: Part 1: rapidly improving stroke symptoms. Stroke 2013; 44:2500. 4. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scienti c rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2016; 47:581. 5. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. Graphic 71462 Version 26.0 https://www.uptodate.com/contents/stroke-after-cardiac-catheterization/print 23/28 7/5/23, 12:07 PM Stroke after cardiac catheterization - UpToDate Indications for mechanical thrombectomy to treat patients with acute ischemic IV: intravenous; tPA: tissue plasminogen activator (alteplase or tenecteplase); CTA: computed tomography an artery occlusion; MT: mechanical thrombectomy; ASPECTS: Alberta Stroke Program Early CT Score; NIHSS: Na tomography; MRI: magnetic resonance imaging; mRS: modified Rankin Scale; MCA: middle cerebral artery; IC recovery. Patients are not ordinarily eligible for IV tPA unless the time last known to be well is <4.5 hours. However, im that is diffusion positive and FLAIR negative) is an option at expert stroke centers to select patients with wake associated UpToDate topics for details. Usually assessed with MRA or CTA, less often with digital subtraction angiography. There is intracranial arterial occlusion of the distal ICA, middle cerebral (M1/M2), or anterior cerebral (A1/A2 MT may be a treatment option for patients with acute ischemic stroke caused by occlusion of the basilar ar stroke centers, but benefit is uncertain. [1] Based upon data from the Aurora study . Reference: https://www.uptodate.com/contents/stroke-after-cardiac-catheterization/print 24/28 7/5/23, 12:07 PM Stroke after cardiac catheterization - UpToDate 1. Albers GW, Lansberg MG, Brown S, et al. Assessment of Optimal Patient Selection for Endovascular Thrombectomy Beyond 6 Hou Neurol 2021; 78:1064. Graphic 117086 Version 3.0 https://www.uptodate.com/contents/stroke-after-cardiac-catheterization/print 25/28 7/5/23, 12:07 PM Stroke after cardiac catheterization - UpToDate Options to treat hypertension before and during reperfusion therapy for acu te ischemic stroke Patient otherwise eligible for acute reperfusion therapy except that blood pressure is >185/110 mmHg* Labetalol 10 to 20 mg intravenously over 1 to 2 minutes, may repeat one time; or Nicardipine 5 mg/hour intravenously, titrate up by 2.5 mg/hour every 5 to 15 minutes, maximum 15 mg/hour; when desired blood pressure reached, adjust to maintain proper blood pressure limits; or Clevidipine 1 to 2 mg/hour intravenously, titrate by doubling the dose every 2 to 5 minutes, maximum 21 mg/hour, until desired blood pressure reached ; or Other agents (hydralazine, enalaprilat, etc) may also be considered If blood pressure is not maintained at or below 185/110 mmHg, do not administer alteplase Management to maintain blood pressure at or below 180/105 mmHg during and after acute reperfusion therapy* Monitor blood pressure every 15 minutes for 2 hours from the start of rtPA therapy, then every 30 minutes for 6 hours, and then every hour for 16 hours If systolic blood pressure is >180 to 230 mmHg or diastolic is >105 to 120 mmHg: Labetalol 10 mg intravenously followed by continuous infusion 2 to 8 mg/min; or Nicardipine 5 mg/hour intravenously, titrate up to desired effect by 2.5 mg/hour every 5 to 15 minutes, maximum 15 mg/hour; or Clevidipine 1 to 2 mg/hour intravenously, titrate by doubling the dose every 2 to 5 minutes, maximum 21 mg/hour, until desired blood pressure reached If blood pressure is not controlled or diastolic blood pressure >140 mmHg, consider intravenous sodium nitroprusside Different treatment options may be appropriate in patients who have comorbid conditions that may benefit from acute reductions in blood pressure, such as acute coronary event, acute heart failure, aortic dissection, or preeclampsia/eclampsia. Clevidipine has been included as part of the 2018 guidelines for the early management of patients with acute ischemic stroke [1] . Reference: 1. Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2018; 49:e46. Adapted with permission. Stroke. 2013: 44:870-947. Copyright 2013 American Heart Association, Inc. https://www.uptodate.com/contents/stroke-after-cardiac-catheterization/print 26/28 7/5/23, 12:07 PM Stroke after cardiac catheterization - UpToDate Graphic 50725 Version 15.0 https://www.uptodate.com/contents/stroke-after-cardiac-catheterization/print 27/28 7/5/23, 12:07 PM Stroke after cardiac catheterization - UpToDate Contributor Disclosures Robert A Taylor, MD Consultant/Advisory Boards: Boston Scientific [Non-valvular atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. Pooja Khatri, MD, MSc Grant/Research/Clinical Trial Support: Bayer [Stroke]; Cerenovus [Stroke]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Donald Cutlip, MD Consultant/Advisory Boards: MedAlliance [Drug-eluting balloon]. Other Financial Interest: Baim Institute for Clinical Research [Clinical research]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Nisha Parikh, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/stroke-after-cardiac-catheterization/print 28/28

7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Approach to reperfusion therapy for acute ischemic stroke : Jamary Oliveira-Filho, MD, MS, PhD, Owen B Samuels, MD : Jos Biller, MD, FACP, FAAN, FAHA, Jonathan A Edlow, MD, FACEP, Alejandro A Rabinstein, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 30, 2023. INTRODUCTION The most important factor in successful reperfusion therapy of acute ischemic stroke is early treatment. Nonetheless, selection of appropriate candidates for reperfusion demands a neurologic evaluation and a neuroimaging study. In addition, reperfusion therapy for acute stroke requires a system that coordinates pre-hospital emergency services, emergency medicine, stroke neurology, intensive care services, interventional neuroradiology, and neurosurgery to provide optimal treatment. This topic will review the use of reperfusion therapy for patients with acute ischemic stroke, focusing on early thrombolytic therapy with intravenous thrombolysis (IVT). The administration of IVT for acute ischemic stroke, including dosing, monitoring, and complications, is reviewed in detail separately. (See "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use".) Mechanical thrombectomy is reviewed in detail elsewhere. (See "Mechanical thrombectomy for acute ischemic stroke".) REPERFUSION THERAPIES The immediate goal of reperfusion therapy for acute ischemic stroke is to restore blood flow to the regions of brain that are ischemic but not yet infarcted. The long-term goal is to improve https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 1/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate outcome by reducing stroke-related disability and mortality. Options for reperfusion therapy that are proven effective include intravenous thrombolysis (IVT) and mechanical thrombectomy (MT). Intravenous thrombolysis Alteplase IVT with alteplase is the mainstay of treatment for acute ischemic stroke, provided that treatment is initiated within 4.5 hours of the time last known well. Eligibility criteria are outlined in the table ( table 1). Because the benefit of alteplase is time dependent, it is critical to treat patients as quickly as possible. Alteplase, a recombinant tissue plasminogen activator (tPA), initiates local fibrinolysis by binding to fibrin in a thrombus (clot) and converting entrapped plasminogen to plasmin. In turn, plasmin breaks up the thrombus. Benefit by time to treatment IVT with alteplase improves functional outcome at three to six months when given within 4.5 hours of ischemic stroke onset [1-8]. The benefit of IVT for acute ischemic stroke decreases continuously over time from symptom onset, as shown in meta-analyses of randomized trials [1,3,4,9] and a registry that analyzed data from over 58,000 patients treated with IVT within 4.5 hours of ischemic stroke symptom onset [2]. In the registry, each 15-minute reduction in the time to initiation of IVT treatment was associated with an increase in the odds of walking independently at discharge (4 percent) and being discharged to home rather than an institution (3 percent) and a decrease in the odds of death before discharge (4 percent) and symptomatic hemorrhagic transformation of infarction (4 percent) [2]. Similarly, another study of over 61,000 patients treated with IVT found that shorter door-to-needle times were associated with lower all-cause mortality at one year and a reduced risk of hospital readmission at one year [10]. A 2014 meta-analysis evaluated individual patient data from 6756 patients (including more than 1700 who were older than age 80 years) with acute ischemic stroke who were allocated to IVT or control in the NINDS, ATLANTIS, ECASS (1, 2, and 3), EPITHET, and IST-3 trials [4]. The primary outcome measure was the proportion of patients achieving a good stroke outcome at three or six months as defined by a modified Rankin scale score ( table 2) of 0 or 1 (ie, no significant disability). The following observations were reported: For treatment within 3 hours of stroke onset, alteplase led to a good outcome for 33 percent, versus 23 percent for control (odds ratio [OR] 1.75, 95% CI 1.35-2.27). The number needed to treat (NNT) for one additional patient to achieve a good outcome was 10. For treatment from 3 to 4.5 hours, the proportion with a good outcome in the alteplase and control groups was 35 and 30 percent (OR 1.26, 95% CI 1.05-1.51, NNT 20). https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 2/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate For treatment beyond 4.5 hours, the proportion with a good outcome in the alteplase and control groups was no longer significant at 33 and 31 percent (OR 1.15, 95% CI 0.95-1.40, NNT 50). The benefit of alteplase was similar regardless of patient age or stroke severity. Alteplase increased the risk of symptomatic intracranial hemorrhage (6.8 percent, versus 1.3 percent for control, OR 5.55, 95% CI 4.01-7.70); the number needed to harm (NNH) for one additional patient to have a symptomatic intracranial hemorrhage was 18. Alteplase also increased the risk of fatal intracranial hemorrhage within seven days (2.7 versus 0.4 percent, OR 7.14, 95% CI 3.98-12.79, NNH 44); this risk was similar regardless of age, stroke severity, or treatment delay. Alteplase treatment had no significant effect on other early or late causes of death. Death at 90 days was slightly higher in the alteplase group (17.9 percent, versus 16.5 percent in the control group, hazard ratio 1.11, 95% CI 0.99-1.25), a result that just missed statistical significance. In agreement with other meta-analyses [1,3,7], these observations confirm that the sooner IVT is initiated, the more likely it is to be beneficial, and that the benefit extends to treatment started within 4.5 hours of stroke onset [4]. The results also show that alteplase is beneficial regardless of patient age, stroke severity, or the associated increased risk of symptomatic or fatal intracranial hemorrhage in the first days after alteplase treatment. The odds of a favorable three-month outcome decrease as the interval from stroke onset to start of alteplase treatment increases ( figure 1) [1]. Beyond 4.5 hours, harm may exceed benefit. Benefit with imaging selection of patients IVT may be beneficial for select patients who wake-up with stroke more than 4.5 hours after they were last known well or those who have unknown time of symptom onset, if they have an acute ischemic brain lesion detected on diffusion magnetic resonance imaging (MRI) but no corresponding hyperintensity on fluid- attenuated inversion recovery (FLAIR) MRI. This imaging mismatch (diffusion positive/FLAIR negative) correlates with a stroke onset time of 4.5 hours or less [11]. Limited clinical trial evidence suggests that IVT is beneficial for select patients who meet imaging criteria indicative of recent cerebral infarction and/or significant salvageable brain tissue, even if they do not qualify based upon traditional time windows, although results have been inconsistent: The placebo-controlled Wake-Up Stroke trial selected 500 adults with unwitnessed stroke onset who had an ischemic parenchymal brain lesion on MRI diffusion-weighted imaging https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 3/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate but no corresponding hyperintensity on FLAIR [12]. Nearly 90 percent of enrolled patients awoke from sleep with stroke symptoms. The trial excluded patients last known to be well within 4.5 hours, since they would fulfill standard eligibility criteria for alteplase; the trial also excluded patients who were to receive MT. At 90 days, a favorable outcome (defined by a score of 0 or 1 on the modified Rankin Scale [mRS]) was more likely for patients assigned to intravenous alteplase compared with those assigned to placebo (53 versus 42 percent, adjusted OR 1.61, 95% CI 1.09-2.36). However, the mortality rate was nonsignificantly higher in the alteplase group (4 versus 1 percent, OR 3.38, 95% CI 0.92-12.52), as was the rate of symptomatic intracranial hemorrhage (2.0 versus 0.4 percent, OR 4.95, 95% CI 0.57- 42.87). Limitations to the trial include stopping early (for lack of funding) and exclusion of patients planned for MT. The EXTEND trial was stopped early after publication of the Wake-Up Stroke trial. EXTEND enrolled 225 adults (of a planned 310) who had hypoperfused but salvageable brain tissue on automated perfusion imaging (with computed tomography [CT] or MRI) and could be treated between 4.5 and 9 hours after the onset of ischemic stroke or awoke with stroke symptoms, if within 9 hours from the midpoint of sleep [13]. Patients were randomly assigned to intravenous alteplase or to placebo. At 90 days, a favorable outcome (defined by a score of 0 or 1 on the mRS) was more likely for the intravenous alteplase group compared with the placebo group, after adjustment for age and clinical severity at baseline (35 versus 30 percent, risk ratio [RR] 1.44, 95% CI 1.01-2.06). However, there was no difference between treatment groups in unadjusted analysis (RR 1.2, 95% CI 0.82-1.76). Symptomatic intracranial hemorrhage within 36 hours of treatment was increased with alteplase (6 versus 1 percent) and mortality was nonsignificantly higher with alteplase (12 versus 9 percent). Limitations to the trial include stopping early and lack of efficacy in unadjusted analyses. In the ECASS 4 trial, stopped early for slow recruitment, 119 patients (of a planned 264) with acute ischemic stroke and salvageable brain tissue identified by MRI were randomly assigned to treatment with alteplase or placebo between 4.5 and 9 hours after the onset of symptoms [14]. At 90 days, there was no difference between the alteplase and placebo groups in the mRS distribution (OR 1.20, 95% CI 0.63-2.27); mortality was nonsignificantly higher with alteplase (12 versus 7 percent). A meta-analysis pooled individual patient data (n = 414) from three trials (EXTEND, ECASS 4, and EPITHET) of intravenous alteplase that used imaging to identify and treat patients with salvageable brain tissue who had ischemic stroke 4.5 to 9 hours after onset or had wake-up stroke [15]. There was a higher rate of excellent functional outcome (defined by a mRS score 0 of 1) at three months for patients assigned to alteplase compared with those assigned to placebo https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 4/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate (36 versus 29 percent, adjusted odds ratio [OR] 1.86, 95% CI 1.15-2.99). Symptomatic intracerebral hemorrhage was more frequent in the alteplase group (5 versus 0.5 percent), but this result did not nullify the overall benefit of alteplase. Limitations to this meta-analysis include small sample size and early stopping of two of the included trials (EXTEND and ECASS 4). Another meta-analysis of four trials (including Wake-Up Stroke, EXTEND, and ECASS 4) with individual patient data from over 843 patients reported similar findings [16]. Although this approach seems promising, additional trials are needed to confirm the efficacy and safety of IVT using imaging selection of patients with a stroke onset time >4.5 hours or an unknown stroke onset time [17]. Imaging with MRI or CT perfusion appears to be essential to determine if the cerebral infarction is recent and if there is significant salvageable brain tissue. Results of the TWIST trial suggest that selecting patients with noncontrast head CT alone (to exclude hemorrhage or large infarction) is unlikely to identify patients with wake-up stroke who will benefit from IVT [18]. Risk of intracerebral hemorrhage Treatment with IVT within 4.5 hours of acute ischemic stroke onset is associated with an increased early risk of intracerebral hemorrhage, but this risk is offset by later benefit in the form of reduced disability (see 'Benefit by time to treatment' above) [4]. In clinical trials of intravenous alteplase, the rates of symptomatic intracerebral hemorrhage were 5 to 7 percent [4,19], using the National Institute of Neurological Disorders and Stroke (NINDS) definition. In addition, most community-based studies of intravenous alteplase have shown similar rates [20-24]. These studies suggest that IVT can be used safely to treat acute ischemic stroke in routine clinical practice. The number needed to harm (NNH) with IVT is very high, because most cases of symptomatic intracerebral hemorrhage occur in patients with severe deficits and poor anticipated prognosis before lysis [25]. Also, some hemorrhages occur in areas of the brain that are already infarcted and so do not result in additional measurable deficits. As an example from the NINDS trials, for an outcome of severely disabled or dead (defined by an mRS score 4) with IVT-related symptomatic hemorrhage, the NNH was 126, and for a worsened outcome (defined by an mRS score 1), the NNH ranged from approximately 30 to 40. Differences in the criteria used to define symptomatic intracerebral hemorrhage likely account for much of the variability in the rates of hemorrhage reported in different trials [26]. The NINDS trial definition of symptomatic intracerebral hemorrhage includes any hemorrhagic transformation temporally related to any neurologic worsening [19], which may be overly inclusive because it captures small petechial hemorrhages associated with minimal neurologic deterioration that are unlikely to have altered long-term functional outcome [27,28]. By contrast, the ECASS 2, ECASS-3 and SITS-MOST definitions of symptomatic intracerebral hemorrhage include only hemorrhage associated with substantial clinical worsening of 4 points on the https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 5/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate National Institutes of Health Stroke Scale (NIHSS) stroke scale [24,29,30], which may be more predictive of intracerebral hemorrhages that adversely affect long-term outcome. As an example, the SITS-MOST study enrolled over 30,000 patients, mainly from Europe, who were treated with intravenous alteplase at 669 centers [24]. Symptomatic intracerebral hemorrhage by the NINDS definition occurred in 7.4 percent, and by the SITS-MOST definition in 1.8 percent. Lower rates have also been reported in other trials using stricter definitions of symptomatic intracerebral hemorrhage, including ECASS 3 [29]. Several risk assessment methods, including the HAT score, DRAGON score, SEDAN score, Stroke- Thrombolytic Predictive Instrument, SPAN-100 index, and the SITS SICH risk score, have been devised to predict the risk of intracerebral hemorrhage and/or prognosis for patients with acute stroke who are treated with IVT [24,31-39]. However, additional validation studies are needed to confirm the utility of these methods before they should be used in clinical practice. Recanalization Full or partial recanalization up to 24 hours after onset of acute stroke is associated with a more favorable outcome than persistent occlusion after thrombolysis [40-44]. In a prospective, multicenter study of 575 patients with acute ischemic stroke and intracranial arterial occlusion on baseline CT angiography (CTA), the rate of successful recanalization detected on repeat CTA was greater for patients who received IVT compared with those who did not (30 versus 13 percent, absolute difference 17 percent, 95% CI 10-26 percent) [45]. As observed in this and other studies, factors associated with the response to thrombolytic therapy include location of the symptomatic occlusive thrombus in the arterial tree, and clot-specific features such as size, composition, and source: Clot size and site Larger clots and more proximal clots (versus more distal location) are more resistant to thrombolysis [45-50]. As an example, internal carotid artery occlusions are more resistant than middle cerebral artery occlusions to IVT treatment. This may be due at least in part to the larger size of clots that lodge in larger vessels [51]. Clot occluding the cervical internal carotid artery may promote adjacent thrombosis extending to the intracranial internal carotid artery, resulting in a very long thrombus that is unlikely to be lysed by IVT alone. In large vessels, in situ thromboses associated with atherosclerotic lesions may be more resistant to recanalization than fibrin rich embolic occlusions arising from the heart [52]. In addition, higher residual flow (a measure of thrombus permeability) of intracranial arteries on baseline angiography is associated with successful recanalization [45]. Clot age and composition The age and composition of thromboembolic material likely affect its response to thrombolytic therapy [53,54]. The ability to recanalize in experimental embolic stroke is related to the amount of red cells in the emboli and inversely related to https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 6/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate the volume of emboli and to the fibrin content and density of the clots [55]. Thrombolytic drugs are unlikely to disrupt other types of embolic material, such as calcific plaque and fat. Other variables affecting outcome Early recanalization is probably the most important determinant of good outcome after thrombolysis, but a number of additional variables may impact neurologic outcome and the risk of intracerebral hemorrhage [56,57]. These include age, sex, stroke severity, availability of collateral blood supply, and early ischemic change on CT or MRI. However, these factors do not necessarily predict which patients will or will not benefit from IVT. The only factor known to independently alter response to IVT is time to treatment. (See 'Benefit by time to treatment' above.) Whenever possible, the potential risks and benefits of thrombolysis should be discussed objectively with the patient and/or family or health care proxy prior to initiating treatment. (See 'Issues regarding consent' below.) Age Patients age 80 years or older appear to benefit from IVT despite a higher mortality rate compared with younger patients. (See 'Age 80 years and older' below.) Stroke severity The severity of neurologic deficit as measured on the NIHSS score ( table 3) is associated with an increased risk of intracerebral hemorrhage [6,58]. However, stroke severity alone cannot be used to select or exclude patients for IVT. A 2014 meta-analysis of individual patient data from 6756 subjects found that the benefit of alteplase was similar regardless of stroke severity [4]. Early ischemic changes on CT The presence of extensive regions of obvious hypodensity consistent with irreversible injury on initial head CT suggests a longer time since stroke onset and is an exclusion for use of IVT ( table 1). This finding should be distinguished from milder early ischemic edema as discussed below. (See 'Early ischemic changes on neuroimaging' below.) Hyperglycemia Hyperglycemia before reperfusion in patients with acute ischemic stroke has been associated with diminished neurologic improvement, greater infarct size, and worse clinical outcome at three months after treatment with IVT [59-61]. Cerebral microbleeds Cerebral microbleeds are small chronic hemorrhages that are best visualized on susceptibility-weighted MRI sequences. Meta-analyses published in 2015 [62], 2016 [63], and 2017 [64] found that the presence of cerebral microbleeds on pretreatment brain MRI was associated with an increased risk of intracerebral hemorrhage (ICH) in patients treated with IVT for acute ischemic stroke. In https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 7/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate one of these reports, the risk of symptomatic ICH was significantly greater for patients with a high burden of cerebral microbleeds (>10) compared with patients who had a lower burden of microbleeds (1 to 10 or 0 to 10) [63]. However, the small number of patients in the subgroup with >10 microbleeds (n = 15) limits the strength of this conclusion. In another meta-analysis, the presence of cerebral microbleeds was not associated with symptomatic ICH but was associated with an increased risk of parenchymal hemorrhage, and the presence of >5 cerebral microbleeds was associated with poor functional outcome at three to six months [64]. Since decisions to proceed IVT treatment are usually made based upon CT imaging without MRI, these results should not affect patient selection or mandate additional imaging that will prolong the time to treatment. Sex There are conflicting data regarding whether benefit from early IVT of acute ischemic stroke differs by sex [65-67]. Tenecteplase Tenecteplase, a type of recombinant tissue plasminogen activator (tPA), is a modified version of alteplase, the only approved tPA for treating acute ischemic stroke. Tenecteplase differs from human tPA by having three amino acid substitutions. Because of the modifications, tenecteplase is more fibrin-specific and has a longer duration of action compared with alteplase. The single bolus dosing of tenecteplase is far easier to give in an emergency department and translates into faster door-to-needle times compared with alteplase [68]. Although not licensed in the US for IVT in acute ischemic stroke treatment, there is moderate- to high-quality evidence that intravenous tenecteplase, given in a single bolus at 0.25 mg/kg (maximum 25 mg), has similar efficacy and safety outcomes compared with alteplase, including rates of excellent functional outcome, symptomatic intracerebral hemorrhage, and mortality at 90 days [68-81]. As an example, the EXTEND-IA TNK trial found that tenecteplase led to better functional outcomes compared with alteplase and higher rates of reperfusion of the involved ischemic territory [70]. Furthermore, in an analysis of pooled individual patient data from several trials and a registry of patients with large vessel occlusion who were treated with intravenous thrombolysis, tenecteplase treatment (n = 492) compared with alteplase treatment (n = 401) was associated with higher rates of prethrombectomy reperfusion, which in turn was associated with improved outcomes [82]. However, higher doses of tenecteplase ( 0.4 mg/kg) should not be used for IVT because such doses may be associated with harm, although the evidence is inconsistent. In the original NOR- TEST trial, most of the 1100 patients had minor strokes (the median NIHSS score was 4), and the https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 8/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate tenecteplase group, treated with 0.4 mg/kg, had similar safety and efficacy outcomes compared with the alteplase group [69]. However, the NOR-TEST 2, part A trial was stopped early, after enrolling only 204 patients, due to higher numbers of symptomatic intracranial hemorrhage in the tenecteplase group [83]. NOR-TEST 2 included patients with moderate to severe ischemic stroke (the median NIHSS was 11) who were within 4.5 hours of the time last known well; the patients were randomly assigned to tenecteplase 0.4 mg/kg or alteplase 0.9 mg/kg. At three months, compared with the alteplase group, the tenecteplase group showed a trend toward an increased rate of symptomatic intracranial hemorrhage (6 versus 1 percent, OR 6.57, 95% CI 0.78-55.62). Furthermore, the tenecteplase group had a lower rate of a favorable outcome, defined as an mRS score of 0 to 1 (32 versus 51 percent, OR 0.45, 95% CI 0.25-0.80), and a higher rate of mortality (16 versus 5 percent, OR 3.56, 95% CI 1.24-10.21). Mechanical thrombectomy (MT) Mechanical thrombectomy is indicated for patients with acute ischemic stroke due to a large artery occlusion in the anterior circulation who meet eligibility criteria and can be treated within 24 hours of the time last known to be well (ie, at neurologic baseline), regardless of whether they receive IVT for the same ischemic stroke event. (See "Mechanical thrombectomy for acute ischemic stroke".) Patient selection for MT is discussed in detail separately. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Patient selection'.) IVT followed by MT Treatment with IVT prior to MT, known as bridging therapy, is recommended for most patients who are candidates for both reperfusion therapies. Patients with ischemic stroke from large vessel occlusion should receive IVT without delay, if eligible, even if MT is being considered [84]. Mechanical thrombectomy treatment should then be started as quickly as possible [85,86], and should not be delayed to assess the response to IVT. Potential advantages of IVT before MT include complete or partial lysis of the thrombus causing the large vessel occlusion (the target of MT), lysis of thrombotic emboli in distal vessels beyond the reach of MT, and faster resolution of brain ischemia [87]. Potential disadvantages of giving IVT first include a delay in the time to the start of the MT procedure, an increased risk of symptomatic brain hemorrhage, and partial lysis of the large vessel thrombus that allows it to travel to more distal vessels beyond the reach of MT. MT alone (without preceding IVT) is an alternative strategy, but the available data, while inconsistent, have not proven the efficacy of this approach compared with the combination of IVT and MT for improved clinical outcomes or safety [88-98]. Rather, the preponderance of the evidence favors bridging therapy over MT alone. https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 9/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate RAPID EVALUATION All adult patients with a clinical diagnosis of acute ischemic stroke should be rapidly screened for treatment with intravenous thrombolysis (IVT). Simultaneously, patients with suspected acute ischemic stroke involving the anterior circulation should be evaluated for mechanical thrombectomy (MT). (See "Mechanical thrombectomy for acute ischemic stroke".) Prehospital recognition and management Emergency medical responders should identify patients with a suspected stroke, preferably using a validated stroke screening tool (see "Use and utility of stroke scales and grading systems", section on 'Stroke diagnosis'), and transport them rapidly to the nearest medical facility that can provide urgent stroke care with the capability to treat with IVT, or IVT and MT. The use of mobile stroke units (MSUs) offers the potential for more rapid identification and treatment of acute ischemic stroke [99,100]. MSUs are ambulances equipped with point-of-care laboratory testing and a CT scanner; they are staffed by medical personnel trained to diagnose and treat patients in the ambulance using thrombolytic therapy and to make triage decisions for mechanical thrombectomy, in conjunction with telemedicine communication to hospital stroke experts. However, MSUs are expensive, and availability is limited to only a few metropolitan areas throughout the world. The potential benefit of MSUs for improving outcome from acute ischemic stroke is illustrated by two prospective, nonrandomized controlled studies. One was a multicenter study from the United States of 1047 patients who were within 4.5 hours after stroke symptom onset; patients were assigned by week of enrollment to receive MSU or standard emergency medical services (EMS) care [101]. Among patients eligible for intravenous thrombolysis, the rate of thrombolysis was higher in the MSU group compared with the EMS group (97.1 versus 79.5 percent), and the median time to thrombolysis was shorter (72 versus 108 minutes). At 90 days, the proportion of patients with no or minimal disability (ie, a score of 0 to 1 on the modified Rankin Scale [mRS]) was greater in the MSU group (55.0 versus 44.4 percent), while mortality was lower (8.9 versus 11.9 percent). The rate of symptomatic intracerebral hemorrhage in each group was 2 percent. In a similar prospective study of over 1500 patients from Berlin, Germany, dispatch of an MSU compared with EMS was associated with a shorter median time to treatment with thrombolysis (50 versus 70 minutes) and a lower level of global disability at 90 days [102]. In a 2022 meta- analysis that included these two nonrandomized studies, MSU use was associated with higher rates of excellent outcome, defined by an mRS score of 0 to 1 at 90 days, compared with usual care (adjusted odds ratio [OR] 1.64, 95% CI 1.27-2.13) [103]. https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 10/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate Further confirmation of clinical benefit along with evidence of cost-effectiveness will be needed before widespread use of MSUs can be considered. Other unproven strategies to reduce time to treatment with MT are being explored, including direct transport to a thrombectomy-capable center [104], and even flying the thrombectomy intervention clinical team to the local stroke center [105]. In-hospital timeline A door-to-needle time of 60 minutes is the benchmark for achieving rapid treatment with IVT [84]. The following in-hospital timeline is suggested as a goal for all patients with acute ischemic stroke who are eligible for treatment with IVT: Evaluation by physician 10 minutes elapsed from arrival Stroke or neurologic expertise contacted (ie, stroke team) 15 minutes elapsed Head CT or MRI scan 25 minutes elapsed Interpretation of neuroimaging scan 45 minutes elapsed Start of IVT 60 minutes elapsed Although IVT is the first priority, evaluation and preparation for possible MT should proceed during and after IVT. Patients with suspected infarction involving the anterior circulation should have cerebral angiography (eg, CT angiography [CTA] or magnetic resonance angiography [MRA]) as soon as possible to determine whether they have a proximal intracranial large artery occlusion that might also benefit from MT. However, IVT should not be delayed by angiography or MT. The administration of IVT for acute ischemic stroke, including dosing, monitoring, and complications, is reviewed in detail separately. (See "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use".) Investigations Diagnostic neuroimaging is essential before considering reperfusion therapy for acute ischemic stroke. The only other test that is mandatory for all patients before initiation of IVT is blood glucose. In most cases, the results of routine laboratory tests including coagulation parameters and platelet count are not required to proceed with IVT. Thrombolytic therapy with alteplase (or tenecteplase) should not be delayed while results are pending unless one of the following conditions is present [84]: Clinical suspicion of a bleeding abnormality or thrombocytopenia Current or recent use of anticoagulants (eg, heparin, warfarin, direct oral anticoagulants [DOACs]) Use of anticoagulants is not known https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 11/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate Potential exclusions to treatment Exclusion criteria for IVT are listed in the table ( table 1); these criteria have evolved with time as experience with IVT has increased. Several clinical issues may complicate the decision to use reperfusion therapy for acute ischemic stroke. Among these are rapidly improving stroke symptoms and early ischemic changes on neuroimaging. Patients on anticoagulants Current anticoagulant use with evidence of anticoagulant effect by laboratory tests is a contraindication to IVT. Coagulation tests For patients without recent use of oral anticoagulants or heparin, treatment with IVT can be started before availability of coagulation test results if there is no reason to suspect a coagulopathy (ie, patients not on anticoagulant therapy who have no known liver disease, hematologic disease, or advanced kidney disease). In such cases, alteplase treatment should be discontinued if the international normalized ratio (INR), prothrombin time (PT), or activated partial thromboplastin time (aPTT) are excessively elevated ( table 1). For patients with inadequate historical information, IVT should not be started until the aPTT and either the PT or the INR are available. Preliminary data suggest that normal coagulation parameters can be predicted on arrival to the emergency department by assessing three questions [106]: Is the patient taking an oral anticoagulant? Is the patient taking heparin or low molecular weight heparin? Is the patient on hemodialysis? In a retrospective study from 2006 (prior to the advent of direct oral anticoagulants) that included 299 patients, "no" answers to all three questions predicted normal range PT and aPTT with a sensitivity of 100 percent, suggesting that this simple screen may permit earlier treatment with alteplase in selected patients with acute stroke [106]. Other data suggest that unsuspected coagulopathy is rarely detected among patients evaluated for IVT [107]. Patients on DOACs Accumulating evidence suggests that recent use of a DOAC is not associated with an increased risk of symptomatic intracerebral hemorrhage following IVT [108,109]. Nevertheless, DOAC use remains a contraindication to IVT unless laboratory tests such as aPTT, INR, platelet count, ecarin clotting time, thrombin time, or appropriate direct factor Xa activity assays are normal or the patient has not received a DOAC dose for more than 48 hours, assuming normal renal function [84]. https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 12/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate DOAC reversal DOAC reversal may provide an option to safely treat with thrombolysis, although this approach is not yet established as safe [110]. An observational cohort study identified 51 patients treated with idarucizumab for dabigatran reversal prior to thrombolysis and found that idarucizumab-treated patients had similar rates of symptomatic intracerebral hemorrhage, early neurologic improvement, and mortality compared with patients not treated with idarucizumab [111]. Rapidly improving stroke symptoms Rapidly improving stroke symptoms (RISS) should be considered an exclusion for reperfusion therapy only for patients who improve to the degree that any remaining deficits are nondisabling [112]. The decision regarding use of IVT or MT should be made based upon monitoring neurologic deficits for no longer than the time needed to prepare and begin treatment; treatment should not be delayed by continued monitoring for improvement. Disabling versus nondisabling stroke deficits Qualifying patients who have an acute ischemic stroke causing a persistent neurologic deficit that is potentially disabling, despite improvement of any degree while being evaluated, should be treated urgently with IVT and/or MT as appropriate. Any of the following should be considered disabling deficits [112]: Complete hemianopia: 2 on the National Institutes of Health Stroke Scale (NIHSS) question 3 ( table 3) Severe aphasia: 2 on NIHSS question 9 ( table 3) Visual extinction: 1 on NIHSS question 11 ( table 3) Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6 ( table 3) Any deficits that lead to a total NIHSS >5 (calculator 1) Any remaining deficit considered potentially disabling by the patient, family, or the treating practitioner For patients with an NIHSS score of 0 to 5, a clearly disabling deficit has also been defined as one that would prevent the patient from performing basic activities of daily living (ie, bathing, walking, toileting, and eating) or returning to work [113]. Whether IVT is beneficial for patients with mild, nondisabling ischemic stroke is unknown, and data are limited. The PRISMS trial enrolled patients with acute ischemic stroke within three hours of symptom onset who had an NIHSS score of 0 to 5 and deficits judged not clearly disabling; there was no difference in the rate of a favorable functional outcome (defined as a modified Rankin Scale score of 0 or 1 at 90 days) for patients assigned to treatment with IVT or to aspirin (78.2 versus 81.5 percent) [113]. However, the trial was stopped very early solely because of slow https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 13/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate recruitment, having enrolled only 313 of a planned 948 subjects, and therefore its findings are not definitive. Early ischemic changes on neuroimaging Minor ischemic changes on CT are not a contraindication to treatment; these include subtle or small areas of hypodensity, loss of gray- white distinction, obscuration of the lentiform nucleus, or the presence of a hyperdense artery sign ( image 1). We suggest withholding thrombolytic therapy with alteplase for patients with extensive regions of obvious hypodensity consistent with irreversible injury on initial head CT ( table 1), although there are few data to determine a threshold of ischemic severity or extent that modifies treatment response to alteplase [114]. Patient selection for MT is reviewed separately. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Role of ASPECTS method'.) Issues regarding consent Alteplase is an approved therapy for acute ischemic stroke because of substantial evidence of safety and efficacy. Consent is not required to administer alteplase as an emergent therapy for an otherwise eligible adult patient with a disabling acute ischemic stroke if patient or surrogate consent is not possible [84]. In such cases, the need for informed consent is outweighed by the need for urgent intervention, and the patient can be treated under the principle of presumption of consent. Furthermore, given the lack of clinical equipoise (the benefit of alteplase clearly outweighs the harms), shared decision-making is not appropriate [115]. Whether to proceed to thrombolysis in an individual patient should be based upon a brief discussion of the risks and benefits with the patient and family or health care proxy, if possible.

coagulation parameters and platelet count are not required to proceed with IVT. Thrombolytic therapy with alteplase (or tenecteplase) should not be delayed while results are pending unless one of the following conditions is present [84]: Clinical suspicion of a bleeding abnormality or thrombocytopenia Current or recent use of anticoagulants (eg, heparin, warfarin, direct oral anticoagulants [DOACs]) Use of anticoagulants is not known https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 11/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate Potential exclusions to treatment Exclusion criteria for IVT are listed in the table ( table 1); these criteria have evolved with time as experience with IVT has increased. Several clinical issues may complicate the decision to use reperfusion therapy for acute ischemic stroke. Among these are rapidly improving stroke symptoms and early ischemic changes on neuroimaging. Patients on anticoagulants Current anticoagulant use with evidence of anticoagulant effect by laboratory tests is a contraindication to IVT. Coagulation tests For patients without recent use of oral anticoagulants or heparin, treatment with IVT can be started before availability of coagulation test results if there is no reason to suspect a coagulopathy (ie, patients not on anticoagulant therapy who have no known liver disease, hematologic disease, or advanced kidney disease). In such cases, alteplase treatment should be discontinued if the international normalized ratio (INR), prothrombin time (PT), or activated partial thromboplastin time (aPTT) are excessively elevated ( table 1). For patients with inadequate historical information, IVT should not be started until the aPTT and either the PT or the INR are available. Preliminary data suggest that normal coagulation parameters can be predicted on arrival to the emergency department by assessing three questions [106]: Is the patient taking an oral anticoagulant? Is the patient taking heparin or low molecular weight heparin? Is the patient on hemodialysis? In a retrospective study from 2006 (prior to the advent of direct oral anticoagulants) that included 299 patients, "no" answers to all three questions predicted normal range PT and aPTT with a sensitivity of 100 percent, suggesting that this simple screen may permit earlier treatment with alteplase in selected patients with acute stroke [106]. Other data suggest that unsuspected coagulopathy is rarely detected among patients evaluated for IVT [107]. Patients on DOACs Accumulating evidence suggests that recent use of a DOAC is not associated with an increased risk of symptomatic intracerebral hemorrhage following IVT [108,109]. Nevertheless, DOAC use remains a contraindication to IVT unless laboratory tests such as aPTT, INR, platelet count, ecarin clotting time, thrombin time, or appropriate direct factor Xa activity assays are normal or the patient has not received a DOAC dose for more than 48 hours, assuming normal renal function [84]. https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 12/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate DOAC reversal DOAC reversal may provide an option to safely treat with thrombolysis, although this approach is not yet established as safe [110]. An observational cohort study identified 51 patients treated with idarucizumab for dabigatran reversal prior to thrombolysis and found that idarucizumab-treated patients had similar rates of symptomatic intracerebral hemorrhage, early neurologic improvement, and mortality compared with patients not treated with idarucizumab [111]. Rapidly improving stroke symptoms Rapidly improving stroke symptoms (RISS) should be considered an exclusion for reperfusion therapy only for patients who improve to the degree that any remaining deficits are nondisabling [112]. The decision regarding use of IVT or MT should be made based upon monitoring neurologic deficits for no longer than the time needed to prepare and begin treatment; treatment should not be delayed by continued monitoring for improvement. Disabling versus nondisabling stroke deficits Qualifying patients who have an acute ischemic stroke causing a persistent neurologic deficit that is potentially disabling, despite improvement of any degree while being evaluated, should be treated urgently with IVT and/or MT as appropriate. Any of the following should be considered disabling deficits [112]: Complete hemianopia: 2 on the National Institutes of Health Stroke Scale (NIHSS) question 3 ( table 3) Severe aphasia: 2 on NIHSS question 9 ( table 3) Visual extinction: 1 on NIHSS question 11 ( table 3) Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6 ( table 3) Any deficits that lead to a total NIHSS >5 (calculator 1) Any remaining deficit considered potentially disabling by the patient, family, or the treating practitioner For patients with an NIHSS score of 0 to 5, a clearly disabling deficit has also been defined as one that would prevent the patient from performing basic activities of daily living (ie, bathing, walking, toileting, and eating) or returning to work [113]. Whether IVT is beneficial for patients with mild, nondisabling ischemic stroke is unknown, and data are limited. The PRISMS trial enrolled patients with acute ischemic stroke within three hours of symptom onset who had an NIHSS score of 0 to 5 and deficits judged not clearly disabling; there was no difference in the rate of a favorable functional outcome (defined as a modified Rankin Scale score of 0 or 1 at 90 days) for patients assigned to treatment with IVT or to aspirin (78.2 versus 81.5 percent) [113]. However, the trial was stopped very early solely because of slow https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 13/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate recruitment, having enrolled only 313 of a planned 948 subjects, and therefore its findings are not definitive. Early ischemic changes on neuroimaging Minor ischemic changes on CT are not a contraindication to treatment; these include subtle or small areas of hypodensity, loss of gray- white distinction, obscuration of the lentiform nucleus, or the presence of a hyperdense artery sign ( image 1). We suggest withholding thrombolytic therapy with alteplase for patients with extensive regions of obvious hypodensity consistent with irreversible injury on initial head CT ( table 1), although there are few data to determine a threshold of ischemic severity or extent that modifies treatment response to alteplase [114]. Patient selection for MT is reviewed separately. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Role of ASPECTS method'.) Issues regarding consent Alteplase is an approved therapy for acute ischemic stroke because of substantial evidence of safety and efficacy. Consent is not required to administer alteplase as an emergent therapy for an otherwise eligible adult patient with a disabling acute ischemic stroke if patient or surrogate consent is not possible [84]. In such cases, the need for informed consent is outweighed by the need for urgent intervention, and the patient can be treated under the principle of presumption of consent. Furthermore, given the lack of clinical equipoise (the benefit of alteplase clearly outweighs the harms), shared decision-making is not appropriate [115]. Whether to proceed to thrombolysis in an individual patient should be based upon a brief discussion of the risks and benefits with the patient and family or health care proxy, if possible. However, neurologic deficits caused by acute stroke often preclude the ability of the patient to participate in the decision. Explaining benefits and risks Procedures for informed decision-making and informed consent vary among different centers; we explain the risks and benefits of alteplase as follows [115]: "There is a treatment for your stroke called alteplase that must be given within 4.5 hours after the stroke started. It is a 'clot-buster' drug. Getting alteplase reduces your risk of being disabled. People who get alteplase for stroke have a better chance of recovering without disability and getting back to the activities they enjoy compared to people who do not receive the treatment. All medicines have some risk. With alteplase, there is a risk of serious bleeding. However, time is https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 14/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate important as well. We know that the sooner we start treatment with alteplase, the greater the chance that patients will have a good outcome." Some patients will accept any risk, including an increased risk of intracranial bleeding, for an increased chance of avoiding severe permanent disability. Others are more risk averse and prefer to accept disability, especially if there is a chance of recovery over time. Need for transfer to stroke center Most hospitals in more economically developed countries are able to treat acute ischemic stroke with IVT. In situations where local stroke expertise is not routinely or immediately available, accumulating data suggest that the decision to administer IVT can be guided safely and effectively via telemedicine (telestroke) [116]. By contrast, MT is not as widely available. Transfer to an expert stroke center may be necessary for patients with acute ischemic stroke in the anterior circulation who present to medical facilities that lack resources and expertise to deliver MT. However, eligible patients can receive standard treatment with IVT if they present to hospitals where thrombectomy is not an option, and those with qualifying anterior circulation strokes can then be transferred to stroke centers where intra-arterial thrombectomy is available, a strategy called "drip and ship" [117,118]. Screening of patients for transfer is aided by the ability of networked hospitals to share brain and neurovascular imaging studies via cloud computing, which allows the stroke center hub to read a CTA (or MRA) done locally and thereby determine whether the patient has a large vessel occlusion, a key requirement for MT. Reducing delay Inordinate treatment delay can occur during any of the steps involved in reperfusion therapy, including emergency department triaging, initial telephone triage by the stroke physician, physician evaluation, neuroimaging, obtaining and waiting for results of blood and laboratory tests, obtaining consent, treating hypertension that would otherwise exclude the use of IVT (ie, systolic blood pressure 185 mmHg or diastolic 110 mmHg), and delivery of alteplase from the pharmacy to the bedside. Expedited stroke protocols may reduce treatment delays and improving patient outcomes. Such protocols may include the following features [119,120]: Prehospital notification by emergency medical personnel/ambulance of a patient with a possible stroke Blast paging of all relevant hospital stroke personnel, including CT technicians In-person triage of all code strokes without telephone triage; the stroke physician on-call proceeds immediately to the bedside Direct transfer of the patient, without fully undressing, from triage onto the CT scanner table via the ambulance stretcher https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 15/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate No delays pending formal neuroimaging interpretation; the on-call stroke physician reads the brain CT or MRI scan Unmixed alteplase is available at the bedside during the evaluation No delays pending electrocardiogram (ECG), coagulation tests, chest radiograph, or stool guaiac unless specifically indicated No delays pending written consent; verbal consent is obtained if the patient is able to consent or if family members or health care proxy are nearby While an expedited evaluation might increase the risk of giving IVT in cases of stroke mimics, data suggest that the intracranial hemorrhage rate in patients who later are diagnosed with a stroke mimic is approximately 1 percent [121,122]. TREATMENT BY TIME FROM SYMPTOM ONSET "Time is brain." The sooner intravenous thrombolysis (IVT) treatment with alteplase is initiated after ischemic stroke, the more likely it is to be beneficial [123-125]. Eligible patients should start treatment as quickly as possible within the appropriate 3- or 4.5-hour time window from stroke onset; treatment should not be delayed until the end of the time window. Mechanical thrombectomy (MT) is also time-dependent, with clear benefit for patients with acute ischemic stroke caused by an intracranial large artery occlusion in the proximal anterior circulation who are treated within 6 hours of symptom onset. Beyond 6 hours, MT may be an option at specialized stroke centers using imaging-based selection of patients with anterior circulation stroke who have symptom onset 6 to 24 hours before treatment. (See "Mechanical thrombectomy for acute ischemic stroke".) Less than 3 hours For eligible patients with acute ischemic stroke causing a potentially disabling neurologic deficit, we recommend IVT with intravenous alteplase (or intravenous tenecteplase) when treatment is initiated within 3 hours of the time last known well. Patients in this time window should also be evaluated to determine if they are candidates for MT. (See 'Benefit by time to treatment' above.) 3 to 4.5 hours The benefit of alteplase extends to 4.5 hours, as discussed above. For otherwise eligible patients who cannot be treated in less than 3 hours, we suggest (ie, a weak recommendation) IVT with alteplase provided that treatment is initiated within 3 to 4.5 hours of the time last known well. Patients in this time window should also be evaluated to determine if they are candidates for MT. (See 'Benefit by time to treatment' above.) https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 16/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate There are additional exclusion criteria ( table 1) for IVT in the 3- to 4.5-hour time window (age >80 years old, an National Institutes of Health Stroke Scale (NIHSS) score >25, a combination of previous stroke and diabetes, and oral anticoagulant use regardless of INR). However, we do not consider these as absolute contraindications to IVT in the 3- to 4.5-hour time window, given evidence that alteplase is still beneficial in patients who would otherwise be excluded by these criteria [4,114,126,127]. The additional exclusions from 3 to 4.5 hours were made to satisfy safety concerns from the European regulatory agency and were employed to select patients for treatment in the ECASS 3 trial [29], which established the benefit of IVT in the 3- to 4.5-hour time window. 4.5 to 6 hours Patients within 4.5 to 6 hours from stroke symptom onset should not routinely receive IVT because harm may exceed benefit, but they should be evaluated to determine if they are candidates for MT. (See 'Benefit by time to treatment' above.) 6 to 24 hours Patients beyond 6 hours from ischemic stroke symptom onset are not eligible for treatment with IVT. However, MT is an option at specialized stroke centers using imaging- based selection of patients with anterior circulation stroke who have were last known to be well at 6 to 24 hours before treatment. This is discussed in detail separately. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Benefit of later (6 to 24 hours) treatment'.) Beyond 24 hours Patients beyond 24 hours from ischemic stroke symptom onset generally are not eligible for treatment with IVT or MT. Limited retrospective data suggest possible benefit for selected patients treated with MT beyond 24 hours of last known well, but confirmation from prospective trials is needed [128]. Unwitnessed stroke onset and "wake-up" stroke When the exact time of stroke onset is not known, it is defined as the last time the patient was known to be normal. For patients whose stroke symptoms are first noted upon awakening from sleep, the last time known to be normal may be the time they went to bed (if the patient can report this reliably) or the last time seen normal by a friend or family member. Such patients are not ordinarily eligible for IVT unless the time last known to be normal is less than 4.5 hours. However, imaging-based criteria (ie, MRI showing an acute ischemic lesion that is diffusion positive and fluid-attenuated inversion recovery [FLAIR] negative) is an option at expert stroke centers to select patients with wake-up stroke or unknown stroke onset time for IVT. (See 'Benefit with imaging selection of patients' above.) Imaging-based selection of patients for treatment with MT who were last known to be normal 6 to 24 hours before treatment is an option at specialized stroke centers. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Benefit of later (6 to 24 hours) treatment'.) https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 17/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate SPECIAL POPULATIONS Different clinical presentations and patient populations may affect the decision to use intravenous thrombolysis (IVT) or mechanical thrombectomy (MT) for acute ischemic stroke, as discussed below. Posterior circulation stroke All eligible patients with acute ischemic stroke should be treated with IVT, including those with stroke in the posterior circulation. Mechanical thrombectomy is beneficial for select patients with acute ischemic stroke caused by a proximal intracranial arterial occlusion in the anterior circulation, but trials that established the benefit of MT largely excluded patients with posterior circulation infarcts. However, endovascular interventions for vertebrobasilar occlusions, including MT, may be treatment options stroke centers with appropriate expertise. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Posterior circulation stroke'.) Age 80 years and older Patients age 80 years or older appear to benefit from IVT despite a higher mortality rate compared with younger patients. Therefore, we do not consider age to be a contraindication to IVT treatment for otherwise eligible patients. However, age >80 years is a relative contraindication in the 3- to 4.5-hour time window. (See '3 to 4.5 hours' above.) A 2014 meta-analysis of individual patient data from 6756 subjects (including more than 1700 subjects older than age 80 years) found that benefit of alteplase was similar regardless of patient age [4]. In a prespecified secondary analysis of individual participant data (n = 6756) from a 2016 meta-analysis of nine trials of alteplase versus control for acute ischemic stroke, the increased risk of intracerebral hemorrhage with alteplase in the first seven days after treatment did not differ by age [6]. Older age is not an exclusion for MT [129]. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Patient selection'.) Prestroke disability or dementia Treatment decisions regarding IVT or MT for patients with significant prestroke disability or dementia should be individualized using shared decision- making that incorporates patient values and preferences [130]. Such patients were largely excluded from randomized trials of reperfusion therapies for acute ischemic stroke. However, observational data suggest that patients with disability or dementia at baseline may still benefit from reperfusion for acute stroke, despite an overall worse prognosis and possibly higher mortality [130]. https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 18/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate Pregnancy Although pregnancy has been considered a relative contraindication to the use of thrombolysis for acute stroke, IVT can be given in pregnancy after careful discussion of the potential risks and benefits. The use of thrombolytic therapy in pregnancy is discussed separately. (See "Cerebrovascular disorders complicating pregnancy", section on 'Acute ischemic stroke'.) Children Safety and efficacy data for reperfusion therapy of acute ischemic stroke are lacking in patients younger than 18 years of age. However, IVT and MT may be options for some children, particularly adolescents (age 13 years), with acute ischemic stroke on neuroimaging who are evaluated and treated at pediatric stroke centers. (See "Ischemic stroke in children: Management and prognosis", section on 'Reperfusion with thrombolysis and thrombectomy'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) SUMMARY AND RECOMMENDATIONS Goals and options for reperfusion The immediate goal of reperfusion therapy for acute ischemic stroke is to restore blood flow to the regions of brain that are ischemic but not yet infarcted. Intravenous thrombolysis (IVT) is the mainstay of reperfusion therapy for acute ischemic stroke. Mechanical thrombectomy (MT) is indicated for patients with acute ischemic stroke caused by an intracranial large artery occlusion in the proximal anterior circulation. (See 'Reperfusion therapies' above.) Benefit of reperfusion therapy IVT improves functional outcome at three to six months for appropriately selected patients when given within 4.5 hours of ischemic stroke onset. (See 'Alteplase' above and 'Tenecteplase' above.) MT improves functional outcome at three months for appropriately selected patients if treatment is started within 24 hours from the time the patient was last known well. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Efficacy of mechanical thrombectomy'.) Evaluation All adult patients with a clinical diagnosis of acute ischemic stroke should be rapidly evaluated for treatment with IVT. Simultaneously, patients with suspected acute https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 19/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate ischemic stroke involving the anterior circulation should be evaluated for MT. (See 'Rapid evaluation' above.) Patient selection For IVT Eligibility criteria for treatment with IVT are outlined in the table ( table 1). For eligible patients with acute ischemic stroke causing a potentially disabling neurologic deficit, we recommend IVT with alteplase, provided that treatment is initiated within 3 hours of the time last known well (Grade 1A). For otherwise eligible patients who cannot be treated in less than 3 hours, we suggest IVT, provided that treatment is initiated within 3 to 4.5 hours of the time last known well (Grade 2A). For patients with wake-up stroke or unknown stroke onset time, imaging-based criteria (ie, MRI showing an acute ischemic lesion that is diffusion positive and fluid-attenuated inversion recovery [FLAIR] negative) is an option at expert stroke centers to determine eligibility for IVT. (See 'Less than 3 hours' above and '3 to 4.5 hours' above and 'Unwitnessed stroke onset and "wake-up" stroke' above.) For MT Intra-arterial mechanical thrombectomy is recommended for patients with ischemic stroke caused by a large artery occlusion in the proximal anterior circulation who can start treatment within 24 hours of the time last known well. Indications and eligibility criteria for MT are discussed in detail elsewhere. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Patient selection'.) IVT administration The administration of IVT for acute ischemic stroke, including dosing, monitoring, and complications, is reviewed in detail separately. 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Endovascular Treatment and Thrombolysis for Acute Ischemic Stroke in Patients With Premorbid Disability or Dementia: A Scientific Statement From the American Heart Association/American Stroke Association. Stroke 2022; 53:e204. Topic 115775 Version 43.0 https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 30/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate GRAPHICS Eligibility criteria for the treatment of acute ischemic stroke with intravenous thrombolysis (recombinant tissue plasminogen activator or tPA) Inclusion criteria Clinical diagnosis of ischemic stroke causing measurable neurologic deficit Onset of symptoms <4.5 hours before beginning treatment; if the exact time of stroke onset is not known, it is defined as the last time the patient was known to be normal or at neurologic baseline Age 18 years Exclusion criteria Patient history Ischemic stroke or severe head trauma in the previous three months Previous intracranial hemorrhage Intra-axial intracranial neoplasm Gastrointestinal malignancy Gastrointestinal hemorrhage in the previous 21 days Intracranial or intraspinal surgery within the prior three months Clinical Symptoms suggestive of subarachnoid hemorrhage Persistent blood pressure elevation (systolic 185 mmHg or diastolic 110 mmHg) Active internal bleeding Presentation consistent with infective endocarditis Stroke known or suspected to be associated with aortic arch dissection Acute bleeding diathesis, including but not limited to conditions defined under 'Hematologic' Hematologic 3 Platelet count <100,000/mm * Current anticoagulant use with an INR >1.7 or PT >15 seconds or aPTT >40 seconds* Therapeutic doses of low molecular weight heparin received within 24 hours (eg, to treat VTE and ACS); this exclusion does not apply to prophylactic doses (eg, to prevent VTE) Current use (ie, last dose within 48 hours in a patient with normal renal function) of a direct thrombin inhibitor or direct factor Xa inhibitor with evidence of anticoagulant effect by laboratory tests such as aPTT, INR, ECT, TT, or appropriate factor Xa activity assays Head CT https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 31/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate Evidence of hemorrhage Extensive regions of obvious hypodensity consistent with irreversible injury Warnings Only minor and isolated neurologic signs or rapidly improving symptoms Serum glucose <50 mg/dL (<2.8 mmol/L) Serious trauma in the previous 14 days Major surgery in the previous 14 days History of gastrointestinal bleeding (remote) or genitourinary bleeding Seizure at the onset of stroke with postictal neurologic impairments Pregnancy** Arterial puncture at a noncompressible site in the previous seven days Large ( 10 mm), untreated, unruptured intracranial aneurysm Untreated intracranial vascular malformation Additional warnings for treatment from 3 to 4.5 hours from symptom onset Age >80 years Oral anticoagulant use regardless of INR Severe stroke (NIHSS score >25) Combination of both previous ischemic stroke and diabetes mellitus ACS: acute coronary syndrome; aPTT: activated partial thromboplastin time; ECT: ecarin clotting time; INR: international normalized ratio; PT: prothrombin time; NIHSS: National Institutes of Health Stroke Scale; tPA: intravenous alteplase; TT: thrombin time; VTE: venous thromboembolism. Although it is desirable to know the results of these tests, thrombolytic therapy should not be delayed while results are pending unless (1) there is clinical suspicion of a bleeding abnormality or thrombocytopenia, (2) the patient is currently on or has recently received anticoagulants (eg, heparin, warfarin, a direct thrombin inhibitor, or a direct factor Xa inhibitor), or (3) use of anticoagulants is not known. Otherwise, treatment with intravenous tPA can be started before availability of coagulation test results but should be discontinued if the INR, PT, or aPTT exceed the limits stated in the table, or 3 if platelet count is <100,000 mm . With careful consideration and weighting of risk-to-benefit, patients may receive intravenous alteplase despite one or more warnings. Patients who have a persistent neurologic deficit that is potentially disabling, despite improvement of any degree, should be treated with tPA in the absence of other contraindications. Any of the following should be considered disabling deficits: Complete hemianopia: 2 on NIHSS question 3, or Severe aphasia: 2 on NIHSS question 9, or Visual or sensory extinction: 1 on NIHSS question 11, or https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 32/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6, or Any deficits that lead to a total NIHSS >5, or Any remaining deficit considered potentially disabling in the view of the patient and the treating practitioner using clinical judgment Patients may be treated with intravenous alteplase if glucose level is subsequently normalized. The potential risks of bleeding with alteplase from injuries related to the trauma should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. The increased risk of surgical site bleeding with alteplase should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. There is a low increased risk of new bleeding with alteplase in the setting of past gastrointestinal or genitourinary bleeding. However, alteplase administration within 21 days of gastrointestinal bleeding is not recommended. Alteplase is reasonable in patients with a seizure at stroke onset if evidence suggests that residual impairments are secondary to acute ischemic stroke and not to a postictal phenomenon. * Alteplase can be given in pregnancy when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding. The safety and efficacy of administering alteplase is uncertain for these relative exclusions. Although these were exclusions in the trial showing benefit in the 3 to 4.5 hour window, intravenous alteplase appears to be safe and may be beneficial for patients with these criteria, including patients taking oral anticoagulants with an INR <1.7. Adapted from: 1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359:1317. 2. Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke Association. Stroke 2009; 40:2945. 3. Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force:, Levine SR, Khatri P, et al. Review, historical context, and clari cations of the NINDS rt-PA stroke trials exclusion criteria: Part 1: rapidly improving stroke symptoms. Stroke 2013; 44:2500. 4. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scienti c rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2016; 47:581. 5. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. Graphic 71462 Version 26.0 https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 33/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate Modified Rankin Scale Score Description 0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties and activities 2 Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent, and requiring constant nursing care and attention 6 Dead Reproduced with permission from: Van Swieten JC, Koudstaa PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988; 19:604. Copyright 1988 Lippincott Williams & Wilkins. Graphic 75411 Version 13.0 https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 34/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate Stroke treatment delay and outcome Relation of stroke onset to start of treatment (OTT) with treatment effect after adjustment for prognostic variables assessed by A) day 90 modified Rankin score 0-1 versus 2-6 (interaction p=0.0269, n=3530 [excluding EPITHET data p=0.0116, n=3431]); B) global test that incorporates modified Rankin score 0-1 versus 2-6, Barthel Index score 95-100 versus 90 or lower and NIHSS score 0-1 versus 2 or more (interaction p=0.0111, n=3535 [excluding EPITHET data p=0.0049, n=3436]); C) mortality (interaction p=0.0444, n=3530 [excluding EPITHET data p=0.0582, n=3431]); and D) parenchymal hemorrhage type 2 (interaction p=0.4140, n=3531 [excluding EPITHET data p=0.4578, n=3431]). Thus, for parenchymal hemorrhage type 2, the fitted line is not statistically distinguishable from a horizontal line. For each graph, the adjusted odds ratio is shown with the 95% CIs. CIs from the models will differ from those shown in the tables because the model uses data from all patients treated within 0-360 min whereas the categorized analyses in the tables are based on subsets of patients: the modeled CIs are deemed to be more reliable. %: percent. Lees, KR, Bluhmki, E, von Kummer, R, et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 2010; 375:1695. Illustration used https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 35/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate with permission of Elsevier Inc. All rights reserved. Graphic 66764 Version 2.0 https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 36/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate National Institutes of Health Stroke Scale (NIHSS) Administer stroke scale items in the order listed. Record performance in each category after each subscale exam. Do not go back and change scores. Follow directions provided for each exam technique. Scores should reflect what the patient does, not what the clinician thinks the patient can do. The clinician should record answers while administering the exam and work quickly. Except where indicated, the patient should not be coached (ie, repeated requests to patient to make a special effort). Instructions Scale definition Score 1a. Level of consciousness: The 0 = Alert; keenly responsive. investigator must choose a response if a full evaluation is prevented by such obstacles as 1 = Not alert; but arousable by minor stimulation to obey, answer, or respond. an endotracheal tube, language barrier, 2 = Not alert; requires repeated stimulation orotracheal trauma/bandages. A 3 is scored only if the patient makes no movement to attend, or is obtunded and requires strong or painful stimulation to make movements (not stereotyped). _____ (other than reflexive posturing) in response to noxious stimulation. 3 = Responds only with reflex motor or autonomic effects or totally unresponsive, flaccid, and areflexic. 1b. Level of consciousness questions: The 0 = Answers both questions correctly. patient is asked the month and his/her age. The answer must be correct - there is no partial credit for being close. Aphasic and stuporous patients who do not comprehend the questions will score 2. Patients unable to speak because of endotracheal intubation, orotracheal trauma, severe dysarthria from 1 = Answers one question correctly. 2 = Answers neither question correctly. _____ any cause, language barrier, or any other problem not secondary to aphasia are given a 1. It is important that only the initial answer be graded and that the examiner not "help" the patient with verbal or non-verbal cues. 1c. Level of consciousness commands: The 0 = Performs both tasks correctly. _____ patient is asked to open and close the eyes and then to grip and release the non-paretic 1 = Performs one task correctly. 2 = Performs neither task correctly. hand. Substitute another one step command if the hands cannot be used. Credit is given if an unequivocal attempt is made but not completed due to weakness. If the patient does not respond to command, the task should be demonstrated to him or her (pantomime), and the result scored (ie, https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 37/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate follows none, one or two commands). Patients with trauma, amputation, or other physical impediments should be given suitable one-step commands. Only the first attempt is scored. 2. Best gaze: Only horizontal eye movements will be tested. Voluntary or 0 = Normal. 1 = Partial gaze palsy; gaze is abnormal in reflexive (oculocephalic) eye movements will one or both eyes, but forced deviation or total gaze paresis is not present. be scored, but caloric testing is not done. If the patient has a conjugate deviation of the 2 = Forced deviation, or total gaze paresis not overcome by the oculocephalic eyes that can be overcome by voluntary or reflexive activity, the score will be 1. If a maneuver. patient has an isolated peripheral nerve paresis (cranial nerves III, IV or VI), score a 1. _____ Gaze is testable in all aphasic patients. Patients with ocular trauma, bandages, pre- existing blindness, or other disorder of visual acuity or fields should be tested with reflexive movements, and a choice made by the investigator. Establishing eye contact and then moving about the patient from side to side will occasionally clarify the presence of a partial gaze palsy. 3. Visual: Visual fields (upper and lower quadrants) are tested by confrontation, using finger counting or visual threat, as appropriate. Patients may be encouraged, 0 = No visual loss. 1 = Partial hemianopia. 2 = Complete hemianopia. but if they look at the side of the moving fingers appropriately, this can be scored as normal. If there is unilateral blindness or enucleation, visual fields in the remaining eye are scored. Score 1 only if a clear-cut 3 = Bilateral hemianopia (blind including cortical blindness). _____ asymmetry, including quadrantanopia, is found. If patient is blind from any cause, score 3. Double simultaneous stimulation is performed at this point. If there is extinction, patient receives a 1, and the results are used to respond to item 11. 4. Facial palsy: Ask - or use pantomime to encourage - the patient to show teeth or 0 = Normal symmetrical movements. _____ 1 = Minor paralysis (flattened nasolabial raise eyebrows and close eyes. Score symmetry of grimace in response to noxious fold, asymmetry on smiling). 2 = Partial paralysis (total or near-total paralysis of lower face). stimuli in the poorly responsive or non- comprehending patient. If facial trauma/bandages, orotracheal tube, tape or https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 38/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate other physical barriers obscure the face, 3 = Complete paralysis of one or both sides these should be removed to the extent (absence of facial movement in the upper possible. and lower face). 5. Motor arm: The limb is placed in the appropriate position: extend the arms 0 = No drift; limb holds 90 (or 45) degrees for full 10 seconds. (palms down) 90 degrees (if sitting) or 45 degrees (if supine). Drift is scored if the arm 1 = Drift; limb holds 90 (or 45) degrees, but drifts down before full 10 seconds; does not falls before 10 seconds. The aphasic patient hit bed or other support. is encouraged using urgency in the voice and pantomime, but not noxious 2 = Some effort against gravity; limb cannot get to or maintain (if cued) 90 (or 45) degrees, drifts down to bed, but has some stimulation. Each limb is tested in turn, beginning with the non-paretic arm. Only in _____ effort against gravity. the case of amputation or joint fusion at the shoulder, the examiner should record the 3 = No effort against gravity; limb falls. score as untestable (UN), and clearly write 4 = No movement. the explanation for this choice. UN = Amputation or joint fusion, explain:________________ 5a. Left arm 5b. Right arm 6. Motor leg: The limb is placed in the appropriate position: hold the leg at 30 degrees (always tested supine). Drift is scored if the leg falls before 5 seconds. The 0 = No drift; leg holds 30-degree position for full 5 seconds. 1 = Drift; leg falls by the end of the 5-second period but does not hit bed. aphasic patient is encouraged using urgency in the voice and pantomime, but not noxious stimulation. Each limb is tested in turn, beginning with the non-paretic leg. Only in the case of amputation or joint fusion at the hip, the examiner should 2 = Some effort against gravity; leg falls to bed by 5 seconds, but has some effort against gravity. _____ 3 = No effort against gravity; leg falls to bed immediately. record the score as untestable (UN), and clearly write the explanation for this choice. 4 = No movement. UN = Amputation or joint fusion, explain:________________ 6a. Left leg 6b. Right leg 7. Limb ataxia: This item is aimed at finding 0 = Absent. _____ evidence of a unilateral cerebellar lesion. Test with eyes open. In case of visual defect, 1 = Present in one limb. 2 = Present in two limbs. ensure testing is done in intact visual field. The finger-nose-finger and heel-shin tests UN = Amputation or joint fusion, explain:________________ are performed on both sides, and ataxia is scored only if present out of proportion to weakness. Ataxia is absent in the patient https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 39/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate who cannot understand or is paralyzed. Only in the case of amputation or joint fusion, the examiner should record the score as untestable (UN), and clearly write the explanation for this choice. In case of blindness, test by having the patient touch nose from extended arm position. 8. Sensory: Sensation or grimace to pinprick 0 = Normal; no sensory loss. when tested, or withdrawal from noxious stimulus in the obtunded or aphasic patient. 1 = Mild-to-moderate sensory loss; patient feels pinprick is less sharp or is dull on the affected side; or there is a loss of superficial Only sensory loss attributed to stroke is scored as abnormal and the examiner pain with pinprick, but patient is aware of being touched.

to attend, or is obtunded and requires strong or painful stimulation to make movements (not stereotyped). _____ (other than reflexive posturing) in response to noxious stimulation. 3 = Responds only with reflex motor or autonomic effects or totally unresponsive, flaccid, and areflexic. 1b. Level of consciousness questions: The 0 = Answers both questions correctly. patient is asked the month and his/her age. The answer must be correct - there is no partial credit for being close. Aphasic and stuporous patients who do not comprehend the questions will score 2. Patients unable to speak because of endotracheal intubation, orotracheal trauma, severe dysarthria from 1 = Answers one question correctly. 2 = Answers neither question correctly. _____ any cause, language barrier, or any other problem not secondary to aphasia are given a 1. It is important that only the initial answer be graded and that the examiner not "help" the patient with verbal or non-verbal cues. 1c. Level of consciousness commands: The 0 = Performs both tasks correctly. _____ patient is asked to open and close the eyes and then to grip and release the non-paretic 1 = Performs one task correctly. 2 = Performs neither task correctly. hand. Substitute another one step command if the hands cannot be used. Credit is given if an unequivocal attempt is made but not completed due to weakness. If the patient does not respond to command, the task should be demonstrated to him or her (pantomime), and the result scored (ie, https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 37/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate follows none, one or two commands). Patients with trauma, amputation, or other physical impediments should be given suitable one-step commands. Only the first attempt is scored. 2. Best gaze: Only horizontal eye movements will be tested. Voluntary or 0 = Normal. 1 = Partial gaze palsy; gaze is abnormal in reflexive (oculocephalic) eye movements will one or both eyes, but forced deviation or total gaze paresis is not present. be scored, but caloric testing is not done. If the patient has a conjugate deviation of the 2 = Forced deviation, or total gaze paresis not overcome by the oculocephalic eyes that can be overcome by voluntary or reflexive activity, the score will be 1. If a maneuver. patient has an isolated peripheral nerve paresis (cranial nerves III, IV or VI), score a 1. _____ Gaze is testable in all aphasic patients. Patients with ocular trauma, bandages, pre- existing blindness, or other disorder of visual acuity or fields should be tested with reflexive movements, and a choice made by the investigator. Establishing eye contact and then moving about the patient from side to side will occasionally clarify the presence of a partial gaze palsy. 3. Visual: Visual fields (upper and lower quadrants) are tested by confrontation, using finger counting or visual threat, as appropriate. Patients may be encouraged, 0 = No visual loss. 1 = Partial hemianopia. 2 = Complete hemianopia. but if they look at the side of the moving fingers appropriately, this can be scored as normal. If there is unilateral blindness or enucleation, visual fields in the remaining eye are scored. Score 1 only if a clear-cut 3 = Bilateral hemianopia (blind including cortical blindness). _____ asymmetry, including quadrantanopia, is found. If patient is blind from any cause, score 3. Double simultaneous stimulation is performed at this point. If there is extinction, patient receives a 1, and the results are used to respond to item 11. 4. Facial palsy: Ask - or use pantomime to encourage - the patient to show teeth or 0 = Normal symmetrical movements. _____ 1 = Minor paralysis (flattened nasolabial raise eyebrows and close eyes. Score symmetry of grimace in response to noxious fold, asymmetry on smiling). 2 = Partial paralysis (total or near-total paralysis of lower face). stimuli in the poorly responsive or non- comprehending patient. If facial trauma/bandages, orotracheal tube, tape or https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 38/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate other physical barriers obscure the face, 3 = Complete paralysis of one or both sides these should be removed to the extent (absence of facial movement in the upper possible. and lower face). 5. Motor arm: The limb is placed in the appropriate position: extend the arms 0 = No drift; limb holds 90 (or 45) degrees for full 10 seconds. (palms down) 90 degrees (if sitting) or 45 degrees (if supine). Drift is scored if the arm 1 = Drift; limb holds 90 (or 45) degrees, but drifts down before full 10 seconds; does not falls before 10 seconds. The aphasic patient hit bed or other support. is encouraged using urgency in the voice and pantomime, but not noxious 2 = Some effort against gravity; limb cannot get to or maintain (if cued) 90 (or 45) degrees, drifts down to bed, but has some stimulation. Each limb is tested in turn, beginning with the non-paretic arm. Only in _____ effort against gravity. the case of amputation or joint fusion at the shoulder, the examiner should record the 3 = No effort against gravity; limb falls. score as untestable (UN), and clearly write 4 = No movement. the explanation for this choice. UN = Amputation or joint fusion, explain:________________ 5a. Left arm 5b. Right arm 6. Motor leg: The limb is placed in the appropriate position: hold the leg at 30 degrees (always tested supine). Drift is scored if the leg falls before 5 seconds. The 0 = No drift; leg holds 30-degree position for full 5 seconds. 1 = Drift; leg falls by the end of the 5-second period but does not hit bed. aphasic patient is encouraged using urgency in the voice and pantomime, but not noxious stimulation. Each limb is tested in turn, beginning with the non-paretic leg. Only in the case of amputation or joint fusion at the hip, the examiner should 2 = Some effort against gravity; leg falls to bed by 5 seconds, but has some effort against gravity. _____ 3 = No effort against gravity; leg falls to bed immediately. record the score as untestable (UN), and clearly write the explanation for this choice. 4 = No movement. UN = Amputation or joint fusion, explain:________________ 6a. Left leg 6b. Right leg 7. Limb ataxia: This item is aimed at finding 0 = Absent. _____ evidence of a unilateral cerebellar lesion. Test with eyes open. In case of visual defect, 1 = Present in one limb. 2 = Present in two limbs. ensure testing is done in intact visual field. The finger-nose-finger and heel-shin tests UN = Amputation or joint fusion, explain:________________ are performed on both sides, and ataxia is scored only if present out of proportion to weakness. Ataxia is absent in the patient https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 39/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate who cannot understand or is paralyzed. Only in the case of amputation or joint fusion, the examiner should record the score as untestable (UN), and clearly write the explanation for this choice. In case of blindness, test by having the patient touch nose from extended arm position. 8. Sensory: Sensation or grimace to pinprick 0 = Normal; no sensory loss. when tested, or withdrawal from noxious stimulus in the obtunded or aphasic patient. 1 = Mild-to-moderate sensory loss; patient feels pinprick is less sharp or is dull on the affected side; or there is a loss of superficial Only sensory loss attributed to stroke is scored as abnormal and the examiner pain with pinprick, but patient is aware of being touched. should test as many body areas (arms [not hands], legs, trunk, face) as needed to 2 = Severe to total sensory loss; patient is not aware of being touched in the face, arm, accurately check for hemisensory loss. A score of 2, "severe or total sensory loss," should only be given when a severe or total loss of sensation can be clearly and leg. _____ demonstrated. Stuporous and aphasic patients will, therefore, probably score 1 or 0. The patient with brainstem stroke who has bilateral loss of sensation is scored 2. If the patient does not respond and is quadriplegic, score 2. Patients in a coma (item 1a=3) are automatically given a 2 on this item. 9. Best language: A great deal of 0 = No aphasia; normal. _____ information about comprehension will be obtained during the preceding sections of the examination. For this scale item, the patient is asked to describe what is happening in the attached picture, to name 1 = Mild-to-moderate aphasia; some obvious loss of fluency or facility of comprehension, without significant limitation on ideas expressed or form of expression. Reduction of speech and/or comprehension, however, makes the items on the attached naming sheet and to read from the attached list of sentences. conversation about provided materials Comprehension is judged from responses here, as well as to all of the commands in difficult or impossible. For example, in conversation about provided materials, the preceding general neurological exam. If examiner can identify picture or naming card content from patient's response. visual loss interferes with the tests, ask the patient to identify objects placed in the 2 = Severe aphasia; all communication is through fragmentary expression; great need hand, repeat, and produce speech. The intubated patient should be asked to write. for inference, questioning, and guessing by the listener. Range of information that can The patient in a coma (item 1a=3) will automatically score 3 on this item. The be exchanged is limited; listener carries burden of communication. Examiner cannot examiner must choose a score for the patient with stupor or limited cooperation, but a score of 3 should be used only if the https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 40/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate patient is mute and follows no one-step identify materials provided from patient commands. response. 3 = Mute, global aphasia; no usable speech or auditory comprehension. 10. Dysarthria: If patient is thought to be normal, an adequate sample of speech must 0 = Normal. 1 = Mild-to-moderate dysarthria; patient be obtained by asking patient to read or slurs at least some words and, at worst, can be understood with some difficulty. repeat words from the attached list. If the patient has severe aphasia, the clarity of 2 = Severe dysarthria; patient's speech is so slurred as to be unintelligible in the absence articulation of spontaneous speech can be rated. Only if the patient is intubated or has _____ of or out of proportion to any dysphasia, or is mute/anarthric. other physical barriers to producing speech, the examiner should record the score as untestable (UN), and clearly write an UN = Intubated or other physical barrier, explanation for this choice. Do not tell the patient why he or she is being tested. explain:________________ 11. Extinction and inattention (formerly 0 = No abnormality. neglect): Sufficient information to identify neglect may be obtained during the prior testing. If the patient has a severe visual loss preventing visual double simultaneous stimulation, and the cutaneous stimuli are normal, the score is normal. If the patient has aphasia but does appear to attend to 1 = Visual, tactile, auditory, spatial, or personal inattention or extinction to bilateral simultaneous stimulation in one of the sensory modalities. 2 = Profound hemi-inattention or extinction to more than one modality; does not recognize own hand or orients to only one side of space. _____ both sides, the score is normal. The presence of visual spatial neglect or anosognosia may also be taken as evidence of abnormality. Since the abnormality is scored only if present, the item is never untestable. _____ Adapted from: Goldstein LB, Samsa GP. Reliability of the National Institutes of Health Stroke Scale. Extension to non- neurologists in the context of a clinical trial. Stroke 1997; 28:307. Graphic 61698 Version 8.0 https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 41/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate Early ischemic changes on noncontrast head CT scan Findings of EIC in a 59-year-old man who presented with acute left hemiparesis. (A and B) NCCT 3.5 hours after symptom onset shows hypodensity and cortical swelling with sulcal effacement. There is loss of gray- white matter differentiation in the right frontal operculum, right temporal operculum, right insular cortex, and right frontoparietal lobes (arrowheads). CT: computed tomography; EIC: early ischemic changes; NCCT: noncontrast-enhanced computed tomography. From: Prakkamakul S, Yoo AJ. ASPECTS CT in Acute Ischemia: Review of Current Data. Top Magn Reson Imaging 2017; 26:103. DOI: 10.1097/RMR.0000000000000122. Copyright 2017. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 121623 Version 2.0 https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 42/43 7/5/23, 12:09 PM Approach to reperfusion therapy for acute ischemic stroke - UpToDate Contributor Disclosures Jamary Oliveira-Filho, MD, MS, PhD No relevant financial relationship(s) with ineligible companies to disclose. Owen B Samuels, MD No relevant financial relationship(s) with ineligible companies to disclose. Jos Biller, MD, FACP, FAAN, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Jonathan A Edlow, MD, FACEP No relevant financial relationship(s) with ineligible companies to disclose. Alejandro A Rabinstein, MD Grant/Research/Clinical Trial Support: Chiesi [Small investigator- initiated project]. Consultant/Advisory Boards: AstraZeneca [Secondary stroke prevention]; Brainomix [AI for stroke diagnostics]; Novo Nordisk [Stroke risk]; Shionogi [Stroke neuroprotection]. Other Financial Interest: Boston Scientific [Adverse event adjudication committee member for stroke risk reduction device in patients with atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/approach-to-reperfusion-therapy-for-acute-ischemic-stroke/print 43/43

7/5/23, 12:09 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Cerebral and cervical artery dissection: Treatment and prognosis : David S Liebeskind, MD : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 22, 2022. INTRODUCTION Arterial dissections are a common cause of stroke in the young but may occur at any age. Dissection occurs when structural integrity of the arterial wall is compromised, allowing blood to collect between layers as an intramural hematoma. Dissections that occur without overt trauma are often labeled as "spontaneous" even though there is often a triggering event or underlying predisposition contributing to the pathogenesis. The optimal treatment of dissection remains a challenge due to limitations in rapidly establishing a definitive diagnosis, the overall low incidence, low recurrence rate, and marked variation in patient characteristics [1]. This topic will review the treatment and prognosis of cerebral and cervical artery dissection. Other aspects of this disorder are reviewed separately. (See "Cerebral and cervical artery dissection: Clinical features and diagnosis".) ACUTE ISCHEMIC STROKE OR TIA DUE TO DISSECTION General management For patients with cervicocephalic dissection who present with transient ischemic attack (TIA) or acute ischemic stroke, standard approaches to management should be rigorously followed including blood pressure regulation, fluid administration, control of hyperglycemia and other metabolic derangements, and airway management. These issues are discussed in detail separately. (See "Initial assessment and management of acute stroke" https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 1/28 7/5/23, 12:09 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate and "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis" and "Initial evaluation and management of transient ischemic attack and minor ischemic stroke".) All patients with acute ischemic stroke should be evaluated to determine eligibility for reperfusion therapy with intravenous thrombolysis and/or mechanical thrombectomy (see 'Reperfusion therapy for eligible patients' below). Reperfusion therapy for eligible patients The immediate goal of reperfusion therapy for acute ischemic stroke is to restore blood flow to the regions of brain that are ischemic but not yet infarcted. The long-term goal is to improve outcome by reducing stroke-related disability and mortality. Options for reperfusion therapy that are proven effective include intravenous thrombolysis with alteplase or tenecteplase, and mechanical thrombectomy. Since the ischemic stroke mechanism is often unknown or unconfirmed at the time of decision-making for intravenous thrombolysis, and since cervical or cerebral artery dissection is not a contraindication, patients with suspected cervical or intracranial dissection should receive intravenous thrombolysis if otherwise eligible. Intravenous thrombolysis Intravenous thrombolysis with alteplase (tPA) or tenecteplase is indicated for eligible patients ( table 1) with acute ischemic stroke, including those with isolated extracranial or intracranial cervical artery dissection. Extension of aortic dissection, however, is a known complication of thrombolysis. (See "Approach to reperfusion therapy for acute ischemic stroke" and "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use".) The major randomized trials of intravenous thrombolysis for acute ischemic stroke did not exclude patients with cervicocephalic arterial dissection. While thrombolysis in the setting of dissection may theoretically cause enlargement of the intramural hematoma, accumulating evidence suggests that the effectiveness and safety of thrombolysis for patients with ischemic stroke related to cervical artery dissection are similar to its effectiveness and safety for patients with ischemic stroke from other causes [2-7]. Perhaps the strongest evidence, although indirect, comes from a 2011 meta-analysis of individual patient data from 14 retrospective series and 22 case reports involving 180 patients with cervical artery dissection who were treated with thrombolysis and followed for a median of three months [4]. When these patients were compared with matched historic controls from the observational SITS-ISTR registry of patients treated with intravenous alteplase for acute ischemic stroke, there were no major differences between groups for rates of symptomatic intracranial hemorrhage, mortality, excellent outcome, or favorable outcome. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 2/28 7/5/23, 12:09 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate There is controversy regarding the use of thrombolysis for ischemic symptoms in patients with isolated intracranial dissection alone or intracranial extension of extracranial dissection because of a presumed increased risk of subarachnoid or symptomatic intracranial hemorrhage. Limited observational data suggest this risk is minimal, but efficacy and safety are still uncertain [8]. Mechanical thrombectomy For select patients with acute ischemic stroke caused by a proximal intracranial arterial occlusion in the anterior circulation, early treatment with mechanical thrombectomy is indicated when performed at stroke centers with appropriate expertise, whether or not the patient received treatment with intravenous thrombolysis. This includes patients with extracranial carotid dissection who have a tandem proximal intracranial artery occlusion amenable to mechanical thrombectomy [9-13]. The efficacy of mechanical thrombectomy for vertebral and basilar artery occlusions is unproven. (See "Mechanical thrombectomy for acute ischemic stroke".) Emergency stenting In addition to mechanical thrombectomy, angioplasty and stenting of arterial dissection may be treatment options for acute stroke at expert centers [14-17]. Choosing between antiplatelet and anticoagulation therapy Antithrombotic therapy is often used for the prevention of new or recurrent ischemic symptoms caused by arterial dissection, but the approach may differ for extracranial versus intracranial dissection. Extracranial dissection For patients with extracranial carotid or vertebral artery dissection, antithrombotic treatment using either antiplatelet or anticoagulation therapy is generally recommended [18-24]. However, there is no clear consensus about which of these is optimal. Some experts, including the author, prefer anticoagulation rather than antiplatelet therapy [25], while other experts advise antiplatelet therapy rather than anticoagulation. The choice between antiplatelet and anticoagulant therapy should be guided by the clinical experience of the treating physician and by shared decision making that incorporates patient values and preferences, comorbid conditions, and tolerance of these agents. The limited available evidence suggests, but does not establish, that there is no difference in efficacy between anticoagulation and antiplatelet treatment for preventing ischemic stroke in patients with extracranial dissection. In an open-label, assessor-blind pilot trial (CADISS), 250 subjects with extracranial carotid and vertebral dissection were randomly assigned to antiplatelet or anticoagulant treatment for three months [26]. At the end of this period, there was no significant difference between the two treatment groups; ipsilateral ischemic stroke occurred in 3 of 126 (2 percent) in the antiplatelet group and 1 of 124 (1 percent) in the anticoagulant group (odds https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 3/28 7/5/23, 12:09 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate ratio 0.34, 95% CI 0.01-4.23). There were no deaths in either group. There was one major bleeding event, a subarachnoid hemorrhage, in a patient assigned to the anticoagulation group who had a vertebral artery dissection with intracranial extension. At 12 months of follow-up, the rate of recurrent stroke remained low (approximately 2.5 percent) in both treatment groups with no difference between groups for any outcome, including no difference in the angiographic recanalization rate among patients with confirmed dissection [27]. Because of the low stroke rate and rarity of outcome events, the CADISS trial was unable to establish which treatment is superior or safer when used to treat cervical artery dissection [1]. The investigators estimated that a definitive trial would require approximately 10,000 participants, making such a trial unfeasible given the slow enrollment rate of the CADISS trial. However, it is highly likely that anticoagulation is associated with a higher risk of hemorrhagic events, since anticoagulation is a known risk factor for bleeding. (See "Risks and prevention of bleeding with oral anticoagulants".) The subsequent TREAT-CAD trial was an open-label, assessor-blind trial that enrolled 194 adult patients who presented with symptomatic extracranial dissection within two weeks of enrollment and were randomly assigned to aspirin monotherapy (300 mg daily) or to anticoagulation with a vitamin K antagonist (target INR 2.0 to 3.0) for 90 days [28]. The trial was designed to test the noninferiority of aspirin compared with vitamin K antagonist anticoagulants. The trialists chose a composite primary endpoint of clinical events (stroke, major hemorrhage, or death) and magnetic resonance imaging findings (new silent ischemic or hemorrhagic brain lesions) in order to achieve sufficient power, and performed a per-protocol analysis of 173 patients who received the allocated treatment and completed the assessment period. The composite endpoint occurred more often in the aspirin group compared with the vitamin K antagonist group (23 versus 15 percent, absolute difference 8 percent, 95% CI -4 to 21 percent); while the difference was not statistically significant, aspirin failed to meet noninferiority criteria because the upper limit of the 95% CI (21 percent) exceeded the predefined noninferiority margin of 12 percent. Ischemic stroke was also more frequent in the aspirin group (8 versus 0 percent), and all ischemic stroke occurred within seven days of trial enrollment. There were no deaths in either group. There was one major extracranial hemorrhage (a gastrointestinal bleed) in a patient from the vitamin K antagonist group and none in the aspirin group. The risk of ischemic stroke in the TREAT-CAD aspirin group (8 percent) was greater than that in the CADISS antiplatelet group (2 percent); one possible explanation for the difference is that TREAT-CAD used aspirin monotherapy, whereas CADISS permitted the use of other antiplatelet agents and dual antiplatelet therapy [29]. However, this is speculative, https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 4/28 7/5/23, 12:09 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate as indirect cross-trial comparisons may be confounded by various issues and lead to erroneous conclusions. A 2012 meta-analysis of nonrandomized studies with over 1600 patients with cervical artery dissection reported no significant difference in recurrent stroke risk or mortality comparing anticoagulation with antiplatelet agents [30]. Similarly, a 2015 meta-analysis of nonrandomized studies with over 1300 patients who had acute carotid artery dissection found no differences in outcome or complication rates comparing anticoagulation with antiplatelet therapy [31]. Intracranial dissection For patients who have ischemic neurologic symptoms caused by intracranial arterial dissection, we suggest antiplatelet therapy rather than anticoagulation [24]. Anticoagulation is generally avoided in the setting of intracranial dissection due to the risk of subarachnoid hemorrhage, although limited evidence suggests that anticoagulation can be used safely for some patients who have intracranial dissection without subarachnoid hemorrhage [32]. Starting antiplatelet therapy For patients selected for antiplatelet therapy (rather than anticoagulation), initiation should be delayed for 24 hours after infusion of intravenous thrombolytic therapy. Otherwise, antiplatelet agents should be started as soon as possible after the diagnosis of TIA or ischemic stroke is confirmed, even before the evaluation for ischemic mechanism is complete. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Treatment on presentation'.) 2 For patients with a low-risk TIA, defined by an ABCD score <4 ( table 2), or moderate to major ischemic stroke, defined by a National Institutes of Health Stroke Scale (NIHSS) score >5 ( table 3), we start treatment with aspirin (162 to 325 mg daily) alone. 2 For patients with a high-risk TIA, defined by an ABCD score 4 ( table 2), or minor ischemic stroke, defined by a NIHSS score 5 ( table 3), we begin with dual antiplatelet therapy (DAPT) for 21 days using aspirin (160 to 325 mg loading dose, followed by 50 to 100 mg daily) plus clopidogrel (300 to 600 mg loading dose, followed by 75 mg daily) rather than aspirin alone. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Efficacy of DAPT'.) Most reports of antiplatelet therapy for acute cervical artery dissection have employed daily aspirin at various doses; there are few data regarding other antiplatelet agents such as clopidogrel, dipyridamole, or combinations of these agents. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 5/28 7/5/23, 12:09 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate Starting anticoagulation therapy For patients selected for anticoagulation rather than antiplatelet therapy, the initiation of therapy is affected by a number of factors. For medically stable patients with a small- or moderate-sized infarct, anticoagulation using heparin or low molecular weight heparin (as a bridge to warfarin) can be started as soon as 24 hours after symptom onset, or at least 24 hours after infusion of thrombolytic therapy, with minimal risk of transformation to hemorrhagic stroke; anticoagulation with a direct oral anticoagulant (DOAC) can be started as soon as 48 hours after stroke onset, as DOACs have a more rapid anticoagulant effect. However, the role of DOACs for treating dissection is uncertain and data are limited [21]. For patients with large infarctions, symptomatic hemorrhagic transformation, or poorly controlled hypertension, withholding oral anticoagulation for one to two weeks is generally recommended. In such cases, we start aspirin if there are no significant bleeding complications; anticoagulation can be started (and aspirin stopped) after one to two weeks if the patient is stable. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Timing of long-term anticoagulation'.) Anticoagulation can be started immediately for patients with a TIA due to dissection. Acute anticoagulation may be achieved with either subcutaneous low molecular weight heparin such as enoxaparin (1 mg/kg twice daily) or dalteparin (100 units/kg twice daily) or with intravenous unfractionated heparin (dose-adjusted to achieve a goal activated partial thromboplastin time of 1.5 to 2 times control). Transition to warfarin (dose adjusted for a goal international normalized ratio [INR] of 2.5 with an acceptable range of 2 to 3) can be pursued in the subacute period for clinically stable patients. Vessel monitoring and repeat imaging After three to six months from symptom onset or diagnosis of dissection, repeat neurovascular imaging is suggested to assess the status of artery or arteries affected by dissection and guide the need for ongoing treatment, particularly if the patient is being treated with anticoagulation. We use transcranial Doppler, carotid duplex, computed tomography angiography (CTA), and/or magnetic resonance angiography (MRA) to help us decide the status of the arterial system prior to discontinuing anticoagulation therapy. Further treatment is tailored to imaging findings. (See 'Duration of antithrombotic therapy' below.) In most cases, arteries with stenosis or luminal irregularities caused by dissection undergo recanalization and healing in the first months after the initial event. In a report of 61 patients with acute vertebral artery dissection who presented with symptoms of vertebrobasilar territory ischemia, complete recanalization of the vertebral artery was observed at six months in 62 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 6/28 7/5/23, 12:09 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate percent [33]. In another study that followed 76 patients with cervical artery dissection involving 105 vessels with a mean follow-up of 58 months, complete recanalization was noted in 51 percent of vessels, nearly all occurring within the first nine months, and hemodynamically significant recanalization in 20 percent [34]. Data from the prospective CADISS study suggest that dissecting aneurysms are inconstant and can either resolve or develop for the first time in the months following the clinical diagnosis of extracranial cervical artery dissection [35]. Residual headache may indicate persistent vascular abnormalities [36]. Duration of antithrombotic therapy For patients treated with anticoagulation in the acute phase, it is reasonable to stop warfarin and start long-term antiplatelet therapy after six months of anticoagulation, as long as symptoms are not recurrent and the arterial lesion is thrombosed or healed on repeat imaging at three to six months. For patients with persistent vascular luminal stenosis, irregularity, or dissecting aneurysm, it is reasonable to continue anticoagulation. For patients treated with antiplatelet therapy in the acute phase, long-term antiplatelet therapy is recommended using aspirin, clopidogrel, aspirin-extended-release dipyridamole, or cilostazol for secondary prevention of stroke. However, there are no concrete data regarding optimal duration of antithrombotic therapy. The time course of healing of the vessel wall or resolution of vascular abnormalities may be used to guide duration of initial treatment. Most arterial abnormalities stabilize in appearance or resolve by three months, and vessels that fail to reconstitute a normal lumen by six months are highly unlikely to recover at later time points [37]. Recurrent ischemia Recurrence of TIA or ischemic stroke may be due to dissection or another stroke mechanism (eg, large artery atherosclerosis, cardiac embolism, small vessel disease, or other determined etiology) and should be thoroughly evaluated for all causes with a history and examination, brain and vessel imaging, and cardiac and laboratory testing. (See "Initial assessment and management of acute stroke" and "Initial evaluation and management of transient ischemic attack and minor ischemic stroke" and "Neuroimaging of acute stroke".) Due to dissection In various reports, the rate of recurrent ischemic symptoms (stroke and transient ischemic attack) after dissection ranges from 0 to 13 percent [38,39], but it is likely that the actual rate of recurrent ischemic stroke caused by dissection is at the lower end of this range. The prospective CADISS trial found that the rate of recurrent ischemic stroke at three months was approximately 2 percent, and all recurrences were within 10 days of randomization, suggesting that the risk beyond the first two weeks is extremely low https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 7/28 7/5/23, 12:09 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate [26]. Prospective data from the CADISS study also suggest that extracranial cervical dissecting aneurysms have a benign prognosis, with a low rate (1 of 48, or approximately 2 percent) of ischemic stroke during 12 months of follow-up, similar to the rate observed in dissections without aneurysm formation [35]. Another study evaluated 432 surviving patients with carotid or vertebral dissection who were followed for a mean time of 31 months [40]. Recurrent ischemic stroke due to initial or recurrent dissection was observed in four patients (0.9 percent), giving an annual incidence of 0.3 percent. Transient ischemic attack was observed in eight patients (1.8 percent), for an annual incidence of 0.6 percent. Endovascular and surgical repair for dissection Endovascular techniques or surgical repair have been used to treat dissection, mainly for patients who have recurrent ischemia despite antithrombotic therapy [23]. Endovascular techniques for the treatment of dissection and dissecting aneurysm include angioplasty, stent placement, embolization with various materials, and combinations of such approaches [23,41]. Angioplasty and stenting may occlude the false lumen and restore true arterial lumen patency. However, data regarding endovascular treatment of dissection is limited to case reports and case series [41-48]. There are no randomized trial data comparing endovascular techniques with medical therapies, and the long-term safety and durability of these methods are unknown. In isolated cases, accessible lesions may be treated by surgical vessel reconstruction or bypass around a dissecting aneurysm [49,50]. Other surgical revascularization procedures include extracranial-intracranial bypass, endarterectomy, thrombectomy, and proximal vessel ligation. SUBARACHNOID HEMORRHAGE DUE TO INTRACRANIAL DISSECTION Subarachnoid hemorrhage is an uncommon complication of intracranial dissection. (See "Nonaneurysmal subarachnoid hemorrhage", section on 'Intracranial arterial dissection'.) It is managed according to the same principles as subarachnoid hemorrhage caused by rupture of a saccular aneurysm (see "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis"), with the exception that the surgical or endovascular treatment of dissecting aneurysm itself may differ from that of a saccular aneurysm because of morphologic differences between the two types of aneurysms. The risk of rebleeding from an intracranial dissecting https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 8/28 7/5/23, 12:09 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate aneurysm is as high as 40 percent in the first week or so after the event [51-54]. Thus, early repair is typically recommended [51]. The morphology of most dissecting aneurysms limits standard surgical clipping. Management is individualized according to location and other anatomic features, and can include proximal occlusion of the artery, trapping or wrapping of the pseudoaneurysm, bypass, embolization, or stenting [52,54]. These are complicated procedures that can incur additional morbidity. NONISCHEMIC LOCAL SYMPTOMS For patients with nonischemic symptoms caused by extracranial or intracranial carotid or vertebral artery dissection, we suggest antiplatelet therapy for prevention of ischemic stroke. Headache and neck pain associated with dissection can usually be managed with simple analgesics such as acetaminophen. Anecdotally, gabapentin may be helpful. Nonsteroidal antiinflammatory drugs (NSAIDs; eg, naproxen sodium, ibuprofen) are generally avoided in patients receiving anticoagulation because of the increased risk of bleeding. There is no specific treatment for other local symptoms of dissection such as Horner syndrome, lower cranial nerve palsy, audible bruit, or tinnitus, but these may improve with time and vessel healing. MEASURES TO REDUCE RISK OF DISSECTION There are no proven methods that reduce the risk of recurrent cervicocephalic arterial dissection. Nevertheless, some experts suggest that patients with dissection should avoid contact sports, chiropractic neck manipulation, and any activity that involves abrupt rotation and flexion-extension of the neck [55,56]. In addition, estrogen-containing compounds should be discontinued, as estrogen may induce proliferation of intimal and fibromuscular arterial tissue. All vascular risk factors including hypertension should be addressed. (See "Overview of secondary prevention of ischemic stroke".) PROGNOSIS Neurologic outcome The prognosis of cerebral and cervical artery dissection is related primarily to the severity of associated ischemic stroke or subarachnoid hemorrhage. Morbidity and mortality of acute cervicocephalic arterial dissection varies according to the specific arteries involved and location of the lesion. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 9/28 7/5/23, 12:09 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate In the CADISP study of 982 patients with extracranial cervical artery dissection, an unfavorable outcome at three months among patients with ischemic stroke, defined as a modified Rankin Scale ( table 4) score >2, was more likely with stroke due to internal carotid artery dissection compared with stroke due to vertebral artery dissection (25 versus 8 percent) [57]. This result was largely driven by stroke severity at onset, which was greater for patients with internal carotid dissection compared with those who had vertebral dissection by mean National Institutes of Health Stroke Scale (NIHSS) score on admission (8 versus 3). Only limited systematic data are available regarding long-term outcomes of dissection. Complete or excellent recovery occurs in 70 to 85 percent of patients with extracranial dissection, with major disabling deficits in 10 to 25 percent, and death in 5 to 10 percent of cases [38,58]. In observational studies, factors associated with poor functional outcome after cervical artery dissection include a high NIHSS score at onset, arterial occlusion, and older age [58-61]. Quality of life may be impaired in almost half of long-term survivors after dissection [62]. Recurrence of dissection The recurrence rate of cervical and intracranial artery dissection, with or without symptoms, is uncertain, and available data are inconsistent. In the CADISP study, which retrospectively and prospectively recruited 982 patients with cervical artery dissection, the recurrence rate for extracranial cervical dissection at three months was 2 percent [57]. Even higher rates were reported by a single-center study of 232 patients with cervical artery dissection who were followed clinically and with serial imaging for at least one year. Over the course of the study, there were 46 new dissections affecting 39 patients (16 percent). Recurrent dissection was detected within one month of the initial event in 9 percent, and beyond one month until up to eight years after the initial event in another 7 percent [63]. Most initial dissections were linked to ischemic stroke, but the majority of recurrent dissections were either asymptomatic or associated with purely local symptoms. Recurrent dissection may affect several vessels at once, even when preceded by initial dissection isolated to one artery [63,64]. Although data are limited, rare patients with familial dissection tend to be young (mean age 36 years) and are probably at high risk for recurrent or multiple dissection [65]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults" and https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 10/28 7/5/23, 12:09 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate "Society guideline links: Stroke in children".) SUMMARY AND RECOMMENDATIONS Acute management of TIA or ischemic stroke For patients with cervicocephalic dissection who present with transient ischemic attack (TIA) or acute ischemic stroke, standard approaches to stroke management should be rigorously followed. All patients with acute ischemic stroke should be evaluated to determine eligibility for reperfusion therapy with intravenous thrombolysis and/or mechanical thrombectomy. (See 'General management' above and 'Reperfusion therapy for eligible patients' above and "Approach to reperfusion therapy for acute ischemic stroke".) Choice of antithrombotic therapy for secondary ischemic stroke prevention Beyond the hyperacute period of acute stroke, antithrombotic therapy with either anticoagulation or antiplatelet drugs is accepted treatment for prevention of new or recurrent ischemic symptoms due to extracranial artery dissection, although there is controversy regarding the choice between the two. (See 'Choosing between antiplatelet and anticoagulation therapy' above.) Ischemia due to extracranial dissection For patients with acute ischemic stroke or TIA caused by extracranial carotid or vertebral artery dissection, antithrombotic treatment using either antiplatelet or anticoagulation therapy is generally recommended. Some experts, including the author, prefer anticoagulation rather than antiplatelet therapy, while other experts advise antiplatelet therapy rather than anticoagulation. The choice between antiplatelet and anticoagulant therapy should be guided by the clinical experience of the treating physician and by patient values and preferences, comorbid conditions, and tolerance of these agents. The limited available evidence suggests (but does not establish) that there no difference in efficacy between anticoagulation and antiplatelet treatment for preventing ischemic stroke in patients with extracranial dissection, although it is likely that anticoagulation is associated with a higher risk of hemorrhagic events. (See 'Extracranial dissection' above.) Nonischemic local symptoms due to extracranial dissection For patients with nonischemic local symptoms caused by extracranial cervical dissection, we suggest antiplatelet therapy for prevention of ischemic stroke (Grade 2C). (See 'Nonischemic local symptoms' above.) Ischemia due to intracranial dissection For patients who have ischemic stroke or TIA caused by intracranial dissection, we suggest antiplatelet therapy rather than https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 11/28 7/5/23, 12:09 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate anticoagulation (Grade 2C). (See 'Intracranial dissection' above.) Initiating therapy The timing and suggested dosing for starting antiplatelet or anticoagulant therapy is detailed in the sections above. (See 'Starting antiplatelet therapy' above and 'Starting anticoagulation therapy' above.) Vessel monitoring and duration of antithrombotic therapy Repeat neurovascular imaging is suggested after three to six months from symptom onset or diagnosis of dissection to assess the status of the artery or arteries affected by dissection. For patients treated with anticoagulation in the acute phase, it is reasonable to stop warfarin and start long-term antiplatelet therapy after six months of anticoagulation, as long as symptoms are not recurrent and the arterial lesion is thrombosed or healed. (See 'Vessel monitoring and repeat imaging' above and 'Duration of antithrombotic therapy' above.) Recurrent ischemia requires evaluation for all causes Recurrence of TIA or ischemic stroke may be due to dissection or another stroke mechanism (eg, large artery atherosclerosis, cardiac embolism, small vessel disease, or other determined etiology) and should be thoroughly evaluated for all causes. (See 'Recurrent ischemia' above.) Subarachnoid hemorrhage due to intracranial dissection Subarachnoid hemorrhage is an uncommon complication of intracranial dissection and has a high risk of early rebleeding. Early repair is typically recommended. (See 'Subarachnoid hemorrhage due to intracranial dissection' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Jeffrey Saver, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Kasner SE. CADISS: a feasibility trial that answered its question. Lancet Neurol 2015; 14:342. 2. Engelter ST, Rutgers MP, Hatz F, et al. Intravenous thrombolysis in stroke attributable to cervical artery dissection. Stroke 2009; 40:3772. 3. Georgiadis D, Baumgartner RW. Thrombolysis in cervical artery dissection. 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Safety and outcomes of intravenous thrombolysis in dissection-related ischemic stroke: an international multicenter study and comprehensive meta-analysis of reported case series. J Neurol 2015; 262:2135. 8. Bernardo F, Nannoni S, Strambo D, et al. Intravenous thrombolysis in acute ischemic stroke due to intracranial artery dissection: a single-center case series and a review of literature. J Thromb Thrombolysis 2019; 48:679. 9. Hoving JW, Marquering HA, Majoie CBLM. Endovascular treatment in patients with carotid artery dissection and intracranial occlusion: a systematic review. Neuroradiology 2017; 59:641. 10. Blassiau A, Gawlitza M, Manceau PF, et al. Mechanical Thrombectomy for Tandem Occlusions of the Internal Carotid Artery-Results of a Conservative Approach for the Extracranial Lesion. Front Neurol 2018; 9:928. 11. Gory B, Piotin M, Haussen DC, et al. Thrombectomy in Acute Stroke With Tandem Occlusions From Dissection Versus Atherosclerotic Cause. Stroke 2017; 48:3145. 12. Marnat G, Mourand I, Eker O, et al. Endovascular Management of Tandem Occlusion Stroke Related to Internal Carotid Artery Dissection Using a Distal to Proximal Approach: Insight from the RECOST Study. AJNR Am J Neuroradiol 2016; 37:1281. 13. Li S, Zi W, Chen J, et al. Feasibility of Thrombectomy in Treating Acute Ischemic Stroke Because of Cervical Artery Dissection. Stroke 2018; 49:3075. 14. Fields JD, Lutsep HL, Rymer MR, et al. Endovascular mechanical thrombectomy for the treatment of acute ischemic stroke due to arterial dissection. Interv Neuroradiol 2012; 18:74. 15. Farouk M, Sato K, Matsumoto Y, Tominaga T. Endovascular Treatment of Internal Carotid Artery Dissection Presenting with Acute Ischemic Stroke. J Stroke Cerebrovasc Dis 2020; 29:104592. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 13/28 7/5/23, 12:09 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate 16. Labeyrie MA, Civelli V, Reiner P, et al. Prevalence and treatment of spontaneous intracranial artery dissections in patients with acute stroke due to intracranial large vessel occlusion. J Neurointerv Surg 2018; 10:761. 17. Marnat G, Lapergue B, Sibon I, et al. Safety and Outcome of Carotid Dissection Stenting During the Treatment of Tandem Occlusions: A Pooled Analysis of TITAN and ETIS. Stroke 2020; 51:3713. 18. Wein T, Lindsay MP, C t R, et al. Canadian stroke best practice recommendations: Secondary prevention of stroke, sixth edition practice guidelines, update 2017. Int J Stroke 2018; 13:420. 19. National Institute for Health and Care Excellence (NICE). Stroke and transient ischaemic atta ck in over 16s: diagnosis and initial management. NICE guideline NG128. Available at: http s://www.nice.org.uk/guidance/ng128/chapter/Recommendations (Accessed on August 25, 2 020). 20. Lansberg MG, O'Donnell MJ, Khatri P, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e601S. 21. Serkin Z, Le S, Sila C. Treatment of Extracranial Arterial Dissection: the Roles of Antiplatelet Agents, Anticoagulants, and Stenting. Curr Treat Options Neurol 2019; 21:48. 22. Biller J, Sacco RL, Albuquerque FC, et al. Cervical arterial dissections and association with cervical manipulative therapy: a statement for healthcare professionals from the american heart association/american stroke association. Stroke 2014; 45:3155. 23. Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association. Stroke 2021; 52:e364. 24. Debette S, Mazighi M, Bijlenga P, et al. ESO guideline for the management of extracranial and intracranial artery dissection. Eur Stroke J 2021; 6:XXXIX. 25. Brott TG, Halperin JL, Abbara S, et al. 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/ SCAI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association, American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 14/28 7/5/23, 12:09 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society for Vascular Surgery. Vasc Med 2011; 16:35. 26. CADISS trial investigators, Markus HS, Hayter E, et al. Antiplatelet treatment compared with anticoagulation treatment for cervical artery dissection (CADISS): a randomised trial. Lancet Neurol 2015; 14:361.

Vessel monitoring and duration of antithrombotic therapy Repeat neurovascular imaging is suggested after three to six months from symptom onset or diagnosis of dissection to assess the status of the artery or arteries affected by dissection. For patients treated with anticoagulation in the acute phase, it is reasonable to stop warfarin and start long-term antiplatelet therapy after six months of anticoagulation, as long as symptoms are not recurrent and the arterial lesion is thrombosed or healed. (See 'Vessel monitoring and repeat imaging' above and 'Duration of antithrombotic therapy' above.) Recurrent ischemia requires evaluation for all causes Recurrence of TIA or ischemic stroke may be due to dissection or another stroke mechanism (eg, large artery atherosclerosis, cardiac embolism, small vessel disease, or other determined etiology) and should be thoroughly evaluated for all causes. (See 'Recurrent ischemia' above.) Subarachnoid hemorrhage due to intracranial dissection Subarachnoid hemorrhage is an uncommon complication of intracranial dissection and has a high risk of early rebleeding. Early repair is typically recommended. (See 'Subarachnoid hemorrhage due to intracranial dissection' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Jeffrey Saver, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Kasner SE. CADISS: a feasibility trial that answered its question. Lancet Neurol 2015; 14:342. 2. Engelter ST, Rutgers MP, Hatz F, et al. Intravenous thrombolysis in stroke attributable to cervical artery dissection. Stroke 2009; 40:3772. 3. Georgiadis D, Baumgartner RW. Thrombolysis in cervical artery dissection. Front Neurol Neurosci 2005; 20:140. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 12/28 7/5/23, 12:09 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate 4. Zinkstok SM, Vergouwen MD, Engelter ST, et al. Safety and functional outcome of thrombolysis in dissection-related ischemic stroke: a meta-analysis of individual patient data. Stroke 2011; 42:2515. 5. Qureshi AI, Chaudhry SA, Hassan AE, et al. Thrombolytic treatment of patients with acute ischemic stroke related to underlying arterial dissection in the United States. Arch Neurol 2011; 68:1536. 6. Engelter ST, Dallongeville J, Kloss M, et al. Thrombolysis in cervical artery dissection data from the Cervical Artery Dissection and Ischaemic Stroke Patients (CADISP) database. Eur J Neurol 2012; 19:1199. 7. Tsivgoulis G, Zand R, Katsanos AH, et al. Safety and outcomes of intravenous thrombolysis in dissection-related ischemic stroke: an international multicenter study and comprehensive meta-analysis of reported case series. J Neurol 2015; 262:2135. 8. Bernardo F, Nannoni S, Strambo D, et al. Intravenous thrombolysis in acute ischemic stroke due to intracranial artery dissection: a single-center case series and a review of literature. J Thromb Thrombolysis 2019; 48:679. 9. Hoving JW, Marquering HA, Majoie CBLM. Endovascular treatment in patients with carotid artery dissection and intracranial occlusion: a systematic review. Neuroradiology 2017; 59:641. 10. Blassiau A, Gawlitza M, Manceau PF, et al. Mechanical Thrombectomy for Tandem Occlusions of the Internal Carotid Artery-Results of a Conservative Approach for the Extracranial Lesion. Front Neurol 2018; 9:928. 11. Gory B, Piotin M, Haussen DC, et al. Thrombectomy in Acute Stroke With Tandem Occlusions From Dissection Versus Atherosclerotic Cause. Stroke 2017; 48:3145. 12. Marnat G, Mourand I, Eker O, et al. Endovascular Management of Tandem Occlusion Stroke Related to Internal Carotid Artery Dissection Using a Distal to Proximal Approach: Insight from the RECOST Study. AJNR Am J Neuroradiol 2016; 37:1281. 13. Li S, Zi W, Chen J, et al. Feasibility of Thrombectomy in Treating Acute Ischemic Stroke Because of Cervical Artery Dissection. Stroke 2018; 49:3075. 14. Fields JD, Lutsep HL, Rymer MR, et al. Endovascular mechanical thrombectomy for the treatment of acute ischemic stroke due to arterial dissection. Interv Neuroradiol 2012; 18:74. 15. Farouk M, Sato K, Matsumoto Y, Tominaga T. Endovascular Treatment of Internal Carotid Artery Dissection Presenting with Acute Ischemic Stroke. J Stroke Cerebrovasc Dis 2020; 29:104592. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 13/28 7/5/23, 12:09 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate 16. Labeyrie MA, Civelli V, Reiner P, et al. Prevalence and treatment of spontaneous intracranial artery dissections in patients with acute stroke due to intracranial large vessel occlusion. J Neurointerv Surg 2018; 10:761. 17. Marnat G, Lapergue B, Sibon I, et al. Safety and Outcome of Carotid Dissection Stenting During the Treatment of Tandem Occlusions: A Pooled Analysis of TITAN and ETIS. Stroke 2020; 51:3713. 18. Wein T, Lindsay MP, C t R, et al. Canadian stroke best practice recommendations: Secondary prevention of stroke, sixth edition practice guidelines, update 2017. Int J Stroke 2018; 13:420. 19. National Institute for Health and Care Excellence (NICE). Stroke and transient ischaemic atta ck in over 16s: diagnosis and initial management. NICE guideline NG128. Available at: http s://www.nice.org.uk/guidance/ng128/chapter/Recommendations (Accessed on August 25, 2 020). 20. Lansberg MG, O'Donnell MJ, Khatri P, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e601S. 21. Serkin Z, Le S, Sila C. Treatment of Extracranial Arterial Dissection: the Roles of Antiplatelet Agents, Anticoagulants, and Stenting. Curr Treat Options Neurol 2019; 21:48. 22. Biller J, Sacco RL, Albuquerque FC, et al. Cervical arterial dissections and association with cervical manipulative therapy: a statement for healthcare professionals from the american heart association/american stroke association. Stroke 2014; 45:3155. 23. Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association. Stroke 2021; 52:e364. 24. Debette S, Mazighi M, Bijlenga P, et al. 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Brott TG, Halperin JL, Abbara S, et al. 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/ SCAI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association, American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 14/28 7/5/23, 12:09 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society for Vascular Surgery. Vasc Med 2011; 16:35. 26. CADISS trial investigators, Markus HS, Hayter E, et al. Antiplatelet treatment compared with anticoagulation treatment for cervical artery dissection (CADISS): a randomised trial. Lancet Neurol 2015; 14:361. 27. Markus HS, Levi C, King A, et al. Antiplatelet Therapy vs Anticoagulation Therapy in Cervical Artery Dissection: The Cervical Artery Dissection in Stroke Study (CADISS) Randomized Clinical Trial Final Results. JAMA Neurol 2019; 76:657. 28. Engelter ST, Traenka C, Gensicke H, et al. Aspirin versus anticoagulation in cervical artery dissection (TREAT-CAD): an open-label, randomised, non-inferiority trial. Lancet Neurol 2021; 20:341. 29. Kasner SE. Antithrombotic therapy for cervical arterial dissection. Lancet Neurol 2021; 20:328. 30. Kennedy F, Lanfranconi S, Hicks C, et al. Antiplatelets vs anticoagulation for dissection: CADISS nonrandomized arm and meta-analysis. Neurology 2012; 79:686. 31. Chowdhury MM, Sabbagh CN, Jackson D, et al. Antithrombotic treatment for acute extracranial carotid artery dissections: a meta-analysis. Eur J Vasc Endovasc Surg 2015; 50:148. 32. Metso TM, Metso AJ, Helenius J, et al. Prognosis and safety of anticoagulation in intracranial artery dissections in adults. Stroke 2007; 38:1837. 33. Arauz A, M rquez JM, Artigas C, et al. Recanalization of vertebral artery dissection. Stroke 2010; 41:717. 34. Baracchini C, Tonello S, Meneghetti G, Ballotta E. Neurosonographic monitoring of 105 spontaneous cervical artery dissections: a prospective study. Neurology 2010; 75:1864. 35. Larsson SC, King A, Madigan J, et al. Prognosis of carotid dissecting aneurysms: Results from CADISS and a systematic review. Neurology 2017; 88:646. 36. Manabe H, Yonezawa K, Kato T, et al. Incidence of intracranial arterial dissection in non- emergency outpatients complaining of headache: preliminary investigation with MRI/MRA examinations. Acta Neurochir Suppl 2010; 107:41. 37. Nedeltchev K, Bickel S, Arnold M, et al. 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Endovascular treatment of distal cervical and intracranial dissections with the neuroform stent. Neurosurgery 2008; 62:636. 43. Ecker RD, Levy EI, Hopkins LN. Acute neuroform stenting of a symptomatic petrous dissection. J Invasive Cardiol 2007; 19:E137. 44. Cohen JE, Leker RR, Gotkine M, et al. Emergent stenting to treat patients with carotid artery dissection: clinically and radiologically directed therapeutic decision making. Stroke 2003; 34:e254. 45. Biondi A, Katz JM, Vallabh J, et al. Progressive symptomatic carotid dissection treated with multiple stents. Stroke 2005; 36:e80. 46. Kadkhodayan Y, Jeck DT, Moran CJ, et al. Angioplasty and stenting in carotid dissection with or without associated pseudoaneurysm. AJNR Am J Neuroradiol 2005; 26:2328. 47. Edgell RC, Abou-Chebl A, Yadav JS. Endovascular management of spontaneous carotid artery dissection. J Vasc Surg 2005; 42:854. 48. Kim BM, Shin YS, Kim SH, et al. Incidence and risk factors of recurrence after endovascular treatment of intracranial vertebrobasilar dissecting aneurysms. Stroke 2011; 42:2425. 49. M ller BT, Luther B, Hort W, et al. Surgical treatment of 50 carotid dissections: indications and results. J Vasc Surg 2000; 31:980. 50. Chiche L, Praquin B, Koskas F, Kieffer E. Spontaneous dissection of the extracranial vertebral artery: indications and long-term outcome of surgical treatment. Ann Vasc Surg 2005; 19:5. 51. Ono H, Nakatomi H, Tsutsumi K, et al. Symptomatic recurrence of intracranial arterial dissections: follow-up study of 143 consecutive cases and pathological investigation. Stroke 2013; 44:126. 52. Debette S, Compter A, Labeyrie MA, et al. Epidemiology, pathophysiology, diagnosis, and management of intracranial artery dissection. Lancet Neurol 2015; 14:640. 53. Mizutani T, Aruga T, Kirino T, et al. Recurrent subarachnoid hemorrhage from untreated ruptured vertebrobasilar dissecting aneurysms. Neurosurgery 1995; 36:905. 54. Bond KM, Krings T, Lanzino G, Brinjikji W. Intracranial dissections: A pictorial review of pathophysiology, imaging features, and natural history. J Neuroradiol 2021; 48:176. https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 16/28 7/5/23, 12:09 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate 55. Paciaroni M, Bogousslavsky J. Cerebrovascular complications of neck manipulation. Eur Neurol 2009; 61:112. 56. Reuter U, H mling M, Kavuk I, et al. Vertebral artery dissections after chiropractic neck manipulation in Germany over three years. J Neurol 2006; 253:724. 57. Debette S, Grond-Ginsbach C, Bodenant M, et al. Differential features of carotid and vertebral artery dissections: the CADISP study. Neurology 2011; 77:1174. 58. Arnold M, Bousser MG, Fahrni G, et al. Vertebral artery dissection: presenting findings and predictors of outcome. Stroke 2006; 37:2499. 59. 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Familial cervical artery dissections: clinical, morphologic, and genetic studies. Stroke 2006; 37:2924. Topic 16649 Version 30.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 17/28 7/5/23, 12:09 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate GRAPHICS Eligibility criteria for the treatment of acute ischemic stroke with intravenous thrombolysis (recombinant tissue plasminogen activator or tPA) Inclusion criteria Clinical diagnosis of ischemic stroke causing measurable neurologic deficit Onset of symptoms <4.5 hours before beginning treatment; if the exact time of stroke onset is not known, it is defined as the last time the patient was known to be normal or at neurologic baseline Age 18 years Exclusion criteria Patient history Ischemic stroke or severe head trauma in the previous three months Previous intracranial hemorrhage Intra-axial intracranial neoplasm Gastrointestinal malignancy Gastrointestinal hemorrhage in the previous 21 days Intracranial or intraspinal surgery within the prior three months Clinical Symptoms suggestive of subarachnoid hemorrhage Persistent blood pressure elevation (systolic 185 mmHg or diastolic 110 mmHg) Active internal bleeding Presentation consistent with infective endocarditis Stroke known or suspected to be associated with aortic arch dissection Acute bleeding diathesis, including but not limited to conditions defined under 'Hematologic' Hematologic 3 Platelet count <100,000/mm * Current anticoagulant use with an INR >1.7 or PT >15 seconds or aPTT >40 seconds* Therapeutic doses of low molecular weight heparin received within 24 hours (eg, to treat VTE and ACS); this exclusion does not apply to prophylactic doses (eg, to prevent VTE) Current use (ie, last dose within 48 hours in a patient with normal renal function) of a direct thrombin inhibitor or direct factor Xa inhibitor with evidence of anticoagulant effect by laboratory tests such as aPTT, INR, ECT, TT, or appropriate factor Xa activity assays Head CT https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 18/28 7/5/23, 12:09 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate Evidence of hemorrhage Extensive regions of obvious hypodensity consistent with irreversible injury Warnings Only minor and isolated neurologic signs or rapidly improving symptoms Serum glucose <50 mg/dL (<2.8 mmol/L) Serious trauma in the previous 14 days Major surgery in the previous 14 days History of gastrointestinal bleeding (remote) or genitourinary bleeding Seizure at the onset of stroke with postictal neurologic impairments Pregnancy** Arterial puncture at a noncompressible site in the previous seven days Large ( 10 mm), untreated, unruptured intracranial aneurysm Untreated intracranial vascular malformation Additional warnings for treatment from 3 to 4.5 hours from symptom onset Age >80 years Oral anticoagulant use regardless of INR Severe stroke (NIHSS score >25) Combination of both previous ischemic stroke and diabetes mellitus ACS: acute coronary syndrome; aPTT: activated partial thromboplastin time; ECT: ecarin clotting time; INR: international normalized ratio; PT: prothrombin time; NIHSS: National Institutes of Health Stroke Scale; tPA: intravenous alteplase; TT: thrombin time; VTE: venous thromboembolism. Although it is desirable to know the results of these tests, thrombolytic therapy should not be delayed while results are pending unless (1) there is clinical suspicion of a bleeding abnormality or thrombocytopenia, (2) the patient is currently on or has recently received anticoagulants (eg, heparin, warfarin, a direct thrombin inhibitor, or a direct factor Xa inhibitor), or (3) use of anticoagulants is not known. Otherwise, treatment with intravenous tPA can be started before availability of coagulation test results but should be discontinued if the INR, PT, or aPTT exceed the limits stated in the table, or 3 if platelet count is <100,000 mm . With careful consideration and weighting of risk-to-benefit, patients may receive intravenous alteplase despite one or more warnings. Patients who have a persistent neurologic deficit that is potentially disabling, despite improvement of any degree, should be treated with tPA in the absence of other contraindications. Any of the following should be considered disabling deficits: Complete hemianopia: 2 on NIHSS question 3, or Severe aphasia: 2 on NIHSS question 9, or Visual or sensory extinction: 1 on NIHSS question 11, or https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 19/28 7/5/23, 12:09 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6, or Any deficits that lead to a total NIHSS >5, or Any remaining deficit considered potentially disabling in the view of the patient and the treating practitioner using clinical judgment Patients may be treated with intravenous alteplase if glucose level is subsequently normalized. The potential risks of bleeding with alteplase from injuries related to the trauma should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. The increased risk of surgical site bleeding with alteplase should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. There is a low increased risk of new bleeding with alteplase in the setting of past gastrointestinal or genitourinary bleeding. However, alteplase administration within 21 days of gastrointestinal bleeding is not recommended. Alteplase is reasonable in patients with a seizure at stroke onset if evidence suggests that residual impairments are secondary to acute ischemic stroke and not to a postictal phenomenon. * Alteplase can be given in pregnancy when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding. The safety and efficacy of administering alteplase is uncertain for these relative exclusions. Although these were exclusions in the trial showing benefit in the 3 to 4.5 hour window, intravenous alteplase appears to be safe and may be beneficial for patients with these criteria, including patients taking oral anticoagulants with an INR <1.7. Adapted from: 1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359:1317. 2. Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke Association. Stroke 2009; 40:2945. 3. Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force:, Levine SR, Khatri P, et al. Review, historical context, and clari cations of the NINDS rt-PA stroke trials exclusion criteria: Part 1: rapidly improving stroke symptoms. Stroke 2013; 44:2500. 4. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scienti c rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2016; 47:581. 5. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. Graphic 71462 Version 26.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 20/28 7/5/23, 12:09 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate 2 ABCD score 2 The ABCD score can be used to estimate the risk of ischemic stroke in the first two days after TIA. The score is tallied as follows: Age: 60 years 1 point <60 years 0 points Blood pressure elevation when first assessed after TIA: Systolic 140 mmHg or diastolic 90 mmHg 1 point Systolic <140 mmHg and diastolic <90 mmHg 0 points Clinical features: Unilateral weakness 2 points Isolated speech disturbance 1 point Other 0 points Duration of TIA symptoms: 60 minutes 2 points 10 to 59 minutes 1 point <10 minutes 0 points Diabetes: Present 1 point Absent 0 points Data from: Johnston SC, Rothwell PM, Nguyen-Huynh MN, et al. Validation and re nement of scores to predict very early stroke risk after transient ischaemic attack. Lancet 2007; 369:283. Graphic 62381 Version 3.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 21/28 7/5/23, 12:09 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate National Institutes of Health Stroke Scale (NIHSS) Administer stroke scale items in the order listed. Record performance in each category after each subscale exam. Do not go back and change scores. Follow directions provided for each exam technique. Scores should reflect what the patient does, not what the clinician thinks the patient can do. The clinician should record answers while administering the exam and work quickly. Except where indicated, the patient should not be coached (ie, repeated requests to patient to make a special effort). Instructions Scale definition Score 1a. Level of consciousness: The investigator must choose a response if a full evaluation is prevented by such obstacles as an endotracheal tube, language barrier, orotracheal trauma/bandages. A 3 is scored only if the patient makes no movement 0 = Alert; keenly responsive. 1 = Not alert; but arousable by minor stimulation to obey, answer, or respond. 2 = Not alert; requires repeated stimulation to attend, or is obtunded and requires strong or painful stimulation to make movements (not stereotyped). _____ (other than reflexive posturing) in response to noxious stimulation. 3 = Responds only with reflex motor or autonomic effects or totally unresponsive, flaccid, and areflexic. 1b. Level of consciousness questions: The patient is asked the month and his/her age. The answer must be correct - there is no partial credit for being close. Aphasic and stuporous patients who do not comprehend 0 = Answers both questions correctly. 1 = Answers one question correctly. 2 = Answers neither question correctly. the questions will score 2. Patients unable to speak because of endotracheal intubation, orotracheal trauma, severe dysarthria from any cause, language barrier, or any other problem not secondary to aphasia are given a 1. It is important that only the initial _____ answer be graded and that the examiner not "help" the patient with verbal or non-verbal cues. 1c. Level of consciousness commands: The patient is asked to open and close the eyes and then to grip and release the non-paretic hand. Substitute another one step command if the hands cannot be used. Credit is given if an unequivocal attempt is 0 = Performs both tasks correctly. _____ 1 = Performs one task correctly. 2 = Performs neither task correctly. made but not completed due to weakness. If the patient does not respond to command, the task should be demonstrated to him or her (pantomime), and the result scored (ie, https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 22/28 7/5/23, 12:09 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate follows none, one or two commands). Patients with trauma, amputation, or other physical impediments should be given suitable one-step commands. Only the first attempt is scored. 2. Best gaze: Only horizontal eye movements will be tested. Voluntary or reflexive (oculocephalic) eye movements will be scored, but caloric testing is not done. If the patient has a conjugate deviation of the 0 = Normal. 1 = Partial gaze palsy; gaze is abnormal in one or both eyes, but forced deviation or total gaze paresis is not present. 2 = Forced deviation, or total gaze paresis not overcome by the oculocephalic eyes that can be overcome by voluntary or reflexive activity, the score will be 1. If a patient has an isolated peripheral nerve paresis (cranial nerves III, IV or VI), score a 1. maneuver. _____ Gaze is testable in all aphasic patients. Patients with ocular trauma, bandages, pre- existing blindness, or other disorder of visual acuity or fields should be tested with reflexive movements, and a choice made by the investigator. Establishing eye contact and then moving about the patient from side to side will occasionally clarify the presence of a partial gaze palsy. 3. Visual: Visual fields (upper and lower 0 = No visual loss. quadrants) are tested by confrontation, using finger counting or visual threat, as 1 = Partial hemianopia. 2 = Complete hemianopia. appropriate. Patients may be encouraged, but if they look at the side of the moving fingers appropriately, this can be scored as 3 = Bilateral hemianopia (blind including cortical blindness). normal. If there is unilateral blindness or enucleation, visual fields in the remaining _____ eye are scored. Score 1 only if a clear-cut asymmetry, including quadrantanopia, is found. If patient is blind from any cause, score 3. Double simultaneous stimulation is performed at this point. If there is extinction, patient receives a 1, and the results are used to respond to item 11. 4. Facial palsy: Ask - or use pantomime to 0 = Normal symmetrical movements. _____ encourage - the patient to show teeth or raise eyebrows and close eyes. Score 1 = Minor paralysis (flattened nasolabial fold, asymmetry on smiling). symmetry of grimace in response to noxious 2 = Partial paralysis (total or near-total stimuli in the poorly responsive or non- comprehending patient. If facial paralysis of lower face). trauma/bandages, orotracheal tube, tape or https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 23/28 7/5/23, 12:09 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate other physical barriers obscure the face, 3 = Complete paralysis of one or both sides these should be removed to the extent (absence of facial movement in the upper possible. and lower face). 5. Motor arm: The limb is placed in the appropriate position: extend the arms 0 = No drift; limb holds 90 (or 45) degrees for full 10 seconds. (palms down) 90 degrees (if sitting) or 45 degrees (if supine). Drift is scored if the arm 1 = Drift; limb holds 90 (or 45) degrees, but drifts down before full 10 seconds; does not hit bed or other support. falls before 10 seconds. The aphasic patient is encouraged using urgency in the voice 2 = Some effort against gravity; limb and pantomime, but not noxious cannot get to or maintain (if cued) 90 (or 45) stimulation. Each limb is tested in turn, beginning with the non-paretic arm. Only in degrees, drifts down to bed, but has some effort against gravity. _____ the case of amputation or joint fusion at the shoulder, the examiner should record the 3 = No effort against gravity; limb falls. score as untestable (UN), and clearly write 4 = No movement. the explanation for this choice. UN = Amputation or joint fusion, explain:________________ 5a. Left arm 5b. Right arm 6. Motor leg: The limb is placed in the appropriate position: hold the leg at 30 0 = No drift; leg holds 30-degree position for full 5 seconds. degrees (always tested supine). Drift is 1 = Drift; leg falls by the end of the 5-second scored if the leg falls before 5 seconds. The aphasic patient is encouraged using urgency period but does not hit bed. 2 = Some effort against gravity; leg falls to in the voice and pantomime, but not noxious stimulation. Each limb is tested in bed by 5 seconds, but has some effort against gravity. turn, beginning with the non-paretic leg. Only in the case of amputation or joint _____ 3 = No effort against gravity; leg falls to fusion at the hip, the examiner should bed immediately. record the score as untestable (UN), and clearly write the explanation for this choice. 4 = No movement. UN = Amputation or joint fusion, explain:________________ 6a. Left leg 6b. Right leg 7. Limb ataxia: This item is aimed at finding evidence of a unilateral cerebellar lesion. 0 = Absent. _____ 1 = Present in one limb. Test with eyes open. In case of visual defect, ensure testing is done in intact visual field. 2 = Present in two limbs. The finger-nose-finger and heel-shin tests are performed on both sides, and ataxia is UN = Amputation or joint fusion, explain:________________ scored only if present out of proportion to weakness. Ataxia is absent in the patient https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 24/28 7/5/23, 12:09 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate who cannot understand or is paralyzed. Only in the case of amputation or joint fusion, the examiner should record the score as untestable (UN), and clearly write the explanation for this choice. In case of blindness, test by having the patient touch nose from extended arm position. 8. Sensory: Sensation or grimace to pinprick 0 = Normal; no sensory loss. when tested, or withdrawal from noxious stimulus in the obtunded or aphasic patient. 1 = Mild-to-moderate sensory loss; patient feels pinprick is less sharp or is dull on the affected side; or there is a loss of superficial Only sensory loss attributed to stroke is scored as abnormal and the examiner pain with pinprick, but patient is aware of should test as many body areas (arms [not being touched. hands], legs, trunk, face) as needed to accurately check for hemisensory loss. A 2 = Severe to total sensory loss; patient is not aware of being touched in the face, arm, score of 2, "severe or total sensory loss," should only be given when a severe or total and leg. _____ loss of sensation can be clearly demonstrated. Stuporous and aphasic patients will, therefore, probably score 1 or 0. The patient with brainstem stroke who has bilateral loss of sensation is scored 2. If the patient does not respond and is quadriplegic, score 2. Patients in a coma (item 1a=3) are automatically given a 2 on this item. 9. Best language: A great deal of information about comprehension will be 0 = No aphasia; normal. _____ 1 = Mild-to-moderate aphasia; some obvious loss of fluency or facility of obtained during the preceding sections of the examination. For this scale item, the comprehension, without significant limitation on ideas expressed or form of patient is asked to describe what is happening in the attached picture, to name expression. Reduction of speech and/or comprehension, however, makes the items on the attached naming sheet and to read from the attached list of sentences. Comprehension is judged from responses conversation about provided materials difficult or impossible. For example, in conversation about provided materials, here, as well as to all of the commands in the preceding general neurological exam. If examiner can identify picture or naming card content from patient's response. visual loss interferes with the tests, ask the patient to identify objects placed in the 2 = Severe aphasia; all communication is hand, repeat, and produce speech. The through fragmentary expression; great need intubated patient should be asked to write. The patient in a coma (item 1a=3) will for inference, questioning, and guessing by the listener. Range of information that can automatically score 3 on this item. The examiner must choose a score for the be exchanged is limited; listener carries burden of communication. Examiner cannot patient with stupor or limited cooperation, but a score of 3 should be used only if the https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 25/28 7/5/23, 12:09 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate patient is mute and follows no one-step identify materials provided from patient commands. response. 3 = Mute, global aphasia; no usable speech or auditory comprehension. 10. Dysarthria: If patient is thought to be 0 = Normal. normal, an adequate sample of speech must be obtained by asking patient to read or 1 = Mild-to-moderate dysarthria; patient slurs at least some words and, at worst, can be understood with some difficulty. repeat words from the attached list. If the patient has severe aphasia, the clarity of 2 = Severe dysarthria; patient's speech is so articulation of spontaneous speech can be _____ slurred as to be unintelligible in the absence rated. Only if the patient is intubated or has other physical barriers to producing speech, of or out of proportion to any dysphasia, or is mute/anarthric. the examiner should record the score as untestable (UN), and clearly write an UN = Intubated or other physical barrier, explanation for this choice. Do not tell the explain:________________ patient why he or she is being tested. 11. Extinction and inattention (formerly 0 = No abnormality. neglect): Sufficient information to identify 1 = Visual, tactile, auditory, spatial, or neglect may be obtained during the prior testing. If the patient has a severe visual loss personal inattention or extinction to bilateral simultaneous stimulation in one of the sensory modalities. preventing visual double simultaneous stimulation, and the cutaneous stimuli are 2 = Profound hemi-inattention or normal, the score is normal. If the patient _____ extinction to more than one modality; does not recognize own hand or orients to has aphasia but does appear to attend to both sides, the score is normal. The only one side of space. presence of visual spatial neglect or anosognosia may also be taken as evidence of abnormality. Since the abnormality is scored only if present, the item is never untestable. _____ Adapted from: Goldstein LB, Samsa GP. Reliability of the National Institutes of Health Stroke Scale. Extension to non- neurologists in the context of a clinical trial. Stroke 1997; 28:307. Graphic 61698 Version 8.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 26/28 7/5/23, 12:09 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate Modified Rankin Scale Score Description 0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties and activities 2 Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent, and requiring constant nursing care and attention 6 Dead Reproduced with permission from: Van Swieten JC, Koudstaa PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988; 19:604. Copyright 1988 Lippincott Williams & Wilkins. Graphic 75411 Version 13.0 https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 27/28 7/5/23, 12:09 PM Cerebral and cervical artery dissection: Treatment and prognosis - UpToDate Contributor Disclosures David S Liebeskind, MD Consultant/Advisory Boards: Cerenovus [Stroke]; Genentech [Stroke]; Medtronic [Stroke]; Stryker [Stroke]. Speaker's Bureau: Astra-Zeneca [Stroke]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/cerebral-and-cervical-artery-dissection-treatment-and-prognosis/print 28/28

7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack : Jamary Oliveira-Filho, MD, MS, PhD, Michael T Mullen, MD : Scott E Kasner, MD, Alejandro A Rabinstein, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 22, 2023. INTRODUCTION The management of patients with acute ischemic stroke involves several phases (see "Initial assessment and management of acute stroke"). The goals in the initial phase include: Ensuring medical stability Determining eligibility for thrombolytic therapy ( table 1) and/or mechanical thrombectomy ( algorithm 1) Determining the pathophysiologic basis of the stroke Timely restoration of blood flow using thrombolytic therapy is the most effective maneuver for salvaging ischemic brain tissue that is not already infarcted. Intravenous thrombolysis can be administered up to 4.5 hours after symptom onset, and mechanical thrombectomy can be administered up to 24 hours after symptom onset. (See "Approach to reperfusion therapy for acute ischemic stroke" and "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use" and "Mechanical thrombectomy for acute ischemic stroke".) In addition to reperfusion therapies for acute treatment, there are two major classes of antithrombotic drugs that can be used to prevent recurrent ischemic stroke: Antiplatelets Anticoagulants https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 1/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate This topic will review the use of antithrombotic treatments for patients in the first days after acute ischemic stroke onset. Chronic antiplatelet and anticoagulation therapies for secondary stroke prevention are discussed separately. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke" and "Stroke in patients with atrial fibrillation" and "Atrial fibrillation in adults: Use of oral anticoagulants".) TREATMENT ON PRESENTATION Evaluate for reperfusion therapy All patients with acute ischemic stroke should be evaluated to determine eligibility for reperfusion therapy with intravenous thrombolysis using recombinant tissue plasminogen activator (tPA; alteplase or tenecteplase) and/or mechanical thrombectomy ( algorithm 1). (See "Approach to reperfusion therapy for acute ischemic stroke".) Start antiplatelets as soon as possible Aspirin and other antithrombotic agents should not be given alone or in combination for the first 24 hours following treatment with intravenous thrombolysis. Otherwise, in the absence of contraindications (see 'Hemorrhagic transformation and systemic bleeding' below) or a known cardiac source that requires anticoagulation, antiplatelet therapy with aspirin alone or with dual antiplatelet therapy (DAPT) should be started as soon as possible after the diagnosis of transient ischemic attack (TIA) or ischemic stroke is confirmed, even before the evaluation for ischemic mechanism is complete ( algorithm 2 and algorithm 3) [1-3]. Note that oral antiplatelets (or any oral medications) should be administered only after a dysphagia screen to evaluate the safety of swallowing. (See "Complications of stroke: An overview", section on 'Dysphagia'.) Once the ischemic mechanism is determined, antithrombotic therapy can be modified as necessary. (See 'Treatment by ischemic mechanism' below.) Aspirin alone Indications for aspirin For patients with a TIA or acute ischemic stroke who do not have a known cardioembolic source at presentation, early aspirin monotherapy (162 to 325 mg daily) is indicated in the following clinical settings: 2 Low-risk TIA, as defined by an ABCD (for Age, Blood pressure, Clinical features, Duration of symptoms, and Diabetes) score <4 ( table 2). https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 2/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate Ischemic stroke of moderate or greater severity, as defined by a National Institutes of Health Stroke Scale (NIHSS) score >5 ( table 3). For patients already on antiplatelet therapy with either aspirin or clopidogrel at the time of stroke onset, we continue their existing antiplatelet regimen when the NIHSS score is >5. Efficacy of aspirin In large randomized controlled trials, early (within 48 hours) initiation of aspirin was beneficial for the treatment of acute ischemic stroke, as shown in two major trials: The International Stroke Trial (IST) enrolled 19,435 patients with suspected acute ischemic stroke [4]. Patients allocated to aspirin (300 mg) within 48 hours of symptom onset experienced significant reductions in the 14-day recurrence of ischemic stroke (2.8 versus 3.9 percent) and in the combined outcome of nonfatal stroke or death (11.3 versus 12.4 percent). In the Chinese Acute Stroke Trial (CAST), 21,100 Chinese patients were randomized to 160 mg of aspirin daily or placebo, also within 48 hours of the onset of acute ischemic stroke [5]. Aspirin-allocated patients experienced a 14 percent relative risk reduction in mortality at four weeks (3.3 versus 3.9 percent). Subsequent studies of pooled data from trials of early aspirin use in acute ischemic stroke (mainly IST and CAST) have made the following additional observations: In a combined analysis of the IST and CAST trials, aspirin therapy in acute ischemic stroke led to a reduction of 11 nonfatal strokes or deaths per 1000 patients in the first few weeks but caused approximately two hemorrhagic strokes [6]. Thus, approximately nine nonfatal strokes or deaths were avoided for every 1000 treated patients. These effects were similar in the presence or absence of atrial fibrillation. Using the endpoint of death or residual impairment leaving the patient dependent, the combined data demonstrated a reduction of 13 per 1000 patients after several weeks to six months of follow-up. A 2022 systematic review of antiplatelet therapy for acute stroke included 11 trials involving over 42,000 participants, but the IST and CAST trials contributed nearly all of the data [7]. The reviewers concluded that starting aspirin (160 to 300 mg daily) within 48 hours of presumed ischemic stroke onset reduced the risk of early recurrent ischemic stroke without a major risk of early hemorrhagic complications and improved long-term outcomes. The number needed to treat to avoid death or dependency was 79. In an analysis of pooled individual patient data from IST and CAST, aspirin reduced the risk of recurrent ischemic stroke for patients with mild and moderate stroke-related neurologic deficits at baseline but not for those with severe deficits [8]. For patients with mild and https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 3/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate moderate deficits, the risk reduction was maximal by the third day after starting aspirin (two- to three-day hazard ratio [HR] 0.37, 95% CI 0.25-0.57). Short-term dual antiplatelet therapy (DAPT) Indications for DAPT For patients with a TIA or acute ischemic stroke who do not have a known cardioembolic source at presentation and who are able to swallow, short-term DAPT using aspirin plus clopidogrel is indicated in the following clinical settings: 2 High-risk TIA, defined as an ABCD score of 4. (See 'Efficacy of DAPT' below.) For patients on antiplatelet therapy with either aspirin or clopidogrel at the time of TIA onset, we switch to DAPT using aspirin plus clopidogrel for the first 21 days for high-risk 2 TIA (ie, an ABCD score of 4). For patients on other antiplatelet agents, the decision should be individualized based upon the underlying indication. Minor ischemic stroke, defined by an NIHSS score 5 ( table 3). (See 'Efficacy of DAPT' below.) Stroke due to intracranial large artery atherosclerosis, defined by ischemic stroke attributed to an intracranial large artery atherosclerotic stenosis of 70 to 99 percent. (See "Intracranial large artery atherosclerosis: Treatment and prognosis", section on 'Antiplatelet therapy'.) Regimen We use aspirin (160 to 325 mg loading dose, followed by 50 to 100 mg daily) plus clopidogrel (300 to 600 mg loading dose, followed by 75 mg daily) for short-term DAPT. An alternative is aspirin (300 to 325 mg on the first day followed by 75 to 100 mg daily) plus ticagrelor (180 mg loading dose followed by 90 mg twice daily). Duration The duration of DAPT is typically limited to 21 days for patients with high-risk TIA or minor ischemic stroke but may be extended to 90 days for patients with stroke due to intracranial large artery atherosclerotic stenosis of 70 to 99 percent. Thereafter, antiplatelet treatment with aspirin alone, clopidogrel alone, or aspirin-extended-release dipyridamole should be continued indefinitely. Benefit is short term In the longer term (beyond 90 days after stroke), DAPT using aspirin and clopidogrel is not recommended for stroke prevention. As an example, the MATCH trial, with over 7500 patients who were treated and followed for 18 months, found that the combined use of aspirin and clopidogrel did not offer greater benefit for stroke prevention than either agent alone but did substantially increase the risk of bleeding https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 4/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate complications [9]. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke", section on 'Aspirin plus clopidogrel'.) Efficacy of DAPT High-risk TIA and minor ischemic stroke There is high-quality evidence that early initiation and short-term use of DAPT for select patients with acute high-risk TIA or minor ischemic stroke reduce the risk of recurrent ischemic stroke, with a possible small increase in the risk of moderate or major bleeding and no apparent impact on mortality [3,10-15]. The broadly similar results from major randomized trials [16-18] and the findings of the network meta-analysis [19] discussed below suggest that DAPT with aspirin and clopidogrel or DAPT with aspirin and ticagrelor are both reasonable options for patients with high-risk TIA or minor stroke. We favor aspirin and clopidogrel as this combination will generally cost less. There is limited evidence from a subgroup analysis of the csps.com trial from Japan supporting treatment with DAPT using cilostazol in combination with aspirin or clopidogrel and started as early as eight days after stroke onset [20]. However, this study has important limitations, including post hoc design, unblinded treatment, homogeneous population studied, and early stopping of the trial. Higher-quality data are needed to determine the effectiveness of cilostazol in this setting, and for now we do not use cilostazol as a component of early DAPT. Some randomized trials have defined minor ischemic stroke as an NIHSS score 3, while others have used an NIHSS 5. UpToDate contributors to this topic generally define minor stroke by a NIHSS score of 5. However, the volume of infarcted tissue should be accounted for, since the risk of hemorrhagic transformation is likely related more closely to infarct size than to the NIHSS score. Some patients with an NIHSS score 5 may have a relatively large volume of infarcted tissue. In such cases, clinical judgment applies, and antiplatelet monotherapy may be preferred over DAPT. Meta-analysis A 2018 meta-analysis pooled data from three eligible trials and over 10,400 patients with acute high-risk TIA or acute minor ischemic stroke who were assigned to DAPT using aspirin and clopidogrel or to aspirin alone started within 24 hours of symptom onset [13]. The two largest trials (POINT [16] and CHANCE [17]) in the meta- 2 analysis contributed 96 percent of the patients. High-risk TIA was defined as an ABCD score of 4 ( table 2). Minor stroke was defined as an NIHSS score of 3 ( table 3). At 90 days, DAPT reduced the risk of nonfatal recurrent stroke compared with aspirin alone (6.3 versus 4.4 percent; relative risk [RR] 0.70, 95% CI 0.61-0.80; absolute risk reduction [ARR] 1.9 percent), possibly increased the risk of moderate or severe extracranial bleeding (RR 1.71, 95% CI 0.92-3.20; absolute risk increase [ARI] 0.2 percent), but had no apparent effect https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 5/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate on mortality (RR 1.27, 95% CI 0.73-2.23). Importantly, most strokes occurred within the first 10 days of randomization; the stroke rates between the treatment groups diverged quickly in the first days of treatment, but there was little or no incremental benefit of DAPT beyond 10 to 20 days. A similar 2021 meta-analysis pooled data from four trials (including POINT [16], CHANCE [17], and THALES [18]) comparing early treatment with DAPT versus aspirin alone for patients (over 21,000) with acute ischemic stroke or TIA [21]. Compared with aspirin alone, the risk of recurrent stroke was reduced with DAPT (5.8 versus 7.7 percent; RR 0.76, 95% CI 0.68-0.83; ARR 1.9 percent), whereas the risk of major bleeding was increased with DAPT (0.7 versus 0.3 percent; RR 2.22, 95% CI 1.14-4.34; ARI 0.4 percent). In a 2022 network meta-analysis of short-term DAPT that included five randomized trials with over 22,000 patients, both clopidogrel plus aspirin and ticagrelor plus aspirin were better than aspirin alone for reducing the risk of recurrent stroke and death, while the risk was similar comparing clopidogrel plus aspirin versus ticagrelor plus aspirin (HR 0.94, 95% CI 0.78-1.13) [19]. POINT and CHANCE trials The international POINT trial randomly assigned 4881 adults within 12 hours of onset of minor ischemic stroke or high-risk TIA to either DAPT using clopidogrel (600 mg loading dose, then 75 mg daily for 90 days) plus aspirin or to placebo plus aspirin for 90 days [16]. The aspirin dose in both groups was 50 to 325 mg daily. At 90 days, the composite outcome of major ischemic events (ischemic stroke, myocardial infarction, or death from an ischemic vascular event) was reduced for the clopidogrel-plus- aspirin group compared with the placebo-plus-aspirin group (5.0 versus 6.5 percent; ARR 1.5 percent; HR 0.75, 95% CI 0.59-0.95), as was the outcome of ischemic or hemorrhagic stroke (4.8 versus 6.4 percent; HR 0.74, 95% CI 0.58-0.94). However, the rate of major hemorrhage was increased for the clopidogrel-plus-aspirin group (0.9 versus 0.4 percent; HR 2.32, 95% CI 1.10-4.87). The CHANCE trial randomly assigned 5170 Chinese patients within 24 hours of onset of high-risk TIA or minor ischemic stroke to DAPT using either clopidogrel and aspirin (clopidogrel 300 mg loading dose, then 75 mg daily for 90 days, plus aspirin 75 mg daily for the first 21 days) or placebo and aspirin (75 mg daily for 90 days) [17]. Over one-half of the subjects in CHANCE had intracranial atherosclerosis. At 90 days, there was a significant reduction in all stroke for the clopidogrel-plus-aspirin group compared with the placebo plus aspirin group (8.2 versus 11.7 percent; ARR 3.5 percent; HR 0.68, 95% CI 0.57-0.81). The rate of hemorrhagic stroke was low in both treatment groups (0.3 percent in each). https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 6/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate The results of the CHANCE and POINT trials are not generalizable to all patients with TIA or acute ischemic stroke. Both trials excluded patients with isolated sensory symptoms, isolated visual changes, or isolated dizziness or vertigo. The POINT trial also excluded patients who were candidates for intravenous thrombolysis, endovascular interventions, and carotid endarterectomy. The Chinese population included in the CHANCE trial has higher rates of large artery intracranial atherosclerotic disease and lower rates of vascular risk factor control relative to other populations (see "Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis", section on 'Epidemiology'). Thus, it is uncertain how to apply the results of these trials to other populations, particularly patients with low-risk TIA, and those with moderate or severe acute ischemic stroke, who may be at higher risk for hemorrhagic transformation with DAPT. THALES trial The THALES trial, published in 2020, was not included in the meta-analysis cited above but provides additional data on the use of DAPT in patients with TIA and minor stroke. THALES randomly assigned 11,016 patients with mild to moderate noncardioembolic stroke (defined by an NIHSS score of 5) or high-risk TIA (defined by an 2 ABCD score of 6 or 7) to DAPT with ticagrelor and aspirin or to placebo and aspirin for 30 days [18]. Ticagrelor was given as a 180 mg loading dose followed by 90 mg twice daily; aspirin was given as 300 to 325 mg on the first day followed by 75 to 100 mg daily. The composite outcome of stroke or death within 30 days was lower for the ticagrelor-plus- aspirin group compared with the placebo-plus-aspirin group (5.5 versus 6.6 percent; ARR 1.1 percent; HR 0.83, 95% CI 0.71-0.96). There were 3314 patients in the THALES trial with an NIHSS score of 4 or 5; these patients would have been excluded from CHANCE and POINT because of their NIHSS score. In subgroup analysis, the benefit of DAPT was similar for patients with an NIHSS score of 4 or 5 and those with lower NIHSS score and/or TIA [22]. Severe bleeding was uncommon but was more frequent for the ticagrelor-plus-aspirin group (0.5 versus 0.1 percent; HR 3.99, 95% CI 1.74-9.14). Disability was similar between the two groups. Based on the results of the THALES trial, the US Food and Drug Administration (FDA) approved ticagrelor in combination with aspirin for the short-term treatment of acute minor ischemic stroke or high-risk TIA [23]. The THALES trial results are comparable to the POINT and CHANCE trials in supporting the role of DAPT for minor noncardioembolic stroke or high-risk TIA. Importantly, THALES supports the use of DAPT in subjects with minor stroke and an NIHSS score 5; DAPT using aspirin and clopidogrel was not studied in patients with an NIHSS score of 4 or 5 as they were not included in the POINT and CHANCE trials. https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 7/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate CYP2C19 variants and clopidogrel metabolism Genetic variation in clopidogrel metabolism due to loss-of-function CYP2C19 variants may affect the efficacy of clopidogrel, but evidence is conflicting. In a subgroup analysis of 2933 subjects in CHANCE who had genotyping for CYP2C19 genetic variants, the CYP2C19 *2 or *3 loss-of-function alleles were present in 59 percent [24]. Combined treatment with clopidogrel plus aspirin significantly reduced the risk of new stroke in noncarriers of the CYP2C19 loss-of-function alleles (6.7 percent, versus 12.4 percent for aspirin alone; HR 0.51, 95% CI 0.35-0.75) but not in carriers of the *2 or *3 loss-of-function alleles (9.4 versus 10.8 percent; HR 0.93, 95% CI 0.69-1.26). The CHANCE-2 trial enrolled 6412 Chinese patients with CYP2C19 loss-of-function alleles and acute minor ischemic stroke or high-risk TIA and randomly assigned them to DAPT for 21 days with either ticagrelor plus aspirin, or clopidogrel plus aspirin [25]. At 90 days, recurrent stroke was reduced in the ticagrelor group (6 versus 7.6 percent; HR 0.77, 95% CI 0.64-0.94). However, in a substudy of the POINT trial with 932 patients genotyped for CYP2C19 alleles, the rate of stroke or major ischemic events was similar for noncarriers and carriers of CYP2C19 loss-of-function alleles [26]. Confidence in this result is limited since the number of patients with CYP2C19 loss-of-function alleles (n = 326) in the POINT substudy was much lower than the cohort evaluated in CHANCE-2, and the event numbers in each group were very low. Notably, the POINT trial used a clopidogrel loading dose of 600 mg, compared with a 300 mg loading dose used in both CHANCE and CHANCE-2. It is possible that a higher clopidogrel loading dose may overcome some of the metabolic differences in patients with and without loss-of-function CYP2C19 variants. The possible relationship of loss-of-function CYP2C19 alleles and clinical outcomes for patients taking clopidogrel is discussed in greater detail separately. (See "Clopidogrel resistance and clopidogrel treatment failure", section on 'Loss of function gene carriers and outcomes'.) Intracranial large artery atherosclerosis It is possible (but not established) that treatment with DAPT (aspirin and clopidogrel) for 90 days in patients who had recently symptomatic intracranial large artery atherosclerosis with severe stenosis (70 to 99 percent) may have contributed to the relatively low rate of combined stroke and death that was observed in the aggressive medical treatment arm of the SAMMPRIS trial [27,28]. (See "Intracranial large artery atherosclerosis: Treatment and prognosis", section on 'Stenting'.) Other antiplatelets We typically do not use other antiplatelets as monotherapy in the setting of acute ischemic stroke, but exceptions may be made in select clinical scenarios, such as when https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 8/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate an allergy to aspirin or clopidogrel is present. Ticagrelor Few randomized trials have tested aspirin directly against other antiplatelet agents for the treatment of ischemic stroke or TIA in the acute period. In the SOCRATES trial of over 13,000 subjects with acute ischemic stroke or TIA, ticagrelor monotherapy was not significantly better than aspirin monotherapy (both started within 24 hours of symptom onset) for the 90-day composite endpoint of stroke, myocardial infarction, or death [29]. However, in a prespecified exploratory analysis, ticagrelor was superior to aspirin in the subgroup of patients who had stroke of possible atherosclerotic origin, which was defined by the presence of ipsilateral atherosclerotic stenosis of an extracranial or intracranial artery (including <50 percent stenosis) or mobile thrombus or thick plaque ( 4 mm) in the aortic arch [30]. These data suggest that patients with atherosclerotic stroke may benefit from antiplatelet therapy other than aspirin. However, the optimal definition of "atherosclerotic" stroke and the optimal treatment strategy are uncertain. Clopidogrel Clopidogrel has not been well studied as monotherapy in trials that start treatment in the first 24 to 48 hours of acute ischemic stroke. However, clopidogrel is a first-line antiplatelet agent for the secondary prevention of ischemic stroke, as demonstrated in trials that started treatment one week or more after the onset of ischemic stroke. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke", section on 'Clopidogrel'.) The short-term use of clopidogrel in combination with aspirin for acute ischemic stroke is discussed below. Cilostazol Cilostazol monotherapy is a reasonable option for long-term secondary ischemic stroke prevention in East Asian populations, and for all populations if other agents are not available or tolerated. This is reviewed separately. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke", section on 'Cilostazol'.) Limited role of early anticoagulation In agreement with the national guidelines [1,31], we recommend not using full-dose parenteral anticoagulation (eg, intravenous heparin) for treatment of unselected patients with acute ischemic stroke because of minimal efficacy and an increased risk of bleeding complications. Instead, we recommend early antiplatelet therapy for most patients with acute ischemic stroke or TIA. (See 'Treatment on presentation' above and 'Treatment by ischemic mechanism' below.) Patients already on anticoagulation For most patients on anticoagulation at the time of acute ischemic stroke onset, anticoagulation should be stopped, at least for the short term, https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 9/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate while determining eligibility for acute reperfusion therapies. However, there is no consensus regarding continuation or temporary stopping of anticoagulation at the time of acute ischemic stroke onset in patients using anticoagulation, and evidence related to this question is limited to observational studies [32]. For patients with uncomplicated minor stroke and an appropriate indication, long-term oral anticoagulation can be restarted when the patient is stable, such as at hospital discharge or 24 to 48 hours after stroke onset, depending upon the agent chosen and individual patient factors. Subtherapeutic anticoagulation intensity may be implicated in patients with atrial fibrillation and should be managed accordingly (see 'Anticoagulant failure' below). For patients with large acute infarction, we start aspirin in the interim if there are no significant bleeding complications; oral anticoagulation can be resumed according to indication (and aspirin stopped) after one to two weeks if the patient is stable. (See 'Atrial fibrillation' below and 'Timing of long-term anticoagulation' below and 'Contraindications' below.) A similar approach, stated by European guidelines, suggests anticoagulation can be started or resumed immediately for patients with a TIA and started or resumed at 3 days after onset for patients with minor ischemic stroke and persisting mild neurologic deficit [33]. For patients with ischemic stroke and a moderate neurologic deficit, anticoagulation can be started or resumed at six to eight days, and for those with a severe neurologic deficit, at 12 to 14 days; in both cases, repeat brain imaging should be obtained to exclude significant hemorrhagic transformation within 24 hours prior to starting or resuming anticoagulation. Indications to start or continue anticoagulation TIA For patients with a clear indication for anticoagulation (eg, atrial fibrillation, venous thromboembolism, mechanical heart valve) at onset of TIA, we recommend starting or continuing anticoagulation rather than antiplatelet therapy. In patients who are subtherapeutically or not anticoagulated at presentation, bridging anticoagulation with heparin, low molecular weight heparin, or a direct oral anticoagulant (DOAC) should be considered. In patients who are therapeutically anticoagulated at presentation, management should be individualized based on the underlying mechanism of the TIA. In some instances, such as when the TIA is more likely due to atherosclerosis than to cardioembolism, it may be reasonable to add antiplatelet therapy. Triple therapy (ie, anticoagulation plus DAPT) is associated with a high risk of hemorrhage and should be avoided. (See 'Anticoagulant failure' below.) Acute ischemic stroke Although benefit is unproven, we suggest early parenteral anticoagulation rather than aspirin only for select patients with acute cardioembolic https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 10/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate ischemic stroke or TIA due to intracardiac thrombus in the left ventricle or thrombus associated with mechanical or native heart valves who are at high short-term risk for recurrent stroke. While many specialists believe it has no role at all in the early acute phase of ischemic stroke, some experts have used early anticoagulation for other ischemic stroke subtypes, including cardioembolic stroke due to atrial fibrillation and stroke due to large artery stenoses or arterial dissection. However, a review of the literature does not support the routine use of anticoagulation in these subgroups [31]. Patients with mechanical heart valves or intracardiac thrombus were either not included or were underrepresented in trials of acute antithrombotic therapy for stroke. In the only trial of intravenous unfractionated heparin in hyperacute stroke, a single center in Italy randomly assigned 418 patients with nonlacunar hemispheric infarction (of cardioembolic, atherothrombotic, or unknown/undetermined origin) to receive either intravenous heparin or saline within three hours of stroke onset [34]. Treatment continued for five days. A favorable outcome at 90 days, the primary endpoint, was significantly more frequent in patients assigned to heparin compared with those assigned to saline (39 versus 29 percent). Heparin use was associated with an increased risk of intracranial and extracranial bleeding but no increase in mortality. A majority of patients enrolled in the trial were eligible for intravenous thrombolysis, but none received it since intravenous thrombolysis had not been approved in Italy at the time. No or uncertain role No benefit for acute stroke due to atrial fibrillation Early treatment with heparin for patients who have an acute cardioembolic stroke does not reduce the risk of recurrent ischemic stroke but is associated with an increased risk of symptomatic intracranial hemorrhage, as discussed below. (See 'Atrial fibrillation' below.) No benefit for progressing stroke Heparin was once widely used to treat patients who continued to have neurologic deterioration in the first hours or days after ischemic stroke (ie, progressing stroke, also referred to as stroke in evolution). The TOAST trial did not find an improvement in outcomes with danaparoid treatment in such patients [35], nor did a nonrandomized study of heparin therapy [36]. These findings do not support a role for heparin in halting neurologic worsening after stroke. No benefit for unselected patients The largest randomized controlled trial (IST) studied two doses of subcutaneous heparin in 19,435 patients with undefined ischemic stroke and found no significant benefit with heparin [4]. A systematic review updated in 2021 https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 11/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate examined the effect of anticoagulant therapy versus control in the early treatment of patients with acute ischemic stroke [37]. This review included 28 trials involving 24,025 subjects; approximately 80 percent of the subjects were from the IST trial. There was considerable variation in the quality of the trials. The anticoagulants tested were standard unfractionated heparin, low molecular weight heparins, heparinoids, oral anticoagulants, and thrombin inhibitors. The following were the major findings [37]: Anticoagulant therapy did not reduce the risk of death from all causes (odds ratio [OR] 0.99, 95% CI 0.90-1.09). Anticoagulants did not reduce the risk of being dead or dependent at the end of follow- up (OR 0.98, 95% CI 0.92-1.03). Anticoagulants reduced the odds of recurrent ischemic stroke (OR 0.75, 95% CI 0.65-0.88) but increased the risk of symptomatic intracranial hemorrhage (OR 2.99, 95% CI 2.24-3.99). Uncertain benefit for large vessel atherosclerotic disease Clinical trials have not adequately evaluated adjusted intravenous anticoagulation in patients with selected stroke subtypes. With this caveat in mind, there are conflicting data regarding the benefit of intravenous unfractionated heparin or low molecular weight heparin in the subgroup of patients with large vessel atherosclerotic disease. Note that these trials included many patients with minor ischemic stroke who would now be treated with short-term DAPT, but the comparator at the time was aspirin monotherapy. The TOAST trial evaluated the efficacy of the low molecular weight heparinoid danaparoid administered as an intravenous bolus within 24 hours of symptom onset and continued for seven days in 1281 patients with acute ischemic stroke [35]. Compared with placebo, danaparoid was associated with no improvement in overall outcome at three months (75 versus 74 percent rates of favorable outcome). However, subgroup analysis suggested a higher rate of favorable outcomes in patients treated with danaparoid who had a large artery atherosclerotic stroke (68 versus 55 percent with placebo). The FISS-tris trial evaluated the low molecular weight heparin nadroparin (3800 anti- factor Xa international units, 0.4 mL subcutaneously twice daily) versus aspirin (160 mg once daily) started within 48 hours of acute ischemic stroke onset and continued for 10 days [38]. The main study population was 353 patients with confirmed large artery occlusive disease, consisting of 300 with intracranial, 11 with extracranial, and 42 with both intracranial and extracranial disease. The mean time to treatment was nearly 30 hours. There was no significant difference between treatment with nadroparin or https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 12/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate aspirin for the proportion of patients with good outcome at six months, defined by a table 4) score of 85 (73 versus 69 percent). However, there was a Barthel Index ( significant benefit to low molecular weight heparin in a prespecified secondary outcome measure, good outcome defined by a modified Rankin Scale ( table 5) score of 0 to 1 (54 versus 44 percent; OR 1.55, 95% CI 1.02-2.35). Contraindications Anticoagulation in the setting of acute stroke may only be considered after a brain imaging study has excluded hemorrhage and estimated the size of the infarct. Early anticoagulation should be avoided when potential contraindications to anticoagulation are present, such as a large infarction (based upon clinical syndrome or brain imaging findings); severe uncontrolled, persistent hypertension (eg, systolic blood pressure 185 or diastolic blood pressure 110 mmHg); symptomatic hemorrhagic infarction; or other bleeding conditions. Although there is no standard definition, many stroke experts consider "large" infarcts to be those that involve more than one-third of the middle cerebral artery territory or more than one- half of the posterior cerebral artery territory based upon neuroimaging with computed tomography (CT) or magnetic resonance imaging (MRI). Infarct size can also be clinically defined, but this process can underestimate the true infarct volume when so-called "silent" areas of association cortex are involved. Clinical estimation of infarct size may be improved by using validated scales that have been correlated with infarct volume and clinical outcome, such as the NIHSS ( table 3). As an example, one study found that an NIHSS score >15 was associated with a median infarct volume 3 of 55.8 cm and worse outcome than NIHSS scores of 1 to 7 (median infarct volume of 7.9 cm ) 3 3 or 8 to 15 (median infarct volume of 31.4 cm ) [39]. Thus, patients with an NIHSS score >15 generally have a large infarct. However, it should be recognized that part of the clinical deficit in the early hours of an acute stroke may be attributed to the penumbra, where the brain is ischemic but not infarcted. Additionally, NIHSS cutoffs may not apply equally well in both hemispheres. It is possible to have a relatively large infarct in the right hemisphere with a low NIHSS [40]. TREATMENT BY ISCHEMIC MECHANISM Once the evaluation for transient ischemic attack (TIA) or ischemic stroke is complete, antithrombotic therapy can be modified as necessary according to the ischemic mechanism ( algorithm 4 and algorithm 5). Cardioembolic source https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 13/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate Atrial fibrillation While parenteral anticoagulation (eg, intravenous heparin) is generally not recommended for treating ischemic stroke in the acute period, oral anticoagulation with warfarin or a direct oral anticoagulant (DOAC) is recommended for secondary stroke prevention in patients with atrial fibrillation and other high-risk sources of cardiogenic embolism. (See "Stroke in patients with atrial fibrillation" and "Atrial fibrillation in adults: Use of oral anticoagulants".) The timing of oral anticoagulation initiation for such patients is mainly dependent on the size of the acute infarct and the presence of factors such as symptomatic hemorrhagic transformation and/or poorly controlled hypertension. Oral anticoagulation can be started immediately for patients with TIA due to atrial fibrillation and soon after onset for medically stable patients with a small- or moderate-sized infarct and no bleeding complications. For patients with large infarctions, symptomatic hemorrhagic transformation, or poorly controlled hypertension, withholding oral anticoagulation for one to two weeks is generally recommended [41]. (See 'Timing of long-term anticoagulation' below.) Although once widely practiced, early treatment with heparin for patients with atrial fibrillation who have an acute cardioembolic stroke causes more harm than good. A 2007 meta-analysis examined seven randomized controlled trials involving 4624 patients and compared heparin or low molecular weight heparins started within 48 hours for acute cardioembolic stroke with other treatments (aspirin or placebo) [42]. The following observations were reported: Parenteral anticoagulants led to a nonsignificant reduction in recurrent ischemic stroke within 7 to 14 days (3.0 versus 4.9 percent; OR 0.68, 95% CI 0.44-1.06) Parenteral anticoagulants led to an increase in symptomatic intracranial hemorrhage (2.5 versus 0.7 percent; OR 2.89, 95% CI 1.19-7.01)

11/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate examined the effect of anticoagulant therapy versus control in the early treatment of patients with acute ischemic stroke [37]. This review included 28 trials involving 24,025 subjects; approximately 80 percent of the subjects were from the IST trial. There was considerable variation in the quality of the trials. The anticoagulants tested were standard unfractionated heparin, low molecular weight heparins, heparinoids, oral anticoagulants, and thrombin inhibitors. The following were the major findings [37]: Anticoagulant therapy did not reduce the risk of death from all causes (odds ratio [OR] 0.99, 95% CI 0.90-1.09). Anticoagulants did not reduce the risk of being dead or dependent at the end of follow- up (OR 0.98, 95% CI 0.92-1.03). Anticoagulants reduced the odds of recurrent ischemic stroke (OR 0.75, 95% CI 0.65-0.88) but increased the risk of symptomatic intracranial hemorrhage (OR 2.99, 95% CI 2.24-3.99). Uncertain benefit for large vessel atherosclerotic disease Clinical trials have not adequately evaluated adjusted intravenous anticoagulation in patients with selected stroke subtypes. With this caveat in mind, there are conflicting data regarding the benefit of intravenous unfractionated heparin or low molecular weight heparin in the subgroup of patients with large vessel atherosclerotic disease. Note that these trials included many patients with minor ischemic stroke who would now be treated with short-term DAPT, but the comparator at the time was aspirin monotherapy. The TOAST trial evaluated the efficacy of the low molecular weight heparinoid danaparoid administered as an intravenous bolus within 24 hours of symptom onset and continued for seven days in 1281 patients with acute ischemic stroke [35]. Compared with placebo, danaparoid was associated with no improvement in overall outcome at three months (75 versus 74 percent rates of favorable outcome). However, subgroup analysis suggested a higher rate of favorable outcomes in patients treated with danaparoid who had a large artery atherosclerotic stroke (68 versus 55 percent with placebo). The FISS-tris trial evaluated the low molecular weight heparin nadroparin (3800 anti- factor Xa international units, 0.4 mL subcutaneously twice daily) versus aspirin (160 mg once daily) started within 48 hours of acute ischemic stroke onset and continued for 10 days [38]. The main study population was 353 patients with confirmed large artery occlusive disease, consisting of 300 with intracranial, 11 with extracranial, and 42 with both intracranial and extracranial disease. The mean time to treatment was nearly 30 hours. There was no significant difference between treatment with nadroparin or https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 12/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate aspirin for the proportion of patients with good outcome at six months, defined by a table 4) score of 85 (73 versus 69 percent). However, there was a Barthel Index ( significant benefit to low molecular weight heparin in a prespecified secondary outcome measure, good outcome defined by a modified Rankin Scale ( table 5) score of 0 to 1 (54 versus 44 percent; OR 1.55, 95% CI 1.02-2.35). Contraindications Anticoagulation in the setting of acute stroke may only be considered after a brain imaging study has excluded hemorrhage and estimated the size of the infarct. Early anticoagulation should be avoided when potential contraindications to anticoagulation are present, such as a large infarction (based upon clinical syndrome or brain imaging findings); severe uncontrolled, persistent hypertension (eg, systolic blood pressure 185 or diastolic blood pressure 110 mmHg); symptomatic hemorrhagic infarction; or other bleeding conditions. Although there is no standard definition, many stroke experts consider "large" infarcts to be those that involve more than one-third of the middle cerebral artery territory or more than one- half of the posterior cerebral artery territory based upon neuroimaging with computed tomography (CT) or magnetic resonance imaging (MRI). Infarct size can also be clinically defined, but this process can underestimate the true infarct volume when so-called "silent" areas of association cortex are involved. Clinical estimation of infarct size may be improved by using validated scales that have been correlated with infarct volume and clinical outcome, such as the NIHSS ( table 3). As an example, one study found that an NIHSS score >15 was associated with a median infarct volume 3 of 55.8 cm and worse outcome than NIHSS scores of 1 to 7 (median infarct volume of 7.9 cm ) 3 3 or 8 to 15 (median infarct volume of 31.4 cm ) [39]. Thus, patients with an NIHSS score >15 generally have a large infarct. However, it should be recognized that part of the clinical deficit in the early hours of an acute stroke may be attributed to the penumbra, where the brain is ischemic but not infarcted. Additionally, NIHSS cutoffs may not apply equally well in both hemispheres. It is possible to have a relatively large infarct in the right hemisphere with a low NIHSS [40]. TREATMENT BY ISCHEMIC MECHANISM Once the evaluation for transient ischemic attack (TIA) or ischemic stroke is complete, antithrombotic therapy can be modified as necessary according to the ischemic mechanism ( algorithm 4 and algorithm 5). Cardioembolic source https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 13/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate Atrial fibrillation While parenteral anticoagulation (eg, intravenous heparin) is generally not recommended for treating ischemic stroke in the acute period, oral anticoagulation with warfarin or a direct oral anticoagulant (DOAC) is recommended for secondary stroke prevention in patients with atrial fibrillation and other high-risk sources of cardiogenic embolism. (See "Stroke in patients with atrial fibrillation" and "Atrial fibrillation in adults: Use of oral anticoagulants".) The timing of oral anticoagulation initiation for such patients is mainly dependent on the size of the acute infarct and the presence of factors such as symptomatic hemorrhagic transformation and/or poorly controlled hypertension. Oral anticoagulation can be started immediately for patients with TIA due to atrial fibrillation and soon after onset for medically stable patients with a small- or moderate-sized infarct and no bleeding complications. For patients with large infarctions, symptomatic hemorrhagic transformation, or poorly controlled hypertension, withholding oral anticoagulation for one to two weeks is generally recommended [41]. (See 'Timing of long-term anticoagulation' below.) Although once widely practiced, early treatment with heparin for patients with atrial fibrillation who have an acute cardioembolic stroke causes more harm than good. A 2007 meta-analysis examined seven randomized controlled trials involving 4624 patients and compared heparin or low molecular weight heparins started within 48 hours for acute cardioembolic stroke with other treatments (aspirin or placebo) [42]. The following observations were reported: Parenteral anticoagulants led to a nonsignificant reduction in recurrent ischemic stroke within 7 to 14 days (3.0 versus 4.9 percent; OR 0.68, 95% CI 0.44-1.06) Parenteral anticoagulants led to an increase in symptomatic intracranial hemorrhage (2.5 versus 0.7 percent; OR 2.89, 95% CI 1.19-7.01) Parenteral anticoagulants and other treatments had a similar rate of death or disability at final follow-up (approximately 74 percent) These results do not support early parenteral anticoagulant treatment of acute cardioembolic stroke [42]. Anticoagulant failure Subtherapeutic anticoagulation intensity is often implicated when patients with atrial fibrillation present with TIA or ischemic stroke [43]. The first step should be to exclude an alternative ischemic mechanism unrelated to cardiogenic embolism. If ischemia is attributed to atrial fibrillation, an attempt should be made to identify and correct the cause (eg, inadequate compliance with anticoagulant therapy, drug/food interaction). Options include continuing warfarin (after temporary interruption if needed for acute ischemic stroke) with https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 14/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate renewed efforts to keep the international normalized ratio (INR) in the 2 to 3 therapeutic range or switching to a DOAC. (See "Stroke in patients with atrial fibrillation", section on 'Anticoagulation failure' and "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Anticoagulant failure'.) Intracardiac thrombus Although benefit is unproven, we suggest early parenteral anticoagulation rather than aspirin only for select patients with acute cardioembolic ischemic stroke who are at high risk for short-term recurrent stroke due to intracardiac thrombus in the left ventricle or thrombus associated with mechanical or native heart valves. This approach is controversial; some experts favor treatment with aspirin rather than anticoagulation in this setting for patients with an acute brain infarction. Our suggestion to use early parenteral anticoagulation for these selected patients applies only to those with a small- to moderate-sized brain infarct and no evidence of hemorrhage on brain imaging. Anticoagulation should not be given for the first 24 hours following treatment with intravenous alteplase. Full-dose anticoagulation should not be used acutely for patients with a large infarction (based upon clinical syndrome or brain imaging findings), uncontrolled hypertension, or other bleeding conditions. (See 'Contraindications' above.) In the selected patients who receive heparin in the acute stroke setting, a bolus is not administered. One group has proposed a weight-based nomogram for heparin infusions that, compared with usual heparin therapy, is associated with fewer complications, fewer mistakes in dose adjustment, improved anticoagulation, and decreased nursing and house staff labor ( table 6) [44]. Enoxaparin 1 mg/kg dose every 12 hours (or other low molecular weight heparins) may be used as an alternative to intravenous heparin in patients with acute stroke when early anticoagulation is desired to prevent recurrent cerebral embolism; the limited available evidence suggests that low molecular weight heparins have similar efficacy, advantages in administration and monitoring, and reduced rates of thrombocytopenia compared with heparin. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'LMW heparin'.) Generally, patients with TIA or ischemic stroke attributed to an intracardiac thrombus should be transitioned to oral anticoagulation soon after initiation of parenteral anticoagulation. Oral anticoagulation is generally continued at least three months for left ventricular thrombus; concurrent antiplatelet therapy may be indicated for left ventricular thrombus after acute myocardial infarction. Chronic anticoagulation is indicated for patients with mechanical heart valves. (See "Left ventricular thrombus after acute myocardial infarction", section on 'Prevention of embolic events' and "Antithrombotic therapy for mechanical heart valves".) https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 15/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate Noncardioembolic etiologies Antiplatelet therapy is the mainstay of secondary stroke prevention for patients with a noncardioembolic source of ischemic stroke. For most patients without atrial fibrillation or another indication for long-term oral anticoagulation, the antiplatelet regimen chosen at presentation can be continued: For patients with low-risk TIA or moderate to severe stroke, we recommend aspirin monotherapy (160 to 325 mg daily). (See 'Aspirin alone' above.) For patients with high-risk TIA or minor ischemic stroke, we recommend short-term dual antiplatelet therapy (DAPT) using aspirin and clopidogrel rather than aspirin alone. (See 'Short-term dual antiplatelet therapy (DAPT)' above.) After the acute period, treatment should continue with aspirin alone, clopidogrel alone, or aspirin-extended-release dipyridamole. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) However, modifications may apply for select stroke mechanisms: Extracranial internal carotid artery stenosis Patients with symptomatic internal carotid artery stenosis as the cause of TIA or ischemic stroke should be treated with early antiplatelet therapy. These patients generally benefit from carotid revascularization to reduce the risk of recurrent ipsilateral ischemic stroke. Aspirin monotherapy is preferred by some experts prior to carotid endarterectomy, while DAPT is preferred by others. DAPT is used prior to and continuing for 30 days after carotid artery stenting. (See "Carotid endarterectomy", section on 'Antiplatelet therapy' and "Overview of carotid artery stenting", section on 'Dual antiplatelet therapy'.) Intracranial large artery atherosclerosis For patients with a recent (within 30 days) TIA or ischemic stroke attributed to atherosclerotic intracranial large artery stenosis of 70 to 99 percent, DAPT with aspirin plus clopidogrel is used by some experts for up to 90 days. The use of antiplatelet therapy for patients with acute ischemic stroke due to intracranial large artery atherosclerosis is reviewed in detail separately. (See "Intracranial large artery atherosclerosis: Treatment and prognosis", section on 'Antiplatelet therapy'.) Dissection The use of antithrombotic therapy for ischemic stroke and TIA caused by cervical or intracranial artery dissection is discussed elsewhere. (See "Cerebral and cervical artery dissection: Treatment and prognosis", section on 'Choosing between antiplatelet and anticoagulation therapy'.) Other determined etiology Several conditions that are uncommon causes of TIA and ischemic stroke are discussed in detail separately: https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 16/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) Moyamoya disease and moyamoya syndrome: Treatment and prognosis Management of antiphospholipid syndrome Nonbacterial thrombotic endocarditis Cryptogenic Patients with cryptogenic TIA and ischemic stroke, including those with embolic stroke of undetermined source (ESUS), are generally treated with antiplatelet therapy while awaiting the results of long-term cardiac monitoring to look for atrial fibrillation as a possible cause of stroke. Thus, initial treatment involves aspirin monotherapy for low-risk TIA and moderate to severe ischemic stroke, or short-term DAPT for high-risk TIA and minor stroke. (See 'Indications for DAPT' above.) For long-term stroke prevention beyond the acute period, antiplatelet therapy with aspirin alone, clopidogrel alone, or aspirin-extended-release dipyridamole is recommended. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) Available data have shown no benefit from anticoagulation for secondary stroke prevention in patients with cryptogenic stroke or ESUS. The evaluation and management of cryptogenic stroke and ESUS is discussed in detail separately. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)".) OTHER TREATMENT ISSUES Hemorrhagic transformation and systemic bleeding For patients who develop severe systemic or intracranial bleeding complications, including symptomatic hemorrhagic transformation of the ischemic infarct, we withhold all anticoagulant and antiplatelet therapy for one to two weeks or until the patient is stable, at which time oral antiplatelet or anticoagulant treatment can be started or resumed as indicated. The development of asymptomatic hemorrhagic transformation of an ischemic infarct does not necessarily preclude the early use of antiplatelets, particularly when the hemorrhage is petechial (ie, scattered and punctate). In this setting, it is likely reasonable to continue aspirin. For asymptomatic parenchymal hematoma (ie, larger confluent bleeding within an infarct), it is not clear that stopping aspirin will have much impact on hematoma progression given the long- https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 17/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate lasting effect of aspirin on platelet function, and it may be reasonable to continue aspirin, although management should be individualized. If antiplatelet therapy has not been started, it may be reasonable to delay initiation of antiplatelet therapy in patients with parenchymal hemorrhage until the patient's neurologic condition becomes stable. We avoid dual antiplatelet therapy (DAPT) in patients with hemorrhagic transformation, including those with petechial or parenchymal hemorrhage. Patients with another indication for chronic anticoagulation Some patients with acute ischemic stroke have indications other than atrial fibrillation or intracardiac thrombus for prolonged anticoagulation, such as acute coronary syndrome, prosthetic heart valve, or venous thromboembolism. In such cases, and in the absence of significant bleeding, we start aspirin if anticoagulation is delayed because of large infarction, high risk of symptomatic hemorrhagic transformation, and/or poorly controlled hypertension. We then stop aspirin once anticoagulation is started unless there is an indication for the use of concurrent antiplatelet therapy. (See 'Timing of long-term anticoagulation' below and 'Contraindications' above.) Venous thromboembolism prophylaxis Aspirin and other antiplatelet agents may be used to treat acute ischemic stroke when subcutaneous heparin or low molecular weight heparin is used for the prevention of venous thromboembolism. The prophylaxis of venous thromboembolism is discussed separately. (See "Prevention and treatment of venous thromboembolism in patients with acute stroke", section on 'Approach to VTE prevention'.) Swallowing difficulty Aspirin may be given rectally for patients with acute stroke who are nil per os (NPO) or those who have not had screening for dysphagia. Clopidogrel is available only as a tablet for oral administration. Timing of long-term anticoagulation There is no clear consensus about when to start or resume anticoagulation after acute ischemic stroke in patients with atrial fibrillation or another appropriate indication for anticoagulation. Different national guidelines have proposed different recommendations [41]. Based mainly on expert consensus, the timing of anticoagulation initiation for patients with an appropriate indication is mainly dependent on the size of the acute infarct and the presence of factors such as symptomatic hemorrhagic transformation and/or poorly controlled hypertension. The size of the infarction is presumed to correlate with the risk of hemorrhagic transformation. TIA For patients with a transient ischemic attack (TIA) and atrial fibrillation, oral anticoagulation can be started immediately. Small- to moderate-sized infarct For medically stable patients with a small- or moderate-sized infarct, warfarin can be initiated or restarted soon (eg, 24 hours) after https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 18/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate admission with minimal risk of transformation to hemorrhagic stroke. We prefer to wait for 48 hours to start a DOAC, as DOACs have a more rapid anticoagulant effect. Large infarct For patients with large infarctions, symptomatic hemorrhagic transformation, or poorly controlled hypertension, withholding oral anticoagulation for one to two weeks is generally recommended [41]. Limited clinical trial data support earlier rather than later initiation of direct oral anticoagulants (DOACs) after ischemic stroke [45,46]. The open-label ELAN trial enrolled 2013 patients with atrial fibrillation and acute ischemic stroke [45]. Patients were randomly assigned in a 1:1 ratio to early anticoagulation (within 48 hours after a minor or moderate stroke or on day six or seven after a major stroke) or later anticoagulation (day three or four after a minor stroke, day six or seven after a moderate stroke, or day 12 through 14 after a major stroke) using a DOAC. Stroke severity was determined by imaging size: an infarct of <1.5 cm was considered minor; an infarct in the distribution of a cortical superficial branch of the anterior, middle, or posterior cerebral artery was considered moderate; a larger infarct in the distributions of those arteries or an infarct >1.5 cm in the brainstem or cerebellum was considered major. The ELAN trial found a nonsignificant trend towards benefit with earlier anticoagulation [45]. At 30 days, the composite outcome (recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death) occurred in 29 participants in the early anticoagulation group compared with 41 in the later anticoagulant group (2.9 versus 4.1 percent, risk difference -1.18 percent, 95% CI -2.84 to 0.47). Recurrent ischemic stroke in the early and later groups occurred in 14 and 22 participants respectively (1.4 versus 2.5 percent, risk difference -1.14, 95% CI -2.41 to 0.13), while the rate of symptomatic intracranial hemorrhage was 0.2 percent in both groups. While not definitive, these findings suggest that early DOAC use is safe and may reduce the risk of recurrent ischemic stroke. Limitations to the ELAN trial include small number of events, a low median NIHSS score (3) at randomization, and exclusion of patients on therapeutic anticoagulation at baseline. For patients with atrial fibrillation in whom the start of anticoagulation will be delayed by more than 48 hours (eg, those with large acute infarction), we start aspirin as soon as possible after the diagnosis of transient ischemic attack (TIA) or ischemic stroke is confirmed if there are no significant bleeding complications; anticoagulation can be resumed according to indication (and aspirin stopped) according to the guidance above if the patient is stable. SOCIETY GUIDELINE LINKS https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 19/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Stroke (The Basics)") Beyond the Basics topics (see "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)" and "Patient education: Ischemic stroke treatment (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Immediate treatment All patients with acute ischemic stroke should be evaluated to determine eligibility for reperfusion therapy with intravenous thrombolysis and/or mechanical thrombectomy ( algorithm 1), and aspirin and other antithrombotic agents should not be given alone or in combination for the first 24 hours following treatment with intravenous thrombolysis. (See 'Evaluate for reperfusion therapy' above and 'Start antiplatelets as soon as possible' above.) Otherwise, antiplatelet agents should be started as soon as possible after the diagnosis of transient ischemic attack (TIA) or ischemic stroke is confirmed, even before the evaluation for ischemic mechanism is complete. For most patients with no indication for long-term oral anticoagulation who have TIA ( algorithm 2) or ischemic stroke ( algorithm 3), we start antiplatelet therapy as follows (see 'Aspirin alone' above and 'Short-term dual antiplatelet therapy (DAPT)' above): https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 20/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate Aspirin alone for low-risk TIA or moderate to severe ischemic stroke For patients 2 with a low-risk TIA, defined by an ABCD (for Age, Blood pressure, Clinical features, Duration of symptoms, and Diabetes) score <4 ( table 2), or moderate to major ischemic stroke, defined by a National Institutes of Health Stroke Scale (NIHSS) score >5 ( table 3), we start treatment with aspirin (162 to 325 mg daily) alone. DAPT for high-risk TIA or minor ischemic stroke For patients with a high-risk TIA, 2 defined by an ABCD score 4 ( table 2), or minor ischemic stroke, defined by an NIHSS score 5 ( table 3), we begin with dual antiplatelet therapy (DAPT) for 21 days using aspirin (160 to 325 mg loading dose, followed by 50 to 100 mg daily) plus clopidogrel (300 to 600 mg loading dose, followed by 75 mg daily) rather than aspirin alone. Aspirin and ticagrelor is an alternative DAPT regimen. Treatment by ischemic mechanism Once the evaluation for TIA or stroke is complete, early antithrombotic therapy can be modified if necessary ( algorithm 4 and algorithm 5) according to the ischemic mechanism (see 'Treatment by ischemic mechanism' above): Atrial fibrillation For patients with TIA or ischemic stroke who have atrial fibrillation, oral anticoagulation with warfarin or a direct oral anticoagulant (DOAC) is recommended for secondary stroke prevention (see "Stroke in patients with atrial fibrillation"). Oral anticoagulation can be started immediately for patients with TIA and soon after stroke onset for medically stable patients with a small- or moderate-sized infarct and no bleeding complications or uncontrolled hypertension. For patients with large infarctions, symptomatic hemorrhagic transformation, or poorly controlled hypertension, withholding oral anticoagulation for one to two weeks is generally advised. (See 'Atrial fibrillation' above and 'Timing of long-term anticoagulation' above.) Intracardiac thrombus For patients with acute cardioembolic TIA or ischemic stroke who have intracardiac thrombus in the left ventricle or associated with mechanical or native heart valves, we suggest early parenteral anticoagulation rather than aspirin (Grade 2C). This approach is controversial. (See 'Limited role of early anticoagulation' above.) Noncardioembolic etiologies For most patients without atrial fibrillation or another indication for long-term oral anticoagulation, the antiplatelet regimen chosen at presentation can be continued: for patients with low-risk TIA or moderate to severe stroke, we recommend aspirin monotherapy (160 to 325 mg daily) (Grade 1A). For patients with high-risk TIA or minor ischemic stroke, we recommend short-term DAPT https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 21/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate using aspirin and clopidogrel rather than aspirin alone (Grade 1A). Thereafter, antiplatelet treatment should continue with aspirin alone, clopidogrel alone, or aspirin- extended-release dipyridamole. (See 'Noncardioembolic etiologies' above.) However, certain additional modifications may apply: Carotid revascularization Aspirin monotherapy is preferred by some experts prior to carotid endarterectomy, while DAPT is preferred by others. DAPT is used prior to and continuing for 30 days after carotid artery stenting. (See "Carotid endarterectomy", section on 'Antiplatelet therapy' and "Overview of carotid artery stenting", section on 'Dual antiplatelet therapy'.) Intracranial large artery atherosclerosis For patients with TIA or ischemic stroke attributed to intracranial large artery atherosclerosis stenosis of 70 to 99 percent, we suggest DAPT for 90 days. (See "Intracranial large artery atherosclerosis: Treatment and prognosis", section on 'Antiplatelet therapy'.) Dissection The antithrombotic treatment of TIA or ischemic stroke caused by large artery dissection is discussed in detail separately. (See "Cerebral and cervical artery dissection: Treatment and prognosis", section on 'Choosing between antiplatelet and anticoagulation therapy'.) Long-term antiplatelet therapy Beyond the acute phase of TIA and ischemic stroke, and in the absence of an indication for oral anticoagulation, long-term antiplatelet therapy for secondary stroke prevention should be continued with aspirin alone, clopidogrel alone, or aspirin-extended-release dipyridamole. Long-term DAPT with aspirin and clopidogrel is not recommended. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Walter J Koroshetz, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 22/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate 1. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. 2. National Institute for Health and Clinical Excellence. Stroke and transient ischaemic attack in over 16s: diagnosis and initial management. Available at: https://www.nice.org.uk/guidanc e/cg68/chapter/1-Guidance#pharmacological-treatments-for-people-with-acute-stroke (Acc essed on January 11, 2019). 3. Dawson J, Merwick , Webb A, et al. European Stroke Organisation expedited recommendation for the use of short-term dual antiplatelet therapy early after minor stroke and high-risk TIA. Eur Stroke J 2021; 6:CLXXXVII. 4. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group. Lancet 1997; 349:1569. 5. CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. CAST (Chinese Acute Stroke Trial) Collaborative Group. Lancet 1997; 349:1641. 6. Chen ZM, Sandercock P, Pan HC, et al. Indications for early aspirin use in acute ischemic stroke : A combined analysis of 40 000 randomized patients from the chinese acute stroke trial and the international stroke trial. On behalf of the CAST and IST collaborative groups. Stroke 2000; 31:1240. 7. Minhas JS, Chithiramohan T, Wang X, et al. Oral antiplatelet therapy for acute ischaemic stroke. Cochrane Database Syst Rev 2022; 1:CD000029. 8. Rothwell PM, Algra A, Chen Z, et al. Effects of aspirin on risk and severity of early recurrent stroke after transient ischaemic attack and ischaemic stroke: time-course analysis of randomised trials. Lancet 2016; 388:365. 9. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004; 364:331. 10. Rahman H, Khan SU, Nasir F, et al. Optimal Duration of Aspirin Plus Clopidogrel After Ischemic Stroke or Transient Ischemic Attack. Stroke 2019; 50:947. 11. Naqvi IA, Kamal AK, Rehman H. Multiple versus fewer antiplatelet agents for preventing early recurrence after ischaemic stroke or transient ischaemic attack. Cochrane Database Syst Rev 2020; 8:CD009716. https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 23/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate 12. Brown DL, Levine DA, Albright K, et al. Benefits and Risks of Dual Versus Single Antiplatelet Therapy for Secondary Stroke Prevention: A Systematic Review for the 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack. Stroke 2021; 52:e468. 13. Hao Q, Tampi M, O'Donnell M, et al. Clopidogrel plus aspirin versus aspirin alone for acute minor ischaemic stroke or high risk transient ischaemic attack: systematic review and meta- analysis. BMJ 2018; 363:k5108. 14. Prasad K, Siemieniuk R, Hao Q, et al. Dual antiplatelet therapy with aspirin and clopidogrel for acute high risk transient ischaemic attack and minor ischaemic stroke: a clinical practice guideline. BMJ 2018; 363:k5130. 15. Pan Y, Elm JJ, Li H, et al. Outcomes Associated With Clopidogrel-Aspirin Use in Minor Stroke or Transient Ischemic Attack: A Pooled Analysis of Clopidogrel in High-Risk Patients With Acute Non-Disabling Cerebrovascular Events (CHANCE) and Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) Trials. JAMA Neurol 2019; 76:1466. 16. Johnston SC, Easton JD, Farrant M, et al. Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA. N Engl J Med 2018; 379:215. 17. Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med 2013; 369:11. 18. Johnston SC, Amarenco P, Denison H, et al. Ticagrelor and Aspirin or Aspirin Alone in Acute Ischemic Stroke or TIA. N Engl J Med 2020; 383:207. 19. Lun R, Dhaliwal S, Zitikyte G, et al. Comparison of Ticagrelor vs Clopidogrel in Addition to Aspirin in Patients With Minor Ischemic Stroke and Transient Ischemic Attack: A Network Meta-analysis. JAMA Neurol 2022; 79:141. 20. Toyoda K, Omae K, Hoshino H, et al. Association of Timing for Starting Dual Antiplatelet Treatment With Cilostazol and Recurrent Stroke: A CSPS.com Trial Post Hoc Analysis. Neurology 2022; 98:e983. 21. Bhatia K, Jain V, Aggarwal D, et al. Dual Antiplatelet Therapy Versus Aspirin in Patients With Stroke or Transient Ischemic Attack: Meta-Analysis of Randomized Controlled Trials. Stroke 2021; 52:e217. 22. Wang Y, Pan Y, Li H, et al. Efficacy and Safety of Ticagrelor and Aspirin in Patients With Moderate Ischemic Stroke: An Exploratory Analysis of the THALES Randomized Clinical Trial. JAMA Neurol 2021; 78:1091. 23. Brilinta (ticagrelor) prescribing information. Available at: https://www.accessdata.fda.gov/dr ugsatfda_docs/label/2020/022433s029lbl.pdf (Accessed on November 12, 2020). https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 24/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate 24. Wang Y, Zhao X, Lin J, et al. Association Between CYP2C19 Loss-of-Function Allele Status and Efficacy of Clopidogrel for Risk Reduction Among Patients With Minor Stroke or Transient Ischemic Attack. JAMA 2016; 316:70. 25. Wang Y, Meng X, Wang A, et al. Ticagrelor versus Clopidogrel in CYP2C19 Loss-of-Function Carriers with Stroke or TIA. N Engl J Med 2021; 385:2520. 26. Meschia JF, Walton RL, Farrugia LP, et al. Efficacy of Clopidogrel for Prevention of Stroke Based on CYP2C19 Allele Status in the POINT Trial. Stroke 2020; 51:2058. 27. Chimowitz MI, Lynn MJ, Derdeyn CP, et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med 2011; 365:993. 28. Derdeyn CP, Chimowitz MI, Lynn MJ, et al. Aggressive medical treatment with or without stenting in high-risk patients with intracranial artery stenosis (SAMMPRIS): the final results of a randomised trial. Lancet 2014; 383:333. 29. Johnston SC, Amarenco P, Albers GW, et al. Ticagrelor versus Aspirin in Acute Stroke or Transient Ischemic Attack. N Engl J Med 2016; 375:35. 30. Amarenco P, Albers GW, Denison H, et al. Efficacy and safety of ticagrelor versus aspirin in acute stroke or transient ischaemic attack of atherosclerotic origin: a subgroup analysis of SOCRATES, a randomised, double-blind, controlled trial. Lancet Neurol 2017; 16:301. 31. Lansberg MG, O'Donnell MJ, Khatri P, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e601S. 32. Groot AE, Vermeij JM, Westendorp WF, et al. Continuation or Discontinuation of Anticoagulation in the Early Phase After Acute Ischemic Stroke. Stroke 2018; 49:1762. 33. Steffel J, Verhamme P, Potpara TS, et al. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 2018; 39:1330. 34. Camerlingo M, Salvi P, Belloni G, et al. Intravenous heparin started within the first 3 hours after onset of symptoms as a treatment for acute nonlacunar hemispheric cerebral infarctions. Stroke 2005; 36:2415. 35. Low molecular weight heparinoid, ORG 10172 (danaparoid), and outcome after acute ischemic stroke: a randomized controlled trial. The Publications Committee for the Trial of

Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. 2. National Institute for Health and Clinical Excellence. Stroke and transient ischaemic attack in over 16s: diagnosis and initial management. Available at: https://www.nice.org.uk/guidanc e/cg68/chapter/1-Guidance#pharmacological-treatments-for-people-with-acute-stroke (Acc essed on January 11, 2019). 3. Dawson J, Merwick , Webb A, et al. European Stroke Organisation expedited recommendation for the use of short-term dual antiplatelet therapy early after minor stroke and high-risk TIA. Eur Stroke J 2021; 6:CLXXXVII. 4. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group. Lancet 1997; 349:1569. 5. CAST: randomised placebo-controlled trial of early aspirin use in 20,000 patients with acute ischaemic stroke. CAST (Chinese Acute Stroke Trial) Collaborative Group. Lancet 1997; 349:1641. 6. Chen ZM, Sandercock P, Pan HC, et al. Indications for early aspirin use in acute ischemic stroke : A combined analysis of 40 000 randomized patients from the chinese acute stroke trial and the international stroke trial. On behalf of the CAST and IST collaborative groups. Stroke 2000; 31:1240. 7. Minhas JS, Chithiramohan T, Wang X, et al. Oral antiplatelet therapy for acute ischaemic stroke. Cochrane Database Syst Rev 2022; 1:CD000029. 8. Rothwell PM, Algra A, Chen Z, et al. Effects of aspirin on risk and severity of early recurrent stroke after transient ischaemic attack and ischaemic stroke: time-course analysis of randomised trials. Lancet 2016; 388:365. 9. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004; 364:331. 10. Rahman H, Khan SU, Nasir F, et al. Optimal Duration of Aspirin Plus Clopidogrel After Ischemic Stroke or Transient Ischemic Attack. Stroke 2019; 50:947. 11. Naqvi IA, Kamal AK, Rehman H. Multiple versus fewer antiplatelet agents for preventing early recurrence after ischaemic stroke or transient ischaemic attack. Cochrane Database Syst Rev 2020; 8:CD009716. https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 23/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate 12. Brown DL, Levine DA, Albright K, et al. Benefits and Risks of Dual Versus Single Antiplatelet Therapy for Secondary Stroke Prevention: A Systematic Review for the 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack. Stroke 2021; 52:e468. 13. Hao Q, Tampi M, O'Donnell M, et al. Clopidogrel plus aspirin versus aspirin alone for acute minor ischaemic stroke or high risk transient ischaemic attack: systematic review and meta- analysis. BMJ 2018; 363:k5108. 14. Prasad K, Siemieniuk R, Hao Q, et al. Dual antiplatelet therapy with aspirin and clopidogrel for acute high risk transient ischaemic attack and minor ischaemic stroke: a clinical practice guideline. BMJ 2018; 363:k5130. 15. Pan Y, Elm JJ, Li H, et al. Outcomes Associated With Clopidogrel-Aspirin Use in Minor Stroke or Transient Ischemic Attack: A Pooled Analysis of Clopidogrel in High-Risk Patients With Acute Non-Disabling Cerebrovascular Events (CHANCE) and Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) Trials. JAMA Neurol 2019; 76:1466. 16. Johnston SC, Easton JD, Farrant M, et al. Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA. N Engl J Med 2018; 379:215. 17. Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med 2013; 369:11. 18. Johnston SC, Amarenco P, Denison H, et al. Ticagrelor and Aspirin or Aspirin Alone in Acute Ischemic Stroke or TIA. N Engl J Med 2020; 383:207. 19. Lun R, Dhaliwal S, Zitikyte G, et al. Comparison of Ticagrelor vs Clopidogrel in Addition to Aspirin in Patients With Minor Ischemic Stroke and Transient Ischemic Attack: A Network Meta-analysis. JAMA Neurol 2022; 79:141. 20. Toyoda K, Omae K, Hoshino H, et al. Association of Timing for Starting Dual Antiplatelet Treatment With Cilostazol and Recurrent Stroke: A CSPS.com Trial Post Hoc Analysis. Neurology 2022; 98:e983. 21. Bhatia K, Jain V, Aggarwal D, et al. Dual Antiplatelet Therapy Versus Aspirin in Patients With Stroke or Transient Ischemic Attack: Meta-Analysis of Randomized Controlled Trials. Stroke 2021; 52:e217. 22. Wang Y, Pan Y, Li H, et al. Efficacy and Safety of Ticagrelor and Aspirin in Patients With Moderate Ischemic Stroke: An Exploratory Analysis of the THALES Randomized Clinical Trial. JAMA Neurol 2021; 78:1091. 23. Brilinta (ticagrelor) prescribing information. Available at: https://www.accessdata.fda.gov/dr ugsatfda_docs/label/2020/022433s029lbl.pdf (Accessed on November 12, 2020). https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 24/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate 24. Wang Y, Zhao X, Lin J, et al. Association Between CYP2C19 Loss-of-Function Allele Status and Efficacy of Clopidogrel for Risk Reduction Among Patients With Minor Stroke or Transient Ischemic Attack. JAMA 2016; 316:70. 25. Wang Y, Meng X, Wang A, et al. Ticagrelor versus Clopidogrel in CYP2C19 Loss-of-Function Carriers with Stroke or TIA. N Engl J Med 2021; 385:2520. 26. Meschia JF, Walton RL, Farrugia LP, et al. Efficacy of Clopidogrel for Prevention of Stroke Based on CYP2C19 Allele Status in the POINT Trial. Stroke 2020; 51:2058. 27. Chimowitz MI, Lynn MJ, Derdeyn CP, et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med 2011; 365:993. 28. Derdeyn CP, Chimowitz MI, Lynn MJ, et al. Aggressive medical treatment with or without stenting in high-risk patients with intracranial artery stenosis (SAMMPRIS): the final results of a randomised trial. Lancet 2014; 383:333. 29. Johnston SC, Amarenco P, Albers GW, et al. Ticagrelor versus Aspirin in Acute Stroke or Transient Ischemic Attack. N Engl J Med 2016; 375:35. 30. Amarenco P, Albers GW, Denison H, et al. Efficacy and safety of ticagrelor versus aspirin in acute stroke or transient ischaemic attack of atherosclerotic origin: a subgroup analysis of SOCRATES, a randomised, double-blind, controlled trial. Lancet Neurol 2017; 16:301. 31. Lansberg MG, O'Donnell MJ, Khatri P, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e601S. 32. Groot AE, Vermeij JM, Westendorp WF, et al. Continuation or Discontinuation of Anticoagulation in the Early Phase After Acute Ischemic Stroke. Stroke 2018; 49:1762. 33. Steffel J, Verhamme P, Potpara TS, et al. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 2018; 39:1330. 34. Camerlingo M, Salvi P, Belloni G, et al. Intravenous heparin started within the first 3 hours after onset of symptoms as a treatment for acute nonlacunar hemispheric cerebral infarctions. Stroke 2005; 36:2415. 35. Low molecular weight heparinoid, ORG 10172 (danaparoid), and outcome after acute ischemic stroke: a randomized controlled trial. The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. JAMA 1998; 279:1265. 36. R d n-J llig A, Britton M. Effectiveness of heparin treatment for progressing ischaemic stroke: before and after study. J Intern Med 2000; 248:287. https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 25/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate 37. Wang X, Ouyang M, Yang J, et al. Anticoagulants for acute ischaemic stroke. Cochrane Database Syst Rev 2021; 10:CD000024. 38. Wong KS, Chen C, Ng PW, et al. Low-molecular-weight heparin compared with aspirin for the treatment of acute ischaemic stroke in Asian patients with large artery occlusive disease: a randomised study. Lancet Neurol 2007; 6:407. 39. Thijs VN, Lansberg MG, Beaulieu C, et al. Is early ischemic lesion volume on diffusion- weighted imaging an independent predictor of stroke outcome? A multivariable analysis. Stroke 2000; 31:2597. 40. Fink JN, Selim MH, Kumar S, et al. Is the association of National Institutes of Health Stroke Scale scores and acute magnetic resonance imaging stroke volume equal for patients with right- and left-hemisphere ischemic stroke? Stroke 2002; 33:954. 41. Seiffge DJ, Werring DJ, Paciaroni M, et al. Timing of anticoagulation after recent ischaemic stroke in patients with atrial fibrillation. Lancet Neurol 2019; 18:117. 42. Paciaroni M, Agnelli G, Micheli S, Caso V. Efficacy and safety of anticoagulant treatment in acute cardioembolic stroke: a meta-analysis of randomized controlled trials. Stroke 2007; 38:423. 43. Cao C, Martinelli A, Spoelhof B, et al. In Potential Stroke Patients on Warfarin, the International Normalized Ratio Predicts Ischemia. Cerebrovasc Dis Extra 2017; 7:111. 44. Toth C, Voll C. Validation of a weight-based nomogram for the use of intravenous heparin in transient ischemic attack or stroke. Stroke 2002; 33:670. 45. Fischer U, Koga M, Strbian D, et al. Early versus Later Anticoagulation for Stroke with Atrial Fibrillation. N Engl J Med 2023; 388:2411. 46. Oldgren J, sberg S, Hijazi Z, et al. Early Versus Delayed Non-Vitamin K Antagonist Oral Anticoagulant Therapy After Acute Ischemic Stroke in Atrial Fibrillation (TIMING): A Registry- Based Randomized Controlled Noninferiority Study. Circulation 2022; 146:1056. Topic 1082 Version 49.0 https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 26/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate GRAPHICS Eligibility criteria for the treatment of acute ischemic stroke with intravenous thrombolysis (recombinant tissue plasminogen activator or tPA) Inclusion criteria Clinical diagnosis of ischemic stroke causing measurable neurologic deficit Onset of symptoms <4.5 hours before beginning treatment; if the exact time of stroke onset is not known, it is defined as the last time the patient was known to be normal or at neurologic baseline Age 18 years Exclusion criteria Patient history Ischemic stroke or severe head trauma in the previous three months Previous intracranial hemorrhage Intra-axial intracranial neoplasm Gastrointestinal malignancy Gastrointestinal hemorrhage in the previous 21 days Intracranial or intraspinal surgery within the prior three months Clinical Symptoms suggestive of subarachnoid hemorrhage Persistent blood pressure elevation (systolic 185 mmHg or diastolic 110 mmHg) Active internal bleeding Presentation consistent with infective endocarditis Stroke known or suspected to be associated with aortic arch dissection Acute bleeding diathesis, including but not limited to conditions defined under 'Hematologic' Hematologic 3 Platelet count <100,000/mm * Current anticoagulant use with an INR >1.7 or PT >15 seconds or aPTT >40 seconds* Therapeutic doses of low molecular weight heparin received within 24 hours (eg, to treat VTE and ACS); this exclusion does not apply to prophylactic doses (eg, to prevent VTE) Current use (ie, last dose within 48 hours in a patient with normal renal function) of a direct thrombin inhibitor or direct factor Xa inhibitor with evidence of anticoagulant effect by laboratory tests such as aPTT, INR, ECT, TT, or appropriate factor Xa activity assays Head CT https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 27/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate Evidence of hemorrhage Extensive regions of obvious hypodensity consistent with irreversible injury Warnings Only minor and isolated neurologic signs or rapidly improving symptoms Serum glucose <50 mg/dL (<2.8 mmol/L) Serious trauma in the previous 14 days Major surgery in the previous 14 days History of gastrointestinal bleeding (remote) or genitourinary bleeding Seizure at the onset of stroke with postictal neurologic impairments Pregnancy** Arterial puncture at a noncompressible site in the previous seven days Large ( 10 mm), untreated, unruptured intracranial aneurysm Untreated intracranial vascular malformation Additional warnings for treatment from 3 to 4.5 hours from symptom onset Age >80 years Oral anticoagulant use regardless of INR Severe stroke (NIHSS score >25) Combination of both previous ischemic stroke and diabetes mellitus ACS: acute coronary syndrome; aPTT: activated partial thromboplastin time; ECT: ecarin clotting time; INR: international normalized ratio; PT: prothrombin time; NIHSS: National Institutes of Health Stroke Scale; tPA: intravenous alteplase; TT: thrombin time; VTE: venous thromboembolism. Although it is desirable to know the results of these tests, thrombolytic therapy should not be delayed while results are pending unless (1) there is clinical suspicion of a bleeding abnormality or thrombocytopenia, (2) the patient is currently on or has recently received anticoagulants (eg, heparin, warfarin, a direct thrombin inhibitor, or a direct factor Xa inhibitor), or (3) use of anticoagulants is not known. Otherwise, treatment with intravenous tPA can be started before availability of coagulation test results but should be discontinued if the INR, PT, or aPTT exceed the limits stated in the table, or 3 if platelet count is <100,000 mm . With careful consideration and weighting of risk-to-benefit, patients may receive intravenous alteplase despite one or more warnings. Patients who have a persistent neurologic deficit that is potentially disabling, despite improvement of any degree, should be treated with tPA in the absence of other contraindications. Any of the following should be considered disabling deficits: Complete hemianopia: 2 on NIHSS question 3, or Severe aphasia: 2 on NIHSS question 9, or Visual or sensory extinction: 1 on NIHSS question 11, or https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 28/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6, or Any deficits that lead to a total NIHSS >5, or Any remaining deficit considered potentially disabling in the view of the patient and the treating practitioner using clinical judgment Patients may be treated with intravenous alteplase if glucose level is subsequently normalized. The potential risks of bleeding with alteplase from injuries related to the trauma should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. The increased risk of surgical site bleeding with alteplase should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. There is a low increased risk of new bleeding with alteplase in the setting of past gastrointestinal or genitourinary bleeding. However, alteplase administration within 21 days of gastrointestinal bleeding is not recommended. Alteplase is reasonable in patients with a seizure at stroke onset if evidence suggests that residual impairments are secondary to acute ischemic stroke and not to a postictal phenomenon. * Alteplase can be given in pregnancy when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding. The safety and efficacy of administering alteplase is uncertain for these relative exclusions. Although these were exclusions in the trial showing benefit in the 3 to 4.5 hour window, intravenous alteplase appears to be safe and may be beneficial for patients with these criteria, including patients taking oral anticoagulants with an INR <1.7. Adapted from: 1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359:1317. 2. Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke Association. Stroke 2009; 40:2945. 3. Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force:, Levine SR, Khatri P, et al. Review, historical context, and clari cations of the NINDS rt-PA stroke trials exclusion criteria: Part 1: rapidly improving stroke symptoms. Stroke 2013; 44:2500. 4. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scienti c rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2016; 47:581. 5. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. Graphic 71462 Version 26.0 https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 29/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate Indications for mechanical thrombectomy to treat patients with acute ischemic IV: intravenous; tPA: tissue plasminogen activator (alteplase or tenecteplase); CTA: computed tomography an artery occlusion; MT: mechanical thrombectomy; ASPECTS: Alberta Stroke Program Early CT Score; NIHSS: Na tomography; MRI: magnetic resonance imaging; mRS: modified Rankin Scale; MCA: middle cerebral artery; IC recovery. Patients are not ordinarily eligible for IV tPA unless the time last known to be well is <4.5 hours. However, im that is diffusion positive and FLAIR negative) is an option at expert stroke centers to select patients with wake associated UpToDate topics for details. Usually assessed with MRA or CTA, less often with digital subtraction angiography. There is intracranial arterial occlusion of the distal ICA, middle cerebral (M1/M2), or anterior cerebral (A1/A2 MT may be a treatment option for patients with acute ischemic stroke caused by occlusion of the basilar ar stroke centers, but benefit is uncertain. [1] Based upon data from the Aurora study . Reference: https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 30/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate 1. Albers GW, Lansberg MG, Brown S, et al. Assessment of Optimal Patient Selection for Endovascular Thrombectomy Beyond 6 Hou Neurol 2021; 78:1064. Graphic 117086 Version 3.0 https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 31/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate Immediate antithrombotic treatment of transient ischemic attack (TIA) This algorithm is intended to provide basic guidance regarding the use of immediate use of antithrombotic therapy for patients with a TIA. For further details, including suggested dosing regimens of antiplatelet and anticoagulant agents, refer to the relevant UpToDate topic reviews. 2 ABCD : age, blood pressure, clinical features, duration of symptoms, and diabetes; DAPT: dual antiplatelet therapy (eg, aspirin and clopidogrel, or aspirin and ticagrelor); BP: blood pressure; SBP: systolic blood pressure; DBP: diastolic blood pressure. Indications for long-term oral anticoagulation include embolism prevention for patients with atrial fibrillation, ventricular thrombus, mechanical heart valve, and treatment of venous thromboembolism. Graphic 131692 Version 1.0 https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 32/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate Immediate antithrombotic treatment of acute ischemic stroke This algorithm is intended to provide basic guidance regarding the immediated use of antithrombotic therapy for patients with an acute ischemic stroke. For further details, including scoring of the NIHSS and suggested dosing regimens of antithrombotic agents, refer to the relevant UpToDate topic reviews. OA: oral anticoagulants; IVT: intravenous thrombolysis; MT: mechanical thrombectomy; NIHSS: National Institutes of Health Stroke Scale; DAPT: dual antiplatelet therapy (eg, aspirin and clopidogrel, or aspirin and ticagrelor). Refer to text and associated algorithm for details. Brain and large vessel imaging, cardiac evaluation, and (for select patients) other laboratory tests. https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 33/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate For severe systemic or symptomatic intracranial bleeding, withhold all anticoagulant and antiplatelet therapy for one to two weeks or until the patient is stable. Graphic 131697 Version 2.0 https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 34/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate 2 ABCD score 2 The ABCD score can be used to estimate the risk of ischemic stroke in the first two days after TIA. The score is tallied as follows: Age: 60 years 1 point <60 years 0 points Blood pressure elevation when first assessed after TIA: Systolic 140 mmHg or diastolic 90 mmHg 1 point Systolic <140 mmHg and diastolic <90 mmHg 0 points Clinical features: Unilateral weakness 2 points Isolated speech disturbance 1 point Other 0 points Duration of TIA symptoms: 60 minutes 2 points 10 to 59 minutes 1 point <10 minutes 0 points Diabetes: Present 1 point Absent 0 points Data from: Johnston SC, Rothwell PM, Nguyen-Huynh MN, et al. Validation and re nement of scores to predict very early stroke risk after transient ischaemic attack. Lancet 2007; 369:283. Graphic 62381 Version 3.0 https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 35/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate National Institutes of Health Stroke Scale (NIHSS) Administer stroke scale items in the order listed. Record performance in each category after each subscale exam. Do not go back and change scores. Follow directions provided for each exam technique. Scores should reflect what the patient does, not what the clinician thinks the patient can do. The clinician should record answers while administering the exam and work quickly. Except where indicated, the patient should not be coached (ie, repeated requests to patient to make a special effort). Instructions Scale definition Score 1a. Level of consciousness: The 0 = Alert; keenly responsive. investigator must choose a response if a full evaluation is prevented by such obstacles as 1 = Not alert; but arousable by minor stimulation to obey, answer, or respond. an endotracheal tube, language barrier, 2 = Not alert; requires repeated stimulation orotracheal trauma/bandages. A 3 is scored only if the patient makes no movement to attend, or is obtunded and requires strong or painful stimulation to make movements (not stereotyped). _____ (other than reflexive posturing) in response to noxious stimulation. 3 = Responds only with reflex motor or autonomic effects or totally unresponsive, flaccid, and areflexic. 1b. Level of consciousness questions: The 0 = Answers both questions correctly. patient is asked the month and his/her age. The answer must be correct - there is no partial credit for being close. Aphasic and stuporous patients who do not comprehend the questions will score 2. Patients unable to speak because of endotracheal intubation, orotracheal trauma, severe dysarthria from 1 = Answers one question correctly. 2 = Answers neither question correctly. _____ any cause, language barrier, or any other problem not secondary to aphasia are given a 1. It is important that only the initial answer be graded and that the examiner not "help" the patient with verbal or non-verbal cues. 1c. Level of consciousness commands: The 0 = Performs both tasks correctly. _____ patient is asked to open and close the eyes and then to grip and release the non-paretic 1 = Performs one task correctly. 2 = Performs neither task correctly. hand. Substitute another one step command if the hands cannot be used. Credit is given if an unequivocal attempt is made but not completed due to weakness. If the patient does not respond to command, the task should be demonstrated to him or her (pantomime), and the result scored (ie, https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 36/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate follows none, one or two commands). Patients with trauma, amputation, or other physical impediments should be given suitable one-step commands. Only the first attempt is scored. 2. Best gaze: Only horizontal eye movements will be tested. Voluntary or 0 = Normal. 1 = Partial gaze palsy; gaze is abnormal in reflexive (oculocephalic) eye movements will one or both eyes, but forced deviation or total gaze paresis is not present. be scored, but caloric testing is not done. If the patient has a conjugate deviation of the 2 = Forced deviation, or total gaze paresis not overcome by the oculocephalic eyes that can be overcome by voluntary or reflexive activity, the score will be 1. If a maneuver. patient has an isolated peripheral nerve paresis (cranial nerves III, IV or VI), score a 1. _____ Gaze is testable in all aphasic patients. Patients with ocular trauma, bandages, pre- existing blindness, or other disorder of visual acuity or fields should be tested with reflexive movements, and a choice made by the investigator. Establishing eye contact and then moving about the patient from side to side will occasionally clarify the presence of a partial gaze palsy. 3. Visual: Visual fields (upper and lower quadrants) are tested by confrontation, using finger counting or visual threat, as appropriate. Patients may be encouraged, 0 = No visual loss. 1 = Partial hemianopia. 2 = Complete hemianopia. but if they look at the side of the moving fingers appropriately, this can be scored as normal. If there is unilateral blindness or enucleation, visual fields in the remaining eye are scored. Score 1 only if a clear-cut 3 = Bilateral hemianopia (blind including cortical blindness). _____ asymmetry, including quadrantanopia, is found. If patient is blind from any cause, score 3. Double simultaneous stimulation is performed at this point. If there is extinction, patient receives a 1, and the results are used to respond to item 11. 4. Facial palsy: Ask - or use pantomime to encourage - the patient to show teeth or 0 = Normal symmetrical movements. _____ 1 = Minor paralysis (flattened nasolabial raise eyebrows and close eyes. Score symmetry of grimace in response to noxious fold, asymmetry on smiling). 2 = Partial paralysis (total or near-total paralysis of lower face). stimuli in the poorly responsive or non- comprehending patient. If facial trauma/bandages, orotracheal tube, tape or https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 37/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate other physical barriers obscure the face, 3 = Complete paralysis of one or both sides these should be removed to the extent (absence of facial movement in the upper possible. and lower face). 5. Motor arm: The limb is placed in the appropriate position: extend the arms 0 = No drift; limb holds 90 (or 45) degrees for full 10 seconds. (palms down) 90 degrees (if sitting) or 45 degrees (if supine). Drift is scored if the arm 1 = Drift; limb holds 90 (or 45) degrees, but drifts down before full 10 seconds; does not falls before 10 seconds. The aphasic patient hit bed or other support. is encouraged using urgency in the voice and pantomime, but not noxious 2 = Some effort against gravity; limb cannot get to or maintain (if cued) 90 (or 45) degrees, drifts down to bed, but has some stimulation. Each limb is tested in turn, beginning with the non-paretic arm. Only in _____ effort against gravity. the case of amputation or joint fusion at the shoulder, the examiner should record the 3 = No effort against gravity; limb falls. score as untestable (UN), and clearly write 4 = No movement. the explanation for this choice. UN = Amputation or joint fusion, explain:________________ 5a. Left arm 5b. Right arm 6. Motor leg: The limb is placed in the appropriate position: hold the leg at 30 degrees (always tested supine). Drift is scored if the leg falls before 5 seconds. The 0 = No drift; leg holds 30-degree position for full 5 seconds. 1 = Drift; leg falls by the end of the 5-second period but does not hit bed. aphasic patient is encouraged using urgency in the voice and pantomime, but not noxious stimulation. Each limb is tested in turn, beginning with the non-paretic leg. Only in the case of amputation or joint fusion at the hip, the examiner should 2 = Some effort against gravity; leg falls to bed by 5 seconds, but has some effort against gravity. _____ 3 = No effort against gravity; leg falls to bed immediately. record the score as untestable (UN), and clearly write the explanation for this choice. 4 = No movement. UN = Amputation or joint fusion, explain:________________ 6a. Left leg 6b. Right leg 7. Limb ataxia: This item is aimed at finding 0 = Absent. _____ evidence of a unilateral cerebellar lesion. Test with eyes open. In case of visual defect, 1 = Present in one limb. 2 = Present in two limbs. ensure testing is done in intact visual field. The finger-nose-finger and heel-shin tests UN = Amputation or joint fusion, explain:________________ are performed on both sides, and ataxia is scored only if present out of proportion to weakness. Ataxia is absent in the patient https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 38/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate who cannot understand or is paralyzed. Only in the case of amputation or joint fusion, the examiner should record the score as untestable (UN), and clearly write the explanation for this choice. In case of blindness, test by having the patient touch nose from extended arm position. 8. Sensory: Sensation or grimace to pinprick 0 = Normal; no sensory loss. when tested, or withdrawal from noxious stimulus in the obtunded or aphasic patient. 1 = Mild-to-moderate sensory loss; patient feels pinprick is less sharp or is dull on the affected side; or there is a loss of superficial Only sensory loss attributed to stroke is scored as abnormal and the examiner pain with pinprick, but patient is aware of being touched. should test as many body areas (arms [not hands], legs, trunk, face) as needed to 2 = Severe to total sensory loss; patient is not aware of being touched in the face, arm, accurately check for hemisensory loss. A score of 2, "severe or total sensory loss," should only be given when a severe or total loss of sensation can be clearly and leg. _____ demonstrated. Stuporous and aphasic patients will, therefore, probably score 1 or 0. The patient with brainstem stroke who has bilateral loss of sensation is scored 2. If the patient does not respond and is quadriplegic, score 2. Patients in a coma (item 1a=3) are automatically given a 2 on this item. 9. Best language: A great deal of 0 = No aphasia; normal. _____ information about comprehension will be obtained during the preceding sections of the examination. For this scale item, the patient is asked to describe what is happening in the attached picture, to name 1 = Mild-to-moderate aphasia; some obvious loss of fluency or facility of comprehension, without significant limitation on ideas expressed or form of expression. Reduction of speech and/or comprehension, however, makes the items on the attached naming sheet and to read from the attached list of sentences. conversation about provided materials Comprehension is judged from responses here, as well as to all of the commands in difficult or impossible. For example, in conversation about provided materials, the preceding general neurological exam. If examiner can identify picture or naming card content from patient's response. visual loss interferes with the tests, ask the patient to identify objects placed in the 2 = Severe aphasia; all communication is through fragmentary expression; great need hand, repeat, and produce speech. The intubated patient should be asked to write. for inference, questioning, and guessing by the listener. Range of information that can The patient in a coma (item 1a=3) will automatically score 3 on this item. The be exchanged is limited; listener carries burden of communication. Examiner cannot examiner must choose a score for the patient with stupor or limited cooperation, but a score of 3 should be used only if the https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 39/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate patient is mute and follows no one-step identify materials provided from patient commands. response. 3 = Mute, global aphasia; no usable speech or auditory comprehension. 10. Dysarthria: If patient is thought to be normal, an adequate sample of speech must 0 = Normal. 1 = Mild-to-moderate dysarthria; patient be obtained by asking patient to read or slurs at least some words and, at worst, can be understood with some difficulty. repeat words from the attached list. If the patient has severe aphasia, the clarity of 2 = Severe dysarthria; patient's speech is so slurred as to be unintelligible in the absence articulation of spontaneous speech can be rated. Only if the patient is intubated or has _____ of or out of proportion to any dysphasia, or is mute/anarthric. other physical barriers to producing speech, the examiner should record the score as untestable (UN), and clearly write an UN = Intubated or other physical barrier, explanation for this choice. Do not tell the patient why he or she is being tested. explain:________________ 11. Extinction and inattention (formerly 0 = No abnormality. neglect): Sufficient information to identify neglect may be obtained during the prior testing. If the patient has a severe visual loss preventing visual double simultaneous stimulation, and the cutaneous stimuli are normal, the score is normal. If the patient has aphasia but does appear to attend to 1 = Visual, tactile, auditory, spatial, or personal inattention or extinction to bilateral simultaneous stimulation in one of the sensory modalities. 2 = Profound hemi-inattention or extinction to more than one modality; does not recognize own hand or orients to only one side of space. _____ both sides, the score is normal. The presence of visual spatial neglect or anosognosia may also be taken as evidence of abnormality. Since the abnormality is scored only if present, the item is never untestable. _____ Adapted from: Goldstein LB, Samsa GP. Reliability of the National Institutes of Health Stroke Scale. Extension to non- neurologists in the context of a clinical trial. Stroke 1997; 28:307. Graphic 61698 Version 8.0 https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 40/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate Barthel Index Activity Score Feeding 0 = Unable 5 = Needs help cutting, spreading butter, etc, or requires modified diet 10 = Independent Bathing 0 = Dependent 5 = Independent (or in shower) Grooming 0 = Needs to help with personal care 5 = Independent face/hair/teeth/shaving (implements provided) Dressing 0 = Dependent 5 = Needs help but can do about half unaided 10 = Independent (including buttons, zips, laces, etc) Bowels 0 = Incontinent (or needs to be given enemas) 5 = Occasional accident 10 = Continent Bladder 0 = Incontinent, or catheterized and unable to manage alone 5 = Occasional accident 10 = Continent Toilet use 0 = Dependent 5 = Needs some help, but can do something alone 10 = Independent (on and off, dressing, wiping) Transfers (bed to chair and back) https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 41/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate 0 = Unable, no sitting balance 5 = Major help (one or two people, physical), can sit 10 = Minor help (verbal or physical) 15 = Independent Mobility (on level surfaces) 0 = Immobile or <50 yards 5 = Wheelchair independent, including corners, >50 yards 10 = Walks with help of one person (verbal or physical) >50 yards 15 = Independent (but may use any aid; for example, stick) >50 yards Stairs 0 = Unable 5 = Needs help (verbal, physical, carrying aid) 10 = Independent Total (0-100): The Barthel ADL Index: Guidelines The index should be used as a record of what a patient does, not as a record of what a patient could do The main aim is to establish degree of independence from any help, physical or verbal, however

1 = Present in one limb. 2 = Present in two limbs. ensure testing is done in intact visual field. The finger-nose-finger and heel-shin tests UN = Amputation or joint fusion, explain:________________ are performed on both sides, and ataxia is scored only if present out of proportion to weakness. Ataxia is absent in the patient https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 38/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate who cannot understand or is paralyzed. Only in the case of amputation or joint fusion, the examiner should record the score as untestable (UN), and clearly write the explanation for this choice. In case of blindness, test by having the patient touch nose from extended arm position. 8. Sensory: Sensation or grimace to pinprick 0 = Normal; no sensory loss. when tested, or withdrawal from noxious stimulus in the obtunded or aphasic patient. 1 = Mild-to-moderate sensory loss; patient feels pinprick is less sharp or is dull on the affected side; or there is a loss of superficial Only sensory loss attributed to stroke is scored as abnormal and the examiner pain with pinprick, but patient is aware of being touched. should test as many body areas (arms [not hands], legs, trunk, face) as needed to 2 = Severe to total sensory loss; patient is not aware of being touched in the face, arm, accurately check for hemisensory loss. A score of 2, "severe or total sensory loss," should only be given when a severe or total loss of sensation can be clearly and leg. _____ demonstrated. Stuporous and aphasic patients will, therefore, probably score 1 or 0. The patient with brainstem stroke who has bilateral loss of sensation is scored 2. If the patient does not respond and is quadriplegic, score 2. Patients in a coma (item 1a=3) are automatically given a 2 on this item. 9. Best language: A great deal of 0 = No aphasia; normal. _____ information about comprehension will be obtained during the preceding sections of the examination. For this scale item, the patient is asked to describe what is happening in the attached picture, to name 1 = Mild-to-moderate aphasia; some obvious loss of fluency or facility of comprehension, without significant limitation on ideas expressed or form of expression. Reduction of speech and/or comprehension, however, makes the items on the attached naming sheet and to read from the attached list of sentences. conversation about provided materials Comprehension is judged from responses here, as well as to all of the commands in difficult or impossible. For example, in conversation about provided materials, the preceding general neurological exam. If examiner can identify picture or naming card content from patient's response. visual loss interferes with the tests, ask the patient to identify objects placed in the 2 = Severe aphasia; all communication is through fragmentary expression; great need hand, repeat, and produce speech. The intubated patient should be asked to write. for inference, questioning, and guessing by the listener. Range of information that can The patient in a coma (item 1a=3) will automatically score 3 on this item. The be exchanged is limited; listener carries burden of communication. Examiner cannot examiner must choose a score for the patient with stupor or limited cooperation, but a score of 3 should be used only if the https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 39/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate patient is mute and follows no one-step identify materials provided from patient commands. response. 3 = Mute, global aphasia; no usable speech or auditory comprehension. 10. Dysarthria: If patient is thought to be normal, an adequate sample of speech must 0 = Normal. 1 = Mild-to-moderate dysarthria; patient be obtained by asking patient to read or slurs at least some words and, at worst, can be understood with some difficulty. repeat words from the attached list. If the patient has severe aphasia, the clarity of 2 = Severe dysarthria; patient's speech is so slurred as to be unintelligible in the absence articulation of spontaneous speech can be rated. Only if the patient is intubated or has _____ of or out of proportion to any dysphasia, or is mute/anarthric. other physical barriers to producing speech, the examiner should record the score as untestable (UN), and clearly write an UN = Intubated or other physical barrier, explanation for this choice. Do not tell the patient why he or she is being tested. explain:________________ 11. Extinction and inattention (formerly 0 = No abnormality. neglect): Sufficient information to identify neglect may be obtained during the prior testing. If the patient has a severe visual loss preventing visual double simultaneous stimulation, and the cutaneous stimuli are normal, the score is normal. If the patient has aphasia but does appear to attend to 1 = Visual, tactile, auditory, spatial, or personal inattention or extinction to bilateral simultaneous stimulation in one of the sensory modalities. 2 = Profound hemi-inattention or extinction to more than one modality; does not recognize own hand or orients to only one side of space. _____ both sides, the score is normal. The presence of visual spatial neglect or anosognosia may also be taken as evidence of abnormality. Since the abnormality is scored only if present, the item is never untestable. _____ Adapted from: Goldstein LB, Samsa GP. Reliability of the National Institutes of Health Stroke Scale. Extension to non- neurologists in the context of a clinical trial. Stroke 1997; 28:307. Graphic 61698 Version 8.0 https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 40/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate Barthel Index Activity Score Feeding 0 = Unable 5 = Needs help cutting, spreading butter, etc, or requires modified diet 10 = Independent Bathing 0 = Dependent 5 = Independent (or in shower) Grooming 0 = Needs to help with personal care 5 = Independent face/hair/teeth/shaving (implements provided) Dressing 0 = Dependent 5 = Needs help but can do about half unaided 10 = Independent (including buttons, zips, laces, etc) Bowels 0 = Incontinent (or needs to be given enemas) 5 = Occasional accident 10 = Continent Bladder 0 = Incontinent, or catheterized and unable to manage alone 5 = Occasional accident 10 = Continent Toilet use 0 = Dependent 5 = Needs some help, but can do something alone 10 = Independent (on and off, dressing, wiping) Transfers (bed to chair and back) https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 41/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate 0 = Unable, no sitting balance 5 = Major help (one or two people, physical), can sit 10 = Minor help (verbal or physical) 15 = Independent Mobility (on level surfaces) 0 = Immobile or <50 yards 5 = Wheelchair independent, including corners, >50 yards 10 = Walks with help of one person (verbal or physical) >50 yards 15 = Independent (but may use any aid; for example, stick) >50 yards Stairs 0 = Unable 5 = Needs help (verbal, physical, carrying aid) 10 = Independent Total (0-100): The Barthel ADL Index: Guidelines The index should be used as a record of what a patient does, not as a record of what a patient could do The main aim is to establish degree of independence from any help, physical or verbal, however minor and for whatever reason The need for supervision renders the patient not independent Patient performance should be established using the best available evidence provided by the patient, family, friends and caregivers; direct observation and common sense are also important, but direct testing is not needed Usually the patient's performance over the preceding 24 to 48 hours is important, but occasionally longer periods will be relevant Middle categories imply that the patient supplies over 50 percent of the effort Use of aids to be independent is allowed ADL: activities of daily living. References: 1. Mahoney FI, Barthel D. Functional evaluation: The Barthel Index. Maryland State Medical Journal 1965; 14:56. Used with permission. 2. Loewen SC, Anderson BA. Predictors of stroke outcome using objective measurement scales. Stroke 1990; 21:78. 3. Gresham GE, Phillips TF, Labi ML. ADL status in stroke: Relative merits of three standard indexes. Arch Phys Med Rehabil 1980; 61:355. 4. Collin C, Wade DT, Davies S, Horne V. The Barthel ADL Index: A reliability study. Int Disability Study 1988; 10:61. https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 42/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate Graphic 77371 Version 3.0 https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 43/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate Modified Rankin Scale Score Description 0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties and activities 2 Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent, and requiring constant nursing care and attention 6 Dead Reproduced with permission from: Van Swieten JC, Koudstaa PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988; 19:604. Copyright 1988 Lippincott Williams & Wilkins. Graphic 75411 Version 13.0 https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 44/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate Antithrombotic therapy according to cause of transient ischemic attack (TIA) This algorithm is intended to provide basic guidance regarding the use of antithrombotic therapy based on mechanism for patients with a TIA. For further details, including suggested dosing regimens of antithrombot agents, refer to the relevant UpToDate topic reviews. ICA: internal carotid artery; CEA: carotid endarterectomy; CAS: carotid artery stenting; DAPT: dual antiplatelet 2 therapy (eg, aspirin and clopidogrel, or aspirin and ticagrelor); ABCD : age, blood pressure, clinical features, duration of symptoms, and diabetes; BP: blood pressure; SBP: systolic blood pressure; DBP: diastolic blood pressure. Indications for long-term oral anticoagulation include atrial fibrillation, ventricular thrombus, mechanical h valve, and treatment of venous thromboembolism. Some experts prefer DAPT based upon observational evidence. Long-term single-agent antiplatelet therapy using aspirin, clopidogrel, or aspirin-extended-release dipyrida Graphic 131695 Version 3.0 https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 45/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate Antithrombotic therapy according to cause of acute ischemic stroke This algorithm is intended to provide basic guidance regarding the immediate use of antithrombotic therapy with an acute ischemic stroke. For further details, including scoring of the NIHSS and suggested dosing regim antithrombotic agents, refer to the relevant UpToDate topic reviews. https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 46/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate HTN: hypertension; SBP: systolic blood pressure; DBP: diastolic blood pressure; ICA: internal carotid artery; C endarterectomy; OA: oral anticoagulation; CAS: carotid artery stenting; DAPT: dual antiplatelet therapy (eg, a clopidogrel, or aspirin and ticagrelor); NIHSS: National Institutes of Health Stroke Scale; CT: computed tomog magnetic resonance imaging. Brain and neurovascular imaging, cardiac evaluation, and (for select patients) other laboratory tests. Indications for long-term oral anticoagulation include atrial fibrillation, ventricular thrombus, mechanical h treatment of venous thromboembolism. "Large" infarcts are defined as those that involve more than one-third of the middle cerebral artery territor one-half of the posterior cerebral artery territory based upon neuroimaging with CT or MRI. Though less relia infarct size can also be defined clinically (eg, NIHSS score >15). Long-term aspirin therapy is alternative (though less effective) if OA contraindicated or refused. Direct oral anticoagulant agents have a more rapid anticoagulant effect than warfarin, a factor that may inf choice of agent and timing of OA initiation. Some experts prefer DAPT, based upon observational evidence. Long-term single-agent antiplatelet therapy for secondary stroke prevention with aspirin, clopidogrel, or as release dipyridamole. Graphic 131701 Version 2.0 https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 47/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate Heparin-adjusted nomogram for stroke Initial dosing for continuous intravenous heparin infusion Weight (kg) Initial infusion (U/hour) <50 500 50 to 59 600 60 to 69 700 70 to 79 800 80 to 89 900 90 to 99 1000 100 to 109 1100 110 to 119 1200 >119 1400 Heparin adjustment based upon aPTT drawn six hours after initiation of therapy aPTT (seconds) Stop infusion Rate change Repeat aPTT <40 No Increase by 250 U/hour 6 hours 40 to 49 No Increase by 150 U/hour 6 hours 50 to 59 No Increase by 100 U/hour 6 hours 60 to 90 No No change Next morning 91 to 100 No Decrease by 100 U/hour 6 hours 101 to 120 No Decrease by 150 U/hour 6 hours >120 No Decrease by 250 U/hour 6 hours No bolus is administered in patients with acute stroke. Data from: Toth C, Voll C. Validation of a weight-based nomogram for the use of intravenous heparin in transient ischemic attack or stroke. Stroke 2002; 33:670. Graphic 53377 Version 2.0 https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 48/49 7/5/23, 12:10 PM Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack - UpToDate Contributor Disclosures Jamary Oliveira-Filho, MD, MS, PhD No relevant financial relationship(s) with ineligible companies to disclose. Michael T Mullen, MD Grant/Research/Clinical Trial Support: NINDS [Asymptomatic carotid disease]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Alejandro A Rabinstein, MD Grant/Research/Clinical Trial Support: Chiesi [Small investigator-initiated project]. Consultant/Advisory Boards: AstraZeneca [Secondary stroke prevention]; Brainomix [AI for stroke diagnostics]; Novo Nordisk [Stroke risk]; Shionogi [Stroke neuroprotection]. Other Financial Interest: Boston Scientific [Adverse event adjudication committee member for stroke risk reduction device in patients with atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/early-antithrombotic-treatment-of-acute-ischemic-stroke-and-transient-ischemic-attack/print 49/49

7/5/23, 12:10 PM Hemorrhagic stroke in children - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Hemorrhagic stroke in children : Evelyn K Shih, MD, PhD, Lauren A Beslow, MD, MSCE : Scott E Kasner, MD, Douglas R Nordli, Jr, MD : Richard P Goddeau, Jr, DO, FAHA All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Oct 17, 2022. INTRODUCTION Although less common than in adults, hemorrhagic stroke can affect children, resulting in significant morbidity and mortality. An overview of hemorrhagic stroke in children beyond the newborn period is provided here. Other clinical aspects of stroke in neonates and children are reviewed elsewhere: (See "Stroke in the newborn: Classification, manifestations, and diagnosis".) (See "Stroke in the newborn: Management and prognosis".) (See "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors".) (See "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis".) (See "Ischemic stroke in children: Management and prognosis".) (See "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease".) (See "Prevention of stroke (initial or recurrent) in sickle cell disease".) (See "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis".) (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".) CLASSIFICATION https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 1/33 7/5/23, 12:10 PM Hemorrhagic stroke in children - UpToDate Hemorrhagic stroke encompasses spontaneous intracerebral hemorrhage (ICH), isolated intraventricular hemorrhage, and nontraumatic subarachnoid hemorrhage [1]. ICH is defined by intraparenchymal hemorrhage or a combination of intraparenchymal and intraventricular hemorrhage ( image 1). Despite its common usage, the term hemorrhagic stroke remains confusing. It has also been used to denote hemorrhagic transformation of arterial ischemic stroke or of cerebral venous sinus thrombosis, but it does not encompass those entities, strictly speaking. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Subsequent imaging'.) EPIDEMIOLOGY Although stroke in children is relatively rare compared with adults, it is a significant cause of childhood death and lifelong disability. A stroke suffered within the first decade may cause functional sequelae for multiple decades to follow. Hemorrhagic stroke is a notable contributor to childhood morbidity and mortality, as it accounts for about half of all childhood strokes, compared with <20 percent of adult strokes [2,3]. The estimated incidence of all types of stroke (ischemic and hemorrhagic) in children ranges 2 to 13 per 100,000 children per year in the developed world [4,5]. A study of a California-wide hospital discharge database for first stroke admission for children ages 1 month through 19 years found an annual incidence rate of 1.1 per 100,000 children for hemorrhagic stroke and 1.2 per 100,000 children for ischemic stroke [4]. Similarly, a retrospective cohort study of 2.3 million children (age <20 years) followed for more than a decade revealed an average annual incidence rate of 1.4 per 100,000 children for hemorrhagic stroke [6]. Among hemorrhagic stroke subtypes, the estimated annual incidence of intracerebral hemorrhage in developed countries ranges from 1.1 to 5.2 per 100,000 children [4,5], while the estimated annual incidence of subarachnoid hemorrhage is 0.4 per 100,000 children [4]. ETIOLOGY AND RISK FACTORS Ruptured vascular malformations are the most common cause of intracerebral hemorrhage (ICH) in children. In contrast, hypertension and amyloid angiopathy are the most frequent causes of ICH in adults. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Risk factors'.) https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 2/33 7/5/23, 12:10 PM Hemorrhagic stroke in children - UpToDate Aneurysms are the most common cause of nontraumatic subarachnoid hemorrhage in both adults and children. (See "Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis".) The etiology and risk factors of perinatal hemorrhagic stroke are reviewed separately. (See "Stroke in the newborn: Classification, manifestations, and diagnosis", section on 'Hemorrhagic stroke'.) Vascular malformations Depending on the series, vascular malformations are responsible for 18 to 90 percent of childhood ICH cases [3,7-9], with arteriovenous malformations (AVMs) being the most common type and cavernous malformations and aneurysms found less frequently ( image 2) [10]. AVMs consist of abnormal direct connections between arteries and veins without intervening capillaries that give rise to high-flow lesions extremely prone to rupture (see "Brain arteriovenous malformations"). The incidence of cerebral AVMs in adults has been estimated to be 1 per 100,000 person-years [11]. Many AVM lesions are thought to be congenital, so this estimate may reflect the incidence in children as well; however, only a small percentage of AVMs (estimated 8 to 20 percent) become symptomatic under the age of 15 years [12,13]. The risk of hemorrhage from a cerebral AVM in children has been estimated at 2 percent per year [14]. AVMs account for 14 to 46 percent of ICH in children and nearly 50 percent of intraparenchymal hemorrhage [15-17]. Although most AVMs are isolated developmental lesions, there are genetic causes that predispose to multiple AVMs. Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder of vascular dysplasia associated with mucocutaneous telangiectasias and AVMs. AVMs in patients with HHT most often occur in the pulmonary, hepatic, and cerebral circulations [18,19]. Multiplicity of brain AVMs is highly predictive of the diagnosis of HHT [20]. Incidence of HHT is reported to be 1 in 5000 to 8000 individuals per year [21], although this is likely to be an underestimate due to the variability in clinical manifestations. Approximately 20 percent of adults with HHT have cerebrovascular malformations [22]. The prevalence of cerebrovascular malformations in children with HHT is unknown but believed to approximate that of adult [23]. In one of the largest case series of pediatric patients with confirmed HHT, 11 of 115 children had cerebral AVMs and >50 percent developed symptomatic ICH [19]. Arteriovenous fistulas differ from AVMs because there is an absence of a discrete nidus between the arterial feeder and draining vein. Arteriovenous fistulas are worth noting as these also carry a significant risk of hemorrhage of 1.5 percent per year. However, arteriovenous fistulas are much rarer, comprising only 4 percent of pediatric cerebral vascular malformations [24,25]. https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 3/33 7/5/23, 12:10 PM Hemorrhagic stroke in children - UpToDate Cavernous malformations (cavernomas or cavernous angiomas) have an estimated annual incidence of 0.56 per 100,000 people, which is approximately one-half that of AVMs [26]. Cavernous malformations consist of dilated sinusoidal vessels lined by endothelium without intervening neural parenchyma. "Leaking" of blood into surrounding tissue can occur due to dysfunctional endothelial cell connections. These are considered to be low-flow lesions. Cavernous malformations have been found to have a prevalence of 0.5 percent in autopsy studies [27,28] and are estimated to account for 20 to 25 percent of pediatric intraparenchymal hemorrhage [3,16,29]. While symptoms may manifest in all age groups, affected children tend to cluster in two age groups: infants and toddlers under the age of 3 years and children in early puberty, ages 12 to 16 years [30,31] While aneurysms are one of the most common vascular anomalies of the central nervous system, they are far less common in children than in adults, with a reported prevalence ranging from 0.5 to 5 percent of the total prevalence of intracranial aneurysms in the general population [32-39]. Aneurysms in children are felt to be different from those in adults in the following respects [33,39-41]: Pediatric aneurysms tend to be larger in size There is a higher incidence of giant aneurysms in children There tends to be a male predominance in children The most common cause of nontraumatic subarachnoid hemorrhage in children and adolescents is rupture of a cerebral aneurysm [6]. Ruptured aneurysms can also cause intraparenchymal hemorrhage or can present with nonhemorrhagic symptoms like headaches or seizures. Hematologic In reports from developed countries, hematologic abnormalities (including thrombocytopenia or platelet dysfunction, hemophilia and other congenital or acquired coagulopathies, and sickle cell disease) were the major risk factor for pediatric hemorrhagic stroke, found in 10 to 30 percent of cases [42]. In resource-limited countries, ICH secondary to underlying hematologic disorders occurs more frequently than hemorrhage due to vascular malformations. A retrospective study of 50 children with ICH at a single institution in Pakistan demonstrated that 52 percent had bleeding disorders compared with 14 percent with vascular malformations [43]. Similarly, a retrospective analysis of 94 children with hemorrhagic stroke in China found that 88 percent of patients had a bleeding diathesis compared with 14 percent with AVM [44]. Special populations with hematologic abnormalities include children with immune thrombocytopenia (ITP), hemophilia, and sickle cell disease: https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 4/33 7/5/23, 12:10 PM Hemorrhagic stroke in children - UpToDate With ITP, intracranial hemorrhage is estimated to occur in up to 1 percent. (See "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis", section on 'Intracranial hemorrhage'.) With hemophilia, the reported ICH prevalence in children is 3 to 12 percent [45-47]. (See "Clinical manifestations and diagnosis of hemophilia", section on 'Intracranial bleeding'.) With sickle cell disease (SCD), affected individuals are at risk for ischemic and hemorrhagic stroke. One report suggested that children with SCD had a >200-fold higher risk of hemorrhagic stroke compared with children without SCD [48]. In other reports, specific factors associated with hemorrhage in children with SCD included premorbid hypertension, transfusion within the last 14 days, treatment with glucocorticoids, low steady-state hemoglobin concentration, high steady-state leukocyte count, and late effects of moyamoya-type vasculopathy [49-51]. (See "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease" and "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis".) Cancer A smaller proportion of hemorrhagic stroke in children is attributable to cancer. In one case series of 69 children with intraparenchymal hemorrhage, brain tumors accounted for 13 percent cases [7]. In another case series from a tertiary cancer center, ICH occurred in 3 percent of over 1000 children with brain tumors and in 1 percent of nearly 1600 children with acute leukemia [52]. [53,54] Other Although much less common than in the adult population, hypertension has also been associated with ICH in children. In one small retrospective cohort study, 45 percent of children th with ICH had elevated blood pressure above the 90 percentile at presentation; however, only 14 percent continued to have persistently elevated blood pressure on follow-up, and none required antihypertensive treatment [55]. Another cause of hemorrhagic stroke in childhood is moyamoya disease. Ischemic cerebrovascular events, either transient ischemic attack or infarction, are more prevalent than hemorrhagic events in children with moyamoya, while hemorrhagic stroke is more common in adults. However, moyamoya can cause either ICH or subarachnoid hemorrhage in children. (See "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis", section on 'Clinical presentations'.) Drugs of abuse, coagulopathies secondary to liver dysfunction, and porphyria are rare causes of hemorrhagic stroke in children. https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 5/33 7/5/23, 12:10 PM Hemorrhagic stroke in children - UpToDate Cohort studies have shown that 9 to 23 percent of childhood ICH remains cryptogenic without a definitive risk factor identified despite extensive evaluation [8,56,57]. However, some proportion of these cryptogenic cases may be due to vascular malformations that have self-obliterated at the time of the incident hemorrhage [58]. CLINICAL FEATURES AND PRESENTATION Among all children who present outside the perinatal period, headache is the most common symptom of hemorrhagic stroke, affecting 46 to 80 percent [7,8,10,17]. Other common presenting symptoms in children include: Nausea and emesis in nearly 60 percent [8] Seizures (either generalized or focal) in 20 to 40 percent [7,8,59] Focal neurologic deficits such as hemiparesis or aphasia, which range in frequency from 13 to 50 percent [8,17,55,58] Neck pain Altered level of consciousness in 50 percent or more [7,8,56,58] The clinical presentation of hemorrhagic stroke can vary based upon the age of the child; younger children are most likely to present with only nonspecific features (eg, altered mentation, seizures, vomiting) while older children are more likely to present with headache, mental status change, and focal neurologic deficits. There is overlap between symptoms in pediatric hemorrhagic stroke, pediatric arterial ischemic stroke, and pediatric cerebral sinovenous thrombosis. All can present with headache, altered mental status, focal neurologic deficits, and seizures. Therefore, neuroimaging is required to differentiate among these entities. However, severe sudden headache with rapid alteration in level of consciousness may be more indicative of a hemorrhage. In a retrospective review of 85 children with nontraumatic intracerebral hemorrhage (ICH) at a tertiary pediatric hospital, the most common clinical signs in young children (<6 years of age) were mental status change, seizures, or vomiting [55]. In contrast, older children ( 6 years of age) often presented with headache and focal neurologic deficits in addition to symptoms of mental status change and nausea/vomiting, allowing clinicians to quickly narrow the differential diagnosis. Another cohort study found that children younger than three years of age at time of hemorrhage onset (n = 9) presented with vague symptoms of general deterioration, increased crying and sleepiness, irritability, feeding difficulty, vomiting, and sepsis-like symptoms with cold extremities [17]. https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 6/33 7/5/23, 12:10 PM Hemorrhagic stroke in children - UpToDate The onset of clinical symptoms due to hemorrhagic stroke is variable and ranges from rapid occurrence over minutes to insidious progression over several hours to days. In a cohort study of 22 children with ICH, the median time to hospital presentation was 70 minutes, but 23 percent of children presented after 24 hours [8]. A prospective study of 53 children with ICH found that acute symptomatic seizures, defined as those occurring from presentation to seven days after onset, occurred in 36 percent [59]. Thus, acute symptomatic seizures with ICH may be more common in children than in adults, where the corresponding rate is estimated to range from 5 to 30 percent (see "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Clinical presentation'). Further, children with ICH may present with seizures more commonly than children with arterial ischemic stroke, in whom seizures at stroke onset have been reported in 22 percent [60]. Cortical involvement of ICH, which is an important predictor of acute symptomatic seizures in adults [61,62], was not related to acute symptomatic seizures in the pediatric ICH cohort [59]. The pace of symptom onset may be related to the underlying etiology, with aneurysm rupture expected to correlate with sudden onset, while other mechanisms may allow for subacute onset, at least in some cases. However, data are sparse. In a small cohort study of children with spontaneous ICH, approximately half had acute onset of symptoms while the other half had a subacute course [17]. Among children with a known onset, there were four with aneurysms, and the presentation was acute in three; among 16 children with arteriovenous malformation and known onset, an acute presentation occurred in 10 cases (63 percent). Other factors that could affect the rapidity of symptom development are size and location of hemorrhage, intraventricular extension, and presence of hydrocephalus. INITIAL EVALUATION AND DIAGNOSIS The diagnosis of hemorrhagic stroke requires confirmation by brain imaging with computed tomography (CT) or magnetic resonance imaging (MRI) [63]. Therefore, clinical suspicion for hemorrhage in the setting of a compatible presentation (eg, headache, mental status changes, seizure, vomiting, or focal neurologic deficits) as described above should prompt urgent imaging. (See 'Clinical features and presentation' above.) For children of school age or older, the acute onset of headache, particularly when severe, (eg, sometimes reported as the "worst headache of life") should prompt evaluation for intracerebral or subarachnoid hemorrhage. However, the diagnosis of hemorrhagic stroke in children can be difficult because the presentation is often nonspecific and subacute. In one small study, most cases with delayed diagnosis (7 of 11) had subacute onset [17]. https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 7/33 7/5/23, 12:10 PM Hemorrhagic stroke in children - UpToDate The initial evaluation should center on rapid diagnosis of the hemorrhage, assessment for presence of elevated intracranial pressure, and identification of easily correctible risk factors such as thrombocytopenia or coagulopathy. Children with hemorrhagic stroke are also at increased risk of subsequent ischemic stroke due to compression of blood vessels from mass effect from the intracerebral hemorrhage, vasospasm after subarachnoid hemorrhage, or underlying vasculopathy (such as moyamoya or cocaine-induced vasculopathy) [64]. Urgent neuroimaging Neuroimaging with CT or MRI as the initial study is necessary to determine the cause, to distinguish hemorrhagic stroke from ischemic stroke, and to distinguish stroke from stroke mimics. In a stable patient, MRI is preferred because of the lack of radiation and the better resolution of the parenchyma. MRI with gradient echo and/or susceptibility- weighted sequences is equally sensitive for acute hemorrhage and more sensitive for chronic hemorrhage than CT [65]. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Brain MRI'.) However, MRI is not universally available and may require sedation [65]. Noncontrast head CT should be performed if a patient with suspected hemorrhage is unstable or if obtaining an MRI might delay diagnosis. CT is quick, widely available, does not require sedation in most cases, and is highly sensitive for acute hemorrhage. Noncontrast head CT reveals the diagnosis of subarachnoid hemorrhage in more than 90 percent of cases if performed within 24 hours of bleeding onset; the sensitivity of modern head CT for detecting SAH is highest in the first six hours after subarachnoid hemorrhage (nearly 100 percent when interpreted by expert reviewers). Limited data suggest that proton density and fluid-attenuated inversion recovery (FLAIR) sequences on brain MRI may be as sensitive as head CT for the detection of acute subarachnoid hemorrhage. If neuroimaging is negative for blood and there is high clinical concern for subarachnoid hemorrhage, lumbar puncture should be performed to detect red blood cells or xanthochromia if there are no contraindications (eg, large hemorrhage with significant edema causing impending herniation). (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Evaluation and diagnosis'.) Laboratory studies First-line laboratory studies should include electrolytes, blood urea nitrogen and creatinine, glucose, complete blood count with platelets, coagulation studies (prothrombin time, international normalized ratio, and activated partial thromboplastin time) [63]. Type and screen should be sent for any child who will undergo surgery. https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 8/33 7/5/23, 12:10 PM Hemorrhagic stroke in children - UpToDate DIFFERENTIAL DIAGNOSIS Hemorrhagic stroke must first be differentiated from other types of acute intracerebral vascular events, such as arterial ischemic stroke and cerebral sinovenous thrombosis, both of which may have concomitant hemorrhagic transformation [66]. (See "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors" and "Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis" and "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".) The differential diagnosis for hemorrhagic stroke ( table 1) also includes a broad list of diagnoses that can mimic stroke syndromes. The most common childhood stroke mimics are: Migraine syndromes (see "Types of migraine and related syndromes in children" and "Migraine-associated stroke: risk factors, diagnosis, and prevention", section on 'Forms of migraine with aura') Postictal (Todd) paralysis (see "Differential diagnosis of transient ischemic attack and acute stroke", section on 'Transient neurologic events') Other conditions that may mimic stroke include the following: Brain tumors (see "Clinical manifestations and diagnosis of central nervous system tumors in children") Posterior reversible encephalopathy syndrome (PRES), also known as reversible posterior leukoencephalopathy syndrome (see "Reversible posterior leukoencephalopathy syndrome") Intracranial infections including abscess, encephalitis, and meningitis White matter diseases ( algorithm 1) including multiple sclerosis, acute disseminated encephalomyelitis, and leukodystrophies (see "Pathogenesis, clinical features, and diagnosis of pediatric multiple sclerosis" and "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis" and "Differential diagnosis of acute central nervous system demyelination in children") Metabolic derangements such as hypoglycemia (see "Approach to hypoglycemia in infants and children") Organic or amino acidurias (see "Inborn errors of metabolism: Classification" and "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features") https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 9/33 7/5/23, 12:10 PM Hemorrhagic stroke in children - UpToDate Mitochondrial diseases such as mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) (see "Mitochondrial myopathies: Clinical features and diagnosis", section on 'MELAS') Methotrexate and other chemotherapeutic agent neurotoxicity (see "Overview of neurologic complications of conventional non-platinum cancer chemotherapy" and "Overview of neurologic complications of platinum-based chemotherapy") Bell's palsy (see "Facial nerve palsy in children") Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (see "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)") Conversion disorders Musculoskeletal conditions Neuroimaging is required to diagnose hemorrhagic stroke and to distinguish stroke from mimics. (See 'Initial evaluation and diagnosis' above.) MANAGEMENT Once diagnosis of hemorrhagic stroke is confirmed (see 'Initial evaluation and diagnosis' above), the focus should shift to stabilization of the patient, treatment of elevated intracranial pressure (if present), and close monitoring for brain herniation. There are currently no established evidence-based diagnostic or management guidelines for children with hemorrhagic stroke. The American Heart Association (AHA) scientific statement for the management of stroke in infants and children includes recommendations for children with hemorrhagic stroke [67], which are mostly extrapolated from adult guidelines or are based on expert opinion derived from small retrospective pediatric studies. Immediate consultations Immediate consultations should be obtained from neurosurgery and neurology; hematology should also be consulted if hematologic abnormalities are present on laboratory studies (eg, activated partial thromboplastin time [aPTT], prothrombin time [PT], international normalized ratio [INR], complete blood count [CBC]) or are suspected. Platelet transfusion may be required if there is thrombocytopenia or concern for platelet dysfunction. Coagulopathy may require intravenous vitamin K and/or fresh frozen plasma, and children with factor VIII or IX deficiency typically require urgent factor replacement. Any child on an anticoagulant medication who presents with hemorrhage should receive blood products, https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 10/33 7/5/23, 12:10 PM Hemorrhagic stroke in children - UpToDate protamine, or vitamin K as warranted. (See "Reversal of anticoagulation in intracranial hemorrhage".) Potential need for decompressive hemicraniectomy and hematoma evacuation should be discussed with neurosurgery. (See 'Surgical management' below.) Supportive measures Subsequent supportive medical management of children with hemorrhagic stroke centers on preventing the progression of brain injury, with primary goals of reducing metabolic demand on brain tissue and avoiding hematoma expansion [63]. Isotonic fluids without glucose should be immediately started to maintain euvolemia, and normothermia should be maintained with acetaminophen and cooling blankets, as temperature elevation >37.5 C increased the likelihood of poor outcome in adult intraparenchymal hemorrhage [68]. Children who present with seizures should be treated with appropriate antiseizure medication (see "Seizures and epilepsy in children: Initial treatment and monitoring"). Prophylactic antiseizure medication treatment is unproven, though there are no high-quality studies of prophylactic antiseizure medication administration in pediatric hemorrhagic stroke. The AHA pediatric stroke guidelines make no recommendations regarding prophylactic antiseizure medication treatment in intracerebral hemorrhage (ICH) [67]. We agree with the AHA guidelines for management of ICH, which recommend against prophylactic antiseizure medications [69]. While treatment of hypertension is a mainstay of hemorrhagic stroke management in adults [63], no clear evidence for managing hypertension after ICH exists in children. It may be a th reasonable goal to lower a child's blood pressure to the 95 percentile for age and sex if elevated after hemorrhage to help prevent hematoma expansion. However, this is not evidence based and may cause a reduction in cerebral perfusion, thereby exacerbating secondary brain injury, particularly if there is elevated intracranial pressure. Any use of antihypertensive medication should be used cautiously. Intracranial pressure Medical management General measures for children with increased intracranial pressure include: Rapid treatment of hypoxia, hypercarbia, and hypotension Elevation of the head of the bed to at least 30 degrees Maintenance of the head and neck midline to facilitate venous drainage Aggressive treatment of fever with antipyretics and cooling blankets Control of shivering in intubated patients with muscle relaxants (eg, vecuronium, rocuronium) https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 11/33 7/5/23, 12:10 PM Hemorrhagic stroke in children - UpToDate Maintenance of adequate analgesia to blunt the response to noxious stimuli Intracranial pressure (ICP) may become precipitously elevated in hemorrhagic stroke due to mass effect from the hemorrhage or from obstructive or communicating hydrocephalus from intraventricular hemorrhage. This contrasts with acute ischemic stroke, in which increased ICP typically develops several days after the incident event as infarcted brain tissue become edematous. To help reduce or prevent elevated ICP, the head of the bed should be elevated to at least 30 degrees, and the neck should be maintained in a midline position to promote venous drainage. Signs and symptoms of elevated ICP should be frequently reassessed, including presence of positional headache, vomiting, irritability or combativeness, declining mental status, sixth nerve palsies, and papilledema. While Cushing's triad (ie, hypertension, bradycardia, and respiratory depression) is highly suggestive of elevated ICP, this is typically a late finding. For any neurologic deterioration, a head computed tomography (CT) should be obtained promptly to assess for worsening hemorrhage, hydrocephalus, edema, or herniation. Direct ongoing measurement of ICP may require placement of an intraventricular catheter, which can also aid in ICP reduction via direct cerebrospinal fluid drainage, or a subdural bolt if an intraventricular catheter is not technically feasible due to small size of a child's ventricles or other reasons. Nonsurgical interventions for management of increased ICP include hyperventilation to PCO of 2 25 to 30 mmHg (if the child is intubated) and hyperosmolar therapy with intravenous mannitol (bolus 1 g/kg, given as an intravenous infusion through an in-line filter over 20 to 30 minutes, followed by infusions of 0.25 to 0.5 g/kg as needed, generally every six to eight hours) or hypertonic saline to promote osmotic diuresis (see "Elevated intracranial pressure (ICP) in children: Management", section on 'Hyperosmolar therapy'). If hyperosmolar therapy is administered, close monitoring of plasma osmoles and electrolytes is required to avoid hypovolemia, hypotension, and renal failure. Glucocorticoids should be avoided because they did not improve outcomes in randomized controlled trials of adults with ICH [70,71], and the resultant hyperglycemia may lead to worse outcomes [72,73]. Surgical management Ultimately, medical interventions for elevated ICP are only temporizing measures, and surgical evacuation of a parenchymal hematoma or decompressive craniectomy may be necessary to control refractory elevations in ICP and/or mass effect. Surgical hemorrhage evacuation for supratentorial ICH is controversial, and no high-quality studies in children have evaluated early surgical hematoma evacuation or hemicraniectomy. In adults, randomized trials have not conclusively demonstrated benefit. (See "Spontaneous https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 12/33 7/5/23, 12:10 PM Hemorrhagic stroke in children - UpToDate intracerebral hemorrhage: Acute treatment and prognosis", section on 'Surgical approaches for selected patients'.) As children typically lack the baseline cerebral atrophy found in older adults that permits expansion of the hematoma without consequent compression of the surrounding parenchyma, it is biologically plausible that children may benefit from hematoma evacuation to reduce ICP. If a child is undergoing resection of an underlying vascular malformation that is at high risk for acute rebleeding, it may be optimal to concurrently evacuate the hematoma. Surgical evaluation also might be warranted if a child is comatose, has elevated intracranial pressure that is refractory to medical management, or a worsening neurological examination. As in adults, cerebellar hemorrhages >3 cm in diameter in a child who is deteriorating or in whom brainstem compression and/or hydrocephalus is developing due to compression on the ventricular system should also be considered for surgical evacuation. If a cerebellar hemorrhage is evacuated, suboccipital craniectomy is typically performed at the same time. While hemicraniectomy has not been studied in the setting of pediatric hemorrhagic stroke, there are some series in which hemicraniectomy was associated with improved function and survival in pediatric arterial ischemic stroke [74,75]. In a child who undergoes surgical hematoma evacuation due to a supratentorial hemorrhage causing elevated intracranial pressure that is refractory to medical management, the surgeon may elect to perform a concomitant hemicraniectomy, particularly if the intracranial pressure remains elevated after hematoma evacuation or if there is herniation out of the craniotomy defect. Identifying the etiology Obtaining dedicated cerebrovascular imaging in the acute setting is critical to guide appropriate interventions given the high rate of vascular malformations underlying hemorrhagic stroke in children. Cerebral angiography is a minimally invasive modality that may be used for diagnosis and treatment of vascular causes of ICH [76]. While conventional cerebral angiography remains the gold standard, many institutions opt to first use noninvasive modalities. One retrospective study found that a combination of magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and magnetic resonance venography (MRV) images accurately identified the cause of ICH in 66 percent of subjects, which was statistically equivalent to the diagnostic yield of conventional cerebral angiography alone (61 percent) [77]. However, another retrospective case series of children with nontraumatic ICH reported identification of the cause of bleeding in 97 percent of children who underwent conventional cerebral angiography compared with 80 percent of children who did not have angiography [7]. Another alternative is CT angiography (CTA), which can be rapidly obtained without the need for sedation in some children, is more widely available than MRA, and may offer superior https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 13/33 7/5/23, 12:10 PM Hemorrhagic stroke in children - UpToDate angioarchitectural visualization compared with MRA [78]. CTA also has a higher sensitivity for detecting aneurysms up to 2 mm in size. However, CTA exposes the child to both ionizing radiation and an iodinated contrast agent, requires a large bore intravenous line, and may be nondiagnostic if the child moves during the study. For children with hemorrhagic stroke and no identified cause despite a thorough evaluation, including appropriate noninvasive vascular imaging, we suggest conventional cerebral angiography. As an acute hemorrhage with large hematoma and significant cerebral edema can obscure visualization of an underlying vascular malformation, vascular studies that are initially nondiagnostic should be repeated weeks to months later once the clot has been reabsorbed if no other cause for the hemorrhage (eg, tumor, coagulopathy) is found [76]. The yield of an extensive evaluation for a bleeding diathesis in children with hemorrhagic stroke is not well-studied. A rational approach is to obtain the screening laboratory studies suggested above (see 'Laboratory studies' above) (ie, a complete blood count with platelets, coagulation studies, prothrombin time, international normalized ratio, and activated partial thromboplastin time) and to pursue additional testing if the screening studies are abnormal or if an underlying vascular lesion or tumor is not found. Higher-level studies may include factor VIII, IX, and XIII levels and von Willebrand disease studies and should be ordered in consultation with a hematologist. (See "Approach to the child with bleeding symptoms" and "Approach to the child with unexplained thrombocytopenia" and "Clinical manifestations and diagnosis of hemophilia" and "Clinical presentation and diagnosis of von Willebrand disease".) Treatment of vascular lesions Endovascular and/or surgical management of vascular malformations may be required in the acute setting depending on the location and vascular anatomy of the lesion in conjunction with the clinical status of the child. Multidisciplinary consultation with neurosurgery, interventional radiology, and neurology is advised to choose the optimal approach to treatment of these lesions [67]. Vascular malformations other than aneurysm typically have a low risk of acute rebleeding (although they may rebleed at later times) [79-81]. Therefore, many centers will await hematoma resolution prior to definitive treatment so that the full extent of the vascular malformation can be elucidated. However, if hematoma evacuation is needed, a vascular malformation may be addressed at the same time. Some arteriovenous malformations that cannot be treated with endovascular or surgical techniques may be amenable to gamma knife or proton beam therapy once the hematoma has retracted. Aneurysms have a higher rate of acute rebleeding [82]. Therefore, aneurysm repair typically occurs in the acute setting. AVMs with an aneurysmal component that may cause acute https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 14/33 7/5/23, 12:10 PM Hemorrhagic stroke in children - UpToDate rebleeding also may require earlier intervention. Follow-up imaging Due to the high risk of recurrence, we suggest follow-up imaging for most children with hemorrhagic stroke due to a vascular malformation. In addition, we suggest follow-up imaging in cases where a vascular cause is not found but is suspected. Even when complete resection of an arteriovenous malformation is achieved, there is a substantial risk of recurrence. In one retrospective report of 28 children who underwent surgical resection of arteriovenous malformations, 4 had recurrence leading to repeat resections [83]. Of note, two of the children in this cohort had arteriovenous malformations that were not detected until 17.7 and 25 months after the incident hemorrhage. While the frequency and modality of follow-up imaging is center-dependent, our suggested protocol is to obtain brain MRI with MRA at three to six months after the first hemorrhage, and/or a conventional angiogram between three and six months. Additional follow-up imaging at later points is typically necessary. In children with an unresected cavernous malformation, periodic imaging with MRI is suggested if the child is having frequent symptoms such as headaches or seizures. Genetic screening Genetic screening may be reasonable if multiple vascular malformations are found on imaging or if there is a suggestive family history [67]. The most common genetic cause of brain AVMs is hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant condition. Patients with HHT may have cerebral or spinal cord involvement with telangiectasias, brain AVMs, aneurysms, or cavernous malformations. (See

intracerebral hemorrhage: Acute treatment and prognosis", section on 'Surgical approaches for selected patients'.) As children typically lack the baseline cerebral atrophy found in older adults that permits expansion of the hematoma without consequent compression of the surrounding parenchyma, it is biologically plausible that children may benefit from hematoma evacuation to reduce ICP. If a child is undergoing resection of an underlying vascular malformation that is at high risk for acute rebleeding, it may be optimal to concurrently evacuate the hematoma. Surgical evaluation also might be warranted if a child is comatose, has elevated intracranial pressure that is refractory to medical management, or a worsening neurological examination. As in adults, cerebellar hemorrhages >3 cm in diameter in a child who is deteriorating or in whom brainstem compression and/or hydrocephalus is developing due to compression on the ventricular system should also be considered for surgical evacuation. If a cerebellar hemorrhage is evacuated, suboccipital craniectomy is typically performed at the same time. While hemicraniectomy has not been studied in the setting of pediatric hemorrhagic stroke, there are some series in which hemicraniectomy was associated with improved function and survival in pediatric arterial ischemic stroke [74,75]. In a child who undergoes surgical hematoma evacuation due to a supratentorial hemorrhage causing elevated intracranial pressure that is refractory to medical management, the surgeon may elect to perform a concomitant hemicraniectomy, particularly if the intracranial pressure remains elevated after hematoma evacuation or if there is herniation out of the craniotomy defect. Identifying the etiology Obtaining dedicated cerebrovascular imaging in the acute setting is critical to guide appropriate interventions given the high rate of vascular malformations underlying hemorrhagic stroke in children. Cerebral angiography is a minimally invasive modality that may be used for diagnosis and treatment of vascular causes of ICH [76]. While conventional cerebral angiography remains the gold standard, many institutions opt to first use noninvasive modalities. One retrospective study found that a combination of magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and magnetic resonance venography (MRV) images accurately identified the cause of ICH in 66 percent of subjects, which was statistically equivalent to the diagnostic yield of conventional cerebral angiography alone (61 percent) [77]. However, another retrospective case series of children with nontraumatic ICH reported identification of the cause of bleeding in 97 percent of children who underwent conventional cerebral angiography compared with 80 percent of children who did not have angiography [7]. Another alternative is CT angiography (CTA), which can be rapidly obtained without the need for sedation in some children, is more widely available than MRA, and may offer superior https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 13/33 7/5/23, 12:10 PM Hemorrhagic stroke in children - UpToDate angioarchitectural visualization compared with MRA [78]. CTA also has a higher sensitivity for detecting aneurysms up to 2 mm in size. However, CTA exposes the child to both ionizing radiation and an iodinated contrast agent, requires a large bore intravenous line, and may be nondiagnostic if the child moves during the study. For children with hemorrhagic stroke and no identified cause despite a thorough evaluation, including appropriate noninvasive vascular imaging, we suggest conventional cerebral angiography. As an acute hemorrhage with large hematoma and significant cerebral edema can obscure visualization of an underlying vascular malformation, vascular studies that are initially nondiagnostic should be repeated weeks to months later once the clot has been reabsorbed if no other cause for the hemorrhage (eg, tumor, coagulopathy) is found [76]. The yield of an extensive evaluation for a bleeding diathesis in children with hemorrhagic stroke is not well-studied. A rational approach is to obtain the screening laboratory studies suggested above (see 'Laboratory studies' above) (ie, a complete blood count with platelets, coagulation studies, prothrombin time, international normalized ratio, and activated partial thromboplastin time) and to pursue additional testing if the screening studies are abnormal or if an underlying vascular lesion or tumor is not found. Higher-level studies may include factor VIII, IX, and XIII levels and von Willebrand disease studies and should be ordered in consultation with a hematologist. (See "Approach to the child with bleeding symptoms" and "Approach to the child with unexplained thrombocytopenia" and "Clinical manifestations and diagnosis of hemophilia" and "Clinical presentation and diagnosis of von Willebrand disease".) Treatment of vascular lesions Endovascular and/or surgical management of vascular malformations may be required in the acute setting depending on the location and vascular anatomy of the lesion in conjunction with the clinical status of the child. Multidisciplinary consultation with neurosurgery, interventional radiology, and neurology is advised to choose the optimal approach to treatment of these lesions [67]. Vascular malformations other than aneurysm typically have a low risk of acute rebleeding (although they may rebleed at later times) [79-81]. Therefore, many centers will await hematoma resolution prior to definitive treatment so that the full extent of the vascular malformation can be elucidated. However, if hematoma evacuation is needed, a vascular malformation may be addressed at the same time. Some arteriovenous malformations that cannot be treated with endovascular or surgical techniques may be amenable to gamma knife or proton beam therapy once the hematoma has retracted. Aneurysms have a higher rate of acute rebleeding [82]. Therefore, aneurysm repair typically occurs in the acute setting. AVMs with an aneurysmal component that may cause acute https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 14/33 7/5/23, 12:10 PM Hemorrhagic stroke in children - UpToDate rebleeding also may require earlier intervention. Follow-up imaging Due to the high risk of recurrence, we suggest follow-up imaging for most children with hemorrhagic stroke due to a vascular malformation. In addition, we suggest follow-up imaging in cases where a vascular cause is not found but is suspected. Even when complete resection of an arteriovenous malformation is achieved, there is a substantial risk of recurrence. In one retrospective report of 28 children who underwent surgical resection of arteriovenous malformations, 4 had recurrence leading to repeat resections [83]. Of note, two of the children in this cohort had arteriovenous malformations that were not detected until 17.7 and 25 months after the incident hemorrhage. While the frequency and modality of follow-up imaging is center-dependent, our suggested protocol is to obtain brain MRI with MRA at three to six months after the first hemorrhage, and/or a conventional angiogram between three and six months. Additional follow-up imaging at later points is typically necessary. In children with an unresected cavernous malformation, periodic imaging with MRI is suggested if the child is having frequent symptoms such as headaches or seizures. Genetic screening Genetic screening may be reasonable if multiple vascular malformations are found on imaging or if there is a suggestive family history [67]. The most common genetic cause of brain AVMs is hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant condition. Patients with HHT may have cerebral or spinal cord involvement with telangiectasias, brain AVMs, aneurysms, or cavernous malformations. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber- Rendu syndrome)", section on 'Genetic testing'.) Familial cases of cavernous malformation are associated with genetic variants of CCM1, CCM2, and CCM3. (See "Vascular malformations of the central nervous system", section on 'Cavernous malformations'.) PROGNOSIS The estimated mortality rate for children with hemorrhagic stroke ranges from 5 to 33 percent, and many studies (largely retrospective) report that neurologic outcomes are poor in approximately 25 to 57 percent of children, as discussed in the sections that follow. Mortality Older studies show that hemorrhagic stroke has a significantly higher mortality than arterial ischemic stroke in children [3,29,84,85] but lower mortality compared with that in https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 15/33 7/5/23, 12:10 PM Hemorrhagic stroke in children - UpToDate the adult population [86]. In a 2005 report, pooled data from multiple heterogeneous studies suggested an average mortality rate of 25 percent in children with hemorrhagic stroke [87]; later studies reported mortality rates ranging from 5 to 33 percent [8,88-90]. Neurologic outcome Neurologic outcome after hemorrhagic stroke has not been well studied in children. Most data are derived from small retrospective cohort studies or case series. Some data suggest neurologic deficits may persist in up to approximately 75 percent, and disability may be present in more than half of survivors [8,90-92]. As an example, a prospective cohort study of pediatric intracerebral hemorrhage (ICH) included 22 children from a single tertiary care center [8]. At follow-up (median 3.5 months), clinically significant disability (defined as moderate disability or worse, with patients unable to function normally and requiring additional care) was present in 57 percent, and neurologic deficits were present in 71 percent. Scholastic performance is frequently impaired in survivors of ICH [8]. In one cohort including 30 survivors of ICH (age 6 to 17 years), most returned to school within a year of onset, but less than one half were attending age-appropriate classes and the remainder required additional educational support [93]. In a retrospective study of 128 children with childhood stroke, of whom 82 had hemorrhagic stroke, 36 percent required special educational services at long-term follow up (median 43 months) [92]. Epilepsy at two years occurred in 13 percent of children in a prospective study of 53 children with ICH [59]. Elevated intracranial pressure that required urgent intervention during the acute hospitalization was a risk factor for a first remote symptomatic seizure and for developing epilepsy. Children with a diagnosis of epilepsy following stroke have worse parent-reported scores of health status than those without this diagnosis [94]. Outcome predictors In adult ICH, initial hematoma volume is the strongest predictor of mortality and functional outcome, and the level of consciousness at presentation is also an important prognostic factor. The 30-day mortality is approximately 90 percent if the size of the 3 hemorrhage exceeds 60 cm and the Glasgow coma scale (GCS) is <9 at presentation. This 3 compares with an estimated 19 percent mortality when the hemorrhage volume is <30 cm and the GCS is 9 [95]. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Risk factors for poor outcomes'.) Similarly, clinical and imaging features of the acute ICH associated with poor functional outcome in children include [8,90]: ICH volume Altered mental status Length of stay in an intensive care unit https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 16/33 7/5/23, 12:10 PM Hemorrhagic stroke in children - UpToDate Hemorrhage volume must be taken in the context of percentage of total brain volume (TBV) to account for the markedly varying brain sizes of children of different ages. In a retrospective report of 30 consecutive children, the strongest association with outcome was the intraparenchymal component of ICH expressed as a percentage of TBV; intraparenchymal hemorrhage 4 percent of TBV was independently associated with poor outcome, defined as severe disability or death (odds ratio [OR] 22.5, 95% CI 1.4-354) [56]. The odds of poor outcome 3 at 30 days increased significantly for every 10 cm of additional hemorrhage volume. Other predictors of poor outcome from retrospective studies include initial GCS 8, coagulopathy, and older age (11 to 18 years) [9,96]. Studies in adults suggest that posterior fossa hemorrhage and presence of intraventricular hemorrhage are predictors of poor outcome (see "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Risk factors for poor outcomes'). However, data from small pediatric cohort studies have not confirmed that these factors predict poor outcome in children [8,56,89,97]. Prediction scores Pediatric ICH score The adult ICH score [98] is the most commonly used clinical grading scale for predicting mortality and functional outcome following adult ICH (see "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Clinical prediction scores'). A similar pediatric ICH score was developed to assist with risk stratification in children following ICH. While the pediatric ICH score mirrors its adult counterpart, several components required alterations. Hemorrhage volume was expressed as a percent of TBV to account for the varying brain sizes of children of different ages. Due to the lack of availability of GCS scores in most children, the presence of herniation was used. Isolated intraventricular hemorrhage had not been predictive of outcome in previous studies and was present in about 40 percent of children, so this variable was replaced with hydrocephalus [99]. Thus, the pediatric ICH score is comprised of the following components: Intraparenchymal hemorrhage volume as percentage of TBV - - <2 percent = 0 points 2 to 3.99 percent = 1 point 4 percent = 2 points Hydrocephalus? - No = 0 points Yes = 1 point https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 17/33 7/5/23, 12:10 PM Hemorrhagic stroke in children - UpToDate Herniation? - No = 0 points Yes = 1 point Infratentorial location? - No = 0 points Yes = 1 point Therefore, the total pediatric ICH score ranges from 0 to 5 points. In one prospective cohort of 60 children with ICH, a pediatric ICH score 2 was sensitive for predicting severe disability or death and a score 1 was sensitive for predicting moderate disability or worse [99]. However, the pediatric ICH score has not been established as generally valid in independent populations. Modified pediatric ICH score The modified pediatric ICH (mPICH) score incorporated early altered mental status, a reported predictor of worse outcome following ICH [8], and intraventricular hemorrhage into the pediatric ICH score to improve prediction sensitivity for moderate or severe disability [100]. The modified pediatric ICH (mPICH) score (range, 0 to 13) is assigns points for presence of six variables as follows: Forebrain herniation, 4 points Altered mental status at initial presentation, 3 points Hydrocephalus, 2 points Infratentorial ICH, 2 points Intraventricular hemorrhage, 1 point ICH volume >2 percent of TBV, 1 point Using a retrospectively selected validation cohort of 43 children, an mPICH score of >4 was sensitive for predicting moderate disability or worse, a score >5 was sensitive for predicting severe disability or worse, and a score >6 was sensitive for predicting vegetative state or death [100]. Hemorrhagic stroke recurrence Data from pooled studies suggest that recurrence risk after hemorrhagic stroke in childhood is approximately 10 percent [87], but the length of follow-up in these studies was highly variable. Limited data suggest that the risk of recurrence depends mainly on etiology; children with untreated or incompletely treated vascular malformations and those with hematologic disorders appear to have the highest risk of recurrence [29,101]. In a population-based retrospective cohort study of 116 children with nontraumatic hemorrhagic stroke in northern California who were followed for a mean of 4.2 years, a recurrent https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 18/33 7/5/23, 12:10 PM Hemorrhagic stroke in children - UpToDate hemorrhagic stroke affected 11 children at a median of approximately three months (range 7 days to 5.7 years) [64]. The highest risk period was the first six months. The estimated five-year cumulative recurrence rate was 10 percent (95% CI 5-18 percent). Among the 11 recurrent hemorrhagic strokes, there were 5 due to cavernous malformations, 2 caused by to arteriovenous malformation, 2 attributed to tumor, 1 with hypertension, and 1 with idiopathic thrombocytopenia. Among the 9 children with a second hemorrhage and a structural cause (vascular malformation or tumor), the lesion was untreated in 6 and partially treated in 2 (partially resected tumor and second cavernous malformation which was not the cause of first hemorrhage). There were no recurrences among 29 children with idiopathic hemorrhagic stroke. Another study monitored adults and children with brain arteriovenous malformations (AVMs) for a total of 3620 person-years in the adult group and 996 person-years in the childhood group, starting from initial presentation [14]. The unadjusted rates of subsequent ICH were similar for children and adults (2.0 and 2.2 percent, respectively) However, compared with adults, children with AVMs were more likely to present with hemorrhage, and after adjusting for the higher proportion of hemorrhagic presentation in children, the risk of a subsequent ICH was lower for children (hazard ratio 0.1, 95% CI 0.01-0.86). These results suggest that cerebral AVMs in children do not need to be treated more aggressively than those in adults. However, although their annualized risk of hemorrhage is similar to adults, their cumulative risk is greater given their greater number of years left to live. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in children".) SUMMARY AND RECOMMENDATIONS Classification Hemorrhagic stroke encompasses spontaneous intracerebral hemorrhage (ICH), isolated intraventricular hemorrhage, and nontraumatic subarachnoid hemorrhage. ICH is defined by intraparenchymal hemorrhage with or without associated intraventricular hemorrhage. (See 'Classification' above.) Epidemiology Hemorrhagic stroke accounts for approximately one-half of all childhood strokes. The annual incidence rate is approximately 1 per 100,000 children. (See 'Epidemiology' above.) https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 19/33 7/5/23, 12:10 PM Hemorrhagic stroke in children - UpToDate Etiologies Hemorrhagic stroke in children living in developed countries is most commonly due to ruptured vascular malformations. Hematologic abnormalities, cancer, and hypertension are less common causes. Aneurysms are the most common cause of nontraumatic subarachnoid hemorrhage. (See 'Etiology and risk factors' above.) Clinical features The most common presenting symptom of hemorrhagic stroke in children is headache. Other common presenting symptoms include nausea and emesis, seizures, neck pain, focal neurologic deficits, and altered level of consciousness. (See 'Clinical features and presentation' above.) Diagnosis The diagnosis of hemorrhagic stroke requires confirmation by brain imaging with computed tomography (CT) or magnetic resonance imaging (MRI). (See 'Urgent neuroimaging' above.) Differential diagnosis and evaluation The differential diagnosis for hemorrhagic stroke includes a broad list of diagnoses that can mimic stroke syndromes ( table 1), with the most common being migraine syndromes and postictal (Todd) paralysis. (See 'Differential diagnosis' above.) Testing to identify underlying causes includes dedicated cerebrovascular imaging and screening laboratory studies. (See 'Identifying the etiology' above.) Management The goals of acute hemorrhagic stroke management include stabilization of the patient, treatment of elevated intracranial pressure (if present), and close monitoring for brain herniation. (See 'Management' above.) We suggest multidisciplinary consultation to choose the optimal endovascular and/or surgical approach of vascular malformations. (See 'Treatment of vascular lesions' above.) Follow-up imaging is warranted in cases where a vascular lesion is suspected but not found during the acute evaluation as well as for most children with hemorrhagic stroke due to a vascular malformation due to the risk of recurrence. (See 'Follow-up imaging' above.) Prognosis The estimated mortality rate for children with hemorrhagic stroke ranges from 5 to 33 percent. Neurologic deficits may persist in up to approximately 75 percent, and disability may be present in more than half of ICH survivors. (See 'Prognosis' above.) Use of UpToDate is subject to the Terms of Use. 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ischemic stroke in childhood. J Pediatr 2011; 159:479. https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 24/33 7/5/23, 12:10 PM Hemorrhagic stroke in children - UpToDate 61. Beghi E, D'Alessandro R, Beretta S, et al. Incidence and predictors of acute symptomatic seizures after stroke. Neurology 2011; 77:1785. 62. De Herdt V, Dumont F, H non H, et al. Early seizures in intracerebral hemorrhage: incidence, associated factors, and outcome. Neurology 2011; 77:1794. 63. Greenberg SM, Ziai WC, Cordonnier C, et al. 2022 Guideline for the Management of Patients With Spontaneous Intracerebral Hemorrhage: A Guideline From the American Heart Association/American Stroke Association. Stroke 2022; 53:e282. 64. Fullerton HJ, Wu YW, Sidney S, Johnston SC. Recurrent hemorrhagic stroke in children: a population-based cohort study. Stroke 2007; 38:2658. 65. Kidwell CS, Chalela JA, Saver JL, et al. Comparison of MRI and CT for detection of acute intracerebral hemorrhage. JAMA 2004; 292:1823. 66. Hutchinson ML, Beslow LA. Hemorrhagic Transformation of Arterial Ischemic and Venous Stroke in Children. Pediatr Neurol 2019; 95:26. 67. Ferriero DM, Fullerton HJ, Bernard TJ, et al. Management of Stroke in Neonates and Children: A Scientific Statement From the American Heart Association/American Stroke Association. Stroke 2019; 50:e51. 68. Schwarz S, H fner K, Aschoff A, Schwab S. Incidence and prognostic significance of fever following intracerebral hemorrhage. Neurology 2000; 54:354. 69. Hemphill JC 3rd, Greenberg SM, Anderson CS, et al. Guidelines for the Management of Spontaneous Intracerebral Hemorrhage: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2015; 46:2032. 70. Poungvarin N, Bhoopat W, Viriyavejakul A, et al. Effects of dexamethasone in primary supratentorial intracerebral hemorrhage. N Engl J Med 1987; 316:1229. 71. Tellez H, Bauer RB. Dexamethasone as treatment in cerebrovascular disease. 1. A controlled study in intracerebral hemorrhage. Stroke 1973; 4:541. 72. Passero S, Ciacci G, Ulivelli M. The influence of diabetes and hyperglycemia on clinical course after intracerebral hemorrhage. Neurology 2003; 61:1351. 73. Weir CJ, Murray GD, Dyker AG, Lees KR. Is hyperglycaemia an independent predictor of poor outcome after acute stroke? Results of a long-term follow up study. BMJ 1997; 314:1303. 74. Smith SE, Kirkham FJ, Deveber G, et al. Outcome following decompressive craniectomy for malignant middle cerebral artery infarction in children. Dev Med Child Neurol 2011; 53:29. 75. Omay SB, Carri n-Grant GM, Kuzmik GA, et al. Decompressive hemicraniectomy for ischemic stroke in the pediatric population. Neurosurg Rev 2013; 36:21. https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 25/33 7/5/23, 12:10 PM Hemorrhagic stroke in children - UpToDate 76. Harrar DB, Sun LR, Goss M, Pearl MS. Cerebral Digital Subtraction Angiography in Acute Intracranial Hemorrhage: Considerations in Critically Ill Children. J Child Neurol 2022; 37:693. 77. Liu AC, Segaren N, Cox TS, et al. Is there a role for magnetic resonance imaging in the evaluation of non-traumatic intraparenchymal haemorrhage in children? Pediatr Radiol 2006; 36:940. 78. Truwit CL. CT angiography versus MR angiography in the evaluation of acute neurovascular disease. Radiology 2007; 245:362. 79. Kondziolka D, McLaughlin MR, Kestle JR. Simple risk predictions for arteriovenous malformation hemorrhage. Neurosurgery 1995; 37:851. 80. Graf CJ, Perret GE, Torner JC. Bleeding from cerebral arteriovenous malformations as part of their natural history. J Neurosurg 1983; 58:331. 81. Ondra SL, Troupp H, George ED, Schwab K. The natural history of symptomatic arteriovenous malformations of the brain: a 24-year follow-up assessment. J Neurosurg 1990; 73:387. 82. Winn HR, Richardson AE, Jane JA. The long-term prognosis in untreated cerebral aneurysms: I. The incidence of late hemorrhage in cerebral aneurysm: a 10-year evaluation of 364 patients. Ann Neurol 1977; 1:358. 83. Lang SS, Beslow LA, Bailey RL, et al. Follow-up imaging to detect recurrence of surgically treated pediatric arteriovenous malformations. J Neurosurg Pediatr 2012; 9:497. 84. Schoenberg BS, Mellinger JF, Schoenberg DG. Cerebrovascular disease in infants and children: a study of incidence, clinical features, and survival. Neurology 1978; 28:763. 85. Livingston JH, Brown JK. Intracerebral haemorrhage after the neonatal period. Arch Dis Child 1986; 61:538. 86. Qureshi AI, Tuhrim S, Broderick JP, et al. Spontaneous intracerebral hemorrhage. N Engl J Med 2001; 344:1450. 87. Lynch JK, Han CJ. Pediatric stroke: what do we know and what do we need to know? Semin Neurol 2005; 25:410. 88. Fox CK, Johnston SC, Sidney S, Fullerton HJ. High critical care usage due to pediatric stroke: results of a population-based study. Neurology 2012; 79:420. 89. Lo WD, Hajek C, Pappa C, et al. Outcomes in children with hemorrhagic stroke. JAMA Neurol 2013; 70:66. 90. Porcari GS, Beslow LA, Ichord RN, et al. Neurologic Outcome Predictors in Pediatric Intracerebral Hemorrhage: A Prospective Study. Stroke 2018; 49:1755. https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 26/33 7/5/23, 12:10 PM Hemorrhagic stroke in children - UpToDate 91. Greenham M, Gordon A, Anderson V, Mackay MT. Outcome in Childhood Stroke. Stroke 2016; 47:1159. 92. Yvon E, Lamotte D, Tiberghien A, et al. Long-term motor, functional, and academic outcome following childhood ischemic and hemorrhagic stroke: A large rehabilitation center-based retrospective study. Dev Neurorehabil 2018; 21:83. 93. Hawks C, Jordan LC, Gindville M, et al. Educational Placement After Pediatric Intracerebral Hemorrhage. Pediatr Neurol 2016; 61:46. 94. Smith SE, Vargas G, Cucchiara AJ, et al. Hemiparesis and epilepsy are associated with worse reported health status following unilateral stroke in children. Pediatr Neurol 2015; 52:428. 95. Broderick JP, Brott TG, Duldner JE, et al. Volume of intracerebral hemorrhage. A powerful and easy-to-use predictor of 30-day mortality. Stroke 1993; 24:987. 96. Huang X, Cheng Z, Xu Y, et al. Associations of Clinical Characteristics and Etiology With Death in Hospitalized Chinese Children After Spontaneous Intracerebral Hemorrhage: A Single-Center, Retrospective Cohort Study. Front Pediatr 2020; 8:576077. 97. Kleinman JT, Beslow LA, Engelmann K, et al. Evaluation of intraventricular hemorrhage in pediatric intracerebral hemorrhage. J Child Neurol 2012; 27:526. 98. Hemphill JC 3rd, Bonovich DC, Besmertis L, et al. The ICH score: a simple, reliable grading scale for intracerebral hemorrhage. Stroke 2001; 32:891. 99. Beslow LA, Ichord RN, Gindville MC, et al. Pediatric intracerebral hemorrhage score: a simple grading scale for intracerebral hemorrhage in children. Stroke 2014; 45:66. 100. Gu don A, Blauwblomme T, Boulouis G, et al. Predictors of Outcome in Patients with Pediatric Intracerebral Hemorrhage: Development and Validation of a Modified Score. Radiology 2018; 286:651. 101. Nelson MD Jr, Maeder MA, Usner D, et al. Prevalence and incidence of intracranial haemorrhage in a population of children with haemophilia. The Hemophilia Growth and Development Study. Haemophilia 1999; 5:306. Topic 107995 Version 14.0 https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 27/33 7/5/23, 12:10 PM Hemorrhagic stroke in children - UpToDate GRAPHICS Hemorrhagic stroke subtypes Hemorrhagic stroke subtypes. (A) Axial head CT demonstrating large left temporal acute IPH (arrows) with surrounding edema and mass ef ventricle (arrowhead) with left to right midline shift. The underlying cause of hemorrhage in this patient was (B) Axial T2/FLAIR MRI sequence showing non-traumatic SAH visible as hyperintense signal within the cerebra right frontal lobe (arrows). (C) Axial head CT with isolated IVH in the third (C, left panel) and fourth (C, right panel) ventricles (arrows) ass hydrocephalus. (D) Axial (D, left panel) and sagittal (D, right panel) T1-weighted MRI sequence demonstrating a large right fro (arrows) with intraventricular extension into the entire right lateral ventricle (arrowheads). CT: computed tomography; IPH: intraparenchymal hemorrhage; FLAIR: fluid-attenuated inversion recovery; M resonance image; SAH: subarachnoid hemorrhage; IVH: intraventricular hemorrhage. Graphic 108187 Version 1.0 https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 28/33 7/5/23, 12:10 PM Hemorrhagic stroke in children - UpToDate Hemorrhagic stroke etiologies (A) Lateral view of conventional cerebral angiogram demonstrating an extensive left parieto-occipital AVM (ar vessels from the left posterior cerebral, middle cerebral, and anterior cerebral arteries with early deep and su veins. (B) Axial T2/FLAIR (B, left panel) and susceptibility-weighted (B, right panel) MRI sequences showing a left fro malformation (arrows) with calcified components within the lesion (hyperintense punctate signals in (B, left p susceptibility (B, right panel) consistent with blood products. (C) Coronal views of a CT angiography (C, left panel) and conventional cerebral angiogram (C, right panel) dem irregular fusiform lobulated aneurysm of the mid-basilar artery (arrowheads). (D) Sagittal (D, left panel) and axial (D, right panel) T2/FLAIR-weighted MRI sequence of a patient with a large (arrowheads) with associated IVH from a posterior fossa primitive neuroectodermal tumor. AVM: arteriovenous malformation; CT: computed tomography; IPH: intraparenchymal hemorrhage; FLAIR: flu inversion recovery; MRI: magnetic resonance image; IVH: intraventricular hemorrhage. Graphic 108188 Version 1.0 https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 29/33 7/5/23, 12:10 PM Hemorrhagic stroke in children - UpToDate Differential diagnosis of hemorrhagic stroke in children Arterial ischemic stroke with or without hemorrhagic transformation Bell's palsy Brain tumor Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) Cerebral infections including abscess, encephalitis, and meningitis Cerebral sinovenous thrombosis with or without venous infarction or hemorrhage Complications of migraine Conversion disorder Metabolic derangements such as hypoglycemia Methotrexate and other chemotherapeutic agent neurotoxicity Mitochondrial disease such as mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) Musculoskeletal disorders Organic or amino acidurias Posterior reversible encephalopathy syndrome (PRES) Postictal (Todd) paralysis White matter diseases including multiple sclerosis, acute disseminated encephalomyelitis, and leukodystrophies Graphic 108249 Version 1.0 https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 30/33 7/5/23, 12:10 PM Hemorrhagic stroke in children - UpToDate MRI algorithm for the diagnosis of white matter disorders https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 31/33 7/5/23, 12:10 PM Hemorrhagic stroke in children - UpToDate MRI: magnetic resonance imaging; PNS: peripheral nervous system; CADASIL: cerebral autosomal dominant Reproduced with permission from: Schi mann R, van der Knaap MS. Invited Article: An MRI-based approach to the diagnosis of white m Graphic 65871 Version 13.0 https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 32/33 7/5/23, 12:10 PM Hemorrhagic stroke in children - UpToDate Contributor Disclosures Evelyn K Shih, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Lauren A Beslow, MD, MSCE No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Douglas R Nordli, Jr, MD No relevant financial relationship(s) with ineligible companies to disclose. Richard P Goddeau, Jr, DO, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 33/33

7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Initial assessment and management of acute stroke : Jamary Oliveira-Filho, MD, MS, PhD, Michael T Mullen, MD : Scott E Kasner, MD, Jonathan A Edlow, MD, FACEP : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 19, 2023. INTRODUCTION The subacute and long-term assessment and management of patients who have suffered a stroke includes physical therapy and testing to determine the precise etiology of the event so as to prevent recurrence. The acute management differs. Immediate goals include minimizing brain injury, treating medical complications, and moving toward uncovering the pathophysiologic basis of the patient's symptoms. Patient assessment and management during the acute phase (first few hours) of an ischemic stroke will be reviewed here. Use of thrombolytic therapy, endovascular thrombectomy, treatment of patients not eligible for reperfusion therapy, the clinical diagnosis of various types of stroke, and the subacute and long-term assessment of patients who have had a stroke are discussed separately. (See "Approach to reperfusion therapy for acute ischemic stroke" and "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack" and "Clinical diagnosis of stroke subtypes" and "Overview of the evaluation of stroke".) INITIAL ASSESSMENT Sudden loss of focal brain function is the core feature of the onset of ischemic stroke. However, patients with conditions other than brain ischemia may present in a similar fashion ( table 1). (See "Differential diagnosis of transient ischemic attack and acute stroke".) In addition, patients suffering a stroke may present with other serious medical conditions. Thus, the initial evaluation requires a rapid but broad assessment. https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 1/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate The goals in the initial phase include: Ensuring medical stability, with particular attention to airway, breathing, and circulation Quickly reversing any conditions that are contributing to the patient's problem Determining if patients with acute ischemic stroke are candidates for intravenous thrombolytic therapy ( table 2) or endovascular thrombectomy (see "Approach to reperfusion therapy for acute ischemic stroke") Moving toward uncovering the pathophysiologic basis of the patient's neurologic symptoms Time is of the essence in the hyperacute evaluation of stroke patients. The history, physical examination, serum glucose, oxygen saturation, and a noncontrast computed tomography (CT) scan are sufficient in most cases to guide acute therapy (see 'Immediate laboratory studies' below). Other tests are considered based upon individual patient characteristics, but the absence or unavailability of any additional tests need not be a reason to delay therapy if otherwise indicated. Airway, breathing and circulation Assessing vital signs and ensuring stabilization of airway, breathing, and circulation is part of the initial evaluation of all patients with critical illness, including those with stroke [1]. Patients with decreased consciousness or bulbar dysfunction may be unable to protect their airway, and those with increased intracranial pressure due to hemorrhage, vertebrobasilar ischemia, or bihemispheric ischemia can present with vomiting, decreased respiratory drive, or muscular airway obstruction. Hypoventilation, with a resulting increase in carbon dioxide, may lead to cerebral vasodilation and elevate intracranial pressure. In these cases, intubation may be necessary to restore adequate ventilation and to protect the airway from aspiration. Patients with adequate ventilation should have the oxygen saturation monitored. Patients who are hypoxic should receive supplemental oxygen to maintain oxygen saturation >94 percent [1]. Supplemental oxygen should not routinely be given to nonhypoxic patients with acute ischemic stroke. History and physical Establishing the time of ischemic stroke symptom onset is critical because it is the main determinant of eligibility for treatment with intravenous thrombolysis ( table 2) and endovascular thrombectomy [2]. For patients who are unable to provide a reliable onset time, symptom onset is defined as the time the patient was last known to be normal or at baseline neurologic status [1]. At times, information from family members, co- workers, or paramedics (who interviewed witnesses to the onset) may establish the time the patient was last known to be normal. For patients presenting within the therapeutic window for intravenous thrombolysis (less than 4.5 hours from symptom onset) or mechanical https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 2/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate thrombectomy (less than 24 hours from symptom onset), the history needs to be accurate but rapid; contraindications to thrombolytic treatment should also be assessed ( table 2). (See "Approach to reperfusion therapy for acute ischemic stroke", section on 'Rapid evaluation'.) The history and physical examination should be used to distinguish between other disorders in the differential diagnosis of brain ischemia ( table 1). As examples, seizures, syncope, migraine, hypoglycemia (see 'Hypoglycemia' below), hyperglycemia, movement disorders, or drug toxicity can mimic acute ischemia [1,3]. The most difficult cases involve patients with the combination of focal signs and altered level of consciousness. It is important to ask the patient, relative, or any reliable informant whether the patient takes insulin or oral hypoglycemic agents, has a history of epilepsy, drug overdose or abuse, or recent trauma. (See "Differential diagnosis of transient ischemic attack and acute stroke".) Diagnosing an intracerebral hemorrhage (ICH) or subarachnoid hemorrhage (SAH) as soon as possible can be lifesaving [4,5]. The history may be helpful in this regard. The presence of acute onset headache and vomiting favor the diagnosis of ICH or SAH compared with a thromboembolic stroke ( figure 1), while the abrupt onset of impaired cerebral function without focal symptoms favors the diagnosis of SAH. Another important element of the history is whether the patient takes anticoagulant drugs. Even with these clues, diagnosing intracranial hemorrhage on clinical grounds is very imprecise, so early neuroimaging with a CT or magnetic resonance imaging (MRI) scan is critical. CT is preferred at most centers, as it can be obtained very rapidly and is effective at distinguishing between ischemic and hemorrhagic stroke (see "Neuroimaging of acute stroke"). It is important to assess and stabilize vital physiologic functions before sending the patient for an imaging study. The physical examination should include careful evaluation of the neck and retroorbital regions for vascular bruits, and palpation of pulses in the neck, arms, and legs to assess for their absence, asymmetry, or irregular rate. The heart should be auscultated for murmurs (see "Auscultation of cardiac murmurs in adults"). The lungs should be assessed for abnormal breath sounds, bronchospasm, fluid overload, or stridor. The skin should be examined for signs of endocarditis, cholesterol emboli, purpura, ecchymoses, or evidence of recent surgery or other invasive procedures, particularly if reliable history is not forthcoming. The funduscopic examination may be helpful if there are cholesterol emboli or papilledema. The head should be examined for signs of trauma. A tongue laceration may suggest a seizure. In cases where there is a report or suspicion of a fall, the neck should be immobilized until evaluated radiographically for evidence of serious trauma. Examination of the extremities is https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 3/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate important to look for evidence of systemic arterial emboli, distal ischemic, cellulitis, and deep vein thrombosis; the latter should raise the possibility that the patient is receiving anticoagulant treatment. Neurologic evaluation Ischemia in different vascular territories presents with specific syndromes ( table 3). The history should focus upon the time of symptom onset, the course of symptoms over time, possible embolic sources, possible recent trauma (which could either represent a contraindication to intravenous thrombolysis or suggest an arterial dissection as a cause), conditions in the differential diagnosis, and concomitant diseases. (See "Clinical diagnosis of stroke subtypes".) The neurologic examination should attempt to confirm the findings from the history and provide a quantifiable examination for further assessment over time. Many scales are available that provide a structured, quantifiable neurologic examination. One of the most widely used and validated scales is the National Institutes of Health Stroke Scale (NIHSS), composed of 11 items ( table 4) adding up to a total score of 0 to 42 (calculator 1); defined cutpoints for mild, moderate, and severe stroke are not well established, but cut-points of NIHSS score <5 for mild, 5 to 9 for moderate, and 10 for severe stroke may be reasonable. The three most predictive examination findings for the diagnosis of acute stroke are facial paresis, arm drift/weakness, and abnormal speech (a combination of dysarthria and language items derived from the NIHSS) [6,7]. The NIHSS score on admission has been correlated to stroke outcome ( table 5) [8,9], and its use is recommended for all patients with suspected stroke [10]. The NIHSS does not capture all stroke-related impairments, particularly with posterior circulation strokes. (See "Use and utility of stroke scales and grading systems", section on 'NIHSS'.) Immediate laboratory studies Urgent brain imaging with CT or MRI is mandatory in all patients with sudden neurologic deterioration or acute stroke. (See 'Neuroimaging' below.) All patients with suspected stroke should have the following studies urgently as part of the acute stroke evaluation [1,4]: Noncontrast brain CT or brain MRI Finger stick blood glucose Oxygen saturation Other immediate tests for the evaluation of ischemic and hemorrhagic stroke include the following [1,4]: https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 4/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate CT angiography of the head and neck with CT perfusion, or MR angiography with diffusion- weighted imaging (DWI), with or without MR perfusion-weighted imaging (PWI), for patients who may be eligible for mechanical thrombectomy MRI with DWI, to identify patients with wake-up stroke or unknown stroke onset time who have lesions that are positive on DWI but negative on fluid-attenuated inversion recovery (FLAIR), suggesting onset within 4.5 hours and eligibility for intravenous thrombolysis Electrocardiogram (this should not delay the noncontrast brain CT) Complete blood count including platelets Troponin Prothrombin time and international normalized ratio (INR) Activated partial thromboplastin time Ecarin clotting time, thrombin time, or appropriate direct factor Xa activity assay if known or suspected that the patient is taking direct thrombin inhibitor or direct factor Xa inhibitor and is otherwise a candidate for intravenous thrombolytic therapy However, thrombolytic therapy for acute ischemic stroke (see 'Acute therapy' below) should not be delayed while awaiting the results of hematologic studies unless the patient has received anticoagulants or there is suspicion of a bleeding abnormality or thrombocytopenia. The only test that is mandatory before initiation of intravenous thrombolysis is blood glucose [1]. The following laboratory studies may be appropriate in selected patients [1,4,5]: Serum electrolytes, urea nitrogen, creatinine Liver function tests Toxicology screen Blood alcohol level Pregnancy test in women of childbearing potential Arterial blood gas if hypoxia is suspected Chest radiograph if lung disease is suspected Lumbar puncture if subarachnoid hemorrhage is suspected and head CT scan is negative for blood; note that lumbar puncture will preclude administration of intravenous thrombolysis, though thrombolysis should not be given if there is suspicion for subarachnoid hemorrhage as the cause of the symptoms Electroencephalogram if seizures are suspected Chest radiography, urinalysis and blood cultures are indicated if fever is present. We also suggest blood for type and cross match in case fresh frozen plasma is needed to reverse a coagulopathy if ICH is present. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis".) https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 5/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate In order to limit medication dosage errors, particularly with the use of intravenous thrombolysis with alteplase or tenecteplase, an accurate body weight should be obtained early during the urgent evaluation [11]. Neuroimaging In the evaluation of the acute stroke patient, imaging studies are necessary to exclude hemorrhage as a cause of the deficit, and they are useful to assess the degree of brain injury and to identify the vascular lesion responsible for the ischemic deficit. Advanced CT and MRI technologies may be able to distinguish between brain tissue that is irreversibly infarcted and that which is potentially salvageable, thereby allowing better selection of patients who are likely to benefit from therapy. This topic is discussed separately. (See "Neuroimaging of acute stroke".) Cardiac studies Electrocardiography (ECG) is important for detecting signs of concomitant acute cardiac ischemia. This test is particularly important in the setting of stroke, as patients with ischemic stroke frequently harbor coronary artery disease but may not be able to report chest pain. Stroke alone can be associated with ECG changes. The sympathetic response to stroke can lead to demand-induced myocardial ischemia. In large strokes, especially subarachnoid hemorrhage, there are centrally mediated changes in the ECG. The ECG and cardiac monitoring are important for the detection of chronic or intermittent arrhythmias that predispose to embolic events (eg, atrial fibrillation) and for detecting indirect evidence of atrial/ventricular enlargement that may predispose to thrombus formation. Current guidelines recommend cardiac monitoring for at least the first 24 hours after the onset of ischemic stroke to look for atrial fibrillation (AF) or atrial flutter [1]. However, paroxysmal AF may be undetected on standard cardiac monitoring such as continuous telemetry and 24- or 48-hour Holter monitors. Extended cardiac event monitoring for patients with ischemic stroke or transient ischemic attack (TIA) who present with sinus rhythm can significantly increase the detection of occult AF. Such monitoring may reduce the risk of recurrent ischemic stroke by prompting the appropriate use of long-term anticoagulation. The optimal monitoring method continuous telemetry, ambulatory electrocardiography, serial electrocardiography, transtelephonic ECG monitoring, or insertable cardiac monitors (ICMs; also sometimes referred to as implantable cardiac monitor or implantable loop recorder) is uncertain, though longer durations of monitoring are likely to obtain the highest diagnostic yield. (See "Overview of the evaluation of stroke", section on 'Monitoring for subclinical atrial fibrillation' and "Stroke in patients with atrial fibrillation", section on 'Long-term anticoagulation'.) https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 6/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate Transthoracic and transesophageal echocardiography adequately detect cardiogenic and aortic sources for cerebral embolism other than atrial fibrillation (see "Echocardiography in detection of cardiac and aortic sources of systemic embolism"). However, their use can be postponed to later in the hospitalization, when the patient is in a more stable clinical condition. Exceptions include patients with a moderate or high suspicion of endocarditis, where echocardiography may provide confirmation of the diagnosis. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis", section on 'Echocardiography' and "Overview of the evaluation of stroke", section on 'Cardiac evaluation'.) STROKE MANAGEMENT ISSUES In addition to stabilization of airway, breathing, and circulation, and rapid neurologic evaluation discussed above, early key management issues that often arise in acute stroke include blood pressure control (see 'Blood pressure management' below), fluid management (see 'Fluids' below), treatment of abnormal blood glucose levels (see 'Hypoglycemia' below and 'Hyperglycemia' below), swallowing assessment (see 'Swallowing assessment' below), and treatment of fever and infection (see 'Fever' below). Care in a dedicated stroke unit (see 'Stroke unit care' below) is associated with better outcomes. Fluids Intravascular volume depletion is frequent in the setting of acute stroke, particularly in older adult patients [12], and may worsen cerebral blood flow. For most patients with acute stroke and volume depletion, isotonic saline without dextrose is the agent of choice for intravascular fluid repletion and maintenance fluid therapy [13]. In general, it is best to avoid excess free water (eg, as in isotonic saline) because hypotonic fluids may exacerbate cerebral edema in acute stroke and are less useful than isotonic solutions for replacing intravascular volume. In addition, it is best to avoid fluids containing glucose, which may exacerbate hyperglycemia. However, fluid management must be individualized based on cardiovascular status, electrolyte disturbances, and other conditions that may perturb fluid balance. (See "Maintenance and replacement fluid therapy in adults".) In particular, hyponatremia following subarachnoid hemorrhage may be due to inappropriate secretion of antidiuretic hormone (SIADH) or rarely, to cerebral salt wasting; these are physiologically distinct and are treated differently, as discussed separately. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Hyponatremia'.) Hypoglycemia Hypoglycemia can cause focal neurologic deficits mimicking stroke, and severe hypoglycemia alone can cause neuronal injury. It is important to check the blood sugar and rapidly correct low serum glucose (<60 mg/dL [3.3 mmol/L]) at the first opportunity [1]. https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 7/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate Hyperglycemia Hyperglycemia, generally defined as a blood glucose level >126 mg/dL (>7.0 mmol/L), is common in patients with acute stroke and is associated with poor functional outcome [14-19]. In a series of 59 patients with acute ischemic stroke, admission hyperglycemia was present in 32 percent of patients without diabetes and 81 percent of patients with diabetes [20]. Stress hyperglycemia may be the most common cause [16], although newly diagnosed diabetes is also important [17]. Hyperglycemia may augment brain injury by several mechanisms, including increased tissue acidosis from anaerobic metabolism, free radical generation, and increased blood brain barrier permeability [21-23]. Hyperglycemia may also rarely present as a stroke mimic [24]. In light of these observations, it is reasonable to treat severe hyperglycemia in the setting of acute stroke. The American Heart Association/American Stroke Association guidelines for acute ischemic stroke recommend treatment for hyperglycemia to achieve serum glucose concentrations in the range of 140 to 180 mg/dL (7.8 to 10 mmol/L) [1]. The European Stroke Initiative guidelines recommend treatment for glucose >180 mg/dL (>10 mmol/L) [25]. Tighter control of glucose with intravenous insulin does not improve functional outcome in patients with acute ischemic stroke. The multicenter SHINE trial randomly assigned over 1100 adults with hyperglycemia and acute ischemic stroke to either intensive treatment of hyperglycemia (continuous insulin infusion with a target blood glucose concentration of 80 to 130 mg/dL) or standard treatment (subcutaneous insulin on a sliding scale with a target glucose of 80 to 179 mg/dL) [26]. At 90 days, there was no difference in the proportion of patients achieving a favorable functional outcome between the intensive and standard treatment groups (20.5 versus 21.6 percent). In addition, treatment withdrawal for hypoglycemia or other adverse events was more common in the intensive treatment group (11.2 versus 3.2 percent). Similarly, a 2014 systematic review identified 11 controlled trials involving nearly over 1500 adults with acute ischemic stroke who were randomly assigned to either intensively monitored insulin infusion therapy or to usual care; there was no difference between the treatment and control groups for the combined outcome of death or dependency, and no difference between groups for the outcome of final neurologic deficit [27]. In addition, the intervention group had a higher rate of symptomatic hypoglycemia. Swallowing assessment Dysphagia is common after stroke and is a major risk factor for developing aspiration pneumonia. It is important to assess swallowing function prior to administering oral medications or food. Thus, prevention of aspiration in patients with acute stroke includes initial nulla per os (NPO) status until swallowing function is evaluated. (See "Complications of stroke: An overview", section on 'Dysphagia'.) Note that aspirin, if and when indicated, can be given rectally. https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 8/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate Head and body position During the acute phase of stroke, the position of the patient and the head of bed should be individualized with respect to the risk of elevated intracranial pressure and aspiration, and the presence of comorbid cardiopulmonary disease [28]. We recommend keeping the head in neutral alignment with the body and elevating the head of the bed to 30 degrees for patients in the acute phase of stroke who are at risk for any of the following problems: Elevated intracranial pressure (ie, intracerebral hemorrhage, cerebral edema >24 hours from stroke onset in patients with large ischemic infarction) Aspiration (eg, those with dysphagia and/or diminished consciousness) Cardiopulmonary decompensation or oxygen desaturation (eg, those with chronic cardiac and pulmonary disease) In the absence of these problems, we suggest keeping the head of bed in the position that is most comfortable for the patient. In addition, a cervical collar or a central intravenous line dressings, if present, should be loose enough so that they do not occlude venous outflow from the head. A number of reports suggest that cerebral perfusion is maximal when patients are in the horizontal position [29-31]. As an example, in a study involving 20 patients with moderately severe ischemic stroke in the middle cerebral artery (MCA) territory, mean flow velocity in the MCA measured by transcranial Doppler increased by an average of 20 percent when the head-of- bed elevation decreased from 30 to 0 degrees, and by an average of 12 percent when head-of- bed elevation decreased from 30 to 15 degrees [30]. Furthermore, some patients with acute ischemic stroke may develop increased ischemic symptoms upon standing, sitting, or elevating the head of the bed, due to reduction in flow through stenotic vessels or collateral pathways [32,33]. Thus, some stroke experts have favored a supine position is preferred for nonhypoxic patients with acute ischemic stroke who are able to tolerate lying flat. When done, keeping the patient flat is a temporary measure that should be discontinued in most patients after 24 to 48 hours. Nevertheless, the benefit of maintaining the head flat in this setting remains unproven [34]. In the HeadPoST controlled trial of over 11,000 subjects with acute stroke (85 percent ischemic) who were randomly assigned to either a lying-flat position or a sitting-up position with the head elevated to at least 30 degrees, there was no difference between treatment groups in disability outcomes, mortality, or serious adverse events [35]. https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 9/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate Mobilization of stable patients after 24 hours may lessen the likelihood of major complications such as pneumonia, deep vein thrombosis, pulmonary embolism, and pressure sores after stroke. Exceptions may include those who exhibit neurologic deterioration upon assuming more upright postures. In addition, there is a potential increased risk of aspiration if a flat position is maintained for a prolonged period [36]. However, very early mobilization, within 24 hours of symptom onset, may be harmful [37]. The multicenter randomized AVERT trial, with over 2000 patients, evaluated a protocol of very early mobilization, which was started within 24 hours of stroke onset and consisted of frequent out- of-bed activity including sitting, standing, and walking. Compared with usual care, very early mobilization and early rehabilitative therapies reduced the odds of a favorable outcome at three months [38]. Fever The source of fever should be investigated and treated, and antipyretics should be used to lower temperature in febrile patients with acute stroke. Common etiologies of fever, including aspiration pneumonia and urinary tract infection, should also be excluded. (See "Complications of stroke: An overview", section on 'Fever and infection'.) We suggest maintaining normothermia for at least the first several days after an acute stroke [39]. However, the clinical utility of this approach has not been established. The Paracetamol (Acetaminophen) In Stroke (PAIS) trial evaluated 1400 adults no later than 12 hours after symptom onset of acute ischemic stroke or intracerebral hemorrhage [40]. Included patients had a body temperature of 36 to 39 C. Compared with placebo, paracetamol (acetaminophen) 1 g six times daily for three days did not improve outcome [40]. However, a post-hoc subgroup analysis of 661 patients with a baseline body temperature of 37 to 39 C suggested benefit for paracetamol. In a systematic review and meta-analysis of five small randomized controlled trials with a total of 293 patients, there was no benefit for pharmacologic temperature reduction for acute stroke [41]. All the trials enrolled patients within 24 hours of stroke onset, and the duration of treatment ranged from 24 hours to five days. With addition of results from the PAIS trial, the updated meta-analysis found no difference between active treatment and control for a favorable outcome (odds ratio [OR] 1.1, 95% CI 0.9-1.3) [40]. Larger trials are needed to determine if pharmacologic temperature reduction improves outcome from acute stroke, particularly for patients with temperature of 37 C, though it seems unlikely that acetaminophen will be effective by itself. In patients who are nil per os (NPO), acetaminophen is now available in the United States as an intravenous preparation. https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 10/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate Induced hypothermia is not currently recommended for patients with ischemic stroke, outside of clinical trials [1]. Stroke unit care Evidence suggests that patients with acute stroke have better outcomes when admitted to a hospital unit that is specialized for the care of patients with all types of acute stroke, including ischemic, intracerebral hemorrhage, and subarachnoid hemorrhage [42-46]. The precise components of an acute stroke unit vary between centers and countries, but generally include a hospital ward with dedicated telemetry beds that is continuously staffed by a team of physicians, nurses and other personnel who specialize in stroke care, emphasizing expertise in vascular neurology and neurosurgery [47,48]. Additional components include prompt availability of neuroimaging (eg, CT, MRI, various types of angiography, ultrasound, transcranial Doppler) and cardiac imaging. Implementation of stroke protocols and disease- performance measures may contribute to improved outcomes and decreased risk of stroke- related complications, as shown in some reports [49,50]. Current national guidelines support stroke unit care, when available, for patients with suspected acute stroke [1,51]. BLOOD PRESSURE MANAGEMENT The approach to blood pressure management in acute ischemic stroke is inherently different from the approach in acute hemorrhagic stroke. For this reason, a neuroimaging study with CT or MRI is critical to help guide blood pressure therapy in patients with acute stroke. Likewise, there are important differences between the blood pressure management in the acute and chronic phases of stroke. The management of blood pressure in acute phase of stroke is reviewed in the sections that follow. The management of blood pressure after the acute phase of stroke is discussed separately. (See "Antihypertensive therapy for secondary stroke prevention".) Blood pressure in acute ischemic stroke The long-term benefit from antihypertensive therapy does not mean that a reduction in blood pressure will be beneficial during initial management of an acute ischemic stroke [52]. In patients with ischemic stroke, the perfusion pressure distal to the obstructed vessel is low, and the distal vessels are dilated. Because of impaired cerebral autoregulation ( figure 2), blood flow in these dilated vessels is thought to be dependent upon the systemic blood pressure. The arterial blood pressure is usually elevated in patients with an acute stroke. This may be due to chronic hypertension, an acute sympathetic response, or other stroke-mediated mechanisms https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 11/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate [53]. In many cases, however, the acutely elevated blood pressure is necessary to maintain brain perfusion in borderline ischemic areas [54]. The observation that the blood pressure frequently rises spontaneously following cerebral ischemia is consistent with this protective hypothesis, although a stress response to the acute event and to hospitalization may also contribute [55]. The hypertensive effect is transient, as blood pressure falls by as much as 20/10 mmHg within 10 days. An analysis from the International Stroke Trial of 17,398 patients with an ischemic stroke noted a U-shaped relationship between baseline systolic blood pressure and outcomes [56]. Elevated systolic blood pressure was associated with an increased risk of recurrent ischemic stroke (50 percent greater risk of recurrence with a systolic blood pressure of >200 mmHg versus 130 mmHg), while low blood pressure (particularly <120 mmHg) was associated with an excess number of deaths from coronary heart disease. A subsequent analysis of 1004 patients with acute ischemic stroke from Okinawa also found a U- shaped relationship between admission blood pressure and death within 30 days after stroke onset [57]. The U-shaped relationship was shifted toward higher pressure in patients who had previous hypertension compared with those who did not have previous hypertension. This finding mirrors the shift seen in cerebral autoregulation that occurs in longstanding hypertension ( figure 2) [58]. Effect of lowering blood pressure There are few data from randomized controlled trials specifically designed to guide blood pressure management in the acute phase of ischemic stroke (ie, the first 24 hours) when the ischemic penumbra may be at risk of irreversible damage if cerebral blood flow is reduced by lowering the blood pressure [59]. The MAPAS trial found no clear benefit for blood pressure lowering within 12 hours of acute ischemic stroke onset, but an adjusted analysis suggested that a goal systolic blood pressure of 161 to 180 mmHg increased the odds of a good outcome compared with higher or lower goal blood pressures [60]. The RIGHT-2 trial found that lowering blood pressure within four hours of onset of suspected stroke did not improve functional outcomes; the results are confounded by inclusion of patients with transient ischemic attack (TIA), intracerebral hemorrhage, and stroke mimics [61]. Lowering the systemic blood pressure in patients within 24 hours of acute ischemic stroke onset has been associated with clinical deterioration in several observational studies [62-64]. Other large trials (eg, CATIS [65], SCAST [66], COSSACS [67], and ENOS [68]) enrolled patients as long as 30 to 48 hours after stroke onset, and are therefore less informative regarding the impact of blood pressure treatment in the first hours of ischemic stroke. In addition, many of these trials, including the meta-analyses discussed below, enrolled patients with intracerebral https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 12/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate hemorrhage, a group that might be expected to benefit from early blood pressure lowering. Keeping these limitations in mind, some of the randomized trial data suggest that initiating blood pressure reduction in acute stroke or merely continuing prestroke blood pressure medications can be harmful: In a 2014 meta-analysis of 16 trials (including ENOS) of antihypertensive medications that included over 19,000 patients with acute stroke, early blood pressure reduction had no effect on functional outcome (OR 1.0, 95% CI 0.93-1.07) [68]. Similarly, a 2015 meta-analysis of 13 randomized trials (also including ENOS) and over 12,000 subjects found that blood pressure lowering started within three days of ischemic stroke onset did not alter the risk of death or dependency at three months or trial end point (relative risk, 1.04, 95% CI 0.96- 1.13) [69]. A meta-analysis of individual patient data from COSSACS and ENOS trials found that continuing versus stopping antihypertensive treatment had no effect on the risk of death or dependency at final follow-up [70]. However, in a subgroup analysis, patients who stopped antihypertensives within 12 hours of stroke onset showed a nonsignificant trend towards less death or dependency. In the ENOS trial itself, the group assigned to continuing blood pressure treatment had an increased likelihood of hospital death or discharge to an institution, an increased risk of death or disability (Barthel index <60) at 90 days, and significantly lower cognition scores at 90 days compared with the group that stopped treatment, even though there was no difference in functional outcome between the two groups [68]. These results are not definitive for the reasons noted above. Blood pressure goals in ischemic stroke Special considerations apply to blood pressure control in patients with acute ischemic stroke who are eligible for intravenous thrombolytic therapy. Before thrombolytic therapy is started, treatment is recommended so that systolic blood pressure is 185 mmHg and diastolic blood pressure is 110 mmHg ( table 6) [1]. The blood pressure should be stabilized and maintained at or below 180/105 mmHg for at least 24 hours after thrombolytic treatment. This issue is discussed in detail separately. (See "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use", section on 'Management of blood pressure'.) For patients with ischemic stroke who are not treated with thrombolytic therapy, blood pressure should not be treated acutely unless the hypertension is extreme (systolic blood pressure >220 mmHg or diastolic blood pressure >120 mmHg), or the patient has active ischemic coronary disease, heart failure, aortic dissection, hypertensive encephalopathy, or pre- https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 13/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate eclampsia/eclampsia [1,71]. When treatment is indicated, cautious lowering of blood pressure by approximately 15 percent during the first 24 hours after stroke onset is suggested. It is reasonable to start or restart antihypertensive medications during hospitalization for patients with blood pressure >140/90 mmHg who are neurologically stable, unless contraindicated [1]. This can be done as early as 24 to 48 hours after stroke onset for most hospitalized patients, with the goal of gradually controlling hypertension within a few days to a week [72]. Importantly, patients with extracranial or intracranial large artery stenoses may require a slower reduction in blood pressure (eg, over 7 to 14 days after ischemic stroke), as some degree of blood pressure elevation may be necessary to maintain cerebral blood flow to ischemic brain regions. For this reason, we suggest not restarting antihypertensive agents until after vascular imaging is completed and a symptomatic large artery stenosis is excluded. If acute antihypertensive therapy is needed, intravenous agents are generally used. (See 'Choice of antihypertensive agent' below.) Systemic hypotension and hypovolemia should be corrected to improve cerebral blood flow and systemic organ function [1]. However, drug-induced hypertension is unproven for the treatment of ischemic stroke. Choice of antihypertensive agent In the acute phase of stroke, there is no good evidence to support the use of any specific antihypertensive agent to achieve recommended blood pressure goals. Nevertheless, reversible and titratable intravenous agents are best suited for precise blood pressure lowering. Consensus guidelines suggest intravenous labetalol, nicardipine, and clevidipine as first-line antihypertensive agents if pharmacologic therapy is necessary in the acute phase, since they allow rapid and safe titration to the goal blood pressure ( table 6) [1]. Intravenous nitroprusside should be considered second-line therapy since it carries added theoretical risks of increasing intracranial pressure or affecting platelet function. Medications likely to cause a prolonged or precipitous decline in blood pressure (eg, rapid-acting formulations of nifedipine) should be avoided. In addition, their use is associated with an

An analysis from the International Stroke Trial of 17,398 patients with an ischemic stroke noted a U-shaped relationship between baseline systolic blood pressure and outcomes [56]. Elevated systolic blood pressure was associated with an increased risk of recurrent ischemic stroke (50 percent greater risk of recurrence with a systolic blood pressure of >200 mmHg versus 130 mmHg), while low blood pressure (particularly <120 mmHg) was associated with an excess number of deaths from coronary heart disease. A subsequent analysis of 1004 patients with acute ischemic stroke from Okinawa also found a U- shaped relationship between admission blood pressure and death within 30 days after stroke onset [57]. The U-shaped relationship was shifted toward higher pressure in patients who had previous hypertension compared with those who did not have previous hypertension. This finding mirrors the shift seen in cerebral autoregulation that occurs in longstanding hypertension ( figure 2) [58]. Effect of lowering blood pressure There are few data from randomized controlled trials specifically designed to guide blood pressure management in the acute phase of ischemic stroke (ie, the first 24 hours) when the ischemic penumbra may be at risk of irreversible damage if cerebral blood flow is reduced by lowering the blood pressure [59]. The MAPAS trial found no clear benefit for blood pressure lowering within 12 hours of acute ischemic stroke onset, but an adjusted analysis suggested that a goal systolic blood pressure of 161 to 180 mmHg increased the odds of a good outcome compared with higher or lower goal blood pressures [60]. The RIGHT-2 trial found that lowering blood pressure within four hours of onset of suspected stroke did not improve functional outcomes; the results are confounded by inclusion of patients with transient ischemic attack (TIA), intracerebral hemorrhage, and stroke mimics [61]. Lowering the systemic blood pressure in patients within 24 hours of acute ischemic stroke onset has been associated with clinical deterioration in several observational studies [62-64]. Other large trials (eg, CATIS [65], SCAST [66], COSSACS [67], and ENOS [68]) enrolled patients as long as 30 to 48 hours after stroke onset, and are therefore less informative regarding the impact of blood pressure treatment in the first hours of ischemic stroke. In addition, many of these trials, including the meta-analyses discussed below, enrolled patients with intracerebral https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 12/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate hemorrhage, a group that might be expected to benefit from early blood pressure lowering. Keeping these limitations in mind, some of the randomized trial data suggest that initiating blood pressure reduction in acute stroke or merely continuing prestroke blood pressure medications can be harmful: In a 2014 meta-analysis of 16 trials (including ENOS) of antihypertensive medications that included over 19,000 patients with acute stroke, early blood pressure reduction had no effect on functional outcome (OR 1.0, 95% CI 0.93-1.07) [68]. Similarly, a 2015 meta-analysis of 13 randomized trials (also including ENOS) and over 12,000 subjects found that blood pressure lowering started within three days of ischemic stroke onset did not alter the risk of death or dependency at three months or trial end point (relative risk, 1.04, 95% CI 0.96- 1.13) [69]. A meta-analysis of individual patient data from COSSACS and ENOS trials found that continuing versus stopping antihypertensive treatment had no effect on the risk of death or dependency at final follow-up [70]. However, in a subgroup analysis, patients who stopped antihypertensives within 12 hours of stroke onset showed a nonsignificant trend towards less death or dependency. In the ENOS trial itself, the group assigned to continuing blood pressure treatment had an increased likelihood of hospital death or discharge to an institution, an increased risk of death or disability (Barthel index <60) at 90 days, and significantly lower cognition scores at 90 days compared with the group that stopped treatment, even though there was no difference in functional outcome between the two groups [68]. These results are not definitive for the reasons noted above. Blood pressure goals in ischemic stroke Special considerations apply to blood pressure control in patients with acute ischemic stroke who are eligible for intravenous thrombolytic therapy. Before thrombolytic therapy is started, treatment is recommended so that systolic blood pressure is 185 mmHg and diastolic blood pressure is 110 mmHg ( table 6) [1]. The blood pressure should be stabilized and maintained at or below 180/105 mmHg for at least 24 hours after thrombolytic treatment. This issue is discussed in detail separately. (See "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use", section on 'Management of blood pressure'.) For patients with ischemic stroke who are not treated with thrombolytic therapy, blood pressure should not be treated acutely unless the hypertension is extreme (systolic blood pressure >220 mmHg or diastolic blood pressure >120 mmHg), or the patient has active ischemic coronary disease, heart failure, aortic dissection, hypertensive encephalopathy, or pre- https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 13/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate eclampsia/eclampsia [1,71]. When treatment is indicated, cautious lowering of blood pressure by approximately 15 percent during the first 24 hours after stroke onset is suggested. It is reasonable to start or restart antihypertensive medications during hospitalization for patients with blood pressure >140/90 mmHg who are neurologically stable, unless contraindicated [1]. This can be done as early as 24 to 48 hours after stroke onset for most hospitalized patients, with the goal of gradually controlling hypertension within a few days to a week [72]. Importantly, patients with extracranial or intracranial large artery stenoses may require a slower reduction in blood pressure (eg, over 7 to 14 days after ischemic stroke), as some degree of blood pressure elevation may be necessary to maintain cerebral blood flow to ischemic brain regions. For this reason, we suggest not restarting antihypertensive agents until after vascular imaging is completed and a symptomatic large artery stenosis is excluded. If acute antihypertensive therapy is needed, intravenous agents are generally used. (See 'Choice of antihypertensive agent' below.) Systemic hypotension and hypovolemia should be corrected to improve cerebral blood flow and systemic organ function [1]. However, drug-induced hypertension is unproven for the treatment of ischemic stroke. Choice of antihypertensive agent In the acute phase of stroke, there is no good evidence to support the use of any specific antihypertensive agent to achieve recommended blood pressure goals. Nevertheless, reversible and titratable intravenous agents are best suited for precise blood pressure lowering. Consensus guidelines suggest intravenous labetalol, nicardipine, and clevidipine as first-line antihypertensive agents if pharmacologic therapy is necessary in the acute phase, since they allow rapid and safe titration to the goal blood pressure ( table 6) [1]. Intravenous nitroprusside should be considered second-line therapy since it carries added theoretical risks of increasing intracranial pressure or affecting platelet function. Medications likely to cause a prolonged or precipitous decline in blood pressure (eg, rapid-acting formulations of nifedipine) should be avoided. In addition, their use is associated with an increased risk of stroke, particularly in older adult patients [73]. Blood pressure in acute hemorrhagic stroke In both intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH), the approach to blood pressure management must take into account the potential benefits (eg, reducing further bleeding) and risks (eg, reducing cerebral perfusion) of blood pressure lowering. Recommendations for blood pressure management in acute ICH and SAH are discussed in detail separately. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Blood pressure management' and https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 14/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Blood pressure control'.) ACUTE THERAPY Ischemic stroke management For eligible patients ( table 2) with acute ischemic stroke, intravenous thrombolysis is first-line therapy, provided that treatment is initiated within 4.5 hours of symptom onset or the time last known to be well (ie, at neurologic baseline). Because the benefit of intravenous thrombolysis is time dependent, it is critical to treat patients as quickly as possible. Mechanical thrombectomy ( algorithm 1) is indicated for patients with acute ischemic stroke due to a large artery occlusion in the anterior circulation who can be treated within 24 hours of symptom onset or the time last known to be well at stroke centers with appropriate expertise, regardless of whether they receive intravenous thrombolytic therapy for the same ischemic stroke event. The eligibility criteria and utility of thrombolytic therapy, endovascular thrombectomy, and the treatment of patients not eligible for thrombolysis are discussed separately. (See "Approach to reperfusion therapy for acute ischemic stroke" and "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".) In addition to intravenous thrombolysis and endovascular thrombectomy, a number of interventions for ischemic stroke are associated with either reduced disability, complications, or stroke recurrence, including: Antithrombotic therapy with aspirin initiated within 48 hours of stroke onset (see "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Efficacy of aspirin') Prophylaxis for deep venous thrombosis and pulmonary embolism (see "Prevention and treatment of venous thromboembolism in patients with acute stroke", section on 'Approach to VTE prevention') Antithrombotic therapy at discharge (see "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke" and "Atrial fibrillation in adults: Use of oral anticoagulants") Lipid lowering with high intensity statin therapy (see "Overview of secondary prevention of ischemic stroke", section on 'LDL-C lowering therapy') https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 15/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate Blood pressure reduction after the acute phase of ischemic stroke has passed (see "Antihypertensive therapy for secondary stroke prevention" and "Overview of secondary prevention of ischemic stroke"); management of blood pressure in the acute phase of ischemic stroke is discussed above (see 'Blood pressure management' above) Behavioral and lifestyle changes including smoking cessation, exercise, weight reduction for patients with obesity, and a Mediterranean style diet (see "Overview of secondary prevention of ischemic stroke" and "Overview of smoking cessation management in adults") Appropriate and timely use of these therapies should be considered as soon as ischemic stroke is recognized. Utilization of these interventions may be improved by the use of standardized stroke care orders or critical pathways beginning with hospital admission through discharge [1,74]. Full-dose anticoagulation is rarely indicated in the hyperacute phase of ischemic stroke, although low-dose heparin anticoagulation is often used for prevention of venous thromboembolism in patients with restricted mobility. (See "Prevention and treatment of venous thromboembolism in patients with acute stroke".) The main indication for oral anticoagulation after ischemic stroke is atrial fibrillation. When indicated, oral anticoagulation can be started immediately for patients with a transient ischemic attack, and soon after ischemic stroke onset for medically stable patients with a small- or moderate-sized infarct and no bleeding complications or uncontrolled hypertension. For patients with atrial fibrillation who have a large infarct, symptomatic hemorrhagic transformation, or poorly controlled hypertension, withholding oral anticoagulation for one to two weeks is generally recommended. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Cardioembolic source'.) Statin therapy For patients with acute ischemic stroke, we suggest starting or continuing statin treatment as soon as oral medications can be used safely. There is clear evidence that long-term intensive statin therapy is associated with a reduced risk of recurrent ischemic stroke and cardiovascular events, as discussed separately (see "Overview of secondary prevention of ischemic stroke", section on 'LDL-C lowering therapy'). The utility of statin therapy during the acute phase of ischemic stroke is less well studied, but is supported by the following observations: A single-center randomized controlled trial of 89 patients who were already treated with a statin and were assigned to continuation or cessation of statin therapy in the acute https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 16/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate phase of ischemic stroke [75]. The rate of death or dependency at three months was significantly lower with continuation of statin treatment (39 versus 60 percent). An observational study, which evaluated over 12,000 subjects hospitalized with ischemic stroke, found that statin use before and during hospitalization was associated with improved outcome at hospital discharge and with improved survival at one year [76,77]. Furthermore, initiation of statin treatment early in hospitalization was associated with improved survival, while statin discontinuation early in hospitalization, even for a short period, was associated with decreased survival. An uncontrolled study of 448 patients reported that new or continued statin treatment in the first 72 hours after acute ischemic stroke was associated with improved early and late (one-year) survival [78]. An observational study of 2072 patients who received intravenous thrombolysis for acute ischemic stroke found that statin treatment started within 72 hours of thrombolysis was associated with a favorable functional outcome and a reduced risk of death at three months [79]. Of the 839 patients treated with statins, 65 percent were statin na ve. SSRIs For patients with hemiparesis but without depression after ischemic stroke, evidence from a few small randomized controlled trials (including the FLAME trial) suggested that early initiation of selective serotonin-reuptake inhibitors (SSRIs) enhanced motor recovery and reduced dependency [80-82]. However, subsequent randomized controlled trials, including the FOCUS, AFFINITY, and EFFECTS trials, which together enrolled over 5900 adult patients with acute ischemic stroke or intracerebral hemorrhage, found no benefit in functional outcome at six months for treatment with fluoxetine compared with placebo [83-85]. Treatment with fluoxetine reduced the risk of developing depression in FOCUS and EFFECTS but increased the risk of bone fractures in all three trials, increased the risks of falls and epileptic seizures in AFFINITY, and increased the risk of hyponatremia in EFFECTS. Intracranial hemorrhage management The treatment of patients with intracerebral hemorrhage or subarachnoid hemorrhage is reviewed in detail elsewhere. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis" and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis" and "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use", section on 'Management of symptomatic intracerebral hemorrhage'.) https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 17/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate Neuroprotective treatment Numerous neuroprotective agents have shown promising results in animal experiments. However, clinical trials have thus far failed to confirm consistent benefit [86]. This failure may be due, at least in part, to limitations of animal models of acute stroke and to shortcomings of clinical trials. The search for effective neuroprotective treatment continues [86-91]. As examples, nerinetide and remote ischemic conditioning have shown signals suggesting benefit in clinical trials [91- 94]. More study is needed to determine if these treatments are safe and effective for acute ischemic stroke. PREVENTION OF COMPLICATIONS The prevention of medical complications of stroke is an important goal of stroke management, and this aspect of care begins with initial evaluation of the patient. Common acute and subacute medical problems associated with stroke include: Myocardial infarction Heart failure Dysphagia Aspiration pneumonia Urinary tract infection Deep vein thrombosis Pulmonary embolism Dehydration Malnutrition Pressure sores Orthopedic complications and contractures The prevention, impact, and management of these complications are discussed separately. (See "Complications of stroke: An overview" and "Prevention and treatment of venous thromboembolism in patients with acute stroke".) Delirium, characterized by a disturbance of consciousness with decreased attention and disorganized thinking, is another potential complication of stroke [95]. Findings from systematic reviews and meta-analyses suggest that the rate of post-stroke delirium is approximately 25 percent [96,97]. Patients with delirium have longer hospital stays and higher inpatient and 12- month mortality rates [96]. Risk factors for developing post-stroke delirium include preexisting cognitive decline, infection, and greater stroke severity [98]. (See "Diagnosis of delirium and https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 18/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate confusional states" and "Delirium and acute confusional states: Prevention, treatment, and prognosis".) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Stroke (The Basics)" and "Patient education: Hemorrhagic stroke (The Basics)") Beyond the Basics topics (see "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)" and "Patient education: Ischemic stroke treatment (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Main goals of initial evaluation The main goals in the initial phase of acute stroke management are to ensure medical stability, to quickly reverse conditions that are contributing to the patient's problem, to determine if patients with acute ischemic stroke are candidates for reperfusion therapy, and to begin to uncover the pathophysiologic basis of the neurologic symptoms. (See 'Initial assessment' above.) https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 19/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate Important aspects of immediate assessment Important aspects of acute stroke evaluation and management include the following: Vital signs Assess vital signs and stabilize airway, breathing, and circulation. (See 'Airway, breathing and circulation' above.) Rapid history and examination Obtain a rapid but accurate history and examination to help distinguish stroke mimics and other disorders in the differential diagnosis ( table 1) of acute stroke. (See 'History and physical' above and 'Neurologic evaluation' above.) Urgent brain imaging Obtain urgent brain imaging (with CT or MRI), neurovascular imaging (with CT angiography or magnetic resonance angiography [MRA]) and other important laboratory studies, including cardiac monitoring during the first 24 hours after the onset of ischemic stroke. (See 'Immediate laboratory studies' above and 'Neuroimaging' above and 'Cardiac studies' above.) Fluid management Manage volume depletion and electrolyte disturbances. (See 'Fluids' above.) Check serum glucose Low serum glucose (<60 mg/dL [3.3 mmol/L]) should be corrected rapidly. It is reasonable to treat hyperglycemia if the glucose level is >180 mg/dL (>10 mmol/L) with a goal of keeping serum glucose levels within a range of 140 to 180 mg/dL (7.8 to 10 mmol/L). Check swallowing All patients with acute stroke should be assessed for ability to swallow in order to prevent aspiration. (See 'Swallowing assessment' above and "Complications of stroke: An overview", section on 'Dysphagia'.) Optimize head of bed position For patients with intracerebral hemorrhage, subarachnoid hemorrhage, or ischemic stroke who are at risk for elevated intracranial pressure, aspiration, cardiopulmonary decompensation, or oxygen desaturation, we recommend keeping the head in neutral alignment with the body and elevating the head of the bed to 30 degrees (Grade 1C). For patients with stroke who are not at high risk for these complications, we suggest keeping the head of the bed in the position that is most comfortable. (See 'Head and body position' above.) Check for fever Evaluate and treat the source of fever, if present; for patients with acute stroke, we suggest maintaining normothermia for at least the first several days after an acute stroke (Grade 2C). (See 'Fever' above.) https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 20/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate Blood pressure management The management of blood pressure in acute stroke depends on the type of stroke and anticipated treatment. (See 'Blood pressure management' above.) Thrombolytic therapy For patients with acute ischemic stroke who will receive intravenous thrombolytic therapy, antihypertensive treatment is recommended so that systolic blood pressure is 185 mmHg and diastolic blood pressure is 110 mmHg prior to treatment and <180/105 mmHg for the first 24 hours after treatment ( table 6). This issue is discussed in detail separately. (See "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use", section on 'Management of blood pressure'.) No thrombolytic therapy For patients with acute ischemic stroke who are not treated with thrombolytic therapy, we suggest treating high blood pressure only if the hypertension is extreme (systolic blood pressure >220 mmHg or diastolic blood pressure >120 mmHg), or if the patient has another clear indication (active ischemic coronary disease, heart failure, aortic dissection, hypertensive encephalopathy, or pre- eclampsia/eclampsia) (Grade 2C). When treatment is indicated, we suggest cautious lowering of blood pressure by approximately 15 percent during the first 24 hours after stroke onset (Grade 2C). (See 'Blood pressure goals in ischemic stroke' above.) Hemorrhagic stroke In both intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH), the approach to blood pressure lowering must account for the potential benefits (eg, reducing further bleeding) and risks (eg, reducing cerebral perfusion). Recommendations for blood pressure management in acute ICH and SAH are discussed in detail separately. (See 'Blood pressure in acute hemorrhagic stroke' above and "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Blood pressure management' and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Blood pressure control'.) Eligibility for reperfusion therapy For eligible patients ( table 2) with acute ischemic stroke, intravenous thrombolytic therapy is first-line therapy, provided that treatment is initiated within 4.5 hours of clearly defined symptom onset. Patients with acute ischemic stroke due to a proximal large artery occlusion who can be treated within 24 hours of time last known to be at neurologic baseline should be evaluated for treatment with mechanical thrombectomy ( algorithm 1). The eligibility criteria and utility of thrombolytic therapy, mechanical thrombectomy, and the treatment of patients not eligible for thrombolysis are discussed separately. (See "Approach to reperfusion therapy for acute ischemic stroke" and "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".) https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 21/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate Other early interventions that improve outcome In addition to reperfusion therapy, a number of interventions for ischemic stroke are associated with either reduced disability, complications, or stroke recurrence, including (see 'Acute therapy' above): Antiplatelet therapy Antiplatelet agents should be started as soon as possible after the diagnosis of ischemic stroke is confirmed, even before the evaluation for ischemic mechanism is complete. 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European Stroke Initiative Executive Committee, EUSI Writing Committee, Olsen TS, et al. European Stroke Initiative Recommendations for Stroke Management-update 2003. Cerebrovasc Dis 2003; 16:311. 26. Johnston KC, Bruno A, Pauls Q, et al. Intensive vs Standard Treatment of Hyperglycemia and Functional Outcome in Patients With Acute Ischemic Stroke: The SHINE Randomized Clinical Trial. JAMA 2019; 322:326. 27. Bellolio MF, Gilmore RM, Ganti L. Insulin for glycaemic control in acute ischaemic stroke. Cochrane Database Syst Rev 2014; :CD005346. 28. Summers D, Leonard A, Wentworth D, et al. Comprehensive overview of nursing and interdisciplinary care of the acute ischemic stroke patient: a scientific statement from the American Heart Association. Stroke 2009; 40:2911. 29. Schwarz S, Georgiadis D, Aschoff A, Schwab S. Effects of body position on intracranial pressure and cerebral perfusion in patients with large hemispheric stroke. 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Topic 1126 Version 77.0 https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 29/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate GRAPHICS Acute stroke differential diagnosis Migraine aura Seizure with postictal paresis (Todd paralysis), aphasia, or neglect Central nervous system tumor or abscess Cerebral venous thrombosis Functional deficit (conversion reaction) Hypertensive encephalopathy Head trauma Mitochondrial disorder (eg, mitochondrial encephalopathy with lactic acidosis and stroke-like episodes or MELAS) Multiple sclerosis Posterior reversible encephalopathy syndrome (PRES) Reversible cerebral vasoconstriction syndromes (RCVS) Spinal cord disorder (eg, compressive myelopathy, spinal dural arteriovenous fistula) Subdural hematoma Syncope Systemic infection Toxic-metabolic disturbance (eg, hypoglycemia, exogenous drug intoxication) Transient global amnesia Viral encephalitis (eg, herpes simplex encephalitis) Wernicke encephalopathy Graphic 69869 Version 7.0 https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 30/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate Eligibility criteria for the treatment of acute ischemic stroke with intravenous thrombolysis (recombinant tissue plasminogen activator or tPA) Inclusion criteria Clinical diagnosis of ischemic stroke causing measurable neurologic deficit Onset of symptoms <4.5 hours before beginning treatment; if the exact time of stroke onset is not known, it is defined as the last time the patient was known to be normal or at neurologic baseline Age 18 years Exclusion criteria Patient history Ischemic stroke or severe head trauma in the previous three months Previous intracranial hemorrhage Intra-axial intracranial neoplasm Gastrointestinal malignancy Gastrointestinal hemorrhage in the previous 21 days Intracranial or intraspinal surgery within the prior three months Clinical Symptoms suggestive of subarachnoid hemorrhage Persistent blood pressure elevation (systolic 185 mmHg or diastolic 110 mmHg) Active internal bleeding Presentation consistent with infective endocarditis Stroke known or suspected to be associated with aortic arch dissection Acute bleeding diathesis, including but not limited to conditions defined under 'Hematologic' Hematologic 3 Platelet count <100,000/mm * Current anticoagulant use with an INR >1.7 or PT >15 seconds or aPTT >40 seconds* Therapeutic doses of low molecular weight heparin received within 24 hours (eg, to treat VTE and ACS); this exclusion does not apply to prophylactic doses (eg, to prevent VTE) Current use (ie, last dose within 48 hours in a patient with normal renal function) of a direct thrombin inhibitor or direct factor Xa inhibitor with evidence of anticoagulant effect by laboratory tests such as aPTT, INR, ECT, TT, or appropriate factor Xa activity assays Head CT Evidence of hemorrhage https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 31/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate Extensive regions of obvious hypodensity consistent with irreversible injury Warnings Only minor and isolated neurologic signs or rapidly improving symptoms Serum glucose <50 mg/dL (<2.8 mmol/L) Serious trauma in the previous 14 days Major surgery in the previous 14 days History of gastrointestinal bleeding (remote) or genitourinary bleeding Seizure at the onset of stroke with postictal neurologic impairments Pregnancy** Arterial puncture at a noncompressible site in the previous seven days Large ( 10 mm), untreated, unruptured intracranial aneurysm Untreated intracranial vascular malformation Additional warnings for treatment from 3 to 4.5 hours from symptom onset Age >80 years Oral anticoagulant use regardless of INR Severe stroke (NIHSS score >25) Combination of both previous ischemic stroke and diabetes mellitus ACS: acute coronary syndrome; aPTT: activated partial thromboplastin time; ECT: ecarin clotting time; INR: international normalized ratio; PT: prothrombin time; NIHSS: National Institutes of Health Stroke Scale; tPA: intravenous alteplase; TT: thrombin time; VTE: venous thromboembolism. Although it is desirable to know the results of these tests, thrombolytic therapy should not be delayed while results are pending unless (1) there is clinical suspicion of a bleeding abnormality or thrombocytopenia, (2) the patient is currently on or has recently received anticoagulants (eg, heparin, warfarin, a direct thrombin inhibitor, or a direct factor Xa inhibitor), or (3) use of anticoagulants is not known. Otherwise, treatment with intravenous tPA can be started before availability of coagulation test results but should be discontinued if the INR, PT, or aPTT exceed the limits stated in the table, or 3 if platelet count is <100,000 mm . With careful consideration and weighting of risk-to-benefit, patients may receive intravenous alteplase despite one or more warnings. Patients who have a persistent neurologic deficit that is potentially disabling, despite improvement of any degree, should be treated with tPA in the absence of other contraindications. Any of the following should be considered disabling deficits: Complete hemianopia: 2 on NIHSS question 3, or Severe aphasia: 2 on NIHSS question 9, or Visual or sensory extinction: 1 on NIHSS question 11, or Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6, or Any deficits that lead to a total NIHSS >5, or https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 32/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate Any remaining deficit considered potentially disabling in the view of the patient and the treating practitioner using clinical judgment Patients may be treated with intravenous alteplase if glucose level is subsequently normalized. The potential risks of bleeding with alteplase from injuries related to the trauma should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. The increased risk of surgical site bleeding with alteplase should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. There is a low increased risk of new bleeding with alteplase in the setting of past gastrointestinal or genitourinary bleeding. However, alteplase administration within 21 days of gastrointestinal bleeding is not recommended. Alteplase is reasonable in patients with a seizure at stroke onset if evidence suggests that residual impairments are secondary to acute ischemic stroke and not to a postictal phenomenon. * Alteplase can be given in pregnancy when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding. The safety and efficacy of administering alteplase is uncertain for these relative exclusions. Although these were exclusions in the trial showing benefit in the 3 to 4.5 hour window, intravenous alteplase appears to be safe and may be beneficial for patients with these criteria, including patients taking oral anticoagulants with an INR <1.7. Adapted from: 1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359:1317. 2. Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke Association. Stroke 2009; 40:2945. 3. Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force:, Levine SR, Khatri P, et al. Review, historical context, and clari cations of the NINDS rt-PA stroke trials exclusion criteria: Part 1: rapidly improving stroke symptoms. Stroke 2013; 44:2500. 4. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scienti c rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2016; 47:581. 5. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. Graphic 71462 Version 26.0 https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 33/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate Headache and vomiting in stroke subtypes The frequency of sentinel headache, onset headache, and vomiting in three subtypes of stroke: subarachnoid hemorrhage, intraparenchymal (intracerebral) hemorrhage, and ischemic stroke. Onset headache was present in virtually all patients with SAH and about one-half of those with IPH; all of these symptoms were infrequent in patients with IS. SAH: subarachnoid hemorrhage; IPH: intraparenchymal (intracerebral) hemorrhage; IS: ischemic stroke. Data from: Gorelick PB, Hier DB, Caplan LR, Langenberg P. Headache in acute cerebrovascular disease. Neurology 1986; 36:1445. Graphic 60831 Version 4.0 https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 34/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate Acute ischemic stroke syndromes according to vascular territory Artery involved Syndrome Anterior cerebral artery Motor and/or sensory deficit (leg > face, arm) Grasp, sucking reflexes Abulia, paratonic rigidity, gait apraxia Middle cerebral artery Dominant hemisphere: aphasia, motor and sensory deficit (face, arm > leg > foot), may be complete hemiplegia if internal capsule involved, homonymous hemianopia Non-dominant hemisphere: neglect, anosognosia, motor and sensory deficit (face, arm > leg > foot), homonymous hemianopia Posterior cerebral artery Homonymous hemianopia; alexia without agraphia (dominant hemisphere); visual hallucinations, visual perseverations (calcarine cortex); sensory loss, choreoathetosis, spontaneous pain (thalamus); III nerve palsy, paresis of vertical eye movement, motor deficit (cerebral peduncle, midbrain) Penetrating vessels Pure motor hemiparesis (classic lacunar syndromes) Pure sensory deficit Pure sensory-motor deficit Hemiparesis, homolateral ataxia Dysarthria/clumsy hand Vertebrobasilar Cranial nerve palsies Crossed sensory deficits Diplopia, dizziness, nausea, vomiting, dysarthria, dysphagia, hiccup Limb and gait ataxia Motor deficit Coma Bilateral signs suggest basilar artery disease Internal carotid artery Progressive or stuttering onset of MCA syndrome, occasionally ACA syndrome as well if insufficient collateral flow Graphic 75487 Version 7.0 https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 35/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate National Institutes of Health Stroke Scale (NIHSS) Administer stroke scale items in the order listed. Record performance in each category after each subscale exam. Do not go back and change scores. Follow directions provided for each exam technique. Scores should reflect what the patient does, not what the clinician thinks the patient can do. The clinician should record answers while administering the exam and work quickly. Except where indicated, the patient should not be coached (ie, repeated requests to patient to make a special effort). Instructions Scale definition Score 1a. Level of consciousness: The 0 = Alert; keenly responsive. investigator must choose a response if a full evaluation is prevented by such obstacles as 1 = Not alert; but arousable by minor stimulation to obey, answer, or respond. an endotracheal tube, language barrier, 2 = Not alert; requires repeated stimulation orotracheal trauma/bandages. A 3 is scored only if the patient makes no movement to attend, or is obtunded and requires strong or painful stimulation to make movements (not stereotyped). _____ (other than reflexive posturing) in response to noxious stimulation. 3 = Responds only with reflex motor or autonomic effects or totally unresponsive, flaccid, and areflexic. 1b. Level of consciousness questions: The 0 = Answers both questions correctly. patient is asked the month and his/her age. The answer must be correct - there is no partial credit for being close. Aphasic and stuporous patients who do not comprehend the questions will score 2. Patients unable to speak because of endotracheal intubation, orotracheal trauma, severe dysarthria from 1 = Answers one question correctly. 2 = Answers neither question correctly. _____ any cause, language barrier, or any other problem not secondary to aphasia are given a 1. It is important that only the initial answer be graded and that the examiner not "help" the patient with verbal or non-verbal cues. 1c. Level of consciousness commands: The 0 = Performs both tasks correctly. _____ patient is asked to open and close the eyes and then to grip and release the non-paretic 1 = Performs one task correctly. 2 = Performs neither task correctly. hand. Substitute another one step command if the hands cannot be used. Credit is given if an unequivocal attempt is made but not completed due to weakness. If the patient does not respond to command, the task should be demonstrated to him or her (pantomime), and the result scored (ie, https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 36/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate follows none, one or two commands). Patients with trauma, amputation, or other physical impediments should be given suitable one-step commands. Only the first attempt is scored. 2. Best gaze: Only horizontal eye movements will be tested. Voluntary or 0 = Normal. 1 = Partial gaze palsy; gaze is abnormal in reflexive (oculocephalic) eye movements will one or both eyes, but forced deviation or total gaze paresis is not present. be scored, but caloric testing is not done. If the patient has a conjugate deviation of the 2 = Forced deviation, or total gaze paresis not overcome by the oculocephalic eyes that can be overcome by voluntary or reflexive activity, the score will be 1. If a maneuver. patient has an isolated peripheral nerve paresis (cranial nerves III, IV or VI), score a 1. _____ Gaze is testable in all aphasic patients. Patients with ocular trauma, bandages, pre- existing blindness, or other disorder of visual acuity or fields should be tested with reflexive movements, and a choice made by the investigator. Establishing eye contact and then moving about the patient from side to side will occasionally clarify the presence of a partial gaze palsy. 3. Visual: Visual fields (upper and lower quadrants) are tested by confrontation, using finger counting or visual threat, as appropriate. Patients may be encouraged, 0 = No visual loss. 1 = Partial hemianopia. 2 = Complete hemianopia. but if they look at the side of the moving fingers appropriately, this can be scored as normal. If there is unilateral blindness or enucleation, visual fields in the remaining eye are scored. Score 1 only if a clear-cut 3 = Bilateral hemianopia (blind including cortical blindness). _____ asymmetry, including quadrantanopia, is found. If patient is blind from any cause, score 3. Double simultaneous stimulation is performed at this point. If there is extinction, patient receives a 1, and the results are used to respond to item 11. 4. Facial palsy: Ask - or use pantomime to encourage - the patient to show teeth or 0 = Normal symmetrical movements. _____ 1 = Minor paralysis (flattened nasolabial raise eyebrows and close eyes. Score symmetry of grimace in response to noxious fold, asymmetry on smiling). 2 = Partial paralysis (total or near-total paralysis of lower face). stimuli in the poorly responsive or non- comprehending patient. If facial trauma/bandages, orotracheal tube, tape or https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 37/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate other physical barriers obscure the face, 3 = Complete paralysis of one or both sides these should be removed to the extent (absence of facial movement in the upper possible. and lower face). 5. Motor arm: The limb is placed in the appropriate position: extend the arms 0 = No drift; limb holds 90 (or 45) degrees for full 10 seconds. (palms down) 90 degrees (if sitting) or 45 degrees (if supine). Drift is scored if the arm 1 = Drift; limb holds 90 (or 45) degrees, but drifts down before full 10 seconds; does not falls before 10 seconds. The aphasic patient hit bed or other support. is encouraged using urgency in the voice and pantomime, but not noxious 2 = Some effort against gravity; limb cannot get to or maintain (if cued) 90 (or 45) degrees, drifts down to bed, but has some stimulation. Each limb is tested in turn, beginning with the non-paretic arm. Only in _____ effort against gravity. the case of amputation or joint fusion at the shoulder, the examiner should record the 3 = No effort against gravity; limb falls. score as untestable (UN), and clearly write 4 = No movement. the explanation for this choice. UN = Amputation or joint fusion, explain:________________ 5a. Left arm 5b. Right arm 6. Motor leg: The limb is placed in the appropriate position: hold the leg at 30 degrees (always tested supine). Drift is scored if the leg falls before 5 seconds. The 0 = No drift; leg holds 30-degree position for full 5 seconds. 1 = Drift; leg falls by the end of the 5-second period but does not hit bed. aphasic patient is encouraged using urgency in the voice and pantomime, but not noxious stimulation. Each limb is tested in turn, beginning with the non-paretic leg. Only in the case of amputation or joint fusion at the hip, the examiner should 2 = Some effort against gravity; leg falls to bed by 5 seconds, but has some effort against gravity. _____ 3 = No effort against gravity; leg falls to bed immediately. record the score as untestable (UN), and clearly write the explanation for this choice. 4 = No movement. UN = Amputation or joint fusion, explain:________________ 6a. Left leg 6b. Right leg 7. Limb ataxia: This item is aimed at finding 0 = Absent. _____ evidence of a unilateral cerebellar lesion. Test with eyes open. In case of visual defect, 1 = Present in one limb. 2 = Present in two limbs. ensure testing is done in intact visual field. The finger-nose-finger and heel-shin tests UN = Amputation or joint fusion, explain:________________ are performed on both sides, and ataxia is scored only if present out of proportion to weakness. Ataxia is absent in the patient https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 38/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate who cannot understand or is paralyzed. Only in the case of amputation or joint fusion, the examiner should record the score as untestable (UN), and clearly write the explanation for this choice. In case of blindness, test by having the patient touch nose from extended arm position. 8. Sensory: Sensation or grimace to pinprick 0 = Normal; no sensory loss. when tested, or withdrawal from noxious stimulus in the obtunded or aphasic patient. 1 = Mild-to-moderate sensory loss; patient feels pinprick is less sharp or is dull on the affected side; or there is a loss of superficial Only sensory loss attributed to stroke is scored as abnormal and the examiner pain with pinprick, but patient is aware of being touched. should test as many body areas (arms [not hands], legs, trunk, face) as needed to 2 = Severe to total sensory loss; patient is not aware of being touched in the face, arm, accurately check for hemisensory loss. A score of 2, "severe or total sensory loss," should only be given when a severe or total loss of sensation can be clearly and leg. _____ demonstrated. Stuporous and aphasic patients will, therefore, probably score 1 or 0. The patient with brainstem stroke who has bilateral loss of sensation is scored 2. If the patient does not respond and is quadriplegic, score 2. Patients in a coma (item 1a=3) are automatically given a 2 on this item. 9. Best language: A great deal of 0 = No aphasia; normal. _____ information about comprehension will be obtained during the preceding sections of the examination. For this scale item, the patient is asked to describe what is happening in the attached picture, to name 1 = Mild-to-moderate aphasia; some obvious loss of fluency or facility of comprehension, without significant limitation on ideas expressed or form of expression. Reduction of speech and/or comprehension, however, makes the items on the attached naming sheet and to read from the attached list of sentences. conversation about provided materials Comprehension is judged from responses here, as well as to all of the commands in difficult or impossible. For example, in conversation about provided materials, the preceding general neurological exam. If examiner can identify picture or naming card content from patient's response. visual loss interferes with the tests, ask the patient to identify objects placed in the 2 = Severe aphasia; all communication is through fragmentary expression; great need hand, repeat, and produce speech. The intubated patient should be asked to write. for inference, questioning, and guessing by the listener. Range of information that can The patient in a coma (item 1a=3) will automatically score 3 on this item. The be exchanged is limited; listener carries burden of communication. Examiner cannot examiner must choose a score for the patient with stupor or limited cooperation, but a score of 3 should be used only if the https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 39/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate patient is mute and follows no one-step identify materials provided from patient commands. response. 3 = Mute, global aphasia; no usable speech or auditory comprehension. 10. Dysarthria: If patient is thought to be normal, an adequate sample of speech must 0 = Normal. 1 = Mild-to-moderate dysarthria; patient be obtained by asking patient to read or slurs at least some words and, at worst, can be understood with some difficulty. repeat words from the attached list. If the patient has severe aphasia, the clarity of 2 = Severe dysarthria; patient's speech is so slurred as to be unintelligible in the absence articulation of spontaneous speech can be rated. Only if the patient is intubated or has _____ of or out of proportion to any dysphasia, or is mute/anarthric. other physical barriers to producing speech, the examiner should record the score as untestable (UN), and clearly write an UN = Intubated or other physical barrier, explanation for this choice. Do not tell the patient why he or she is being tested. explain:________________ 11. Extinction and inattention (formerly 0 = No abnormality. neglect): Sufficient information to identify neglect may be obtained during the prior testing. If the patient has a severe visual loss preventing visual double simultaneous stimulation, and the cutaneous stimuli are normal, the score is normal. If the patient has aphasia but does appear to attend to 1 = Visual, tactile, auditory, spatial, or personal inattention or extinction to bilateral simultaneous stimulation in one of the sensory modalities. 2 = Profound hemi-inattention or extinction to more than one modality; does not recognize own hand or orients to only one side of space. _____ both sides, the score is normal. The presence of visual spatial neglect or anosognosia may also be taken as evidence of abnormality. Since the abnormality is scored only if present, the item is never untestable. _____ Adapted from: Goldstein LB, Samsa GP. Reliability of the National Institutes of Health Stroke Scale. Extension to non- neurologists in the context of a clinical trial. Stroke 1997; 28:307. Graphic 61698 Version 8.0 https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 40/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate Stroke outcome at three months in the placebo group of the NINDS trial Percent with favorable outcome Baseline NIHSS score (three-month NIHSS score = 0 or 1) Age <60 y 0-9 42 10-14 18 15-20 27 >20 12 Age 61-68 y 0-9 37 10-14 25 15-20 25 >20 0 Age 69-75 y 0-9 54 10-14 27 15-20 0 >20 0 Age >75 y 0-9 36 10-14 15 15-20 6 >20 0

2 = Some effort against gravity; limb cannot get to or maintain (if cued) 90 (or 45) degrees, drifts down to bed, but has some stimulation. Each limb is tested in turn, beginning with the non-paretic arm. Only in _____ effort against gravity. the case of amputation or joint fusion at the shoulder, the examiner should record the 3 = No effort against gravity; limb falls. score as untestable (UN), and clearly write 4 = No movement. the explanation for this choice. UN = Amputation or joint fusion, explain:________________ 5a. Left arm 5b. Right arm 6. Motor leg: The limb is placed in the appropriate position: hold the leg at 30 degrees (always tested supine). Drift is scored if the leg falls before 5 seconds. The 0 = No drift; leg holds 30-degree position for full 5 seconds. 1 = Drift; leg falls by the end of the 5-second period but does not hit bed. aphasic patient is encouraged using urgency in the voice and pantomime, but not noxious stimulation. Each limb is tested in turn, beginning with the non-paretic leg. Only in the case of amputation or joint fusion at the hip, the examiner should 2 = Some effort against gravity; leg falls to bed by 5 seconds, but has some effort against gravity. _____ 3 = No effort against gravity; leg falls to bed immediately. record the score as untestable (UN), and clearly write the explanation for this choice. 4 = No movement. UN = Amputation or joint fusion, explain:________________ 6a. Left leg 6b. Right leg 7. Limb ataxia: This item is aimed at finding 0 = Absent. _____ evidence of a unilateral cerebellar lesion. Test with eyes open. In case of visual defect, 1 = Present in one limb. 2 = Present in two limbs. ensure testing is done in intact visual field. The finger-nose-finger and heel-shin tests UN = Amputation or joint fusion, explain:________________ are performed on both sides, and ataxia is scored only if present out of proportion to weakness. Ataxia is absent in the patient https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 38/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate who cannot understand or is paralyzed. Only in the case of amputation or joint fusion, the examiner should record the score as untestable (UN), and clearly write the explanation for this choice. In case of blindness, test by having the patient touch nose from extended arm position. 8. Sensory: Sensation or grimace to pinprick 0 = Normal; no sensory loss. when tested, or withdrawal from noxious stimulus in the obtunded or aphasic patient. 1 = Mild-to-moderate sensory loss; patient feels pinprick is less sharp or is dull on the affected side; or there is a loss of superficial Only sensory loss attributed to stroke is scored as abnormal and the examiner pain with pinprick, but patient is aware of being touched. should test as many body areas (arms [not hands], legs, trunk, face) as needed to 2 = Severe to total sensory loss; patient is not aware of being touched in the face, arm, accurately check for hemisensory loss. A score of 2, "severe or total sensory loss," should only be given when a severe or total loss of sensation can be clearly and leg. _____ demonstrated. Stuporous and aphasic patients will, therefore, probably score 1 or 0. The patient with brainstem stroke who has bilateral loss of sensation is scored 2. If the patient does not respond and is quadriplegic, score 2. Patients in a coma (item 1a=3) are automatically given a 2 on this item. 9. Best language: A great deal of 0 = No aphasia; normal. _____ information about comprehension will be obtained during the preceding sections of the examination. For this scale item, the patient is asked to describe what is happening in the attached picture, to name 1 = Mild-to-moderate aphasia; some obvious loss of fluency or facility of comprehension, without significant limitation on ideas expressed or form of expression. Reduction of speech and/or comprehension, however, makes the items on the attached naming sheet and to read from the attached list of sentences. conversation about provided materials Comprehension is judged from responses here, as well as to all of the commands in difficult or impossible. For example, in conversation about provided materials, the preceding general neurological exam. If examiner can identify picture or naming card content from patient's response. visual loss interferes with the tests, ask the patient to identify objects placed in the 2 = Severe aphasia; all communication is through fragmentary expression; great need hand, repeat, and produce speech. The intubated patient should be asked to write. for inference, questioning, and guessing by the listener. Range of information that can The patient in a coma (item 1a=3) will automatically score 3 on this item. The be exchanged is limited; listener carries burden of communication. Examiner cannot examiner must choose a score for the patient with stupor or limited cooperation, but a score of 3 should be used only if the https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 39/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate patient is mute and follows no one-step identify materials provided from patient commands. response. 3 = Mute, global aphasia; no usable speech or auditory comprehension. 10. Dysarthria: If patient is thought to be normal, an adequate sample of speech must 0 = Normal. 1 = Mild-to-moderate dysarthria; patient be obtained by asking patient to read or slurs at least some words and, at worst, can be understood with some difficulty. repeat words from the attached list. If the patient has severe aphasia, the clarity of 2 = Severe dysarthria; patient's speech is so slurred as to be unintelligible in the absence articulation of spontaneous speech can be rated. Only if the patient is intubated or has _____ of or out of proportion to any dysphasia, or is mute/anarthric. other physical barriers to producing speech, the examiner should record the score as untestable (UN), and clearly write an UN = Intubated or other physical barrier, explanation for this choice. Do not tell the patient why he or she is being tested. explain:________________ 11. Extinction and inattention (formerly 0 = No abnormality. neglect): Sufficient information to identify neglect may be obtained during the prior testing. If the patient has a severe visual loss preventing visual double simultaneous stimulation, and the cutaneous stimuli are normal, the score is normal. If the patient has aphasia but does appear to attend to 1 = Visual, tactile, auditory, spatial, or personal inattention or extinction to bilateral simultaneous stimulation in one of the sensory modalities. 2 = Profound hemi-inattention or extinction to more than one modality; does not recognize own hand or orients to only one side of space. _____ both sides, the score is normal. The presence of visual spatial neglect or anosognosia may also be taken as evidence of abnormality. Since the abnormality is scored only if present, the item is never untestable. _____ Adapted from: Goldstein LB, Samsa GP. Reliability of the National Institutes of Health Stroke Scale. Extension to non- neurologists in the context of a clinical trial. Stroke 1997; 28:307. Graphic 61698 Version 8.0 https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 40/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate Stroke outcome at three months in the placebo group of the NINDS trial Percent with favorable outcome Baseline NIHSS score (three-month NIHSS score = 0 or 1) Age <60 y 0-9 42 10-14 18 15-20 27 >20 12 Age 61-68 y 0-9 37 10-14 25 15-20 25 >20 0 Age 69-75 y 0-9 54 10-14 27 15-20 0 >20 0 Age >75 y 0-9 36 10-14 15 15-20 6 >20 0 NIHSS: National Institutes of Health Stroke Scale. Adapted from: NINDS t-PA Stroke Study Group, Stroke 1997; 28:2119. Graphic 81859 Version 4.0 https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 41/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate Cerebral autoregulation in hypertension Schematic representation of autoregulation of cerebral blood flow in normotensive and hypertensive subjects. In both groups, initial increases or decreases in mean arterial pressure are associated with maintenance of cerebral blood flow due to appropriate changes in arteriolar resistance. More marked changes in pressure are eventually associated with loss of autoregulation, leading to a reduction (with hypotension) or an elevation (with marked hypertension) in cerebral blood flow. These changes occur at higher pressures in patients with hypertension, presumably due to arteriolar thickening. Thus, aggressive antihypertensive therapy will produce cerebral ischemia at a higher mean arterial pressure in patients with underlying hypertension. Redrawn from: Kaplan NM. Management of hypertensive emergencies. Lancet 1994; 344:1335. Based on data from: Strandgaard S, Paulson OB. Cerebral blood ow and its pathophysiology in hypertension. Am J Hypertens 1989; 2:486. Graphic 57676 Version 5.0 https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 42/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate Options to treat hypertension before and during reperfusion therapy for acu te ischemic stroke Patient otherwise eligible for acute reperfusion therapy except that blood pressure is >185/110 mmHg* Labetalol 10 to 20 mg intravenously over 1 to 2 minutes, may repeat one time; or Nicardipine 5 mg/hour intravenously, titrate up by 2.5 mg/hour every 5 to 15 minutes, maximum 15 mg/hour; when desired blood pressure reached, adjust to maintain proper blood pressure limits; or Clevidipine 1 to 2 mg/hour intravenously, titrate by doubling the dose every 2 to 5 minutes, maximum 21 mg/hour, until desired blood pressure reached ; or Other agents (hydralazine, enalaprilat, etc) may also be considered If blood pressure is not maintained at or below 185/110 mmHg, do not administer alteplase Management to maintain blood pressure at or below 180/105 mmHg during and after acute reperfusion therapy* Monitor blood pressure every 15 minutes for 2 hours from the start of rtPA therapy, then every 30 minutes for 6 hours, and then every hour for 16 hours If systolic blood pressure is >180 to 230 mmHg or diastolic is >105 to 120 mmHg: Labetalol 10 mg intravenously followed by continuous infusion 2 to 8 mg/min; or Nicardipine 5 mg/hour intravenously, titrate up to desired effect by 2.5 mg/hour every 5 to 15 minutes, maximum 15 mg/hour; or Clevidipine 1 to 2 mg/hour intravenously, titrate by doubling the dose every 2 to 5 minutes, maximum 21 mg/hour, until desired blood pressure reached If blood pressure is not controlled or diastolic blood pressure >140 mmHg, consider intravenous sodium nitroprusside Different treatment options may be appropriate in patients who have comorbid conditions that may benefit from acute reductions in blood pressure, such as acute coronary event, acute heart failure, aortic dissection, or preeclampsia/eclampsia. Clevidipine has been included as part of the 2018 guidelines for the early management of patients with acute ischemic stroke [1] . Reference: 1. Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2018; 49:e46. Adapted with permission. Stroke. 2013: 44:870-947. Copyright 2013 American Heart Association, Inc. https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 43/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate Graphic 50725 Version 15.0 https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 44/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate Indications for mechanical thrombectomy to treat patients with acute ischemic IV: intravenous; tPA: tissue plasminogen activator (alteplase or tenecteplase); CTA: computed tomography an artery occlusion; MT: mechanical thrombectomy; ASPECTS: Alberta Stroke Program Early CT Score; NIHSS: Na tomography; MRI: magnetic resonance imaging; mRS: modified Rankin Scale; MCA: middle cerebral artery; IC recovery. Patients are not ordinarily eligible for IV tPA unless the time last known to be well is <4.5 hours. However, im that is diffusion positive and FLAIR negative) is an option at expert stroke centers to select patients with wake associated UpToDate topics for details. Usually assessed with MRA or CTA, less often with digital subtraction angiography. There is intracranial arterial occlusion of the distal ICA, middle cerebral (M1/M2), or anterior cerebral (A1/A2 MT may be a treatment option for patients with acute ischemic stroke caused by occlusion of the basilar ar stroke centers, but benefit is uncertain. [1] Based upon data from the Aurora study . Reference: https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 45/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate 1. Albers GW, Lansberg MG, Brown S, et al. Assessment of Optimal Patient Selection for Endovascular Thrombectomy Beyond 6 Hou Neurol 2021; 78:1064. Graphic 117086 Version 3.0 https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 46/47 7/5/23, 12:11 PM Initial assessment and management of acute stroke - UpToDate Contributor Disclosures Jamary Oliveira-Filho, MD, MS, PhD No relevant financial relationship(s) with ineligible companies to disclose. Michael T Mullen, MD Grant/Research/Clinical Trial Support: NINDS [Asymptomatic carotid disease]. All of the relevant financial relationships listed have been mitigated. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Jonathan A Edlow, MD, FACEP No relevant financial relationship(s) with ineligible companies to disclose. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/initial-assessment-and-management-of-acute-stroke/print 47/47

7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Initial evaluation and management of transient ischemic attack and minor ischemic stroke : Natalia S Rost, MD, MPH, Hugo J Aparicio, MD, MPH : Scott E Kasner, MD, Jonathan A Edlow, MD, FACEP : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: May 10, 2022. INTRODUCTION Patients with transient ischemic attack (TIA) or minor (ie, nondisabling) stroke are at increased risk of recurrent stroke and therefore require urgent evaluation and treatment since immediate intervention may substantially reduce the risk of recurrent stroke. This topic will review the diagnostic approach and early management of TIA and minor, nondisabling ischemic stroke. Other aspects of transient cerebral ischemia are discussed separately. (See "Definition, etiology, and clinical manifestations of transient ischemic attack" and "Differential diagnosis of transient ischemic attack and acute stroke".) The management of patients hospitalized with acute stroke is reviewed elsewhere. (See "Initial assessment and management of acute stroke".) DIAGNOSIS AND TRIAGE Clinical diagnosis of TIA and minor stroke The diagnosis of TIA (in the absence of tissue infarction) is clinical and is based upon a determination that the symptoms of the attack are more likely caused by brain ischemia than another cause ( table 1). This determination can be challenging and is usually subjective because the symptoms of TIA are transient, highly variable https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 1/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate ( table 2), and often minor. (See "Definition, etiology, and clinical manifestations of transient ischemic attack", section on 'Diagnosis' and "Differential diagnosis of transient ischemic attack and acute stroke", section on 'Symptoms of TIA' and "Differential diagnosis of transient ischemic attack and acute stroke", section on 'Distinguishing transient attacks'.) How is TIA defined? TIA is now defined as a transient episode of neurologic dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction [1]. The end point, ischemic stroke, is biologic (tissue injury) rather than arbitrary ( 24 hours of symptoms). In keeping with this definition of TIA, ischemic stroke is defined as an infarction of central nervous system tissue. (See "Definition, etiology, and clinical manifestations of transient ischemic attack", section on 'Definition of TIA'.) TIA was originally defined as a sudden onset of a focal neurologic symptom and/or sign lasting less than 24 hours and caused by reversible cerebral ischemia. However, this classic, time-based definition of TIA was inadequate for several reasons. Most notably, there is risk of permanent tissue injury (ie, infarction) even when focal transient neurologic symptoms last less than one hour. About one-half of patients with time-based TIA syndromes (<24 hours in duration) have corresponding appropriate ischemic lesions by brain magnetic resonance imaging (MRI) on diffusion-weighted or perfusion-weighted imaging. (See "Definition, etiology, and clinical manifestations of transient ischemic attack", section on 'Symptom duration and infarction'.) Although the revised tissue-based definition is favored by guidelines, the traditional time-based definition of TIA is still widely used in clinical practice; this time-based definition was created in an era prior to thrombolytic treatment for stroke and availability of MRI and prior to recognition of the hyperacute stroke risk following TIA [2]. 2 How is high-risk TIA defined? A simple but suboptimal assessment called the ABCD score (ie, ABCD squared, for Age, Blood pressure, Clinical features, Duration of symptoms, and Diabetes) was designed to identify patients at high risk of ischemic stroke in the first seven days after TIA ( table 3) [3]. However, its predictive performance is unsatisfactory; subsequent studies have found that the score does not provide an accurate estimate of stroke risk [4], and 2 clinical decisions based on an ABCD score cut-off are subject to significant misclassification 2 error. Importantly, one in five patients with TIA and a low ABCD score (<4) will have treatable vascular pathology, such as a symptomatic internal carotid or intracranial large artery stenosis, or atrial fibrillation [5]. 2 Nevertheless, the ABCD score is being used to select patients for treatment with dual antiplatelet therapy after a time-based TIA. (See 'Immediate antiplatelet treatment' below.) 2 The ABCD score is tallied as follows (calculator 1): https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 2/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate Age ( 60 years = 1 point) Blood pressure elevation when first assessed after TIA (systolic 140 mmHg or diastolic 90 mmHg = 1 point) Clinical features (unilateral weakness = 2 points; isolated speech disturbance = 1 point; other = 0 points) Duration of TIA symptoms ( 60 minutes = 2 points; 10 to 59 minutes = 1 point; <10 minutes = 0 points) Diabetes (present = 1 point) Other factors associated with an increased risk of stroke after a time-based TIA include a relevant large vessel stenosis or DWI lesion on MRI. Stroke risk after TIA is reviewed in greater detail separately. (See "Definition, etiology, and clinical manifestations of transient ischemic attack", section on 'Risk of recurrent stroke'.) How is minor, nondisabling stroke defined? The presence of persistent but minor, nondisabling neurologic deficits is the main factor that distinguishes minor ischemic stroke from a time-based TIA. However, both are associated with an increased risk of recurrent ischemic stroke [6,7]. This increased risk of stroke may be more related to the presence of infarction on diffusion-weighted MRI studies than to the duration of minor neurologic deficit. Minor ischemic stroke has been defined in various ways, most often by a low score on the National Institutes of Health Stroke Scale (NIHSS) [8,9], and there is no unified definition. We prefer to define minor stroke by the absence of a persistent neurologic deficit that is potentially disabling. Any of the following should be considered disabling deficits [10]: Any deficits that lead to a total NIHSS >5 (calculator 2) Complete hemianopia: 2 on the NIHSS question 3 ( table 4) Severe aphasia: 2 on NIHSS question 9 Visual or sensory extinction: 1 on NIHSS question 11 Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6 Inability to walk Any remaining deficit considered potentially disabling by the patient, family, or the treating practitioner Patients who present within the appropriate time window after ischemic symptom onset with a persistent neurologic deficit that is potentially disabling, despite improvement of any degree, should be treated with intravenous thrombolysis in the absence of other contraindications ( table 5) and screened for treatment with mechanical thrombectomy ( algorithm 1). In practical terms, one would never "wait" or delay treatment to see if the symptoms resolve in https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 3/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate patients who present with a persistent neurologic deficit. (See "Approach to reperfusion therapy for acute ischemic stroke" and "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use" and "Mechanical thrombectomy for acute ischemic stroke".) Differential diagnosis Several neurologic disorders give rise to transient focal neurologic symptoms, and these should be considered before establishing a diagnosis of TIA. In addition to TIAs, the most important and frequent causes of discrete self-limited attacks include: Seizure Migraine aura Syncope Less frequent causes include: Peripheral vestibulopathy that causes transient episodic dizziness Pressure- or position-related peripheral nerve or nerve root compression that causes transient paresthesia and numbness Metabolic perturbations such as hypoglycemia and hepatic, renal, and pulmonary encephalopathies that can produce temporary aberrations in behavior and movement Transient global amnesia Cerebral amyloid angiopathy The differential diagnosis of TIA and stroke is discussed in greater detail elsewhere. (See "Differential diagnosis of transient ischemic attack and acute stroke".) Importance of early evaluation and treatment For patients who present with TIA or minor ischemic stroke, we recommend implementation of appropriate diagnostic evaluation and stroke prevention treatment without delay, preferably within one day of the ischemic event. TIA is a neurologic emergency because patients with a time-based TIA (ie, symptoms lasting less than 24 hours) or minor, nondisabling ischemic stroke are at increased risk of recurrent and potentially disabling ischemic stroke, especially in the days following the index event. Accumulating evidence suggests that immediate intervention after a TIA or minor, nondisabling ischemic stroke can reduce the risk of recurrent stroke compared with delayed intervention. The prospective EXPRESS study evaluated the impact of expediting outpatient treatment for TIA or minor ischemic stroke [11]. In order to compare traditional with expedited treatment, the study was conducted in two phases. In phase one, 323 patients were seen in a traditional clinic setting where evaluation required a scheduled appointment and treatment recommendations were made to referring physicians. In phase two, 297 patients were seen in an urgent walk-in stroke clinic without having to arrange an appointment, evaluated with readily available https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 4/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate diagnostic studies (including brain MRI, carotid duplex ultrasound, electrocardiography, and baseline blood tests); treatment was implemented immediately by clinic practitioners. In both phases, treatment of confirmed TIA or stroke was individualized according to patient characteristics, but generally included antiplatelet or anticoagulant therapy, statin therapy, antihypertensive medication, and carotid endarterectomy as required. In EXPRESS, the median delay to assessment in the outpatient clinic was significantly reduced from phase 1 to phase 2 (3 days versus <1 day), as was the median delay to first prescription of treatment (20 days versus 1 day) [11]. The risk of recurrent stroke at 90 days was significantly lower for patients seen in phase 2 than for those seen in phase 1 (2.1 versus 10.3 percent; adjusted hazard ratio 0.20, 95% CI 0.08-0.49), and the lower stroke risk was sustained at 10 years in a follow-up study [12]. Although EXPRESS was not a randomized trial, the study was nested in an ongoing population-based study of stroke and TIA, thus minimizing the potential problems of incomplete ascertainment and selection bias that complicate observational studies. The observational SOS-TIA study analyzed the rapid assessment of 1085 patients with suspected TIA in a hospital-based clinic with 24-hour access [13]. Patients were evaluated within four hours of admission, and those with a final diagnosis of confirmed or possible TIA (n = 845) received immediate treatment with a stroke prevention program that included antiplatelet or anticoagulant treatment and/or carotid revascularization as appropriate. At 90 days, the 2 observed stroke rate was much lower than an expected stroke rate predicted by the ABCD scores (1.24 versus 5.96 percent). The results of this study should be interpreted with caution 2 because of methodologic limitations, including the use of ABCD scores to predict stroke risk, rather than determination of stroke risk in a control population [14]. (See "Definition, etiology, and clinical manifestations of transient ischemic attack", section on 'Stroke risk stratification'.) Hospital or outpatient evaluation? Whether hospitalization is required for TIA evaluation is not clear, but urgent assessment and management is essential regardless of inpatient or outpatient status [1,15-19]. The key guiding principle is that the incidence of a recurrent stroke is highest in the 48 hours following the TIA [20-22], and therefore the rapidity with which the evaluation is performed and treatments initiated is more important than the physical location of where the evaluation takes place [23,24]. Outpatient evaluation can now occur in specialty-run TIA clinics [11,13,25] and in emergency department-based observation units [26,27]; in both settings, the evaluation begins immediately following a TIA diagnosis. Both of these processes of care have led to marked reduction in stroke outcome. Possible advantages of hospitalization include facilitated early use of thrombolytic therapy, mechanical thrombectomy, and other medical management if symptoms recur, expedited TIA evaluation, and expedited institution of secondary prevention [15]. https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 5/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate We suggest hospitalization for patients with a first TIA within the past 72 hours if any of the following conditions are present: High risk of early stroke after TIA or minor stroke as suggested by: The presence of a known cardiac, arterial, or systemic etiology of brain ischemia that is amenable to treatment The presence of acute infarction on diffusion-weighted magnetic resonance imaging (MRI) (see "Definition, etiology, and clinical manifestations of transient ischemic attack", section on 'Factors that affect stroke risk') Certain other clinical and imaging features ( table 6) Uncertainty that the diagnostic workup can be completed within 24 to 48 hours as an outpatient Concurrent serious acute medical issues Patients who need urgent evaluation and are not hospitalized should have rapid access to the following studies (see 'Urgent investigations' below): Brain imaging with head computed tomography (CT) and/or MRI Vascular imaging studies such as CT angiography (CTA), magnetic resonance angiography (MRA), and/or ultrasound Electrocardiogram (ECG) All patients with a suspected TIA within the past two weeks who are not hospitalized should undergo investigations within 24 to 48 hours to determine the mechanism of ischemia and subsequent preventive therapy. Even patients with atypical TIA symptoms (eg, isolated vertigo, ataxia, bilateral decreased vision, or numbness in one body segment) may be at increased risk for early stroke [28]. Patients who are not admitted should be informed that they need to go to an Emergency Department immediately if symptoms recur. IMMEDIATE ANTIPLATELET TREATMENT For most patients with TIA and minor ischemic stroke who do not have a known cardioembolic source at presentation, we start antiplatelet therapy immediately while evaluating the ischemic mechanism ( algorithm 2 and algorithm 3 and table 1). Exceptions are patients who are on oral anticoagulation or have a clear new indication for anticoagulation. https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 6/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate Dual antiplatelet therapy We start dual antiplatelet therapy (DAPT) using aspirin (160 to 325 mg loading dose, followed by 50 to 100 mg daily) plus clopidogrel (300 to 600 mg loading dose, followed by 75 mg daily) for the first 21 days for patients with high-risk TIA, 2 defined as an ABCD score of 4 (calculator 1), and for patients with minor ischemic stroke, defined by a National Institutes of Health Stroke Scale (NIHSS) score 5 (calculator 2). DAPT using aspirin (300 to 325 mg loading dose, followed by 75 to 100 mg daily) plus ticagrelor (180 mg loading dose followed by 90 mg twice daily) is a reasonable alternative for patients not amenable to therapy with clopidogrel. The rationale and evidence for short-term DAPT in this setting is reviewed in detail separately. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Efficacy of DAPT'.) Aspirin monotherapy We start aspirin (162 to 325 mg/daily) alone for low-risk TIA, 2 defined by an ABCD score <4 (calculator 1). The approach to antithrombotic treatment of acute stroke and TIA is reviewed in detail separately. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".) URGENT INVESTIGATIONS Goals of evaluation Patients who have a suspected TIA or minor stroke require urgent evaluation ( algorithm 4) due to the high stroke risk associated with TIA as defined by time- based criteria [1]; immediate intervention may prevent a significant number of strokes. (See "Definition, etiology, and clinical manifestations of transient ischemic attack", section on 'Risk of recurrent stroke'.) Urgent evaluation is necessary for confirming the diagnosis of TIA or ischemic stroke, excluding stroke mimics, and determining the ischemic mechanism, which has important implications for directing targeted treatment for secondary stroke prevention. The urgent evaluation proceeds in tandem with immediate implementation of antiplatelet therapy. (See 'Immediate antiplatelet treatment' above.) The initial evaluation of suspected TIA and minor, nondisabling ischemic stroke includes brain imaging, vascular imaging, cardiac evaluation, and basic laboratory studies that are suggested by the history and physical examination. Laboratory testing is helpful in ruling out metabolic and hematologic causes of neurologic symptoms, including hypoglycemia, hyponatremia, and thrombocytosis. https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 7/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate Timing We recommend that appropriate diagnostic evaluation and stroke prevention treatment be implemented without delay, preferably within one day of the ischemic event, for patients who present with TIA or minor, nondisabling ischemic stroke. Brain imaging Early brain imaging with MRI or CT is indicated for all patients with suspected TIA or minor, nondisabling stroke, particularly for those with symptoms suggestive of hemispheric TIA [1,15]. Brain MRI with diffusion-weighted imaging has a greater sensitivity than CT for detecting small infarcts in patients with TIA; thus, CT is a suboptimal alternative. The 2009 American Heart Association/American Stroke Association (AHA/ASA) guidelines for evaluation of TIA recommend neuroimaging within 24 hours of symptom onset and further recommend MRI with diffusion-weighted imaging (DWI) as a preferred modality [1]. Head CT is recommended if MRI cannot be performed. The presence of a brain infarct on MRI or CT scan located in an area suggested by the anatomy of the TIA or stroke identifies an ischemic etiology of symptoms. Many patients whose clinical history and neurologic examination is suggestive of TIA have infarcts in brain areas appropriate to the neurologic symptoms. (See "Definition, etiology, and clinical manifestations of transient ischemic attack", section on 'Symptom duration and infarction'.) Advantages of DWI Infarction is more likely to be identified acutely on MRI than on CT. DWI and the apparent diffusion coefficient (ADC) map that is derived from DWI can discriminate tissue injury very early after the onset of ischemic symptoms. In most but not all cases of TIA and minor (nondisabling) stroke, early DWI and ADC can confirm whether only ischemia has occurred or if there has also been an element of infarction, thereby differentiating stroke from TIA within the first hours after symptom onset. (See "Neuroimaging of acute stroke", section on 'Parenchymal changes on DWI'.) DWI is advantageous for evaluating patients who have transient symptoms because it is highly sensitive for detecting infarction, thereby confirming an ischemic cause. A systematic review found that DWI detects corresponding appropriate ischemic lesions in 16 to 67 percent of patients with classically defined (ie, time-based) TIA [29]. Also, the combination of DWI with MRI and magnetic resonance angiography (MRA) often provides clues to the underlying pathophysiology. DWI also has an advantage in differentiating acute infarction from chronic lesions. One study estimated that the amount of error potentially imposed by the use of conventional MRI in identifying the clinically responsible infarct in patients with time-based TIA could be as high as 50 percent when compared with DWI [30]. This is in large part because infarctions associated with time-based TIA are often very small. A volumetric study of time- https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 8/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate based TIA-related infarcts showed that 96 percent of all infarcts were smaller than 1 mL [31]. The smallest single lesion that was associated with a time-based TIA was 0.17 mL in volume. The mean infarct volume was 0.66 1.20 mL. The timing of DWI scan is important. In some cases, lesions identified by early DWI may reverse back to normal with rapid reconstitution of blood flow to the ischemic brain tissue [32]. (See "Definition, etiology, and clinical manifestations of transient ischemic attack", section on 'Symptom duration and infarction'.) Infarcts missed by DWI In a minority of cases, early DWI may fail to identify an ischemic mechanism. DWI may occasionally miss small infarctions, especially in the brain stem, often in patients presenting with a lacunar TIA [33-35]. DWI-negative strokes occur five times more often in posterior circulation events [35]. In these cases, an acute thin-section brainstem DWI (coronal, sagittal, or combination) may reveal a small brainstem lesion, or a follow-up MRI or CT may confirm an infarct [36,37]. In some patients, the reduction in blood flow causing ischemic symptoms may not be severe enough to cause an abnormal signal on DWI [38]. In such cases, perfusion-weighted MRI can provide additional information for determining the presence of tissue ischemia [39-42]. Other diseases that mimic TIAs may be identified by neuroimaging techniques, although pathological biopsy examination is occasionally needed (eg, temporal artery biopsy or examination of the cerebrospinal fluid). In rare cases, brain biopsy is indicated. (See "Differential diagnosis of transient ischemic attack and acute stroke".) Vascular imaging The single most important issue to resolve in the initial evaluation of TIA and ischemic stroke is whether or not there is an obstructive lesion in a larger artery supplying the affected territory. Noninvasive options for evaluation of large vessel occlusive disease include MRA, CTA, carotid duplex ultrasonography (CDUS), and transcranial Doppler ultrasonography (TCD). The choice among these depends upon local availability and expertise as well as individual patient characteristics and preferences [1]. (See "Neuroimaging of acute stroke".) The 2009 AHA/ASA guidelines recommend routine noninvasive imaging of the cervicocephalic vessels as part of the evaluation of patients with suspected TIA [1]. The guidelines note that it is reasonable to obtain noninvasive testing of the intracranial vasculature if knowledge of an intracranial stenosis or occlusion will alter management. https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 9/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate A focused Doppler and neuroimaging test (eg, MRA or CTA) can be used to establish an arterial source of the embolism or low flow. These tests can exclude an arterial source in cases where the symptoms are due to proximal embolism from the heart, aorta, or an unknown source, and in cases where the symptoms are due to small vessel disease (see "Evaluation of carotid artery stenosis"). The following are important aspects regarding such testing: Color Doppler ultrasonography and transcranial Doppler studies require considerable technical skill to perform and an experienced interpreter. They should be used only if there is adequate confidence that the testing and interpretation is reliable. Conventional cerebral angiography is associated with a small risk of stroke and should be performed by experienced physicians. It should only be considered when the diagnosis is uncertain by noninvasive methods, and when proof of the diagnosis is essential for proper stroke preventive therapy. As an example, if one of the stroke-producing arterial lesions noted above is suspected but not confirmed by conventional noninvasive Doppler, MRI, or CT methods, then angiography can be considered. The distinction between artery-to-artery and other (mainly cardiac) sources of embolism can be difficult. Suspicion of the former typically arises once vascular pathology in a large vessel has been identified (eg, with noninvasive testing). Repetitive spells within a single vascular territory are also suggestive of an artery-to-artery source, as is a normal echocardiogram. Infrequently, patients can have multiple sources of embolism (eg, tandem carotid stenosis or concomitant arterial stenosis and atrial fibrillation). Cardiac evaluation A possible cardiac source should be considered in patients with TIA or ischemic stroke caused by embolism. At minimum, such patients should have a standard 12-lead electrocardiogram as soon as possible after symptom onset [1]. Cardiac monitoring Cardiac monitoring is an essential part of evaluation to exclude atrial fibrillation in the setting of embolic TIA or stroke. Cardiac rhythm monitoring with inpatient or observation unit telemetry or Holter monitor is useful for patients without a clear etiology after initial brain imaging and electrocardiography [1]. For patients with a cryptogenic TIA and no evidence of atrial fibrillation on ECG and 24-hour cardiac monitoring, we suggest ambulatory cardiac monitoring for several weeks [43]. (See "Overview of the evaluation of stroke", section on 'Monitoring for subclinical atrial fibrillation'.) Echocardiography Echocardiography is reasonable when no cause for TIA or ischemic stroke has been identified by other aspects of the work-up [1]. Transthoracic echocardiogram (TTE) is the preferred initial test for the majority of patients with a https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 10/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate suspected cardiac or aortic source of emboli, including (see "Echocardiography in detection of cardiac and aortic sources of systemic embolism", section on 'Choosing between TTE and TEE'): Patients 45 years with a cerebrovascular event Patients with a high suspicion of left ventricular thrombus Patients in whom transesophageal echocardiogram (TEE) is contraindicated (eg, esophageal stricture, unstable hemodynamic status) or who refuse TEE TEE is the preferred initial test to localize the source of embolism in the following circumstances: Patients <45 years without known cardiovascular disease (ie, absence of myocardial infarction or valvular disease history) Patients with a high pretest probability of a cardiac embolic source ( table 7) in whom a negative TTE would be likely to be falsely negative Patients with atrial fibrillation and suspected left atrial or left atrial appendage thrombus, especially in the absence of therapeutic anticoagulation, but only if the TEE would impact management Patients with a mechanical heart valve Patients with suspected aortic pathology The use of echocardiography for the detection of cardiac sources of embolism is discussed in greater detail separately. (See "Echocardiography in detection of cardiac and aortic sources of systemic embolism".) Blood cultures, an erythrocyte sedimentation rate, or antinuclear antibody testing are indicated if bacterial or nonbacterial endocarditis is suspected. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis" and "Prosthetic valve endocarditis: Epidemiology, clinical manifestations, and diagnosis" and "Overview of management of infective endocarditis in adults" and "Nonbacterial thrombotic endocarditis" and "Infective endocarditis in children".) Blood tests In most patients with suspected TIA, the following blood tests should be obtained as indicated [1,15,44]: Complete blood count (CBC) Prothrombin time and partial thromboplastin time Serum electrolytes and creatinine Fasting blood glucose, hemoglobin A1c, and lipids https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 11/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) when there is suspicion for an inflammatory stroke mechanism, particularly in older patients Suspicion for blood disorders as potential sources of cerebral ischemia should be raised in the following settings [44]: Cryptogenic stroke or TIA Age 45 years or younger History of clotting dysfunction Multiple venous and arterial occlusions Suspected or confirmed cancer Family history of thrombotic events In these settings, additional blood and coagulation studies should be considered. This topic is discussed elsewhere. (See "Overview of the evaluation of stroke", section on 'Blood tests'.) TARGETED TREATMENT FOR SECONDARY PREVENTION The preferred approach to the secondary prevention of TIA and ischemic stroke is to determine the pathophysiology of the event and treat accordingly ( table 1). This is reviewed here briefly and discussed in detail elsewhere. (See "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack".) Intensive medical management Most patients with TIA or ischemic stroke should receive antithrombotic therapy ( algorithm 5 and algorithm 6) and be treated with all available risk reduction strategies ( table 1). Effective strategies include treatment of hypertension, low density lipoprotein-cholesterol (LDL-C) lowering with high-intensity statin therapy, and lifestyle modification, including smoking cessation, exercise, low-salt and Mediterranean diet, weight control, and no or limited alcohol consumption. These interventions are discussed in greater detail separately. (See "Overview of secondary prevention of ischemic stroke".) Large artery disease Options for the secondary prevention of TIA or ischemic stroke caused by large artery disease include revascularization (mainly for symptomatic cervical internal carotid artery stenosis) and intensive medical therapy (ie, antiplatelet, antihypertensive, and LDL-C lowering therapy) for multifactorial risk reduction. (See "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack", section on 'Large artery disease'.) https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 12/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate Selected patients with recently symptomatic cervical internal carotid artery stenosis of 50 to 99 percent who have a life expectancy of at least five years are generally treated with revascularization via carotid endarterectomy or carotid artery stenting. A pooled analysis of the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and European Carotid Surgery Trial (ECST) found that early carotid endarterectomy (within two weeks of a nondisabling stroke or TIA) significantly improved outcome compared with later surgery [45]. Thus, early identification of symptomatic carotid disease is critical. (See "Management of symptomatic carotid atherosclerotic disease", section on 'Timing of revascularization'.) Patients with TIA or ischemic stroke having carotid endarterectomy are usually treated with aspirin monotherapy at a dose of 81 to 325 mg/day started before surgery, so clopidogrel should be stopped at the discretion of the surgeon if it was started as part of dual antiplatelet therapy (DAPT) prior to determination of carotid stenosis as the stroke mechanism. Patients having carotid artery stenting are treated with dual antiplatelet therapy prior to and continuing for 30 days after stenting. (See "Management of symptomatic carotid atherosclerotic disease" and "Carotid endarterectomy", section on 'Antiplatelet therapy' and "Overview of carotid artery stenting", section on 'Dual antiplatelet therapy'.) Symptomatic intracranial large artery atherosclerosis is associated with a high risk of recurrent stroke, but randomized controlled trials have found that endovascular treatment with stenting leads to harm. Recommended treatment includes short-term (eg, 90 days) use of DAPT with 2 aspirin and clopidogrel, regardless of ABCD score, followed by long-term single-agent antiplatelet therapy, and intensive risk factor management. (See "Intracranial large artery atherosclerosis: Treatment and prognosis".) Small vessel disease For patients with TIA or stroke caused by small vessel disease, medical management (see 'Intensive medical management' above) (ie, antiplatelet, antihypertensive, glucose control, and LDL-C lowering therapy) is the mainstay for secondary stroke prevention. 2 Patients with low-risk TIA (ABCD score <4) attributed to small vessel disease should continue on 2 long-term single-agent antiplatelet therapy, while patients with high-risk TIA (ABCD score 4) or minor ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] 5) should continue DAPT for 21 days, followed by long-term single-agent antiplatelet therapy. (See "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack", section on 'Small artery disease' and "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) Atrial fibrillation For most patients with atrial fibrillation and a recent ischemic stroke or TIA, we recommend oral anticoagulation with warfarin or a direct oral anticoagulant (DOAC); once https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 13/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate anticoagulation is started, antiplatelet treatment should be stopped. (See "Atrial fibrillation in adults: Use of oral anticoagulants".) DAPT may offer an alternative to therapy with aspirin alone in high-risk patients with atrial fibrillation who cannot be treated with warfarin or a DOAC due to a strong patient preference, following careful consideration of the advantages of oral anticoagulation. However, DAPT is thought to have similar bleeding risk as oral anticoagulation. Although high-quality evidence is lacking, patients with an unacceptably high long-term bleeding risk may be treated with left atrial appendage occlusion if short-term anticoagulation around the time of the procedure can be tolerated. These issues are discussed in separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants" and "Atrial fibrillation: Left atrial appendage occlusion".) Cryptogenic stroke Most patients with a cryptogenic TIA or ischemic stroke should be treated with antiplatelet therapy as described above (see 'Immediate antiplatelet treatment' above) and intensive risk factor management with blood pressure control, LDL-C lowering 2 therapy, and lifestyle modification. Patients with cryptogenic low-risk TIA (ABCD score <4) should continue on long-term single-agent antiplatelet therapy, while patients with cryptogenic 2 high-risk TIA (ABCD score 4) or minor ischemic stroke (NIHSS 5) should continue DAPT for 21 days, followed by long-term single-agent antiplatelet therapy. However, the optimal antithrombotic therapy of patients with cryptogenic stroke who have patent foramen ovale, atrial septal aneurysm, atheromatous aortic disease, or coagulation disorders is uncertain. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Secondary prevention'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 14/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Stroke (The Basics)" and "Patient education: Transient

algorithm 5 and algorithm 6) and be treated with all available risk reduction strategies ( table 1). Effective strategies include treatment of hypertension, low density lipoprotein-cholesterol (LDL-C) lowering with high-intensity statin therapy, and lifestyle modification, including smoking cessation, exercise, low-salt and Mediterranean diet, weight control, and no or limited alcohol consumption. These interventions are discussed in greater detail separately. (See "Overview of secondary prevention of ischemic stroke".) Large artery disease Options for the secondary prevention of TIA or ischemic stroke caused by large artery disease include revascularization (mainly for symptomatic cervical internal carotid artery stenosis) and intensive medical therapy (ie, antiplatelet, antihypertensive, and LDL-C lowering therapy) for multifactorial risk reduction. (See "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack", section on 'Large artery disease'.) https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 12/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate Selected patients with recently symptomatic cervical internal carotid artery stenosis of 50 to 99 percent who have a life expectancy of at least five years are generally treated with revascularization via carotid endarterectomy or carotid artery stenting. A pooled analysis of the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and European Carotid Surgery Trial (ECST) found that early carotid endarterectomy (within two weeks of a nondisabling stroke or TIA) significantly improved outcome compared with later surgery [45]. Thus, early identification of symptomatic carotid disease is critical. (See "Management of symptomatic carotid atherosclerotic disease", section on 'Timing of revascularization'.) Patients with TIA or ischemic stroke having carotid endarterectomy are usually treated with aspirin monotherapy at a dose of 81 to 325 mg/day started before surgery, so clopidogrel should be stopped at the discretion of the surgeon if it was started as part of dual antiplatelet therapy (DAPT) prior to determination of carotid stenosis as the stroke mechanism. Patients having carotid artery stenting are treated with dual antiplatelet therapy prior to and continuing for 30 days after stenting. (See "Management of symptomatic carotid atherosclerotic disease" and "Carotid endarterectomy", section on 'Antiplatelet therapy' and "Overview of carotid artery stenting", section on 'Dual antiplatelet therapy'.) Symptomatic intracranial large artery atherosclerosis is associated with a high risk of recurrent stroke, but randomized controlled trials have found that endovascular treatment with stenting leads to harm. Recommended treatment includes short-term (eg, 90 days) use of DAPT with 2 aspirin and clopidogrel, regardless of ABCD score, followed by long-term single-agent antiplatelet therapy, and intensive risk factor management. (See "Intracranial large artery atherosclerosis: Treatment and prognosis".) Small vessel disease For patients with TIA or stroke caused by small vessel disease, medical management (see 'Intensive medical management' above) (ie, antiplatelet, antihypertensive, glucose control, and LDL-C lowering therapy) is the mainstay for secondary stroke prevention. 2 Patients with low-risk TIA (ABCD score <4) attributed to small vessel disease should continue on 2 long-term single-agent antiplatelet therapy, while patients with high-risk TIA (ABCD score 4) or minor ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] 5) should continue DAPT for 21 days, followed by long-term single-agent antiplatelet therapy. (See "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack", section on 'Small artery disease' and "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) Atrial fibrillation For most patients with atrial fibrillation and a recent ischemic stroke or TIA, we recommend oral anticoagulation with warfarin or a direct oral anticoagulant (DOAC); once https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 13/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate anticoagulation is started, antiplatelet treatment should be stopped. (See "Atrial fibrillation in adults: Use of oral anticoagulants".) DAPT may offer an alternative to therapy with aspirin alone in high-risk patients with atrial fibrillation who cannot be treated with warfarin or a DOAC due to a strong patient preference, following careful consideration of the advantages of oral anticoagulation. However, DAPT is thought to have similar bleeding risk as oral anticoagulation. Although high-quality evidence is lacking, patients with an unacceptably high long-term bleeding risk may be treated with left atrial appendage occlusion if short-term anticoagulation around the time of the procedure can be tolerated. These issues are discussed in separately. (See "Atrial fibrillation in adults: Use of oral anticoagulants" and "Atrial fibrillation: Left atrial appendage occlusion".) Cryptogenic stroke Most patients with a cryptogenic TIA or ischemic stroke should be treated with antiplatelet therapy as described above (see 'Immediate antiplatelet treatment' above) and intensive risk factor management with blood pressure control, LDL-C lowering 2 therapy, and lifestyle modification. Patients with cryptogenic low-risk TIA (ABCD score <4) should continue on long-term single-agent antiplatelet therapy, while patients with cryptogenic 2 high-risk TIA (ABCD score 4) or minor ischemic stroke (NIHSS 5) should continue DAPT for 21 days, followed by long-term single-agent antiplatelet therapy. However, the optimal antithrombotic therapy of patients with cryptogenic stroke who have patent foramen ovale, atrial septal aneurysm, atheromatous aortic disease, or coagulation disorders is uncertain. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Secondary prevention'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 14/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Stroke (The Basics)" and "Patient education: Transient ischemic attack (The Basics)") Beyond the Basics topics (see "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)" and "Patient education: Transient ischemic attack (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS TIA and minor, nondisabling ischemic stroke represent a neurologic emergency Patients with a time-based TIA (ie, symptoms lasting less than 24 hours) or minor, nondisabling ischemic stroke are at increased risk of recurrent and potentially disabling ischemic stroke, especially in the days following the index event. Accumulating evidence suggests that immediate intervention after a TIA or minor, nondisabling ischemic stroke can reduce the risk of recurrent stroke compared with delayed intervention. For patients who present with TIA or minor ischemic stroke, implementation of appropriate diagnostic evaluation and stroke prevention treatment should proceed without delay, preferably within one day of the ischemic event. (See 'Importance of early evaluation and treatment' above.) Immediate antiplatelet treatment For most patients with TIA who do not have a known cardioembolic source at presentation, we start antiplatelet therapy immediately while evaluating the ischemic mechanism ( table 1). We start aspirin alone for low-risk TIA, 2 2 defined by an ABCD score <4 (calculator 1). For high-risk TIA, defined by an ABCD score of 4, we start dual antiplatelet therapy (DAPT) using aspirin plus clopidogrel (or aspirin plus ticagrelor) for the first 21 days. Doses are listed above. Exceptions are patients who are on oral anticoagulation or have a clear new indication for anticoagulation. (See 'Immediate antiplatelet treatment' above.) Urgent investigations Urgent evaluation of suspected TIA and minor, nondisabling ischemic stroke is necessary for confirming the diagnosis of TIA or ischemic stroke, excluding stroke mimics, and determining the ischemic mechanism, which has important implications for directing targeted treatment for secondary stroke prevention. The https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 15/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate evaluation includes urgent brain imaging, vascular imaging, a cardiac evaluation, and laboratory testing ( algorithm 4). The evaluation proceeds in tandem with initiation of antiplatelet therapy; both should be implemented without delay, preferably within one day of the ischemic event. (See 'Urgent investigations' above.) Risk factor reduction Most patients with TIA or ischemic stroke should be treated with all available risk factor reduction strategies. Viable strategies include treatment of hypertension, LDL-C lowering with high-intensity statin therapy, and lifestyle modification, including smoking cessation. These interventions are discussed in greater detail separately. (See "Overview of secondary prevention of ischemic stroke".) Treatment for specific causes An overview of the treatment for secondary prevention of specific causes of TIA and ischemic stroke (eg, atrial fibrillation, large artery disease, small vessel disease, and others) is provided separately. (See "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack".) ACKNOWLEDGMENTS The UpToDate editorial staff acknowledges J Philip Kistler, MD, Hakan Ay, MD, and Karen L Furie, MD, MPH, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Easton JD, Saver JL, Albers GW, et al. Definition and evaluation of transient ischemic attack: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association Stroke Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease. The American Academy of Neurology affirms the value of this statement as an educational tool for neurologists. Stroke 2009; 40:2276. 2. Edlow JA. Managing Patients With Transient Ischemic Attack. Ann Emerg Med 2018; 71:409. 3. Johnston SC, Rothwell PM, Nguyen-Huynh MN, et al. 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Risk of stroke early after transient ischaemic attack: a systematic review and meta-analysis. Lancet Neurol 2007; 6:1063. 39. Lee SH, Nah HW, Kim BJ, et al. Role of Perfusion-Weighted Imaging in a Diffusion-Weighted- Imaging-Negative Transient Ischemic Attack. J Clin Neurol 2017; 13:129. 40. Grams RW, Kidwell CS, Doshi AH, et al. Tissue-Negative Transient Ischemic Attack: Is There a Role for Perfusion MRI? AJR Am J Roentgenol 2016; 207:157. 41. Krol AL, Coutts SB, Simon JE, et al. Perfusion MRI abnormalities in speech or motor transient ischemic attack patients. Stroke 2005; 36:2487. 42. Choi JH, Park MG, Choi SY, et al. Acute Transient Vestibular Syndrome: Prevalence of Stroke and Efficacy of Bedside Evaluation. Stroke 2017; 48:556. 43. Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association. Stroke 2021; 52:e364. 44. Flemming KD, Brown RD Jr, Petty GW, et al. Evaluation and management of transient ischemic attack and minor cerebral infarction. Mayo Clin Proc 2004; 79:1071. 45. Rothwell PM, Eliasziw M, Gutnikov SA, et al. Endarterectomy for symptomatic carotid stenosis in relation to clinical subgroups and timing of surgery. Lancet 2004; 363:915. Topic 1123 Version 66.0 https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 19/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate GRAPHICS Transient ischemic attack (TIA) and minor ischemic stroke: Rapid overview of emergency management Clinical features Typical TIAs are characterized by transient, focal neurologic symptoms that can be localized to a single vascular territory within the brain, including one or more of the following: Transient monocular blindness (amaurosis fugax) Aphasia or dysarthria Hemianopia Hemiparesis and/or hemisensory loss (complete or partial) Atypical TIAs may present with transient isolated neurologic symptoms: Isolated vertigo Isolated ataxia Isolated diplopia Isolated speech disturbance (slurred speech) without aphasia Isolated bilateral decreased vision Isolated unilateral sensory loss involving only one body part Differential diagnosis Seizure Migraine aura Syncope Transient global amnesia Central nervous system demyelinating disorder (eg, multiple sclerosis) Peripheral vestibulopathy Metabolic disorder (eg, hypoglycemia) Myasthenia gravis Cranial/peripheral neuropathy Cerebral amyloid angiopathy Subdural hematoma Subarachnoid or intracerebral hemorrhage Transient neurologic attack not otherwise specified Immediate treatment while evaluating the ischemic mechanism For patients with TIA or minor, nondisabling acute ischemic stroke (and thus not eligible for thrombolytic therapy or mechanical thrombectomy), start antiplatelet therapy immediately while the evaluation is in progress: https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 20/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate Start DAPT (aspirin plus clopidogrel, or aspirin plus ticagrelor) for patients with one of the following: 2 High-risk TIA, defined by an ABCD score 4 Time-based TIA with a relevant large artery stenosis or DWI lesion on MRI (if imaging available at this stage) Minor, nondisabling ischemic stroke, defined by an NIHSS score 5 Start aspirin monotherapy for patients who do not meet the above criteria (ie, TIA with an ABCD score <4 and no relevant large artery stenosis or DWI lesion on MRI [if imaging 2 available at this stage]) Once the ischemic mechanism is determined, antithrombotic therapy can be modified as necessary Urgent evaluation Brain imaging with diffusion-weighted MRI (preferred) or CT to identify infarction and rule out nonischemic causes Vascular imaging of extracranial and intracranial large arteries with MRA or CTA to identify large artery cause Cardiac evaluation (ECG, cardiac monitoring, echocardiography) to identify atrial fibrillation or other cardioembolic source Laboratories: CBC, PT and PTT, serum electrolytes, creatinine, fasting blood glucose or HbA1c, lipids, and (as indicated for selected patients) ESR and CRP Targeted treatment by mechanism for secondary prevention Cardiogenic embolism due to atrial fibrillation: Stop antiplatelet agents and start long-term anticoagulation Symptomatic internal carotid artery stenosis: Carotid revascularization with CEA or CAS and long-term antiplatelet therapy Intracranial large artery atherosclerosis with 70 to 99% stenosis: Continue DAPT for 21 to 90 days, then switch to long-term single-agent antiplatelet therapy Small vessel disease, extracranial vertebral artery stenosis, intracranial large artery atherosclerosis with 50 to 69% stenosis, or cryptogenic: Continue DAPT for 21 days, then switch to long-term single-agent antiplatelet therapy for: 2 High-risk TIA (ABCD score 4), or TIA with a relevant DWI lesion on MRI, or extracranial stenosis not amenable to revascularization Minor ischemic stroke (NIHSS 5) 2 Continue long-term single-agent antiplatelet therapy for low-risk TIA (ABCD score <4), and TIA without a relevant large artery stenosis or DWI lesion on MRI Intensive risk factor management Antihypertensive therapy for patients with known or newly established hypertension LDL-cholesterol lowering with high-intensity statin therapy Glucose control to near normoglycemic levels for patients with diabetes Lifestyle modification as appropriate: https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 21/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate Moderate to vigorous exercise most days of the week for those capable Smoking cessation for recent or current tobacco users Mediterranean diet Weight reduction for patients with obesity Reduced alcohol consumption for heavy drinkers This rapid overview presents a general approach to the management of TIA and minor stroke. Please refer to UpToDate content for details, including descriptions and calculators for the NIHSS and 2 ABCD scores. 2 DAPT: dual antiplatelet therapy; ABCD : Age, Blood pressure, Clinical features, Duration of symptoms, and Diabetes; NIHSS: National Institutes of Health Stroke Scale; DWI: diffusion-weighted imaging; MRI: magnetic resonance imaging; CT: computed tomography; MRA: magnetic resonance angiography; CTA: computed tomographic angiography; ECG: electrocardiography; CBC: complete blood count; PT: prothrombin time; PTT: partial thromboplastin time; HbA1c: glycated hemoglobin; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; CEA: carotid endarterectomy; CAS: carotid artery stenting; LDL: low density lipoprotein; ICAS: intracranial larger artery atherosclerosis. Graphic 131201 Version 4.0 https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 22/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate Symptoms of transient ischemic attacks and the vascular territories involved ICA/MCA VA/BA PCA SVD Visual abnormalities Transient ++++ monocular blindness Hemianopia + +++ Blindness ++ ++ Motor abnormalities Hemiparesis + + ++ Quadriparesis ++++ Single part weakness Face + ++ + Arm/hand +++ + Thigh/leg/foot ++ + + Crossed weakness* ++++ Limb ++ ++ ataxia/weakness Gait ataxia +++ + Sensory abnormalities Hemisensory + ++ ++ Single part sensory Face + ++ + ++ Arm/hand ++ ++ + Thigh/leg/foot + + + + Crossed sensory* ++++ Cognitive abnormalities Aphasia ++++ + Amnesia + +++ Alexia +++ +++ https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 23/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate Abulia ++ + + Brainstem and cranial nerve symptoms Dizziness/vertigo + +++ Diplopia ++++ Dysarthria + ++ ++ Dysphagia ++ ++ Tinnitus/hearing loss ++++ ICA: internal carotid arteries; MCA: middle cerebral arteries; VA: vertebral arteries; BA: basilar artery; PCA: posterior cerebral arteries; SVD: small vessel disease. Crossed weakness or crossed sensory refers to one side of the cranial structures and the opposite side limbs and trunk. Graphic 71676 Version 5.0 https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 24/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate 2 ABCD score 2 The ABCD score can be used to estimate the risk of ischemic stroke in the first two days after TIA. The score is tallied as follows: Age: 60 years 1 point <60 years 0 points Blood pressure elevation when first assessed after TIA: Systolic 140 mmHg or diastolic 90 mmHg 1 point Systolic <140 mmHg and diastolic <90 mmHg 0 points Clinical features: Unilateral weakness 2 points Isolated speech disturbance 1 point Other 0 points Duration of TIA symptoms: 60 minutes 2 points 10 to 59 minutes 1 point <10 minutes 0 points Diabetes: Present 1 point Absent 0 points Data from: Johnston SC, Rothwell PM, Nguyen-Huynh MN, et al. Validation and re nement of scores to predict very early stroke risk after transient ischaemic attack. Lancet 2007; 369:283. Graphic 62381 Version 3.0 https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 25/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate National Institutes of Health Stroke Scale (NIHSS) Administer stroke scale items in the order listed. Record performance in each category after each subscale exam. Do not go back and change scores. Follow directions provided for each exam technique. Scores should reflect what the patient does, not what the clinician thinks the patient can do. The clinician should record answers while administering the exam and work quickly. Except where indicated, the patient should not be coached (ie, repeated requests to patient to make a special effort). Instructions Scale definition Score 1a. Level of consciousness: The 0 = Alert; keenly responsive. investigator must choose a response if a full evaluation is prevented by such obstacles as 1 = Not alert; but arousable by minor stimulation to obey, answer, or respond. an endotracheal tube, language barrier, 2 = Not alert; requires repeated stimulation orotracheal trauma/bandages. A 3 is scored only if the patient makes no movement to attend, or is obtunded and requires strong or painful stimulation to make movements (not stereotyped). _____ (other than reflexive posturing) in response to noxious stimulation. 3 = Responds only with reflex motor or autonomic effects or totally unresponsive, flaccid, and areflexic. 1b. Level of consciousness questions: The 0 = Answers both questions correctly. patient is asked the month and his/her age. The answer must be correct - there is no partial credit for being close. Aphasic and stuporous patients who do not comprehend the questions will score 2. Patients unable to speak because of endotracheal intubation, orotracheal trauma, severe dysarthria from 1 = Answers one question correctly. 2 = Answers neither question correctly. _____ any cause, language barrier, or any other problem not secondary to aphasia are given a 1. It is important that only the initial answer be graded and that the examiner not "help" the patient with verbal or non-verbal cues. 1c. Level of consciousness commands: The 0 = Performs both tasks correctly. _____ patient is asked to open and close the eyes and then to grip and release the non-paretic 1 = Performs one task correctly. 2 = Performs neither task correctly. hand. Substitute another one step command if the hands cannot be used. Credit is given if an unequivocal attempt is made but not completed due to weakness. If the patient does not respond to command, the task should be demonstrated to him or her (pantomime), and the result scored (ie, https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 26/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate follows none, one or two commands). Patients with trauma, amputation, or other physical impediments should be given suitable one-step commands. Only the first attempt is scored. 2. Best gaze: Only horizontal eye movements will be tested. Voluntary or 0 = Normal. 1 = Partial gaze palsy; gaze is abnormal in reflexive (oculocephalic) eye movements will one or both eyes, but forced deviation or total gaze paresis is not present. be scored, but caloric testing is not done. If the patient has a conjugate deviation of the 2 = Forced deviation, or total gaze paresis not overcome by the oculocephalic eyes that can be overcome by voluntary or reflexive activity, the score will be 1. If a maneuver. patient has an isolated peripheral nerve paresis (cranial nerves III, IV or VI), score a 1. _____ Gaze is testable in all aphasic patients. Patients with ocular trauma, bandages, pre- existing blindness, or other disorder of visual acuity or fields should be tested with reflexive movements, and a choice made by the investigator. Establishing eye contact and then moving about the patient from side to side will occasionally clarify the presence of a partial gaze palsy. 3. Visual: Visual fields (upper and lower quadrants) are tested by confrontation, using finger counting or visual threat, as appropriate. Patients may be encouraged, 0 = No visual loss. 1 = Partial hemianopia. 2 = Complete hemianopia. but if they look at the side of the moving fingers appropriately, this can be scored as normal. If there is unilateral blindness or enucleation, visual fields in the remaining eye are scored. Score 1 only if a clear-cut 3 = Bilateral hemianopia (blind including cortical blindness). _____ asymmetry, including quadrantanopia, is found. If patient is blind from any cause, score 3. Double simultaneous stimulation is performed at this point. If there is extinction, patient receives a 1, and the results are used to respond to item 11. 4. Facial palsy: Ask - or use pantomime to encourage - the patient to show teeth or 0 = Normal symmetrical movements. _____ 1 = Minor paralysis (flattened nasolabial raise eyebrows and close eyes. Score symmetry of grimace in response to noxious fold, asymmetry on smiling). 2 = Partial paralysis (total or near-total paralysis of lower face). stimuli in the poorly responsive or non- comprehending patient. If facial trauma/bandages, orotracheal tube, tape or https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 27/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate other physical barriers obscure the face, 3 = Complete paralysis of one or both sides these should be removed to the extent (absence of facial movement in the upper possible. and lower face). 5. Motor arm: The limb is placed in the appropriate position: extend the arms 0 = No drift; limb holds 90 (or 45) degrees for full 10 seconds. (palms down) 90 degrees (if sitting) or 45 degrees (if supine). Drift is scored if the arm 1 = Drift; limb holds 90 (or 45) degrees, but drifts down before full 10 seconds; does not falls before 10 seconds. The aphasic patient hit bed or other support. is encouraged using urgency in the voice and pantomime, but not noxious 2 = Some effort against gravity; limb cannot get to or maintain (if cued) 90 (or 45) degrees, drifts down to bed, but has some stimulation. Each limb is tested in turn, beginning with the non-paretic arm. Only in _____ effort against gravity. the case of amputation or joint fusion at the shoulder, the examiner should record the 3 = No effort against gravity; limb falls. score as untestable (UN), and clearly write 4 = No movement. the explanation for this choice. UN = Amputation or joint fusion, explain:________________ 5a. Left arm 5b. Right arm 6. Motor leg: The limb is placed in the appropriate position: hold the leg at 30 degrees (always tested supine). Drift is scored if the leg falls before 5 seconds. The 0 = No drift; leg holds 30-degree position for full 5 seconds. 1 = Drift; leg falls by the end of the 5-second period but does not hit bed. aphasic patient is encouraged using urgency in the voice and pantomime, but not noxious stimulation. Each limb is tested in turn, beginning with the non-paretic leg. Only in the case of amputation or joint fusion at the hip, the examiner should 2 = Some effort against gravity; leg falls to bed by 5 seconds, but has some effort against gravity. _____ 3 = No effort against gravity; leg falls to bed immediately. record the score as untestable (UN), and clearly write the explanation for this choice. 4 = No movement. UN = Amputation or joint fusion, explain:________________ 6a. Left leg 6b. Right leg 7. Limb ataxia: This item is aimed at finding 0 = Absent. _____ evidence of a unilateral cerebellar lesion. Test with eyes open. In case of visual defect, 1 = Present in one limb. 2 = Present in two limbs. ensure testing is done in intact visual field. The finger-nose-finger and heel-shin tests UN = Amputation or joint fusion, explain:________________ are performed on both sides, and ataxia is scored only if present out of proportion to weakness. Ataxia is absent in the patient https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 28/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate who cannot understand or is paralyzed. Only in the case of amputation or joint fusion, the examiner should record the score as untestable (UN), and clearly write the explanation for this choice. In case of blindness, test by having the patient touch nose from extended arm position. 8. Sensory: Sensation or grimace to pinprick 0 = Normal; no sensory loss. when tested, or withdrawal from noxious stimulus in the obtunded or aphasic patient. 1 = Mild-to-moderate sensory loss; patient feels pinprick is less sharp or is dull on the affected side; or there is a loss of superficial Only sensory loss attributed to stroke is scored as abnormal and the examiner pain with pinprick, but patient is aware of being touched. should test as many body areas (arms [not hands], legs, trunk, face) as needed to 2 = Severe to total sensory loss; patient is not aware of being touched in the face, arm, accurately check for hemisensory loss. A score of 2, "severe or total sensory loss," should only be given when a severe or total loss of sensation can be clearly and leg. _____ demonstrated. Stuporous and aphasic patients will, therefore, probably score 1 or 0. The patient with brainstem stroke who has bilateral loss of sensation is scored 2. If the patient does not respond and is quadriplegic, score 2. Patients in a coma (item 1a=3) are automatically given a 2 on this item. 9. Best language: A great deal of 0 = No aphasia; normal. _____ information about comprehension will be obtained during the preceding sections of the examination. For this scale item, the patient is asked to describe what is happening in the attached picture, to name 1 = Mild-to-moderate aphasia; some obvious loss of fluency or facility of comprehension, without significant limitation on ideas expressed or form of expression. Reduction of speech and/or comprehension, however, makes the items on the attached naming sheet and to read from the attached list of sentences. conversation about provided materials Comprehension is judged from responses here, as well as to all of the commands in difficult or impossible. For example, in conversation about provided materials, the preceding general neurological exam. If

26/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate follows none, one or two commands). Patients with trauma, amputation, or other physical impediments should be given suitable one-step commands. Only the first attempt is scored. 2. Best gaze: Only horizontal eye movements will be tested. Voluntary or 0 = Normal. 1 = Partial gaze palsy; gaze is abnormal in reflexive (oculocephalic) eye movements will one or both eyes, but forced deviation or total gaze paresis is not present. be scored, but caloric testing is not done. If the patient has a conjugate deviation of the 2 = Forced deviation, or total gaze paresis not overcome by the oculocephalic eyes that can be overcome by voluntary or reflexive activity, the score will be 1. If a maneuver. patient has an isolated peripheral nerve paresis (cranial nerves III, IV or VI), score a 1. _____ Gaze is testable in all aphasic patients. Patients with ocular trauma, bandages, pre- existing blindness, or other disorder of visual acuity or fields should be tested with reflexive movements, and a choice made by the investigator. Establishing eye contact and then moving about the patient from side to side will occasionally clarify the presence of a partial gaze palsy. 3. Visual: Visual fields (upper and lower quadrants) are tested by confrontation, using finger counting or visual threat, as appropriate. Patients may be encouraged, 0 = No visual loss. 1 = Partial hemianopia. 2 = Complete hemianopia. but if they look at the side of the moving fingers appropriately, this can be scored as normal. If there is unilateral blindness or enucleation, visual fields in the remaining eye are scored. Score 1 only if a clear-cut 3 = Bilateral hemianopia (blind including cortical blindness). _____ asymmetry, including quadrantanopia, is found. If patient is blind from any cause, score 3. Double simultaneous stimulation is performed at this point. If there is extinction, patient receives a 1, and the results are used to respond to item 11. 4. Facial palsy: Ask - or use pantomime to encourage - the patient to show teeth or 0 = Normal symmetrical movements. _____ 1 = Minor paralysis (flattened nasolabial raise eyebrows and close eyes. Score symmetry of grimace in response to noxious fold, asymmetry on smiling). 2 = Partial paralysis (total or near-total paralysis of lower face). stimuli in the poorly responsive or non- comprehending patient. If facial trauma/bandages, orotracheal tube, tape or https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 27/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate other physical barriers obscure the face, 3 = Complete paralysis of one or both sides these should be removed to the extent (absence of facial movement in the upper possible. and lower face). 5. Motor arm: The limb is placed in the appropriate position: extend the arms 0 = No drift; limb holds 90 (or 45) degrees for full 10 seconds. (palms down) 90 degrees (if sitting) or 45 degrees (if supine). Drift is scored if the arm 1 = Drift; limb holds 90 (or 45) degrees, but drifts down before full 10 seconds; does not falls before 10 seconds. The aphasic patient hit bed or other support. is encouraged using urgency in the voice and pantomime, but not noxious 2 = Some effort against gravity; limb cannot get to or maintain (if cued) 90 (or 45) degrees, drifts down to bed, but has some stimulation. Each limb is tested in turn, beginning with the non-paretic arm. Only in _____ effort against gravity. the case of amputation or joint fusion at the shoulder, the examiner should record the 3 = No effort against gravity; limb falls. score as untestable (UN), and clearly write 4 = No movement. the explanation for this choice. UN = Amputation or joint fusion, explain:________________ 5a. Left arm 5b. Right arm 6. Motor leg: The limb is placed in the appropriate position: hold the leg at 30 degrees (always tested supine). Drift is scored if the leg falls before 5 seconds. The 0 = No drift; leg holds 30-degree position for full 5 seconds. 1 = Drift; leg falls by the end of the 5-second period but does not hit bed. aphasic patient is encouraged using urgency in the voice and pantomime, but not noxious stimulation. Each limb is tested in turn, beginning with the non-paretic leg. Only in the case of amputation or joint fusion at the hip, the examiner should 2 = Some effort against gravity; leg falls to bed by 5 seconds, but has some effort against gravity. _____ 3 = No effort against gravity; leg falls to bed immediately. record the score as untestable (UN), and clearly write the explanation for this choice. 4 = No movement. UN = Amputation or joint fusion, explain:________________ 6a. Left leg 6b. Right leg 7. Limb ataxia: This item is aimed at finding 0 = Absent. _____ evidence of a unilateral cerebellar lesion. Test with eyes open. In case of visual defect, 1 = Present in one limb. 2 = Present in two limbs. ensure testing is done in intact visual field. The finger-nose-finger and heel-shin tests UN = Amputation or joint fusion, explain:________________ are performed on both sides, and ataxia is scored only if present out of proportion to weakness. Ataxia is absent in the patient https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 28/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate who cannot understand or is paralyzed. Only in the case of amputation or joint fusion, the examiner should record the score as untestable (UN), and clearly write the explanation for this choice. In case of blindness, test by having the patient touch nose from extended arm position. 8. Sensory: Sensation or grimace to pinprick 0 = Normal; no sensory loss. when tested, or withdrawal from noxious stimulus in the obtunded or aphasic patient. 1 = Mild-to-moderate sensory loss; patient feels pinprick is less sharp or is dull on the affected side; or there is a loss of superficial Only sensory loss attributed to stroke is scored as abnormal and the examiner pain with pinprick, but patient is aware of being touched. should test as many body areas (arms [not hands], legs, trunk, face) as needed to 2 = Severe to total sensory loss; patient is not aware of being touched in the face, arm, accurately check for hemisensory loss. A score of 2, "severe or total sensory loss," should only be given when a severe or total loss of sensation can be clearly and leg. _____ demonstrated. Stuporous and aphasic patients will, therefore, probably score 1 or 0. The patient with brainstem stroke who has bilateral loss of sensation is scored 2. If the patient does not respond and is quadriplegic, score 2. Patients in a coma (item 1a=3) are automatically given a 2 on this item. 9. Best language: A great deal of 0 = No aphasia; normal. _____ information about comprehension will be obtained during the preceding sections of the examination. For this scale item, the patient is asked to describe what is happening in the attached picture, to name 1 = Mild-to-moderate aphasia; some obvious loss of fluency or facility of comprehension, without significant limitation on ideas expressed or form of expression. Reduction of speech and/or comprehension, however, makes the items on the attached naming sheet and to read from the attached list of sentences. conversation about provided materials Comprehension is judged from responses here, as well as to all of the commands in difficult or impossible. For example, in conversation about provided materials, the preceding general neurological exam. If examiner can identify picture or naming card content from patient's response. visual loss interferes with the tests, ask the patient to identify objects placed in the 2 = Severe aphasia; all communication is through fragmentary expression; great need hand, repeat, and produce speech. The intubated patient should be asked to write. for inference, questioning, and guessing by the listener. Range of information that can The patient in a coma (item 1a=3) will automatically score 3 on this item. The be exchanged is limited; listener carries burden of communication. Examiner cannot examiner must choose a score for the patient with stupor or limited cooperation, but a score of 3 should be used only if the https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 29/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate patient is mute and follows no one-step identify materials provided from patient commands. response. 3 = Mute, global aphasia; no usable speech or auditory comprehension. 10. Dysarthria: If patient is thought to be normal, an adequate sample of speech must 0 = Normal. 1 = Mild-to-moderate dysarthria; patient be obtained by asking patient to read or slurs at least some words and, at worst, can be understood with some difficulty. repeat words from the attached list. If the patient has severe aphasia, the clarity of 2 = Severe dysarthria; patient's speech is so slurred as to be unintelligible in the absence articulation of spontaneous speech can be rated. Only if the patient is intubated or has _____ of or out of proportion to any dysphasia, or is mute/anarthric. other physical barriers to producing speech, the examiner should record the score as untestable (UN), and clearly write an UN = Intubated or other physical barrier, explanation for this choice. Do not tell the patient why he or she is being tested. explain:________________ 11. Extinction and inattention (formerly 0 = No abnormality. neglect): Sufficient information to identify neglect may be obtained during the prior testing. If the patient has a severe visual loss preventing visual double simultaneous stimulation, and the cutaneous stimuli are normal, the score is normal. If the patient has aphasia but does appear to attend to 1 = Visual, tactile, auditory, spatial, or personal inattention or extinction to bilateral simultaneous stimulation in one of the sensory modalities. 2 = Profound hemi-inattention or extinction to more than one modality; does not recognize own hand or orients to only one side of space. _____ both sides, the score is normal. The presence of visual spatial neglect or anosognosia may also be taken as evidence of abnormality. Since the abnormality is scored only if present, the item is never untestable. _____ Adapted from: Goldstein LB, Samsa GP. Reliability of the National Institutes of Health Stroke Scale. Extension to non- neurologists in the context of a clinical trial. Stroke 1997; 28:307. Graphic 61698 Version 8.0 https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 30/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate Eligibility criteria for the treatment of acute ischemic stroke with intravenous thrombolysis (recombinant tissue plasminogen activator or tPA) Inclusion criteria Clinical diagnosis of ischemic stroke causing measurable neurologic deficit Onset of symptoms <4.5 hours before beginning treatment; if the exact time of stroke onset is not known, it is defined as the last time the patient was known to be normal or at neurologic baseline Age 18 years Exclusion criteria Patient history Ischemic stroke or severe head trauma in the previous three months Previous intracranial hemorrhage Intra-axial intracranial neoplasm Gastrointestinal malignancy Gastrointestinal hemorrhage in the previous 21 days Intracranial or intraspinal surgery within the prior three months Clinical Symptoms suggestive of subarachnoid hemorrhage Persistent blood pressure elevation (systolic 185 mmHg or diastolic 110 mmHg) Active internal bleeding Presentation consistent with infective endocarditis Stroke known or suspected to be associated with aortic arch dissection Acute bleeding diathesis, including but not limited to conditions defined under 'Hematologic' Hematologic 3 Platelet count <100,000/mm * Current anticoagulant use with an INR >1.7 or PT >15 seconds or aPTT >40 seconds* Therapeutic doses of low molecular weight heparin received within 24 hours (eg, to treat VTE and ACS); this exclusion does not apply to prophylactic doses (eg, to prevent VTE) Current use (ie, last dose within 48 hours in a patient with normal renal function) of a direct thrombin inhibitor or direct factor Xa inhibitor with evidence of anticoagulant effect by laboratory tests such as aPTT, INR, ECT, TT, or appropriate factor Xa activity assays Head CT Evidence of hemorrhage https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 31/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate Extensive regions of obvious hypodensity consistent with irreversible injury Warnings Only minor and isolated neurologic signs or rapidly improving symptoms Serum glucose <50 mg/dL (<2.8 mmol/L) Serious trauma in the previous 14 days Major surgery in the previous 14 days History of gastrointestinal bleeding (remote) or genitourinary bleeding Seizure at the onset of stroke with postictal neurologic impairments Pregnancy** Arterial puncture at a noncompressible site in the previous seven days Large ( 10 mm), untreated, unruptured intracranial aneurysm Untreated intracranial vascular malformation Additional warnings for treatment from 3 to 4.5 hours from symptom onset Age >80 years Oral anticoagulant use regardless of INR Severe stroke (NIHSS score >25) Combination of both previous ischemic stroke and diabetes mellitus ACS: acute coronary syndrome; aPTT: activated partial thromboplastin time; ECT: ecarin clotting time; INR: international normalized ratio; PT: prothrombin time; NIHSS: National Institutes of Health Stroke Scale; tPA: intravenous alteplase; TT: thrombin time; VTE: venous thromboembolism. Although it is desirable to know the results of these tests, thrombolytic therapy should not be delayed while results are pending unless (1) there is clinical suspicion of a bleeding abnormality or thrombocytopenia, (2) the patient is currently on or has recently received anticoagulants (eg, heparin, warfarin, a direct thrombin inhibitor, or a direct factor Xa inhibitor), or (3) use of anticoagulants is not known. Otherwise, treatment with intravenous tPA can be started before availability of coagulation test results but should be discontinued if the INR, PT, or aPTT exceed the limits stated in the table, or 3 if platelet count is <100,000 mm . With careful consideration and weighting of risk-to-benefit, patients may receive intravenous alteplase despite one or more warnings. Patients who have a persistent neurologic deficit that is potentially disabling, despite improvement of any degree, should be treated with tPA in the absence of other contraindications. Any of the following should be considered disabling deficits: Complete hemianopia: 2 on NIHSS question 3, or Severe aphasia: 2 on NIHSS question 9, or Visual or sensory extinction: 1 on NIHSS question 11, or Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6, or Any deficits that lead to a total NIHSS >5, or https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 32/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate Any remaining deficit considered potentially disabling in the view of the patient and the treating practitioner using clinical judgment Patients may be treated with intravenous alteplase if glucose level is subsequently normalized. The potential risks of bleeding with alteplase from injuries related to the trauma should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. The increased risk of surgical site bleeding with alteplase should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. There is a low increased risk of new bleeding with alteplase in the setting of past gastrointestinal or genitourinary bleeding. However, alteplase administration within 21 days of gastrointestinal bleeding is not recommended. Alteplase is reasonable in patients with a seizure at stroke onset if evidence suggests that residual impairments are secondary to acute ischemic stroke and not to a postictal phenomenon. * Alteplase can be given in pregnancy when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding. The safety and efficacy of administering alteplase is uncertain for these relative exclusions. Although these were exclusions in the trial showing benefit in the 3 to 4.5 hour window, intravenous alteplase appears to be safe and may be beneficial for patients with these criteria, including patients taking oral anticoagulants with an INR <1.7. Adapted from: 1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359:1317. 2. Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke Association. Stroke 2009; 40:2945. 3. Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force:, Levine SR, Khatri P, et al. Review, historical context, and clari cations of the NINDS rt-PA stroke trials exclusion criteria: Part 1: rapidly improving stroke symptoms. Stroke 2013; 44:2500. 4. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scienti c rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2016; 47:581. 5. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. Graphic 71462 Version 26.0 https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 33/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate Indications for mechanical thrombectomy to treat patients with acute ischemic IV: intravenous; tPA: tissue plasminogen activator (alteplase or tenecteplase); CTA: computed tomography an artery occlusion; MT: mechanical thrombectomy; ASPECTS: Alberta Stroke Program Early CT Score; NIHSS: Na tomography; MRI: magnetic resonance imaging; mRS: modified Rankin Scale; MCA: middle cerebral artery; IC recovery. Patients are not ordinarily eligible for IV tPA unless the time last known to be well is <4.5 hours. However, im that is diffusion positive and FLAIR negative) is an option at expert stroke centers to select patients with wake associated UpToDate topics for details. Usually assessed with MRA or CTA, less often with digital subtraction angiography. There is intracranial arterial occlusion of the distal ICA, middle cerebral (M1/M2), or anterior cerebral (A1/A2 MT may be a treatment option for patients with acute ischemic stroke caused by occlusion of the basilar ar stroke centers, but benefit is uncertain. [1] Based upon data from the Aurora study . Reference: https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 34/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate 1. Albers GW, Lansberg MG, Brown S, et al. Assessment of Optimal Patient Selection for Endovascular Thrombectomy Beyond 6 Hou Neurol 2021; 78:1064. Graphic 117086 Version 3.0 https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 35/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate Risk factors for recurrent ischemic stroke after TIA Age: Age 60 years History: Earlier TIA or ischemic stroke within 30 days of index event History of diabetes Blood pressure elevation when first assessed after TIA: Systolic 140 mmHg or diastolic 90 mmHg Clinical features: Unilateral weakness Isolated speech disturbance Duration of TIA symptoms >10 minutes Imaging features: Acute infarction on diffusion-weighted MRI (ie, TIA with infarction) Acute or chronic ischemic lesions on CT Multiple acute infarcts Simultaneous acute infarcts in both hemispheres or in both anterior and posterior circulations Multiple infarcts of different ages (combination of acute and subacute infarcts) Isolated cortical infarcts (without accompanying deep or subcortical infarcts) TIA etiology: Large artery atherosclerosis TIA: transient ischemic attack; MRI: magnetic resonance imaging; CT: computed tomography. Graphic 107037 Version 1.0 https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 36/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate Immediate antithrombotic treatment of transient ischemic attack (TIA) This algorithm is intended to provide basic guidance regarding the use of immediate use of antithrombotic therapy for patients with a TIA. For further details, including suggested dosing regimens of antiplatelet and anticoagulant agents, refer to the relevant UpToDate topic reviews. 2 ABCD : age, blood pressure, clinical features, duration of symptoms, and diabetes; DAPT: dual antiplatelet therapy (eg, aspirin and clopidogrel, or aspirin and ticagrelor); BP: blood pressure; SBP: systolic blood pressure; DBP: diastolic blood pressure. Indications for long-term oral anticoagulation include embolism prevention for patients with atrial fibrillation, ventricular thrombus, mechanical heart valve, and treatment of venous thromboembolism. Graphic 131692 Version 1.0 https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 37/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate Immediate antithrombotic treatment of acute ischemic stroke This algorithm is intended to provide basic guidance regarding the immediated use of antithrombotic therapy for patients with an acute ischemic stroke. For further details, including scoring of the NIHSS and suggested dosing regimens of antithrombotic agents, refer to the relevant UpToDate topic reviews. OA: oral anticoagulants; IVT: intravenous thrombolysis; MT: mechanical thrombectomy; NIHSS: National Institutes of Health Stroke Scale; DAPT: dual antiplatelet therapy (eg, aspirin and clopidogrel, or aspirin and ticagrelor). Refer to text and associated algorithm for details. Brain and large vessel imaging, cardiac evaluation, and (for select patients) other laboratory tests. https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 38/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate For severe systemic or symptomatic intracranial bleeding, withhold all anticoagulant and antiplatelet therapy for one to two weeks or until the patient is stable. Graphic 131697 Version 2.0 https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 39/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate Evaluation of patient presenting with acute symptoms of possible TIA or minor ischemic stroke This algorithm should be used in conjunction with UpToDate topics on the initial evaluation and management of TIA and ischemic stroke. CDUS: carotid duplex ultrasonography; CNS: central nervous system; CT: computed tomography; CTA: computed tomography angiography; ECG: electrocardiography; IV: intravenous; MRA: magnetic resonance angiography; MRI: magnetic resonance imaging; TIA: transient ischemic attack; TCD: transcranial Doppler. Patients who present within the appropriate time window after ischemic symptom onset and have a persistent neurologic deficit that is potentially disabling, despite https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 40/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate improvement of any degree, should be treated with intravenous thrombolysis and/or mechanical thrombectomy in the absence of other contraindications. Further management of these patients is similar to that of other patients with a potentially disabling stroke. Can begin aspirin and statin therapy while awaiting results of remaining diagnostic studies if imaging is negative for hemorrhage and other nonischemic cause of symptoms. Viable strategies include antihypertensive therapy, antithrombotic therapy, statin therapy, and lifestyle modification; select patients with symptomatic cervical internal carotid artery disease may benefit from carotid revascularization. Graphic 107065 Version 1.0 https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 41/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate Cardioaortic sources of cerebral embolism Sources with high primary risk for Sources with low or uncertain primary ischemic stroke risk for ischemic stroke Atrial fibrillation Cardiac sources of embolism: Paroxysmal atrial fibrillation Mitral annular calcification Left atrial thrombus Patent foramen ovale Left ventricular thrombus Atrial septal aneurysm Sick sinus syndrome Atrial septal aneurysm and patent foramen ovale Atrial flutter Left ventricular aneurysm without thrombus Recent myocardial infarction (within one month prior to stroke) Left atrial spontaneous echo contrast ("smoke") Mitral stenosis or rheumatic valve disease Congestive heart failure with ejection fraction <30% Mechanical heart valves Bioprosthetic heart valves Chronic myocardial infarction together with low Apical akinesia ejection fraction (<28%) Dilated cardiomyopathy (prior established diagnosis or left ventricular dilatation with an ejection fraction of <40% or fractional shortening of <25%) Wall motion abnormalities (hypokinesia, akinesia, dyskinesia) other than apical akinesia Nonbacterial thrombotic endocarditis Hypertrophic cardiomyopathy Infective endocarditis Left ventricular hypertrophy Papillary fibroelastoma Left ventricular hypertrabeculation/non- compaction Left atrial myxoma Recent aortic valve replacement or coronary artery bypass graft surgery Presence of left ventricular assist device Paroxysmal supraventricular tachycardia Aortic sources of embolism: Complex atheroma in the ascending aorta or proximal arch (protruding with >4 mm thickness, or mobile debris, or plaque ulceration) The high- and low-risk cardioaortic sources in this table are separated using an arbitrary 2% annual https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 42/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate or one-time primary stroke risk threshold. Data from: 1. Ay H, Benner T, Arsava EM, et al. A computerized algorithm for etiologic classi cation of ischemic stroke: the Causative Classi cation of Stroke System. Stroke 2007; 38:2979. 2. Ay H, Furie KL, Singhal A, et al. An evidence-based causative classi cation system for acute ischemic stroke. Ann Neurol 2005; 58:688. 3. Arsava EM, Ballabio E, Benner T, et al. The Causative Classi cation of Stroke system: an international reliability and optimization study. Neurology 2010; 75:1277. 4. Kamel H, Elkind MS, Bhave PD, et al. Paroxysmal supraventricular tachycardia and the risk of ischemic stroke. Stroke 2013; 44:1550. 5. Kirklin JK, Pagani FD, Kormos RL, et al. Eighth annual INTERMACS report: Special focus on framing the impact of adverse events. J Heart Lung Transplant 2017; 36:1080. Reproduced and modi ed with permission from: Ay H, Furie KL, Singhal A, et al. An evidence-based causative classi cation system for acute ischemic stroke. Ann Neurol 2005; 58:688. Copyright 2005 American Neurological Association. Graphic 60843 Version 11.0 https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 43/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate Antithrombotic therapy according to cause of transient ischemic attack (TIA) This algorithm is intended to provide basic guidance regarding the use of antithrombotic therapy based on mechanism for patients with a TIA. For further details, including suggested dosing regimens of antithrombot agents, refer to the relevant UpToDate topic reviews. ICA: internal carotid artery; CEA: carotid endarterectomy; CAS: carotid artery stenting; DAPT: dual antiplatelet 2 therapy (eg, aspirin and clopidogrel, or aspirin and ticagrelor); ABCD : age, blood pressure, clinical features, duration of symptoms, and diabetes; BP: blood pressure; SBP: systolic blood pressure; DBP: diastolic blood pressure. Indications for long-term oral anticoagulation include atrial fibrillation, ventricular thrombus, mechanical h valve, and treatment of venous thromboembolism. Some experts prefer DAPT based upon observational evidence. Long-term single-agent antiplatelet therapy using aspirin, clopidogrel, or aspirin-extended-release dipyrida Graphic 131695 Version 3.0 https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 44/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate Antithrombotic therapy according to cause of acute ischemic stroke This algorithm is intended to provide basic guidance regarding the immediate use of antithrombotic therapy with an acute ischemic stroke. For further details, including scoring of the NIHSS and suggested dosing regim antithrombotic agents, refer to the relevant UpToDate topic reviews. https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 45/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate HTN: hypertension; SBP: systolic blood pressure; DBP: diastolic blood pressure; ICA: internal carotid artery; C endarterectomy; OA: oral anticoagulation; CAS: carotid artery stenting; DAPT: dual antiplatelet therapy (eg, a clopidogrel, or aspirin and ticagrelor); NIHSS: National Institutes of Health Stroke Scale; CT: computed tomog magnetic resonance imaging. Brain and neurovascular imaging, cardiac evaluation, and (for select patients) other laboratory tests. Indications for long-term oral anticoagulation include atrial fibrillation, ventricular thrombus, mechanical h treatment of venous thromboembolism. "Large" infarcts are defined as those that involve more than one-third of the middle cerebral artery territor one-half of the posterior cerebral artery territory based upon neuroimaging with CT or MRI. Though less relia infarct size can also be defined clinically (eg, NIHSS score >15). Long-term aspirin therapy is alternative (though less effective) if OA contraindicated or refused. Direct oral anticoagulant agents have a more rapid anticoagulant effect than warfarin, a factor that may inf choice of agent and timing of OA initiation. Some experts prefer DAPT, based upon observational evidence. Long-term single-agent antiplatelet therapy for secondary stroke prevention with aspirin, clopidogrel, or as release dipyridamole. Graphic 131701 Version 2.0 https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 46/47 7/5/23, 12:11 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate Contributor Disclosures Natalia S Rost, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Hugo J Aparicio, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Jonathan A Edlow, MD, FACEP No relevant financial relationship(s) with ineligible companies to disclose. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 47/47

7/5/23, 12:12 PM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use : Jamary Oliveira-Filho, MD, MS, PhD, Owen B Samuels, MD : Jos Biller, MD, FACP, FAAN, FAHA, Alejandro A Rabinstein, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 30, 2023. INTRODUCTION The most important factor in successful reperfusion therapy of acute ischemic stroke is early treatment. Nonetheless, selection of appropriate candidates for reperfusion demands a neurologic evaluation and a neuroimaging study. In addition, reperfusion therapy for acute stroke requires a system that coordinates emergency services, stroke neurology, intensive care services, neuroimaging, and neurosurgery to provide optimal treatment. This topic will review the administration of intravenous thrombolytic therapy for patients with acute ischemic stroke. The approach to reperfusion therapy and selection of appropriate patients for treatment is discussed elsewhere. (See "Approach to reperfusion therapy for acute ischemic stroke".) Mechanical thrombectomy is reviewed in detail separately. (See "Mechanical thrombectomy for acute ischemic stroke".) Other aspects of acute ischemic stroke care are discussed elsewhere. (See "Initial assessment and management of acute stroke" and "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack" and "Neuroimaging of acute stroke".) OVERVIEW OF THERAPY https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 1/19 7/5/23, 12:13 PM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate The immediate goal of reperfusion therapy for acute ischemic stroke is to restore blood flow to the regions of brain that are ischemic but not yet infarcted. The long-term goal is to improve outcome by reducing stroke-related disability and mortality. There are two options for reperfusion therapy that are proven effective: Intravenous thrombolytic therapy is the mainstay of treatment for acute ischemic stroke, provided that treatment is initiated within 4.5 hours of clearly defined symptom onset time or within 4.5 hours of the time the patient was last known to be well ( table 1). (See "Approach to reperfusion therapy for acute ischemic stroke", section on 'Benefit by time to treatment'.) For patients with wake-up stroke or unknown time last known well, imaging-based criteria to determine eligibility for intravenous thrombolysis (ie, an MRI showing an acute ischemic lesion that is diffusion positive and fluid-attenuated inversion recovery [FLAIR] negative) is an option at expert stroke centers to determine eligibility for IVT. (See "Approach to reperfusion therapy for acute ischemic stroke", section on 'Benefit with imaging selection of patients'.) Because the benefit is time-dependent, it is critical to treat eligible patients as quickly as possible. Alteplase, a recombinant tissue plasminogen activator (tPA), initiates local fibrinolysis by binding to fibrin in a thrombus (clot) and converting entrapped plasminogen to plasmin. In turn, plasmin breaks up the thrombus. The pivotal randomized trials that established the efficacy of intravenous thrombolytic therapy for acute stroke used alteplase as the thrombolytic agent. (See "Approach to reperfusion therapy for acute ischemic stroke", section on 'Alteplase'.) Tenecteplase is a thrombolytic agent that is more fibrin-specific and has a longer duration of action compared with alteplase. Although not licensed in the United States for intravenous thrombolysis in acute ischemic stroke treatment, there is evidence that intravenous tenecteplase has similar efficacy and safety outcomes compared with alteplase. (See "Approach to reperfusion therapy for acute ischemic stroke", section on 'Tenecteplase'.) Mechanical thrombectomy is indicated for patients with acute ischemic stroke due to a large artery occlusion in the anterior circulation who can be treated within 24 hours of the time last known to be well (ie, at neurologic baseline), regardless of whether they receive intravenous thrombolysis for the same ischemic stroke event. (See "Mechanical thrombectomy for acute ischemic stroke".) https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 2/19 7/5/23, 12:13 PM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Eligible patients should receive intravenous thrombolysis without delay even if mechanical thrombectomy is being considered [1]. ADMINISTRATION OF THROMBOLYTIC THERAPY "Time is brain." The sooner intravenous thrombolysis is initiated after ischemic stroke, the more likely it is to be beneficial. The benefits and risks of thrombolytic therapy with alteplase or tenecteplase are discussed in detail separately (see "Approach to reperfusion therapy for acute ischemic stroke"). The selection of appropriate patients for such therapy is summarized in the table ( table 1). Preparing for treatment Prior to treatment, all patients require confirmation of the following: The diagnosis is acute ischemic stroke Treatment is commencing within the required 4.5-hour time window after the onset of symptoms, defined as the time last seen normal or at baseline There is a persistent, measurable, disabling neurologic deficit Eligibility criteria are met ( table 1) Serum glucose must be checked to rule out hypoglycemia as a cause of neurologic deficit The noncontrast head computed tomography (CT) or brain magnetic resonance imaging (MRI) is without hemorrhage or other contraindication Blood pressure parameters are met (see 'Management of blood pressure' below) Two intravenous lines, preferably large bore, are in place Accurate body weight has been determined [2] Management of blood pressure Strict blood pressure control is critical prior to and during the first 24 hours after thrombolytic therapy. The blood pressure must be at or below 185 mmHg systolic and 110 mmHg diastolic before administering thrombolysis. Patients with blood pressure above this range should be treated with intravenous agents such as intravenous labetalol or nicardipine, or clevidipine ( table 2) [1]. Alternative agents include hydralazine and enalaprilat. If intravenous treatment does not bring the blood pressure into the acceptable range, the patient should not be treated with thrombolysis because the risk of intracerebral hemorrhage with thrombolytic therapy may be increased. Once thrombolytic therapy has been administered, the blood pressure must be maintained below 180/105 mmHg during and for 24 hours following thrombolytic therapy ( table 2). https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 3/19 7/5/23, 12:13 PM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Intravenous labetalol, nicardipine, or clevidipine are suggested agents of first choice [1]. Frequent blood pressure monitoring is recommended to ensure that the blood pressure remains in the acceptable range. Current guidelines recommend monitoring every 15 minutes for the first 2 hours after starting thrombolytic treatment, then every 30 minutes for the next 6 hours, then every hour until 24 hours after starting treatment. The frequency of blood pressure monitoring should be increased if the systolic blood pressure is >180 mmHg or if the diastolic blood pressure is >105 mmHg. For patients with stroke caused by a known large artery occlusion (documented by computed tomography angiography [CTA] or magnetic resonance angiography [MRA]), we suggest keeping systolic blood pressure between 150 to 180 mmHg prior to reperfusion, and targeting systolic blood pressure to <140 mmHg once reperfusion is achieved with intravenous thrombolysis or mechanical thrombectomy (see "Mechanical thrombectomy for acute ischemic stroke", section on 'Blood pressure management'). These recommendations regarding blood pressure control are based on consensus, since there are no data supporting the use of any specific antihypertensive agent or regimen for patients with acute ischemic stroke treated with thrombolysis. The optimal lower end of the range of desired blood pressure is unclear in those requiring antihypertensive treatment for thrombolysis. Maintaining the blood pressure below 180/105 mmHg for at least the first 24 hours after administration of thrombolytic therapy is the only guideline recommendation [1]. In this situation, there is still a risk of worsening blood flow within the ischemic penumbra if blood pressure is driven too low. Therefore, it is important to avoid excessive blood pressure lowering when using intravenous antihypertensive treatment. Despite concerns about reducing perfusion, more intensive blood pressure reduction might reduce the risk of symptomatic intracerebral hemorrhage and thereby improve outcomes. The blood pressure control assessment arm of the open-label, international ENCHANTED trial tested this strategy and found that a target blood pressure of 130 to 140 mmHg with intravenous thrombolytic therapy did not appear to be beneficial or harmful. The ENCHANTED trial enrolled over 2200 alteplase-eligible patients with acute ischemic stroke and randomly assigned them to intensive blood pressure lowering (to a target systolic blood pressure of 130 to 140 mmHg within one hour) or guideline blood pressure lowering (target <180 mmHg) over 72 hours [3]. The mean systolic blood pressure over 24 hours in the intensive and guideline groups was 144.3 mmHg and 149.8 mmHg, respectively. At 90 days, there was no difference in functional status between groups. Intracranial hemorrhage was less frequent in the intensive group compared with the guideline group (14.8 versus 18.7 percent), but there was no significant difference between groups in rates of symptomatic intracerebral hemorrhage or serious adverse events. https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 4/19 7/5/23, 12:13 PM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Dosing Alteplase dose A dedicated intravenous line is required for alteplase, and all patients should have at least one additional large bore intravenous line. The alteplase dose is calculated at 0.9 mg/kg of actual body weight, with a maximum dose of 90 mg Ten percent of the dose is given as an intravenous bolus over one minute and the remainder is infused over one hour It is advisable to remove any excess alteplase from the bottle prior to administration, in order to avoid overdosage if the intravenous pump is inaccurately calibrated. In Japan, the approved dose of alteplase for acute ischemic stroke is 0.6 mg/kg, based upon the results of a small open-label study suggesting that this dose was associated with a lower risk of intracerebral hemorrhage and similar efficacy compared with the standard alteplase dose of 0.9 mg/kg [4]. However, in the ENCHANTED trial, which enrolled over 3300 subjects (63 percent Asian) with acute ischemic stroke, low-dose alteplase (0.6 mg/kg) did not meet noninferiority criteria compared with standard-dose alteplase (0.9 mg/kg) for the outcome of death and disability at 90 days [5]. Tenecteplase dose The dose of tenecteplase is 0.25 mg/kg (maximum total dose 25 mg) given in a single intravenous bolus over 5 seconds, followed by a saline flush [6,7]. Monitoring All patients treated with intravenous thrombolysis for acute ischemic stroke should be admitted to an intensive care unit or dedicated stroke unit for at least 24 hours of close neurologic and cardiac monitoring [1]. Symptomatic intracerebral hemorrhage should be suspected in any patient who develops sudden neurologic deterioration, a decline in level of consciousness, new headache, nausea and vomiting, or a sudden rise in blood pressure after thrombolytic therapy is administered, especially within the first 24 hours of treatment. (See 'Management of symptomatic intracerebral hemorrhage' below.) Important measures during the first 24 hours of treatment with thrombolytic therapy include the following [1]: Vital signs and neurologic status should be checked every 15 minutes for two hours, then every 30 minutes for six hours, then every 60 minutes until 24 hours from the start of thrombolysis. Blood pressure must be maintained at or below 180/105 mmHg during the first 24 hours. (See 'Management of blood pressure' above.) https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 5/19 7/5/23, 12:13 PM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Antithrombotic agents, such as heparin, warfarin, direct oral anticoagulants, or antiplatelet drugs, should not be administered for at least 24 hours after the alteplase infusion or tenecteplase bolus is completed, unless their administration is absolutely necessary. Placement of intra-arterial catheters, indwelling bladder catheters, and nasogastric tubes should be avoided for at least 24 hours if the patient can be safely managed without them. A follow-up noncontrast CT (or MRI) brain scan should be obtained 24 hours after thrombolysis is initiated before starting treatment with antiplatelet or anticoagulant agents [1]. COMPLICATIONS The most feared complication of thrombolytic therapy is symptomatic intracerebral hemorrhage. Asymptomatic intracerebral hemorrhage, systemic bleeding, and angioedema are additional complications that may arise. Intracerebral hemorrhage Treatment with intravenous (IV) thrombolysis within 4.5 hours of acute ischemic stroke onset is associated with an increased early risk of intracerebral hemorrhage, which was in the range of 5 to 7 percent; lower rates have been observed using stricter definitions of symptomatic intracerebral hemorrhage. This risk is offset by later benefit in the form of reduced disability. (See "Approach to reperfusion therapy for acute ischemic stroke", section on 'Alteplase' and "Approach to reperfusion therapy for acute ischemic stroke", section on 'Risk of intracerebral hemorrhage'.) Management of symptomatic intracerebral hemorrhage Symptomatic intracerebral hemorrhage should be suspected in any patient who develops sudden neurologic deterioration, a decline in level of consciousness, new headache, nausea and vomiting, or a sudden rise in blood pressure after thrombolytic therapy is administered, especially within the first 24 hours of treatment. In patients with suspected intracerebral hemorrhage, the alteplase infusion should be discontinued and a stat noncontrast head computed tomography (CT) or magnetic resonance imaging (MRI) scan should be arranged ( table 3) [1]. Blood should be drawn for typing and cross matching, and measurement of prothrombin time, activated partial thromboplastin time, platelet count, and fibrinogen. Treatment options for intracerebral hemorrhage related to intravenous thrombolytic treatment are unproven but include the administration of agents to reverse the effects of thrombolytic therapy and antithrombotic therapy [1,8-13]: https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 6/19 7/5/23, 12:13 PM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Cryoprecipitate, 10 units immediately (infused over 10 to 30 minutes) and more as needed to achieve a serum fibrinogen level of 150 to 200 mg/dL Antifibrinolytic agents: aminocaproic acid 4 to 5 g IV during first hour, followed by 1 g/hour for 8 hours until bleeding is controlled, or tranexamic acid 10 to 15 mg/kg IV over 10 to 20 minutes Prothrombin complex concentrate as adjunctive therapy to cryoprecipitate for patients on warfarin prior to thrombolytic treatment Fresh frozen plasma as adjunctive therapy to cryoprecipitate for patients on warfarin prior to thrombolytic treatment if prothrombin complex concentrate is not available Vitamin K as adjunctive therapy for patients on warfarin prior to thrombolytic treatment Six to eight units of platelets for patients with thrombocytopenia (platelet count <100,000/microL) In patients receiving unfractionated heparin (UFH) for any reason, it is reasonable to treat with 1 mg of protamine for every 100 units of UFH given in the preceding 4 hours Urgent neurosurgery and hematology consultations are indicated for patients with symptomatic intracranial hemorrhage associated with thrombolysis [1]. Supportive therapy includes management of blood pressure, intracranial pressure, cerebral perfusion pressure, and glucose control. The efficacy of neurosurgical evacuation in this setting is unproven. However, in a retrospective analysis of data from the GUSTO-I trial of thrombolysis for myocardial infarction, 30-day survival was significantly higher with neurosurgical hematoma evacuation than without (65 versus 35 percent), and there was a trend towards improved functional outcome due to a higher incidence of nondisabling stroke in those with evacuation compared with those without (20 versus 12 percent) [14]. However, no definitive conclusions can be drawn from this retrospective, nonrandomized study. Systemic bleeding Mild systemic bleeding usually occurs in the form of oozing from intravenous catheter sites, ecchymoses (especially under automated blood pressure cuffs), and gum bleeding; these complications do not require cessation of treatment. More serious bleeding, such as from the gastrointestinal or genitourinary system, may require discontinuation of alteplase depending on the severity. Rarely, patients who suffer stroke after a recent myocardial infarction can develop bleeding into the pericardium, resulting in life-threatening tamponade [15,16]. Consequently, patients who become hypotensive after thrombolytic therapy should be evaluated with urgent echocardiography. https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 7/19 7/5/23, 12:13 PM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Angioedema Orolingual angioedema occurs in 1 to 8 percent of patients treated with alteplase or tenecteplase for ischemic stroke [17-20], and it is typically mild, transient, and contralateral to the ischemic hemisphere [18,21]. Patients taking angiotensin converting enzyme inhibitors and those with CT evidence of ischemia in the frontal and insular cortex may be at increased risk. Severe orolingual angioedema is rare but may cause partial airway obstruction and require emergent airway management [1,18,21,22]. CT of the tongue can distinguish hematoma from angioedema in this setting [23]. The patient with angioedema near or involving the tongue, uvula, soft palate, or larynx must be immediately assessed for signs of airway compromise. If intubation is necessary, the airway should be managed by the most experienced person available, because intubation in the presence of laryngeal angioedema can be difficult due to distortion of the normal anatomy. Angioedema of the lips or mouth sometimes spreads to involve the throat, and frequent monitoring of airway patency is critical throughout treatment. (See "An overview of angioedema: Clinical features, diagnosis, and management".) Treating centers should be aware of the potential need for stopping the drug infusion, administering antihistamines and glucocorticoids, and intubating patients who develop stridor. Specific management recommendations for orolingual angioedema include the following [1]: Maintain airway: Endotracheal intubation may not be necessary if edema is limited to anterior tongue and lips. Edema involving larynx, palate, floor of mouth, or oropharynx with rapid progression (within 30 minutes) poses higher risk of requiring intubation. Awake fiberoptic intubation is optimal. Nasotracheal intubation may be necessary but is associated with a risk of epistaxis after treatment with IV thrombolysis. Emergency cricothyrotomy is rarely needed and is also problematic after IV thrombolysis treatment, but in a life-threatening circumstance the need to establish an airway supersedes this concern. (See "Approach to the difficult airway in adults for emergency medicine and critical care" and "The difficult pediatric airway for emergency medicine".) Discontinue alteplase infusion and hold angiotensin converting enzyme inhibitor Give in rapid sequence: IV methylprednisolone 125 mg https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 8/19 7/5/23, 12:13 PM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate IV diphenhydramine 50 mg IV famotidine 20 mg If there is further increase in angioedema, give epinephrine (0.1 percent) 0.3 mL subcutaneously or 0.5 mL by nebulizer, but note that epinephrine has a theoretical risk of blood pressure elevation and hemorrhage Additional treatment options for refractory angioedema include icatibant and plasma-derived C1 inhibitor concentrate, which have been used to treat hereditary angioedema and angiotensin converting enzyme inhibitor-related angioedema [1]. (See "ACE inhibitor-induced angioedema", section on 'Therapies of unproven efficacy'.) SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Stroke (The Basics)") Beyond the Basics topics (see "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)" and "Patient education: Ischemic stroke treatment (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 9/19 7/5/23, 12:13 PM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Time is brain Intravenous thrombolysis is the mainstay of treatment for acute ischemic stroke, provided that treatment is initiated within 4.5 hours of clearly defined symptom onset. Because the benefit of is time-dependent, it is critical to treat patients as quickly as possible. (See 'Overview of therapy' above.) Patient selection Prior to treatment, eligibility should be confirmed ( table 1), two intravenous lines, preferably large bore, should be placed, and accurate body weight determined. (See 'Preparing for treatment' above.) Blood pressure management Strict blood pressure control is critical prior to and during the first 24 hours after thrombolytic therapy. The blood pressure must be at or below 185/110 mmHg before starting treatment. The blood pressure must be maintained at or below 180/105 mmHg for 24 hours following thrombolytic treatment ( table 2). (See 'Management of blood pressure' above.) Dosing The alteplase dose is calculated at 0.9 mg/kg of actual body weight, with a maximum dose of 90 mg. Ten percent of the dose is given as an intravenous bolus over one minute and the remainder is infused over one hour. In Japan, however, the approved dose of alteplase for acute ischemic stroke is 0.6 mg/kg. The tenecteplase dose is 0.25 mg/kg (maximum total dose 25 mg) given in a single intravenous bolus over 5 seconds, followed by a saline flush. (See 'Dosing' above.) No antithrombotics for 24 hours Treatment with anticoagulant or antiplatelet agents should not be started within the first 24 hours of thrombolytic therapy in patients with acute ischemic stroke. Antiplatelet therapy should be started for most patients 24 to 48 hours after thrombolytic therapy. (See 'Monitoring' above and "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack".) Adverse effects The most feared complication of thrombolytic therapy is symptomatic intracerebral hemorrhage. Asymptomatic intracerebral hemorrhage, systemic bleeding, and angioedema are additional complications that may arise. (See 'Complications' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 10/19 7/5/23, 12:13 PM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. 2. Michaels AD, Spinler SA, Leeper B, et al. Medication errors in acute cardiovascular and stroke patients: a scientific statement from the American Heart Association. Circulation 2010; 121:1664. 3. Anderson CS, Huang Y, Lindley RI, et al. Intensive blood pressure reduction with intravenous thrombolysis therapy for acute ischaemic stroke (ENCHANTED): an international, randomised, open-label, blinded-endpoint, phase 3 trial. Lancet 2019; 393:877. 4. Yamaguchi T, Mori E, Minematsu K, et al. Alteplase at 0.6 mg/kg for acute ischemic stroke within 3 hours of onset: Japan Alteplase Clinical Trial (J-ACT). Stroke 2006; 37:1810. 5. Anderson CS, Robinson T, Lindley RI, et al. Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke. N Engl J Med 2016; 374:2313. 6. Campbell BCV, Mitchell PJ, Churilov L, et al. Effect of Intravenous Tenecteplase Dose on Cerebral Reperfusion Before Thrombectomy in Patients With Large Vessel Occlusion Ischemic Stroke: The EXTEND-IA TNK Part 2 Randomized Clinical Trial. JAMA 2020; 323:1257. 7. Mitchell PJ, Yan B, Churilov L, et al. Endovascular thrombectomy versus standard bridging thrombolytic with endovascular thrombectomy within 4 5 h of stroke onset: an open-label, blinded-endpoint, randomised non-inferiority trial. Lancet 2022; 400:116. 8. Yaghi S, Eisenberger A, Willey JZ. Symptomatic intracerebral hemorrhage in acute ischemic stroke after thrombolysis with intravenous recombinant tissue plasminogen activator: a review of natural history and treatment. JAMA Neurol 2014; 71:1181. 9. Yaghi S, Boehme AK, Dibu J, et al. Treatment and Outcome of Thrombolysis-Related Hemorrhage: A Multicenter Retrospective Study. JAMA Neurol 2015; 72:1451. 10. French KF, White J, Hoesch RE. Treatment of intracerebral hemorrhage with tranexamic acid after thrombolysis with tissue plasminogen activator. Neurocrit Care 2012; 17:107. 11. Yaghi S, Willey JZ, Cucchiara B, et al. Treatment and Outcome of Hemorrhagic Transformation After Intravenous Alteplase in Acute Ischemic Stroke: A Scientific Statement for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2017; 48:e343. 12. Frontera JA, Lewin JJ 3rd, Rabinstein AA, et al. Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage: A Statement for Healthcare Professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care 2016; 24:6. 13. O'Carroll CB, Aguilar MI. Management of Postthrombolysis Hemorrhagic and Orolingual Angioedema Complications. Neurohospitalist 2015; 5:133. https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 11/19 7/5/23, 12:13 PM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate 14. Mahaffey KW, Granger CB, Sloan MA, et al. Neurosurgical evacuation of intracranial hemorrhage after thrombolytic therapy for acute myocardial infarction: experience from the GUSTO-I trial. Global Utilization of Streptokinase and tissue-plasminogen activator (tPA) for Occluded Coronary Arteries. Am Heart J 1999; 138:493. 15. Kasner SE, Villar-Cordova CE, Tong D, Grotta JC. Hemopericardium and cardiac tamponade after thrombolysis for acute ischemic stroke. Neurology 1998; 50:1857. 16. Marto JP, Kauppila LA, Jorge C, et al. Intravenous Thrombolysis for Acute Ischemic Stroke After Recent Myocardial Infarction: Case Series and Systematic Review. Stroke 2019; 50:2813. 17. Hill MD, Buchan AM, Canadian Alteplase for Stroke Effectiveness Study (CASES) Investigators. Thrombolysis for acute ischemic stroke: results of the Canadian Alteplase for Stroke Effectiveness Study. CMAJ 2005; 172:1307. 18. Hurford R, Rezvani S, Kreimei M, et al. Incidence, predictors and clinical characteristics of orolingual angio-oedema complicating thrombolysis with tissue plasminogen activator for ischaemic stroke. J Neurol Neurosurg Psychiatry 2015; 86:520. 19. Myslimi F, Caparros F, Dequatre-Ponchelle N, et al. Orolingual Angioedema During or After Thrombolysis for Cerebral Ischemia. Stroke 2016; 47:1825. 20. Zhong CS, Beharry J, Salazar D, et al. Routine Use of Tenecteplase for Thrombolysis in Acute Ischemic Stroke. Stroke 2021; 52:1087. 21. Hill MD, Lye T, Moss H, et al. Hemi-orolingual angioedema and ACE inhibition after alteplase treatment of stroke. Neurology 2003; 60:1525. 22. Chodirker WB. Reactions to alteplase in patients with acute thrombotic stroke. CMAJ 2000; 163:387. 23. Engelter ST, Fluri F, Buitrago-T llez C, et al. Life-threatening orolingual angioedema during thrombolysis in acute ischemic stroke. J Neurol 2005; 252:1167. Topic 16134 Version 61.0 https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 12/19 7/5/23, 12:13 PM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate GRAPHICS Eligibility criteria for the treatment of acute ischemic stroke with intravenous thrombolysis (recombinant tissue plasminogen activator or tPA) Inclusion criteria Clinical diagnosis of ischemic stroke causing measurable neurologic deficit Onset of symptoms <4.5 hours before beginning treatment; if the exact time of stroke onset is not known, it is defined as the last time the patient was known to be normal or at neurologic baseline Age 18 years Exclusion criteria Patient history Ischemic stroke or severe head trauma in the previous three months Previous intracranial hemorrhage Intra-axial intracranial neoplasm Gastrointestinal malignancy Gastrointestinal hemorrhage in the previous 21 days Intracranial or intraspinal surgery within the prior three months Clinical Symptoms suggestive of subarachnoid hemorrhage Persistent blood pressure elevation (systolic 185 mmHg or diastolic 110 mmHg) Active internal bleeding Presentation consistent with infective endocarditis Stroke known or suspected to be associated with aortic arch dissection Acute bleeding diathesis, including but not limited to conditions defined under 'Hematologic' Hematologic 3 Platelet count <100,000/mm * Current anticoagulant use with an INR >1.7 or PT >15 seconds or aPTT >40 seconds* Therapeutic doses of low molecular weight heparin received within 24 hours (eg, to treat VTE and ACS); this exclusion does not apply to prophylactic doses (eg, to prevent VTE) Current use (ie, last dose within 48 hours in a patient with normal renal function) of a direct thrombin inhibitor or direct factor Xa inhibitor with evidence of anticoagulant effect by laboratory tests such as aPTT, INR, ECT, TT, or appropriate factor Xa activity assays Head CT https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 13/19 7/5/23, 12:13 PM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Evidence of hemorrhage Extensive regions of obvious hypodensity consistent with irreversible injury Warnings Only minor and isolated neurologic signs or rapidly improving symptoms Serum glucose <50 mg/dL (<2.8 mmol/L) Serious trauma in the previous 14 days Major surgery in the previous 14 days History of gastrointestinal bleeding (remote) or genitourinary bleeding Seizure at the onset of stroke with postictal neurologic impairments Pregnancy** Arterial puncture at a noncompressible site in the previous seven days Large ( 10 mm), untreated, unruptured intracranial aneurysm Untreated intracranial vascular malformation Additional warnings for treatment from 3 to 4.5 hours from symptom onset Age >80 years Oral anticoagulant use regardless of INR Severe stroke (NIHSS score >25) Combination of both previous ischemic stroke and diabetes mellitus ACS: acute coronary syndrome; aPTT: activated partial thromboplastin time; ECT: ecarin clotting time; INR: international normalized ratio; PT: prothrombin time; NIHSS: National Institutes of Health Stroke Scale; tPA: intravenous alteplase; TT: thrombin time; VTE: venous thromboembolism. Although it is desirable to know the results of these tests, thrombolytic therapy should not be delayed while results are pending unless (1) there is clinical suspicion of a bleeding abnormality or thrombocytopenia, (2) the patient is currently on or has recently received anticoagulants (eg, heparin, warfarin, a direct thrombin inhibitor, or a direct factor Xa inhibitor), or (3) use of anticoagulants is not known. Otherwise, treatment with intravenous tPA can be started before availability of coagulation test results but should be discontinued if the INR, PT, or aPTT exceed the limits stated in the table, or 3 if platelet count is <100,000 mm . With careful consideration and weighting of risk-to-benefit, patients may receive intravenous alteplase despite one or more warnings. Patients who have a persistent neurologic deficit that is potentially disabling, despite improvement of any degree, should be treated with tPA in the absence of other contraindications. Any of the following should be considered disabling deficits: Complete hemianopia: 2 on NIHSS question 3, or Severe aphasia: 2 on NIHSS question 9, or Visual or sensory extinction: 1 on NIHSS question 11, or https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 14/19 7/5/23, 12:13 PM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6, or Any deficits that lead to a total NIHSS >5, or Any remaining deficit considered potentially disabling in the view of the patient and the treating practitioner using clinical judgment Patients may be treated with intravenous alteplase if glucose level is subsequently normalized. The potential risks of bleeding with alteplase from injuries related to the trauma should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. The increased risk of surgical site bleeding with alteplase should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. There is a low increased risk of new bleeding with alteplase in the setting of past gastrointestinal or genitourinary bleeding. However, alteplase administration within 21 days of gastrointestinal bleeding is not recommended. Alteplase is reasonable in patients with a seizure at stroke onset if evidence suggests that residual impairments are secondary to acute ischemic stroke and not to a postictal phenomenon. * Alteplase can be given in pregnancy when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding. The safety and efficacy of administering alteplase is uncertain for these relative exclusions. Although these were exclusions in the trial showing benefit in the 3 to 4.5 hour window, intravenous alteplase appears to be safe and may be beneficial for patients with these criteria, including patients taking oral anticoagulants with an INR <1.7. Adapted from: 1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359:1317. 2. Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke Association. Stroke 2009; 40:2945. 3. Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force:, Levine SR, Khatri P, et al. Review, historical context, and clari cations of the NINDS rt-PA stroke trials exclusion criteria: Part 1: rapidly improving stroke symptoms. Stroke 2013; 44:2500. 4. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scienti c rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2016; 47:581. 5. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. Graphic 71462 Version 26.0 https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 15/19 7/5/23, 12:13 PM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Options to treat hypertension before and during reperfusion therapy for acu te ischemic stroke Patient otherwise eligible for acute reperfusion therapy except that blood pressure is >185/110 mmHg* Labetalol 10 to 20 mg intravenously over 1 to 2 minutes, may repeat one time; or Nicardipine 5 mg/hour intravenously, titrate up by 2.5 mg/hour every 5 to 15 minutes, maximum 15 mg/hour; when desired blood pressure reached, adjust to maintain proper blood pressure limits; or Clevidipine 1 to 2 mg/hour intravenously, titrate by doubling the dose every 2 to 5 minutes, maximum 21 mg/hour, until desired blood pressure reached ; or

Ischemic stroke or severe head trauma in the previous three months Previous intracranial hemorrhage Intra-axial intracranial neoplasm Gastrointestinal malignancy Gastrointestinal hemorrhage in the previous 21 days Intracranial or intraspinal surgery within the prior three months Clinical Symptoms suggestive of subarachnoid hemorrhage Persistent blood pressure elevation (systolic 185 mmHg or diastolic 110 mmHg) Active internal bleeding Presentation consistent with infective endocarditis Stroke known or suspected to be associated with aortic arch dissection Acute bleeding diathesis, including but not limited to conditions defined under 'Hematologic' Hematologic 3 Platelet count <100,000/mm * Current anticoagulant use with an INR >1.7 or PT >15 seconds or aPTT >40 seconds* Therapeutic doses of low molecular weight heparin received within 24 hours (eg, to treat VTE and ACS); this exclusion does not apply to prophylactic doses (eg, to prevent VTE) Current use (ie, last dose within 48 hours in a patient with normal renal function) of a direct thrombin inhibitor or direct factor Xa inhibitor with evidence of anticoagulant effect by laboratory tests such as aPTT, INR, ECT, TT, or appropriate factor Xa activity assays Head CT https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 13/19 7/5/23, 12:13 PM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Evidence of hemorrhage Extensive regions of obvious hypodensity consistent with irreversible injury Warnings Only minor and isolated neurologic signs or rapidly improving symptoms Serum glucose <50 mg/dL (<2.8 mmol/L) Serious trauma in the previous 14 days Major surgery in the previous 14 days History of gastrointestinal bleeding (remote) or genitourinary bleeding Seizure at the onset of stroke with postictal neurologic impairments Pregnancy** Arterial puncture at a noncompressible site in the previous seven days Large ( 10 mm), untreated, unruptured intracranial aneurysm Untreated intracranial vascular malformation Additional warnings for treatment from 3 to 4.5 hours from symptom onset Age >80 years Oral anticoagulant use regardless of INR Severe stroke (NIHSS score >25) Combination of both previous ischemic stroke and diabetes mellitus ACS: acute coronary syndrome; aPTT: activated partial thromboplastin time; ECT: ecarin clotting time; INR: international normalized ratio; PT: prothrombin time; NIHSS: National Institutes of Health Stroke Scale; tPA: intravenous alteplase; TT: thrombin time; VTE: venous thromboembolism. Although it is desirable to know the results of these tests, thrombolytic therapy should not be delayed while results are pending unless (1) there is clinical suspicion of a bleeding abnormality or thrombocytopenia, (2) the patient is currently on or has recently received anticoagulants (eg, heparin, warfarin, a direct thrombin inhibitor, or a direct factor Xa inhibitor), or (3) use of anticoagulants is not known. Otherwise, treatment with intravenous tPA can be started before availability of coagulation test results but should be discontinued if the INR, PT, or aPTT exceed the limits stated in the table, or 3 if platelet count is <100,000 mm . With careful consideration and weighting of risk-to-benefit, patients may receive intravenous alteplase despite one or more warnings. Patients who have a persistent neurologic deficit that is potentially disabling, despite improvement of any degree, should be treated with tPA in the absence of other contraindications. Any of the following should be considered disabling deficits: Complete hemianopia: 2 on NIHSS question 3, or Severe aphasia: 2 on NIHSS question 9, or Visual or sensory extinction: 1 on NIHSS question 11, or https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 14/19 7/5/23, 12:13 PM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6, or Any deficits that lead to a total NIHSS >5, or Any remaining deficit considered potentially disabling in the view of the patient and the treating practitioner using clinical judgment Patients may be treated with intravenous alteplase if glucose level is subsequently normalized. The potential risks of bleeding with alteplase from injuries related to the trauma should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. The increased risk of surgical site bleeding with alteplase should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. There is a low increased risk of new bleeding with alteplase in the setting of past gastrointestinal or genitourinary bleeding. However, alteplase administration within 21 days of gastrointestinal bleeding is not recommended. Alteplase is reasonable in patients with a seizure at stroke onset if evidence suggests that residual impairments are secondary to acute ischemic stroke and not to a postictal phenomenon. * Alteplase can be given in pregnancy when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding. The safety and efficacy of administering alteplase is uncertain for these relative exclusions. Although these were exclusions in the trial showing benefit in the 3 to 4.5 hour window, intravenous alteplase appears to be safe and may be beneficial for patients with these criteria, including patients taking oral anticoagulants with an INR <1.7. Adapted from: 1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359:1317. 2. Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke Association. Stroke 2009; 40:2945. 3. Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force:, Levine SR, Khatri P, et al. Review, historical context, and clari cations of the NINDS rt-PA stroke trials exclusion criteria: Part 1: rapidly improving stroke symptoms. Stroke 2013; 44:2500. 4. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scienti c rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2016; 47:581. 5. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. Graphic 71462 Version 26.0 https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 15/19 7/5/23, 12:13 PM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Options to treat hypertension before and during reperfusion therapy for acu te ischemic stroke Patient otherwise eligible for acute reperfusion therapy except that blood pressure is >185/110 mmHg* Labetalol 10 to 20 mg intravenously over 1 to 2 minutes, may repeat one time; or Nicardipine 5 mg/hour intravenously, titrate up by 2.5 mg/hour every 5 to 15 minutes, maximum 15 mg/hour; when desired blood pressure reached, adjust to maintain proper blood pressure limits; or Clevidipine 1 to 2 mg/hour intravenously, titrate by doubling the dose every 2 to 5 minutes, maximum 21 mg/hour, until desired blood pressure reached ; or Other agents (hydralazine, enalaprilat, etc) may also be considered If blood pressure is not maintained at or below 185/110 mmHg, do not administer alteplase Management to maintain blood pressure at or below 180/105 mmHg during and after acute reperfusion therapy* Monitor blood pressure every 15 minutes for 2 hours from the start of rtPA therapy, then every 30 minutes for 6 hours, and then every hour for 16 hours If systolic blood pressure is >180 to 230 mmHg or diastolic is >105 to 120 mmHg: Labetalol 10 mg intravenously followed by continuous infusion 2 to 8 mg/min; or Nicardipine 5 mg/hour intravenously, titrate up to desired effect by 2.5 mg/hour every 5 to 15 minutes, maximum 15 mg/hour; or Clevidipine 1 to 2 mg/hour intravenously, titrate by doubling the dose every 2 to 5 minutes, maximum 21 mg/hour, until desired blood pressure reached If blood pressure is not controlled or diastolic blood pressure >140 mmHg, consider intravenous sodium nitroprusside Different treatment options may be appropriate in patients who have comorbid conditions that may benefit from acute reductions in blood pressure, such as acute coronary event, acute heart failure, aortic dissection, or preeclampsia/eclampsia. Clevidipine has been included as part of the 2018 guidelines for the early management of patients with acute ischemic stroke [1] . Reference: 1. Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2018; 49:e46. Adapted with permission. Stroke. 2013: 44:870-947. Copyright 2013 American Heart Association, Inc. https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 16/19 7/5/23, 12:13 PM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Graphic 50725 Version 15.0 https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 17/19 7/5/23, 12:13 PM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Management of intracerebral hemorrhage after thrombolysis for ischemic stroke 1. Consider bleeding the likely cause of neurologic worsening after use of a thrombolytic drug until a brain scan confirms or refutes hemorrhage 2. Immediately discontinue ongoing infusion of thrombolytic drug 3. Obtain stat noncontrast head CT or MRI 4. Obtain blood samples for type and cross match, complete blood count, platelet count, PT, INR, aPTT, and fibrinogen 5. If symptomatic intracerebral hemorrhage is confirmed by imaging: Give cryoprecipitate 10 units infused over 10 to 30 minutes and more as needed to achieve a serum fibrinogen level of 150 to 200 mg/dL Consider aminocaproic acid 4 to 5 g IV over one hour followed by 1 g/hour for 8 hours until bleeding is controlled, or tranexamic acid 10 to 15 mg/kg IV over 10 to 20 minutes For patients on warfarin therapy prior to alteplase treatment, consider vitamin K and PCC as adjunctive therapy to cryoprecipitate, or FFP if PCC is not available For patients with thrombocytopenia (platelet count <100,000/microL), give 6 to 8 units of platelets For patients receiving unfractionated heparin for any reason, give 1 mg of protamine for every 100 units of UFH received in the preceding four hours 6. Obtain neurosurgery and hematology consultations; consider evacuation of the hematoma CT: computed tomography; MRI: magnetic resonance imaging; PT: prothrombin time; INR: international normalized ratio; aPTT: activated partial thromboplastin time; IV: intravenous; PCC: prothrombin complex concentrate; FFP: fresh frozen plasma; UFH: unfractionated heparin. Graphic 68717 Version 7.0 https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 18/19 7/5/23, 12:13 PM Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use - UpToDate Contributor Disclosures Jamary Oliveira-Filho, MD, MS, PhD No relevant financial relationship(s) with ineligible companies to disclose. Owen B Samuels, MD No relevant financial relationship(s) with ineligible companies to disclose. Jos Biller, MD, FACP, FAAN, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Alejandro A Rabinstein, MD Grant/Research/Clinical Trial Support: Chiesi [Small investigator- initiated project]. Consultant/Advisory Boards: AstraZeneca [Secondary stroke prevention]; Brainomix [AI for stroke diagnostics]; Novo Nordisk [Stroke risk]; Shionogi [Stroke neuroprotection]. Other Financial Interest: Boston Scientific [Adverse event adjudication committee member for stroke risk reduction device in patients with atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/intravenous-thrombolytic-therapy-for-acute-ischemic-stroke-therapeutic-use/print 19/19

7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Mechanical thrombectomy for acute ischemic stroke : Jamary Oliveira-Filho, MD, MS, PhD, Owen B Samuels, MD : Jos Biller, MD, FACP, FAAN, FAHA, Alejandro A Rabinstein, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 30, 2023. INTRODUCTION Timely restoration of cerebral blood flow using reperfusion therapy is the most effective maneuver for salvaging ischemic brain tissue that is not already infarcted. There is a narrow window during which this can be accomplished since the benefit of reperfusion decreases over time. This topic will review the use of mechanical thrombectomy (MT) for acute ischemic stroke. The approach to reperfusion therapy for acute ischemic stroke, including the use of intravenous thrombolytic therapy (recombinant tissue plasminogen activator or tPA), is reviewed elsewhere. (See "Approach to reperfusion therapy for acute ischemic stroke" and "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use".) OVERVIEW OF REPERFUSION THERAPY For eligible patients with acute ischemic stroke, intravenous thrombolytic therapy with alteplase or tenecteplase is first-line therapy, provided that treatment is initiated within 4.5 hours since the time the patient was last known to be well ( table 1). Because the benefit is time dependent, it is critical to treat patients as quickly as possible; eligible patients should receive intravenous thrombolytic therapy without delay even if mechanical thrombectomy (MT) is being considered. (See "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use".) MT is indicated for patients with acute ischemic stroke due to a large artery occlusion in the anterior circulation who can be treated within 24 hours of the time last known to be well (ie, at https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 1/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate neurologic baseline), regardless of whether they receive intravenous thrombolytic therapy for the same ischemic stroke event, as discussed in the sections that follow. Two issues may limit the widespread clinical use of MT. First, only an estimated 10 percent of patients with acute ischemic stroke have a proximal large artery occlusion in the anterior circulation and present early enough to qualify for MT within 6 hours [1-4], while approximately 9 percent of patients presenting in the 6- to 24-hour time window may qualify for MT [5]. Second, only a few stroke centers have sufficient resources and expertise to deliver this therapy [6]. However, eligible patients should receive standard treatment with intravenous thrombolysis if they present to hospitals where thrombectomy is not an option, and those with qualifying anterior circulation strokes from large artery occlusion should then be transferred, if at all possible, to tertiary stroke centers in which intra-arterial thrombectomy is available, a strategy called "drip and ship" [7]. PATIENT SELECTION Patients with ischemic stroke caused by a proximal large artery occlusion in the anterior circulation are candidates for intra-arterial mechanical thrombectomy (MT) if they present to, or can be transferred expeditiously to, a stroke center with expertise in the use of second- generation stent retrievers for acute ischemic stroke. Intra-arterial MT can be used in addition to treatment with intravenous thrombolysis using alteplase or tenecteplase. MT treatment should be started as quickly as possible and should not be delayed to assess the response to intravenous tissue plasminogen activator (tPA). Treatment with intravenous thrombolysis prior to MT is also known as bridging therapy. The potential efficacy of bridging therapy compared with MT alone is reviewed separately. (See "Approach to reperfusion therapy for acute ischemic stroke", section on 'IVT followed by MT'.) Who to treat For patients with acute ischemic stroke, we recommend treatment with intra- arterial MT, whether or not the patient received treatment with intravenous thrombolytic therapy, if the following conditions are met: Brain imaging using computed tomography (CT) without contrast or diffusion-weighted magnetic resonance imaging (DWI) excludes hemorrhage and is consistent with an Alberta Stroke Program Early CT Score (ASPECTS) 3. (See 'Role of ASPECTS method' below.) CT angiography (CTA) or MR angiography (MRA) demonstrates a proximal large vessel occlusion in the anterior circulation as the cause of the ischemic stroke. https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 2/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate The patient has a persistent, potentially disabling neurologic deficit; some guidelines table 2) of 6 points require a National Institutes of Health Stroke Scale (NIHSS) score ( (calculator 1) [8]. Thrombectomy can be started within 24 hours of the time the patient was last known to be well. This recommendation applies when thrombectomy is performed at a stroke center with appropriate expertise in the use of endovascular therapy. Benefit may be most likely for patients who start treatment within 6 hours, or when imaging confirms the presence of salvageable brain tissue (eg, a mismatch by DAWN or DEFUSE 3 criteria) for patients who start treatment in the 6- to 24-hour time window. (See 'Benefit with a clinical or tissue mismatch defined by imaging' below.) Additional considerations Selection with CTP or DWI/PWI using automated infarct core analysis At stroke centers that have advanced imaging capability, using CT perfusion (CTP) imaging or DWI with perfusion-weighted magnetic resonance imaging (PWI), along with automated software imaging analysis to determine infarct volume, patients with acute anterior circulation ischemic stroke due to large vessel occlusion can be selected for MT if they have salvageable brain tissue, with a mismatch between a relatively larger area of ischemia (ie, hypoperfused brain tissue) and a smaller area of infarct core (ie, irreversibly injured brain tissue). The DAWN and DEFUSE 3 trials selected patients for treatment beyond 6 hours using these methods. Patients with little or no salvageable brain tissue were excluded from MT in these trials. (See 'Benefit with a clinical or tissue mismatch defined by imaging' below and "Neuroimaging of acute stroke", section on 'Mismatch and salvageable brain tissue'.) However, with increasing experience and evidence from clinical trials, the need for CTP or DWI/PWI to select patients for MT in the late time window (6 to 24 hours) is no longer considered essential [9]. Selection without automated infarct core analysis At stroke centers without CTP or automated infarct volume determination, patients with acute anterior circulation ischemic stroke due to large vessel occlusion can be selected for MT by several evidence-based methods: The presence of a large ischemic core (eg, defined by an ASPECTS 3 to 5 or a core volume 50 mL) (see 'Role of ASPECTS method' below and 'Benefit for large core infarcts' below) https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 3/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate Preserved collateral flow by CTA in the ischemic territory (see 'Benefit with collateral flow' below and "Neuroimaging of acute stroke", section on 'Collateral blood flow') Comorbidities Patients with severe comorbidities prior to stroke onset (eg, pre-existing severe disability, life expectancy less than six months) are unlikely to benefit from MT, particularly if they have a large core infarct. However, findings from an observational study suggest that patients with slight or moderate prestroke disability, defined by a modified Rankin Scale (mRS) score ( table 3) of 2 or 3, have a similar likelihood of recovery to their prestroke level of function after treatment with MT compared with patients who are independent at baseline [10]. Prior intravenous thrombolysis Many patients who are eligible for MT will be treated with intravenous thrombolytic therapy using alteplase or tenecteplase prior to MT. Patients who are not candidates for intravenous thrombolytic therapy can still be treated with MT if otherwise eligible according to the criteria outlined here and above (see 'Who to treat' above). As an example, patients with infective endocarditis, which is a contraindication to intravenous thrombolysis, may still undergo MT if otherwise eligible [11]. Who not to treat While eligibility for MT has expanded since 2015 with trials showing benefit of MT in the 6- to 24-hour time window using several different selection criteria (see 'Benefit of later (6 to 24 hours) treatment' below), there are still scenarios where treatment may be futile if not dangerous. We would not treat patients with MT who have any of the following clinical and imaging findings: Presence of a large established hypodensity on head CT beyond the more subtle, early ischemic changes assessed by ASPECTS. (See 'Role of ASPECTS method' below.) No ischemic penumbra (ie, no mismatch suggesting no salvageable brain tissue) on CTP or DWI/PWI if these studies are performed, particularly if the infarct core is large. However, doing CTP or magnetic resonance imaging (MRI) before MT is not indispensable, even in patients with low ASPECTS on CT. Presence of a large core infarct (eg, defined by an ASPECTS 3 to 5 or imaging showing a core volume 50 mL) and severe prestroke comorbidities (eg, pre-existing severe disability such as mRS 4 to 5, or life expectancy less than six months). Individualized decisions The decision to employ MT needs to be carefully individualized for patients with anterior circulation stroke who do not precisely match all the inclusion or exclusion criteria as listed above. Examples include patients with imaging evidence of salvageable brain tissue who are beyond the 24-hour time window [12,13], with distal medium vessel occlusion https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 4/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate (eg, anterior cerebral artery beyond the A1 segment, middle cerebral artery beyond the proximal M2 segment) [14,15], or with minor stroke (NIHSS 5) [16]. The less severe the stroke deficits, the more difficult the treatment decision becomes because there is more to lose in case of a symptomatic hemorrhage. Role of ASPECTS method The ASPECTS was developed to provide a simple and reliable method of assessing ischemic changes on head CT scan in order to identify acute stroke patients unlikely to make an independent recovery despite thrombolytic treatment [17]. The ASPECTS method has also been adopted to assess the extent of ischemia on DWI; the ability to detect early ischemic changes by ASPECTS was similar on noncontrast CT and DWI [18]. Original (MCA territory) ASPECTS The ASPECTS value is calculated from two standard axial CT cuts; one at the level of the thalamus and basal ganglia, and one just rostral to the basal ganglia ( figure 1) [17,19]. The ASPECTS method divides the middle cerebral artery (MCA) territory into 10 regions of interest. Subcortical structures are allotted three points: one each for caudate, lentiform nucleus, and internal capsule. MCA cortex is allotted seven points: Four of these points come from the axial CT cut at the level of the basal ganglia, with one point for insular cortex and one point each for M1, M2, and M3 regions (anterior, lateral, and posterior MCA cortex). Three points come from the CT cut just rostral to the basal ganglia, with one point each for M4, M5, and M6 regions (anterior, lateral, and posterior MCA cortex). One point is subtracted for an area of early ischemic change, such as focal swelling or parenchymal hypoattenuation, for each of the defined regions. Therefore, a normal CT scan without ischemic change has an ASPECTS value of 10 points, while diffuse ischemic change throughout the MCA territory gives a value of 0. Posterior circulation ASPECTS The pc-ASPECTS subtracts one point for each ischemic lesion (right or left) of the thalamus, cerebellar hemisphere, or posterior cerebral artery territory, and two points for each lesion in the mesencephalon or pons [20,21]. A normal pc-ASPECTS has a value of 10 points; lower scores indicate greater extent of infarction. https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 5/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate EFFICACY OF MECHANICAL THROMBECTOMY Early (within 24 hours) intra-arterial treatment with second-generation mechanical thrombectomy (MT) devices is safe and effective for reducing disability and is superior to standard treatment with intravenous thrombolysis alone for the treatment of acute ischemic stroke caused by a documented large artery occlusion in the proximal anterior circulation ( figure 2 and figure 3). Anterior circulation stroke Benefit of early (within 6 hours) treatment Landmark trials demonstrating benefit Five multicenter, open-label randomized controlled trials (MR CLEAN [22,23], ESCAPE [24], SWIFT PRIME [25], EXTEND-IA [26], and REVASCAT [27]) demonstrated that early intra-arterial treatment with second-generation MT devices is safe and effective for reducing disability and is superior to standard treatment with intravenous thrombolysis alone for ischemic stroke caused by a documented large artery occlusion in the proximal anterior circulation [1,28-34]. The number needed to treat (NNT) for one additional person to achieve functional independence in these trials ranged from approximately 3 to 7.5 [22-27,35]. When the positive results of the MR CLEAN trial were announced in late 2014 [22], the remaining trials (ESCAPE [24], SWIFT PRIME [25], EXTEND-IA [26], and REVASCAT [27]) were stopped early on the basis of positive interim efficacy analyses. All of these trials enrolled overlapping but not identical patient populations and had generally similar results. These trials included patients with a proximal large artery occlusion in the anterior circulation as the cause of the ischemic stroke who could start treatment (femoral puncture) within 6 hours of symptom onset. They excluded patients with large core infarcts, restricting eligibility to patients with an Alberta Stroke Program Early CT Score (ASPECTS) 6 or an infarct core volume <50 mL as determined by CT perfusion (CTP) or diffusion-weighted MRI (DWI) and perfusion-weighted MRI (PWI). However, subsequent randomized trials have shown that MT also leads to better functional outcomes for patients with a large ischemic core. (See 'Benefit for large core infarcts' below.) HERMES meta-analysis In the HERMES meta-analysis of these trials, with pooled patient- level data for 1287 subjects, the rate of functional independence (ie, a 90-day modified Rankin Scale [mRS] score of 0 to 2) was significantly greater for the intervention group compared with the control group (46 versus 27 percent, odds ratio [OR] 2.35, 95% CI 1.85- https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 6/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate 2.98) [28]. Similarly, MT led to significantly reduced disability as indicated by an improvement of 1 point on the mRS at 90 days (adjusted OR 2.49, 95% CI 1.76-3.53). MT was beneficial across a wide range of patient subgroups, including age 80 years, high initial stroke severity, and those not treated with intravenous thrombolytic therapy. There was no significant difference between the MT and control groups for rates of symptomatic intracranial hemorrhage or 90-day mortality. Other trials demonstrating benefit Several additional trials (THERAPY [36], PISTE [37], EASI [38], and RESILIENT [39]) also had point estimates suggesting improved functional outcomes for patients treated with MT. The RESILIENT trial, conducted in 12 public hospitals in Brazil, showed that MT can be efficacious in a country with limited health care resources [39]. Earlier trials failed to show benefit Earlier trials (SYNTHESIS Expansion [40], IMS III [41], and MR RESCUE [42]) failed to show benefit for intra-arterial treatment of acute ischemic stroke, in part because they used older-generation thrombectomy devices, which were less likely to achieve reperfusion (see 'Devices' below), and because they did not require routine vessel imaging to confirm a large artery occlusion as the cause of the stroke [43]. Benefit of later (6 to 24 hours) treatment MT is also effective when used from 6 to 24 hours for patients selected by several different strategies. These strategies include imaging that confirms either the presence of salvageable brain tissue (eg, a tissue mismatch as defined by DAWN or DEFUSE 3 criteria), or demonstrates a large core infarct, or demonstrates collateral flow (by CTA [CT angiography]) ipsilateral to the ischemic hemisphere. Thus, selection of patients for MT in the late time window (6 to 24 hours) may be done using noncontrast CT alone as an alternative to advanced imaging with CTP or DWI/PWI [44-46]. Benefit with a clinical or tissue mismatch defined by imaging MT improves outcomes for patients with acute ischemic stroke due to occlusion of the intracranial carotid or proximal middle cerebral artery (MCA) who fulfill either the DAWN trial criteria for a clinical mismatch profile or the DEFUSE 3 trial criteria for a target perfusion mismatch profile [47]. DAWN trial The open-label DAWN trial enrolled 206 adults with acute ischemic stroke who were last known to be well 6 to 24 hours earlier; all had a stroke caused by occlusion of the intracranial internal carotid artery (ICA) or the proximal MCA and had a clinical mismatch between the severity of the neurologic deficit, as measured by the National Institutes of Health Stroke Scale (NIHSS; median score 17 at baseline), and the infarct volume, as measured by automated software analysis using DWI/PWI or CTP (median approximately 8 mL) [48]. Approximately 55 percent of the patients in the trial had a "wake- https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 7/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate up" stroke (ie, they were last known to be well before going to bed and stroke symptoms were first noted upon awakening). Patients were randomly assigned to thrombectomy plus standard care or to standard care alone (control). The trial was stopped early for efficacy at the first interim analysis. The following observations were noted: At 90 days, the rate of functional independence, as defined by a score of 0 to 2 on the mRS, was greater for the thrombectomy group compared with the control group (49 versus 13 percent, adjusted difference 33 percent, 95% CI 24-44). The NNT for one additional patient to achieve functional independence was 3. All other efficacy outcome measures also favored thrombectomy. There was no significant difference between the thrombectomy and control groups in the rate of symptomatic intracranial hemorrhage (6 and 3 percent) or mortality (19 and 18 percent). Eligibility criteria for the DAWN trial were as follows [48]: Treatment could be started (femoral puncture) within 6 to 24 hours of time last known to be well Failed or contraindicated for intravenous thrombolytic therapy with alteplase or tenecteplase table 2) of 10 points (calculator 1) A deficit on the NIHSS ( No significant prestroke disability: baseline mRS score 1 Baseline infarct involving less than one-third of the territory of the MCA on CT or MRI Intracranial arterial occlusion of the ICA or the M1 segment of the MCA A clinical-core mismatch according to age: - - Age 80 years: NIHSS 10 and an infarct volume <21 mL Age <80 years: NIHSS 10 to 19 and an infarct volume <31 mL Age <80 years: NIHSS 20 and an infarct volume <51 mL DEFUSE 3 trial The open-label DEFUSE 3 trial enrolled patients with ischemic stroke due to occlusion of the proximal MCA or ICA who were last known to be well 6 to 16 hours earlier [49]. Patients were required to have a target perfusion mismatch characterized by an infarct size of <70 mL and a ratio of ischemic tissue volume to infarct volume of 1.8, as measured by automated software processing of DWI/PWI or CTP imaging. The DEFUSE 3 trial was stopped early for efficacy after randomly assigning 182 patients to thrombectomy plus standard care or to standard care alone. Approximately one-half of the patients in the trial had a "wake-up" stroke. Patients assigned to thrombectomy were treated with stent retrievers or aspiration catheters. At 90 days, the percentage of patients who were https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 8/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate functionally independent, defined as an mRS score of 0 to 2, was higher with endovascular therapy compared with medical therapy alone (45 versus 17 percent, difference 28 percent), and therefore the NNT for one additional patient to achieve functional independence was 3.6. There was also a trend to lower mortality with endovascular therapy (14 versus 26 percent). There was no significant difference between groups in the rate of symptomatic intracranial hemorrhage (7 and 4 percent) or serious adverse events (43 and 53 percent). Eligibility criteria for DEFUSE 3 were as follows [49]: Treatment could be started (femoral puncture) within 6 to 24 hours of time last known to be well table 2) of 6 points (calculator 1) A deficit on the NIHSS ( Only slight or no prestroke disability: baseline mRS score 2 Arterial occlusion of the cervical or intracranial ICA (with or without tandem MCA lesions) or the M1 segment of the MCA demonstrated on MR angiography (MRA) or CTA A target mismatch profile on CTP or DWI/PWI defined as an ischemic core volume <70 mL, a mismatch ratio (the volume of the perfusion lesion divided by the volume of the ischemic core) >1.8, and a mismatch volume (volume of perfusion lesion minus the volume of the ischemic core) >15 mL Age 18 to 90 years AURORA study The AURORA study analyzed pooled patient-level data from 505 individuals from six randomized controlled trials of MT, including DAWN and DEFUSE 3, that included patients enrolled beyond 6 hours after they were last known to be well and who received treatment with a second-generation stent retriever [50]. At 90 days, MT led to higher rates of independence in activities of daily living, defined by an mRS of 0 to 2, compared with best medical therapy alone (45.9 versus 19.3 percent, adjusted relative risk [RR] 2.19, 95% CI 1.44-3.34, absolute risk reduction 26.6 percent). The NNT for one additional person to achieve functional independence in AURORA was approximately 4. The MT and best medical treatment groups had similar rates of mortality (16.5 versus 19.3 percent) and symptomatic intracerebral hemorrhage (5.3 versus 3.3 percent). The AURORA investigators also compared outcomes among three subgroups: first, patients (n = 295) who met criteria for a clinical mismatch profile as used in the DAWN trial; second, patients (n = 359) who met criteria for a target perfusion mismatch profile as used in the DEFUSE 3 trial; and third, patients (n = 132) with an undetermined mismatch profile due to the absence of an adequate CT or MRI perfusion study [51]. At 90 days, MT led to reduced disability for both the clinical mismatch subgroup (OR 3.57, 95% CI 2.29-5.57) and the https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 9/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate target perfusion mismatch subgroup (OR 3.13, 95% CI 2.10-4.66). Importantly, the benefit was significant in both subgroups for the entire 6- to 24-hour time window. There was a trend toward benefit for patients with an undetermined profile that did not reach statistical significance (OR 1.59, 95% CI 0.82-3.06). Limitations to these trials include stopping early, which can overestimate treatment effects. However, this drawback is at least partially offset by the relatively large effect size demonstrated in the trials and meta-analysis [48-50]. Although not definitive, evidence from a retrospective study of patients with anterior circulation large vessel occlusion presenting in the 6- to 24-hour time window who did not meet DAWN or DEFUSE 3 inclusion criteria found that treatment with MT (n = 102), performed at the discretion of the treating neurointerventionalist, was associated with higher odds of an improved functional outcome at three months compared with medical treatment alone (n = 88) as measured by a shift in the mRS score (adjusted common OR 1.46, 95% CI 1.02-2.10) [52]. Benefit for large core infarcts MT improves outcomes for patients with acute anterior circulation ischemic stroke due to large vessel occlusion who have a large ischemic core (eg, defined by an ASPECTS 3 to 5 or by a core volume 50 mL), as shown by randomized controlled trials including RESCUE-Japan LIMIT [53], SELECT2 [54], and ANGEL-ASPECT [55]. Despite differences in design, patient ethnicity, geographic location, and imaging criteria, all three trials showed benefit of thrombectomy for patients with large ischemic strokes treated within 24 hours from the time they were last known to be well [56]. Positive results from the RESCUE-Japan LIMIT trial prompted interim analyses that determined efficacy of the SELECT2 and ANGEL-ASPECT trials [53-55]. Both trials were then stopped early, which can result in overestimation of treatment effects. However, this concern is partially mitigated by the consistent benefit of thrombectomy shown in all three trials. In a 2023 meta- analysis of these three trials, functional independence (ie, an mRS score of 0 to 2) was more likely with thrombectomy compared with medical management alone (23.5 versus 9.0 percent, RR 2.59, 95% CI 1.89-3.57) [57]. The NNT for one additional person to achieve functional independence (ie, an mRS score of 0 to 2) was approximately 7. Note that all three trials enrolled patients who had very severe stroke deficits at baseline and enrolled very few octogenarians or excluded them entirely. Despite the benefit of MT, the majority of these patients were left with substantial disability; in the MT arms in SELECT2 and ANGEL-ASPECT at 90 days, the median mRS score was 4. Nevertheless, MT should now be considered the standard for patients with very disabling deficits, even if they have large ischemic core. https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 10/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate RESCUE-Japan LIMIT trial The earlier requirement for a small infarct core as a criterion for MT eligibility was first challenged in 2022 by results from the RESCUE-Japan LIMIT trial, which enrolled 203 patients (18 years of age or older) with acute ischemic stroke due to a proximal MCA or ICA occlusion and a low ASPECTS of 3 to 5 on CT or DWI, consistent with a large infarct core (see 'Role of ASPECTS method' above) [53]. Patients were randomly assigned in a 1:1 ratio to endovascular therapy with medical care or medical care alone; enrolled patients were within 6 hours after the time last known to be well (n = 145) or within 6 to 24 hours after the time last known to be well if fluid-attenuated inversion recovery (FLAIR) MRI showed no signal change (n = 58), suggesting very recent infarction. At 90 days, more patients had a "good" outcome, defined by an mRS score of 0 to 3, in the endovascular therapy group compared with the medical care group (31.0 versus 12.7 percent, RR 2.43, 95% CI 1.35-4.37) [53]. For the outcome of an mRS of 0 to 2 (ie, functional independence), there was a trend towards benefit with endovascular therapy (14 versus 7.8 percent, RR 1.79, 95% CI 0.78-4.07). The endovascular group had a nonsignificantly higher rate of symptomatic intracranial hemorrhage (9 versus 4.9 percent, RR 1.84, 95% CI 0.64- 5.29) and a higher rate of any intracranial hemorrhage (58 versus 31.4 percent, RR 1.84, 95% CI 1.33-2.58). Limitations of this trial include concerns about generalizability beyond the Japanese population, and relatively small patient numbers in the 6- to 24-hour treatment subgroup [53]. SELECT2 trial This trial enrolled adult patients 18 to 85 years of age with a large ischemic core, defined by an ASPECTS of 3 to 5 or a core volume of 50 mL [54]. There were 31 participating sites across the United States, Canada, Europe, Australia, and New Zealand. Patients were randomly assigned to thrombectomy plus medical care (n = 178) or medical care only (n = 174) within 24 hours of the time last known to be well. The median age was 66.5 years, the median NIHSS was 19, and the median time to randomization was 9.3 hours. The trial was stopped early for efficacy. At 90 days, there was a shift in the distribution of the mRS scores toward better outcomes for the thrombectomy group (OR 1.51, 95% CI 1.20-1.89). Functional independence (ie, an mRS score of 0 to 2) was also more likely with thrombectomy (20 percent, versus 7 percent with medical care, RR 2.97, 95% CI 1.60-5.51). Mortality was similar for the thrombectomy and medical care groups (38.4 versus 41.5 percent). Symptomatic intracranial hemorrhage occurred in only one patient in the thrombectomy group and two in the medical care group. Early neurologic worsening was more frequent with thrombectomy (24.7 versus 15.5 percent) and was associated with larger baseline infarct size and worse outcomes. Procedural complications, including https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 11/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate dissection and cerebral vessel perforation, affected approximately 20 percent of patients in the thrombectomy group. ANGEL-ASPECT trial This trial enrolled patients 18 to 80 years of age with a large ischemic core, defined by an ASPECTS of 3 to 5 or an infarct core volume of 70 to 100 mL [55]. The trial was conducted at 46 stroke centers in China. Patients were randomly assigned to thrombectomy plus medical management (n = 231) or medical management alone (n = 225). The median age was 68 years, the median NIHSS was 16, and the median time to randomization was 7.6 hours. The trial was stopped early for efficacy. At 90 days, there was a shift in the distribution of the mRS scores toward better outcomes for the thrombectomy group (OR 1.37, 95% CI 1.11-1.69). Functional independence (ie, an mRS score of 0 to 2) was more likely for the thrombectomy group compared with the medical treatment group (30.0 versus 11.6 percent, OR 2.62, 95% CI 1.69-4.06). Mortality was similar for the thrombectomy and medical care groups (21.7 versus 20 percent). The thrombectomy group had a higher numerical rate of symptomatic intracranial hemorrhage (6.1 versus 2.7 percent, OR 2.07, 95% CI 0.79-5.41), but the difference was not statistically significant. Benefit with collateral flow MT improves outcomes for patients who have preserved collateral flow by CTA in the ischemic territory, as shown by the MR CLEAN-LATE trial [58]. The trial enrolled 535 adults presenting in the 6- to 24-hour time window with an acute anterior circulation stroke due to large vessel occlusion who had some degree of collateral flow in the MCA territory of the affected hemisphere by single-phase CTA or the arterial phase of multiphase CTA; patients eligible for MT by DAWN or DEFUSE 3 trials were excluded. Enrolled patients were randomly assigned in a 1:1 ratio to MT or no MT (control). The median age was 74 years, the median NIHSS score was 10, the median ASPECTS was 9 and 8 in the treatment and control groups, respectively, and the median time to randomization was approximately 11.5 hours. At 90 days, functional independence (an mRS score of 0 to 2) was achieved by more patients in the thrombectomy group compared with the control group (39 versus 34 percent), but the difference just missed statistical significance (OR 1.54, 95% CI 0.98-2.43). The thrombectomy group had improved outcomes compared with the control group by the median mRS (3 versus 4) and a shift in the distribution of the mRS scores favoring thrombectomy (OR 1.67, 95% CI 1.20-2.32). Mortality was lower in the thrombectomy group, but the difference was not statistically significant (24 versus 30 percent, OR 0.72, 95% CI 0.44-1.18), while symptomatic intracranial hemorrhage was more frequent in the thrombectomy group (7 versus 4 percent, OR 4.59, 95% CI 1.49-14.10). Earlier studies also suggested that moderate to good collateral flow status on CTA is useful for identifying patients who are likely to benefit from MT [8,24,59,60]. https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 12/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate Posterior circulation stroke Although the benefits are uncertain, MT may be a reasonable treatment option for patients with acute ischemic stroke caused by occlusion of the basilar artery, vertebral arteries, or posterior cerebral arteries when performed at centers with appropriate expertise [8,61-67]. Basilar artery occlusion There is moderate-quality evidence that MT is beneficial for patients of Chinese ancestry who can be treated within 24 hours of moderate to severe stroke (an NIHSS score 10) caused by a basilar artery occlusion if the posterior circulation ASPECTS (pc- ASPECTS) score is consistent with a limited extent of ischemia [68,69]. ATTENTION trial The ATTENTION trial evaluated patients from China with moderate to severe stroke (with an NIHSS 10) due to basilar artery occlusion who were within 12 hours of the estimated time of stroke onset and had a limited degree of early ischemic change, as quantified by the pc-ASPECTS [68]. Patients were randomly assigned in a 2:1 ratio to medical care plus endovascular thrombectomy or medical care alone (control). At baseline, the median NIHSS score was 24 in each group. Approximately one-third of patients in each group received intravenous thrombolysis. At 90 days, the rate of good functional status (ie, an mRS score of 0 to 3) was higher in the thrombectomy group compared with the control group (46 versus 23 percent, adjusted RR 2.06, 95% CI 1.46-2.91) and the mortality rate was lower in the thrombectomy group (37 versus 55 percent, RR 0.66, 95% CI 0.52-0.82). The rate of functional independence (ie, an mRS score of 0 to 2) was also higher in the thrombectomy group (33 versus 11 percent, RR 3.17, 95% CI 1.84-5.46), and results for most secondary outcomes favored thrombectomy. Symptomatic intracranial hemorrhage occurred in 5 percent of cases in the thrombectomy group versus none in the control group. MT was associated with procedural complications in 14 percent of patients, including one death caused by arterial perforation. BAOCHE trial The BAOCHE trial from China evaluated patients within 6 to 24 hours after stroke onset due to basilar artery occlusion [69]. Patients were randomly assigned in a 1:1 ratio to MT plus medical care with medical care alone. The trial was stopped early after an interim analysis suggested superiority of thrombectomy. At baseline, the median NIHSS was 20 for the thrombectomy group and 19 for the control group. The rate of intravenous thrombolysis was 14 percent in the thrombectomy group and 21 percent in the control group. At 90 days, the rate of good functional status (ie, an mRS score of 0 to 3) was higher in the thrombectomy group compared with the control group (46 versus 24 percent, RR 1.81, 95% CI 1.26-2.60), and the rate of functional independence (ie, an mRS score of 0 to 2) was also higher in the thrombectomy group (39 versus 14 percent, RR 2.64, 95% CI 1.54- 4.50). There was a trend for lower mortality at 90 days favoring the thrombectomy group (31 versus 42 percent, RR 0.75, 95% CI 0.54-1.04). Symptomatic intracranial hemorrhage https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 13/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate occurred more often in the thrombectomy group (6 versus 1 percent, RR 5.18, 95% CI 0.64- 42.18). Procedural complications occurred in 11 percent of the thrombectomy group. The ATTENTION and BAOCHE trial results are not generalizable to all patients with basilar artery stroke. The Chinese population has higher rates of large artery intracranial atherosclerotic disease relative to other populations, and many patients in the thrombectomy groups of both trials were also treated with angioplasty and/or stenting of the basilar artery. The low rates of treatment with intravenous thrombolysis in both trials may have reduced the rates of good outcomes particularly affecting the control groups and biased the results in favor of thrombectomy. Earlier trials were also limited by methodologic issues. A randomized trial (BEST) comparing endovascular treatment (MT) with standard medical care for patients with acute vertebrobasilar occlusion who could be treated within eight hours was stopped early for slow recruitment and high crossover rate after enrolling 131 patients [61]. Compared with standard medical care, patients assigned to endovascular therapy had similar rates of favorable outcome and 90-day mortality by intention-to-treat analysis. The BASICS trial of 300 patients with acute ischemic stroke attributed to basilar artery occlusion found no statistically significant difference in outcomes for endovascular therapy compared with medical therapy [63]. However, there was a nonsignificant trend of benefit with endovascular treatment in both trials [61,63]. Larger randomized controlled trials in more diverse populations are needed to assess the efficacy of endovascular therapy for posterior circulation stroke due to large artery occlusion. PROCEDURE Overview General anesthesia or conscious sedation may be used for the procedure, depending upon local preference and experience. (See 'Anesthesia' below.) Catheterization is commonly performed with femoral artery puncture. The catheter is guided to the internal carotid artery (ICA) and beyond to the site of the intracranial large artery occlusion. The stent retriever is then inserted through the catheter to reach the clot. The stent retriever is deployed and grabs the clot, which is removed as the device is pulled back. The initial goal is to achieve reperfusion, defined by a modified Thrombolysis in Cerebral Infarction (mTICI) perfusion grade 2b (anterograde reperfusion of more than half in the downstream target arterial territory)

thrombectomy group had a higher numerical rate of symptomatic intracranial hemorrhage (6.1 versus 2.7 percent, OR 2.07, 95% CI 0.79-5.41), but the difference was not statistically significant. Benefit with collateral flow MT improves outcomes for patients who have preserved collateral flow by CTA in the ischemic territory, as shown by the MR CLEAN-LATE trial [58]. The trial enrolled 535 adults presenting in the 6- to 24-hour time window with an acute anterior circulation stroke due to large vessel occlusion who had some degree of collateral flow in the MCA territory of the affected hemisphere by single-phase CTA or the arterial phase of multiphase CTA; patients eligible for MT by DAWN or DEFUSE 3 trials were excluded. Enrolled patients were randomly assigned in a 1:1 ratio to MT or no MT (control). The median age was 74 years, the median NIHSS score was 10, the median ASPECTS was 9 and 8 in the treatment and control groups, respectively, and the median time to randomization was approximately 11.5 hours. At 90 days, functional independence (an mRS score of 0 to 2) was achieved by more patients in the thrombectomy group compared with the control group (39 versus 34 percent), but the difference just missed statistical significance (OR 1.54, 95% CI 0.98-2.43). The thrombectomy group had improved outcomes compared with the control group by the median mRS (3 versus 4) and a shift in the distribution of the mRS scores favoring thrombectomy (OR 1.67, 95% CI 1.20-2.32). Mortality was lower in the thrombectomy group, but the difference was not statistically significant (24 versus 30 percent, OR 0.72, 95% CI 0.44-1.18), while symptomatic intracranial hemorrhage was more frequent in the thrombectomy group (7 versus 4 percent, OR 4.59, 95% CI 1.49-14.10). Earlier studies also suggested that moderate to good collateral flow status on CTA is useful for identifying patients who are likely to benefit from MT [8,24,59,60]. https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 12/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate Posterior circulation stroke Although the benefits are uncertain, MT may be a reasonable treatment option for patients with acute ischemic stroke caused by occlusion of the basilar artery, vertebral arteries, or posterior cerebral arteries when performed at centers with appropriate expertise [8,61-67]. Basilar artery occlusion There is moderate-quality evidence that MT is beneficial for patients of Chinese ancestry who can be treated within 24 hours of moderate to severe stroke (an NIHSS score 10) caused by a basilar artery occlusion if the posterior circulation ASPECTS (pc- ASPECTS) score is consistent with a limited extent of ischemia [68,69]. ATTENTION trial The ATTENTION trial evaluated patients from China with moderate to severe stroke (with an NIHSS 10) due to basilar artery occlusion who were within 12 hours of the estimated time of stroke onset and had a limited degree of early ischemic change, as quantified by the pc-ASPECTS [68]. Patients were randomly assigned in a 2:1 ratio to medical care plus endovascular thrombectomy or medical care alone (control). At baseline, the median NIHSS score was 24 in each group. Approximately one-third of patients in each group received intravenous thrombolysis. At 90 days, the rate of good functional status (ie, an mRS score of 0 to 3) was higher in the thrombectomy group compared with the control group (46 versus 23 percent, adjusted RR 2.06, 95% CI 1.46-2.91) and the mortality rate was lower in the thrombectomy group (37 versus 55 percent, RR 0.66, 95% CI 0.52-0.82). The rate of functional independence (ie, an mRS score of 0 to 2) was also higher in the thrombectomy group (33 versus 11 percent, RR 3.17, 95% CI 1.84-5.46), and results for most secondary outcomes favored thrombectomy. Symptomatic intracranial hemorrhage occurred in 5 percent of cases in the thrombectomy group versus none in the control group. MT was associated with procedural complications in 14 percent of patients, including one death caused by arterial perforation. BAOCHE trial The BAOCHE trial from China evaluated patients within 6 to 24 hours after stroke onset due to basilar artery occlusion [69]. Patients were randomly assigned in a 1:1 ratio to MT plus medical care with medical care alone. The trial was stopped early after an interim analysis suggested superiority of thrombectomy. At baseline, the median NIHSS was 20 for the thrombectomy group and 19 for the control group. The rate of intravenous thrombolysis was 14 percent in the thrombectomy group and 21 percent in the control group. At 90 days, the rate of good functional status (ie, an mRS score of 0 to 3) was higher in the thrombectomy group compared with the control group (46 versus 24 percent, RR 1.81, 95% CI 1.26-2.60), and the rate of functional independence (ie, an mRS score of 0 to 2) was also higher in the thrombectomy group (39 versus 14 percent, RR 2.64, 95% CI 1.54- 4.50). There was a trend for lower mortality at 90 days favoring the thrombectomy group (31 versus 42 percent, RR 0.75, 95% CI 0.54-1.04). Symptomatic intracranial hemorrhage https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 13/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate occurred more often in the thrombectomy group (6 versus 1 percent, RR 5.18, 95% CI 0.64- 42.18). Procedural complications occurred in 11 percent of the thrombectomy group. The ATTENTION and BAOCHE trial results are not generalizable to all patients with basilar artery stroke. The Chinese population has higher rates of large artery intracranial atherosclerotic disease relative to other populations, and many patients in the thrombectomy groups of both trials were also treated with angioplasty and/or stenting of the basilar artery. The low rates of treatment with intravenous thrombolysis in both trials may have reduced the rates of good outcomes particularly affecting the control groups and biased the results in favor of thrombectomy. Earlier trials were also limited by methodologic issues. A randomized trial (BEST) comparing endovascular treatment (MT) with standard medical care for patients with acute vertebrobasilar occlusion who could be treated within eight hours was stopped early for slow recruitment and high crossover rate after enrolling 131 patients [61]. Compared with standard medical care, patients assigned to endovascular therapy had similar rates of favorable outcome and 90-day mortality by intention-to-treat analysis. The BASICS trial of 300 patients with acute ischemic stroke attributed to basilar artery occlusion found no statistically significant difference in outcomes for endovascular therapy compared with medical therapy [63]. However, there was a nonsignificant trend of benefit with endovascular treatment in both trials [61,63]. Larger randomized controlled trials in more diverse populations are needed to assess the efficacy of endovascular therapy for posterior circulation stroke due to large artery occlusion. PROCEDURE Overview General anesthesia or conscious sedation may be used for the procedure, depending upon local preference and experience. (See 'Anesthesia' below.) Catheterization is commonly performed with femoral artery puncture. The catheter is guided to the internal carotid artery (ICA) and beyond to the site of the intracranial large artery occlusion. The stent retriever is then inserted through the catheter to reach the clot. The stent retriever is deployed and grabs the clot, which is removed as the device is pulled back. The initial goal is to achieve reperfusion, defined by a modified Thrombolysis in Cerebral Infarction (mTICI) perfusion grade 2b (anterograde reperfusion of more than half in the downstream target arterial territory) or grade 3 (complete anterograde reperfusion of the downstream target arterial territory) ( table 4), as early as possible [8,70]. In a meta-analysis of five trials that evaluated treatment within 6 hours of symptom onset, over 500 patients received mechanical thrombectomy (MT), https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 14/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate and substantial reperfusion (mTICI score of 2b or 3) was achieved in 71 percent of this group [34]. Following the procedure, most centers monitor patients in an intensive care unit setting until stable. Devices Both second-generation stent retrievers and catheter aspiration devices can be used for MT. The choice between them depends mainly upon local expertise and availability [71]. In some cases, treatment using stent retrievers and aspiration techniques in combination may be appropriate. Stent retrievers Several MT devices are approved in the United States and Europe for clot removal in patients with acute ischemic stroke due to large artery occlusion. These include the first-generation Merci Retriever and Penumbra System devices, the second- generation Solitaire Flow Restoration Device and Trevo Retriever, and the third-generation Tigertriever. The first-generation Merci and Penumbra devices may increase recanalization rates in carefully selected patients, but their clinical utility for improving outcomes after stroke is unproven [72-74]. When compared directly with the Merci retriever in small randomized trials, the second-generation Solitaire and Trevo neurothrombectomy devices achieved significantly higher reperfusion rates and better patient outcomes [75,76]. In a single-arm study, the Tigertriever device achieved higher reperfusion rates, improved patient outcomes, and had similar safety outcomes compared with historical controls from studies of the Solitaire and Trevo devices [77]. In light of these data and the positive thrombectomy trials discussed above [22,24-27], which preferentially used the second-generation devices, only the second-generation or later devices should be used to treat patients with acute ischemic stroke. Catheter aspiration devices Catheter aspiration devices are another option for MT. This method employs a catheter to aspirate the thrombus as the first approach to performing thrombectomy; if aspiration alone does not achieve reperfusion after one or more passes, a stent retriever can be inserted through the catheter to complete the thrombectomy. Mounting evidence suggests that catheter aspiration devices can attain rates of revascularization [36,78] and good functional outcome [79,80] that are similar to the rates achieved with second-generation stent retrievers. The open-label, multicenter COMPASS trial randomly assigned 270 patients within 6 hours of symptom onset to MT with either catheter aspiration as first-pass treatment or stent retriever first-line [79]. At 90 days, a good functional outcome (modified Rankin Scale [mRS] score of 0 to 2) was achieved by a similar number of patients in each treatment group (52 versus 50 percent for aspiration https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 15/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate first-pass and stent retriever first-line, respectively), indicating that aspiration first-pass was noninferior to stent retriever first-line treatment. In addition, secondary efficacy and angiographic outcome measures did not differ between treatment groups, and there were no significant differences in mortality, symptomatic intracranial hemorrhage, or other safety outcomes. One trial found a trend to higher rates of near-total or total reperfusion for combined stent retriever plus aspiration compared with stent retriever alone, but the difference did not achieve statistical significance (64.5 versus 57.9 percent, risk difference 6.6 percent, 95% CI -3.0 to 16.2) [81]. Anesthesia Either monitored anesthesia care (also called conscious sedation) or general anesthesia may be used for procedural sedation during MT. The anesthetic technique should be chosen based upon individual patient risk factors, preferences, and institutional experience [8]. (See "Anesthesia for endovascular therapy for acute ischemic stroke in adults", section on 'Choice of anesthetic technique: General anesthesia versus monitored anesthesia care'.) The type of anesthesia used for MT in patients with ischemic stroke may have some impact on short- and long-term outcomes, as reviewed in detail separately. (See "Anesthesia for endovascular therapy for acute ischemic stroke in adults", section on 'Literature comparing general anesthesia with monitored anesthesia care or conscious sedation'.) Risk of periprocedural antithrombotics There is no indication for the routine use of periprocedural antithrombotic agents. Based upon the results of the MR CLEAN-MED trial, the use of periprocedural aspirin or unfractionated heparin in patients undergoing endovascular therapy for acute ischemic stroke increases the risk of symptomatic hemorrhagic transformation and may increase the risk of worse outcomes [82]. However, antithrombotic agents may be indicated in specific instances (eg, if a stent gets deployed, or if there is distal embolism). Blood pressure management Admission systolic blood pressure (SBP) does not seem to impact the benefit of MT, as shown by the HERMES meta-analysis of seven trials with individual data from 1753 patients randomly assigned to MT or standard care (control) [83]. The meta- analysis found a nonlinear association between admission SBP and functional outcome measured by the mRS, with an inflection point at an SBP of 140 mmHg. Admission SBPs above 140 mmHg were associated with worse functional outcomes and higher mortality rates. However, there was no interaction between admission SBP and the effect of MT. At 90 days, the median mRS was lower (ie, functional outcome was better) with MT for both patients with an admission SBP <140 mmHg (median mRS 2, versus 3 for controls) and patients with an admission SBP 140 mmHg (median mRS 3, versus 4 for controls). The benefit of MT for a shift https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 16/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate towards a better functional outcome ordinal mRS was also similar for patients with admission SBP <140 mmHg (adjusted common OR 2.06, 95% CI 1.56-2.71) and patients with admission SBP 140 mmHg (OR 1.84, 95% CI 1.46-2.31). We suggest keeping SBP between 150 and 180 mmHg prior to reperfusion; SBP 150 mmHg may be useful for maintaining adequate collateral blood flow during the time the large artery remains occluded [8,24]. Some experts suggest no use of antihypertensives prior to reperfusion unless SBP exceeds 200 mmHg for patients not being treated with intravenous thrombolysis, or unless SBP exceeds 185 mmHg for patients who are candidates for intravenous thrombolysis [84]. However, the optimal blood pressure range with MT is not well defined, and there is no proven benefit of aggressive early blood pressure reduction after reperfusion [8,85-88]. Earlier evidence supported keeping SBP <160 to 170 mmHg for patients with successful reperfusion (ie, mTICI 2b or 3) and targeting SBP of 170 mmHg for patients with less successful reperfusion (ie, mTICI 0 to 2a) [84]. Other reports suggested targeting SBP to <140 mmHg after successful reperfusion [48,89]. More intensive blood pressure lowering (eg, targeting SBP <120 mmHg) may be harmful, particularly in Asian populations where the prevalence of large artery atherosclerosis is high [90,91]. Many patients undergoing MT will have been treated with intravenous thrombolytic therapy (recombinant tissue plasminogen activator or tPA) in the first hours after stroke symptom onset and should be managed accordingly, with systolic/diastolic blood pressure maintained at 180/105 mmHg during and for 24 hours following alteplase infusion or tenecteplase injection; a higher blood pressure may increase the risk of hemorrhage in ischemic brain regions even when thrombolytic agents are not used. (See "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use", section on 'Management of blood pressure'.) Adverse effects In the MR CLEAN trial, clinical signs of a new ischemic stroke in a different vascular territory within 90 days of treatment were more common in the intra-arterial group compared with no endovascular therapy (5.6 versus 0.4 percent) [22]. Device-related serious adverse events are uncommon but include access site hematoma and pseudoaneurysm, arterial perforation, and arterial dissection [24-27]. Transient intraprocedural vasospasm is also uncommon but is sometimes treated. MT in general is not associated with increased rates of symptomatic intracranial hemorrhage (sICH) or mortality. In a meta-analysis of five trials, with pooled patient-level data for 1287 subjects, there was no significant difference between the intervention population and control population for 90-day sICH (4.4 versus 4.3 percent) or mortality (15 versus 19 percent) [28]. https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 17/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate Limited evidence suggests recent anticoagulation with an oral vitamin K antagonist (VKA), but not a direct oral anticoagulant (DOAC), may increase the risk of sICH or mortality for patients undergoing MT [92,93]. In a 2022 meta-analysis of 15 nonrandomized studies, VKA use compared with no oral anticoagulant use was associated with an increased risk of sICH (8.4 versus 6.5 percent, OR 1.49, 95% CI 1.10-2.02) and mortality (32.8 versus 24.2 percent, OR 1.67, 95% CI 1.35-2.06), whereas DOAC use compared with no oral anticoagulant use was associated with no increased risk of sICH (2.7 versus 5.9 percent, OR 0.80, 95% CI 0.45-1.44) or mortality (26.9 versus 23.0 percent, OR 1.27, 95% CI 0.96-1.70) [92]. Approach to tandem lesions Fifteen to 30 percent of patients eligible for MT present with tandem lesions characterized by extracranial carotid artery stenosis or occlusion and a downstream, ipsilateral intracranial large vessel occlusion [22,24,27,94]. MT is directed at revascularization of the intracranial occlusion, but the best approach to management of the extracranial carotid lesion is uncertain [94,95]. Options include acute treatment of the extracranial carotid lesion with stent placement (anterograde or retrograde), angioplasty alone, or thrombo-aspiration alone, versus deferred or no revascularization of the extracranial carotid artery lesion ( figure 4) [96]. Deferred revascularization options include eventual carotid endarterectomy or carotid artery stenting. (See "Management of symptomatic carotid atherosclerotic disease".) Available data from observational studies suggest that acute carotid stenting for patients with tandem lesions who are undergoing MT is associated with a higher rate of favorable outcomes at 90 days compared with no stenting [97,98]. A subgroup analysis from one study further suggests that stenting is associated with improved outcomes in patients with carotid lesions caused by atherosclerosis but not in patients with carotid lesions caused by dissection [98]. Rescue therapy for failed MT Approximately 8 to 30 percent of patients fail to achieve substantial reperfusion with MT, with failure defined by mTICI scores ( table 4) of 2a or less [28,99-101]. In such cases, urgent rescue therapy with intracranial angioplasty/stenting, intravenous glycoprotein IIb/IIIa inhibitors, or intravenous P2Y12 receptor inhibitors is sometimes attempted [99]. Limited observational data suggest that these interventions are safe [99,102], but prospective studies are lacking, and the optimal approach is uncertain. Intracranial stenting is the best-studied option [103-105]. The retrospective, multicenter SAINT study of patients who failed MT compared those who received acute rescue stenting (n = 107) with propensity-score matched patients who did not receive rescue stenting (n = 107) [103]. At 90 days, rescue stenting was associated with a shift to lower rates of disability in the overall mRS score distribution (adjusted OR 3.74, 95% CI 2.16-6.57), increased functional independence (34.6 versus 6.5 percent, OR 10.91, 95% CI 4.11-28.92), decreased mortality (29.9 versus 43.0 percent, https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 18/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate OR 0.49, 95% CI 0.25-0.94), and comparable rates of symptomatic intracranial hemorrhage (7.5 versus 11.2 percent, OR 0.87, 95% CI 0.31-2.42). These results are limited by retrospective design and wide confidence intervals, and further study is needed to determine the benefit of this intervention for failed MT. Adjunct intra-arterial thrombolysis Some patients have poor clinical outcomes after MT despite successful reperfusion (ie, a modified Thrombolysis in Cerebral Infarction [mTICI] 2b or 3) of the target large artery; one possible but controversial explanation is persisting impaired reperfusion of the microcirculation (the "no-reflow" phenomenon) [106,107]. The Chemical Optimization of Cerebral Embolectomy (CHOICE) trial investigated the use of adjunct intra- arterial thrombolysis with alteplase to treat hypothesized persistent thrombi in the microcirculation after angiographically successful MT [108]. At 90 days, more patients achieved an excellent neurologic outcome (an mRS score of 0 to 1) with intra-arterial alteplase compared with placebo (59 versus 40.4 percent, adjusted absolute risk reduction 18.4 percent, 95% CI 0.3- 36.4 percent). There was no increased risk of intracranial hemorrhage or mortality with intra- arterial alteplase. Limitations of the CHOICE trial include early stopping (due to slow recruitment and inability to obtain placebo), which can lead to overestimation of treatment effects, small patient numbers (and resulting wide confidence intervals with a lower limit of only 0.3 percent absolute risk reduction), and the protocol allowing premature stopping (and therefore potential underdosing) of intravenous alteplase infusion started before the onset of thrombectomy [108,109]. Thus, the benefit of this approach requires confirmation in larger trials. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) SUMMARY AND RECOMMENDATIONS Efficacy of mechanical thrombectomy Early intra-arterial treatment with mechanical thrombectomy (MT) is safe and effective for reducing disability and is superior to standard treatment with intravenous thrombolysis alone for ischemic stroke caused by a documented large artery occlusion in the proximal anterior circulation. (See 'Efficacy of mechanical thrombectomy' above.) Patient selection for anterior circulation stroke https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 19/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate Who to treat For patients with acute ischemic stroke, we recommend treatment with intra-arterial MT, whether or not the patient received treatment with intravenous thrombolytic therapy, if the following conditions are met (Grade 1B): Brain imaging using CT without contrast or diffusion-weighted MRI (DWI) excludes hemorrhage and is consistent with an Alberta Stroke Program Early CT Score (ASPECTS) 3. (See 'Role of ASPECTS method' above.) CT angiography (CTA) or MR angiography (MRA) demonstrates a proximal large artery occlusion in the anterior circulation as the cause of the ischemic stroke. The patient has a persistent, potentially disabling neurologic deficit (eg, a National Institutes of Health Stroke Scale [NIHSS] score 6). The patient can start treatment (femoral puncture) within 24 hours of the time last known to be well. This recommendation applies when thrombectomy is performed at a stroke center with appropriate expertise in the use of endovascular therapy. Benefit may be most likely when imaging confirms the presence of salvageable brain tissue (eg, a mismatch by DAWN or DEFUSE 3 criteria). Who not to treat We would not treat with MT for patients who have any of the following findings (see 'Who not to treat' above): Presence of a large established hypodensity on head CT beyond the more subtle, early ischemic changes assessed by ASPECTS (see 'Role of ASPECTS method' above) No ischemic penumbra (ie, no mismatch suggesting no salvageable brain tissue) identified if CT perfusion (CTP) or DWI/PWI (perfusion-weighted MRI) is performed, particularly if the infarct core is large Presence of a large core infarct (eg, defined by an ASPECTS <6 or imaging showing a core volume 50 mL) and severe prestroke comorbidities (eg, pre-existing severe disability such as modified Rankin Scale [mRS] 4 to 5 or life expectancy less than six months) Individualized decisions The decision to employ MT needs to be carefully individualized for patients with anterior circulation stroke who do not precisely match the inclusion or exclusion criteria as listed above. Examples include patients with imaging evidence of salvageable brain tissue who are beyond the 24-hour time window, https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 20/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate medium vessel occlusion (eg, anterior cerebral artery beyond the A1 segment, middle cerebral artery [MCA] beyond the proximal M2 segment), or minor stroke (NIHSS 5). Use in posterior circulation stroke Although the benefits are uncertain, MT within 24 hours of the time last known to be well may be a reasonable treatment option for patients with acute ischemic stroke caused by occlusion of the basilar artery, vertebral arteries, or posterior cerebral arteries when performed at centers with appropriate expertise. Moderate-quality evidence supports the benefit of MT for patients of Chinese ancestry with basilar artery occlusion who have an NIHSS score 10, indicating a moderate to severe stroke; a posterior circulation ASPECTS (pc-ASPECTS) of 6, indicating a limited extent of ischemic change on brain imaging; and who can be treated within 24 hours of time last known to be well. (See 'Posterior circulation stroke' above.) Procedure Second-generation stent retriever devices or catheter aspiration devices should be used for MT. Other aspects of the MT procedure, including anesthesia, blood pressure management, and adverse events, are discussed above. (See 'Procedure' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Campbell BC, Donnan GA, Lees KR, et al. Endovascular stent thrombectomy: the new standard of care for large vessel ischaemic stroke. Lancet Neurol 2015; 14:846. 2. Furlan AJ. Endovascular therapy for stroke it's about time. N Engl J Med 2015; 372:2347. 3. 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treatment of ischemic stroke. N Engl J Med 2015; 372:1019. 25. Saver JL, Goyal M, Bonafe A, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t- PA alone in stroke. N Engl J Med 2015; 372:2285. 26. Campbell BC, Mitchell PJ, Kleinig TJ, et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med 2015; 372:1009. 27. Jovin TG, Chamorro A, Cobo E, et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke. N Engl J Med 2015; 372:2296. 28. Goyal M, Menon BK, van Zwam WH, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet 2016; 387:1723. 29. Marmagkiolis K, Hakeem A, Cilingiroglu M, et al. Safety and Efficacy of Stent Retrievers for the Management of Acute Ischemic Stroke: Comprehensive Review and Meta-Analysis. JACC Cardiovasc Interv 2015; 8:1758. 30. 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JAMA 2017; 318:443. 79. Turk AS 3rd, Siddiqui A, Fifi JT, et al. Aspiration thrombectomy versus stent retriever thrombectomy as first-line approach for large vessel occlusion (COMPASS): a multicentre, randomised, open label, blinded outcome, non-inferiority trial. Lancet 2019; 393:998. 80. Bernsen MLE, Goldhoorn RB, Lingsma HF, et al. Importance of Occlusion Site for Thrombectomy Technique in Stroke: Comparison Between Aspiration and Stent Retriever. Stroke 2021; 52:80. 81. Lapergue B, Blanc R, Costalat V, et al. Effect of Thrombectomy With Combined Contact Aspiration and Stent Retriever vs Stent Retriever Alone on Revascularization in Patients With Acute Ischemic Stroke and Large Vessel Occlusion: The ASTER2 Randomized Clinical Trial. JAMA 2021; 326:1158. 82. van der Steen W, van de Graaf RA, Chalos V, et al. Safety and efficacy of aspirin, unfractionated heparin, both, or neither during endovascular stroke treatment (MR CLEAN- MED): an open-label, multicentre, randomised controlled trial. Lancet 2022; 399:1059. 83. Samuels N, van de Graaf RA, Mulder MJHL, et al. Admission systolic blood pressure and effect of endovascular treatment in patients with ischaemic stroke: an individual patient data meta-analysis. Lancet Neurol 2023; 22:312. 84. Biller J, Bulwa Z, Gomez CR, Morales-Vidal S. Stroke snapshot: Blood pressure management after acute ischemic stroke. Pract Neurol (Fort Washington, Pa.) 2019; March/April:13. 85. Ma er B, Fahed R, Khoury N, et al. Association of Blood Pressure During Thrombectomy for Acute Ischemic Stroke With Functional Outcome: A Systematic Review. Stroke 2019; 50:2805. 86. Mazighi M, Richard S, Lapergue B, et al. Safety and efficacy of intensive blood pressure lowering after successful endovascular therapy in acute ischaemic stroke (BP-TARGET): a multicentre, open-label, randomised controlled trial. Lancet Neurol 2021; 20:265. 87. Mistry E, Hart K, Davis L, et al. Blood pressure after endovascular stroke treatment (BEST)-II: A randomized clinical trial. Presented at: 2023 International Stroke Conference; February 8-1 https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 27/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate 0; Dallas, TX. LB18. 88. Morris NA, Jindal G, Chaturvedi S. Intensive Blood Pressure Control After Mechanical Thrombectomy for Acute Ischemic Stroke. Stroke 2023; 54:1457. 89. Anadani M, Arthur AS, Tsivgoulis G, et al. Blood Pressure Goals and Clinical Outcomes after Successful Endovascular Therapy: A Multicenter Study. Ann Neurol 2020; 87:830. 90. Yang P, Song L, Zhang Y, et al. Intensive blood pressure control after endovascular thrombectomy for acute ischaemic stroke (ENCHANTED2/MT): a multicentre, open-label, blinded-endpoint, randomised controlled trial. Lancet 2022; 400:1585. 91. Mistry EA, Nguyen TN. Blood pressure goals after mechanical thrombectomy: a moving target. Lancet 2022; 400:1558. 92. Chen JH, Hong CT, Chung CC, et al. Safety and efficacy of endovascular thrombectomy in acute ischemic stroke treated with anticoagulants: a systematic review and meta-analysis. Thromb J 2022; 20:35. 93. Mac Grory B, Holmes DN, Matsouaka RA, et al. Recent Vitamin K Antagonist Use and Intracranial Hemorrhage After Endovascular Thrombectomy for Acute Ischemic Stroke. JAMA 2023; 329:2038. 94. Jadhav AP, Zaidat OO, Liebeskind DS, et al. Emergent Management of Tandem Lesions in Acute Ischemic Stroke. Stroke 2019; 50:428. 95. Jacquin G, Poppe AY, Labrie M, et al. Lack of Consensus Among Stroke Experts on the Optimal Management of Patients With Acute Tandem Occlusion. Stroke 2019; 50:1254. 96. Poppe AY, Jacquin G, Roy D, et al. Tandem Carotid Lesions in Acute Ischemic Stroke: Mechanisms, Therapeutic Challenges, and Future Directions. AJNR Am J Neuroradiol 2020; 41:1142. 97. Dufort G, Chen BY, Jacquin G, et al. Acute carotid stenting in patients undergoing thrombectomy: a systematic review and meta-analysis. J Neurointerv Surg 2021; 13:141. 98. Anadani M, Marnat G, Consoli A, et al. Endovascular Therapy of Anterior Circulation Tandem Occlusions: Pooled Analysis From the TITAN and ETIS Registries. Stroke 2021; 52:3097. 99. Abdalla RN, Cantrell DR, Shaibani A, et al. Refractory Stroke Thrombectomy: Prevalence, Etiology, and Adjunctive Treatment in a North American Cohort. AJNR Am J Neuroradiol 2021; 42:1258. 100. Flottmann F, Leischner H, Broocks G, et al. Recanalization Rate per Retrieval Attempt in Mechanical Thrombectomy for Acute Ischemic Stroke. Stroke 2018; 49:2523. 101. Tsang COA, Cheung IHW, Lau KK, et al. Outcomes of Stent Retriever versus Aspiration-First Thrombectomy in Ischemic Stroke: A Systematic Review and Meta-Analysis. AJNR Am J https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 28/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate Neuroradiol 2018; 39:2070. 102. Marnat G, Delvoye F, Finitsis S, et al. A Multicenter Preliminary Study of Cangrelor following Thrombectomy Failure for Refractory Proximal Intracranial Occlusions. AJNR Am J Neuroradiol 2021; 42:1452. 103. Mohammaden MH, Haussen DC, Al-Bayati AR, et al. Stenting and Angioplasty in Neurothrombectomy: Matched Analysis of Rescue Intracranial Stenting Versus Failed Thrombectomy. Stroke 2022; 53:2779. 104. Maingard J, Phan K, Lamanna A, et al. Rescue Intracranial Stenting After Failed Mechanical Thrombectomy for Acute Ischemic Stroke: A Systematic Review and Meta-Analysis. World Neurosurg 2019; 132:e235. 105. Hassan AE, Ringheanu VM, Preston L, et al. Acute intracranial stenting with mechanical thrombectomy is safe and efficacious in patients diagnosed with underlying intracranial atherosclerotic disease. Interv Neuroradiol 2022; 28:419. 106. Ng FC, Churilov L, Yassi N, et al. Prevalence and Significance of Impaired Microvascular Tissue Reperfusion Despite Macrovascular Angiographic Reperfusion (No-Reflow). Neurology 2022; 98:e790. 107. Ter Schiphorst A, Charron S, Hassen WB, et al. Tissue no-reflow despite full recanalization following thrombectomy for anterior circulation stroke with proximal occlusion: A clinical study. J Cereb Blood Flow Metab 2021; 41:253. 108. Ren A, Mill n M, San Rom n L, et al. Effect of Intra-arterial Alteplase vs Placebo Following Successful Thrombectomy on Functional Outcomes in Patients With Large Vessel Occlusion Acute Ischemic Stroke: The CHOICE Randomized Clinical Trial. JAMA 2022; 327:826. 109. Khatri P. Intra-arterial Thrombolysis to Target Occlusions in Distal Arteries and the Microcirculation. JAMA 2022; 327:821. Topic 115663 Version 40.0 https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 29/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate GRAPHICS Eligibility criteria for the treatment of acute ischemic stroke with intravenous thrombolysis (recombinant tissue plasminogen activator or tPA) Inclusion criteria Clinical diagnosis of ischemic stroke causing measurable neurologic deficit Onset of symptoms <4.5 hours before beginning treatment; if the exact time of stroke onset is not known, it is defined as the last time the patient was known to be normal or at neurologic baseline Age 18 years Exclusion criteria Patient history Ischemic stroke or severe head trauma in the previous three months Previous intracranial hemorrhage Intra-axial intracranial neoplasm Gastrointestinal malignancy Gastrointestinal hemorrhage in the previous 21 days Intracranial or intraspinal surgery within the prior three months Clinical Symptoms suggestive of subarachnoid hemorrhage Persistent blood pressure elevation (systolic 185 mmHg or diastolic 110 mmHg) Active internal bleeding Presentation consistent with infective endocarditis Stroke known or suspected to be associated with aortic arch dissection Acute bleeding diathesis, including but not limited to conditions defined under 'Hematologic' Hematologic 3 Platelet count <100,000/mm * Current anticoagulant use with an INR >1.7 or PT >15 seconds or aPTT >40 seconds* Therapeutic doses of low molecular weight heparin received within 24 hours (eg, to treat VTE and ACS); this exclusion does not apply to prophylactic doses (eg, to prevent VTE) Current use (ie, last dose within 48 hours in a patient with normal renal function) of a direct thrombin inhibitor or direct factor Xa inhibitor with evidence of anticoagulant effect by laboratory tests such as aPTT, INR, ECT, TT, or appropriate factor Xa activity assays Head CT https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 30/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate Evidence of hemorrhage Extensive regions of obvious hypodensity consistent with irreversible injury Warnings Only minor and isolated neurologic signs or rapidly improving symptoms Serum glucose <50 mg/dL (<2.8 mmol/L) Serious trauma in the previous 14 days Major surgery in the previous 14 days History of gastrointestinal bleeding (remote) or genitourinary bleeding Seizure at the onset of stroke with postictal neurologic impairments Pregnancy** Arterial puncture at a noncompressible site in the previous seven days Large ( 10 mm), untreated, unruptured intracranial aneurysm Untreated intracranial vascular malformation Additional warnings for treatment from 3 to 4.5 hours from symptom onset Age >80 years Oral anticoagulant use regardless of INR Severe stroke (NIHSS score >25) Combination of both previous ischemic stroke and diabetes mellitus ACS: acute coronary syndrome; aPTT: activated partial thromboplastin time; ECT: ecarin clotting time; INR: international normalized ratio; PT: prothrombin time; NIHSS: National Institutes of Health Stroke Scale; tPA: intravenous alteplase; TT: thrombin time; VTE: venous thromboembolism. Although it is desirable to know the results of these tests, thrombolytic therapy should not be delayed while results are pending unless (1) there is clinical suspicion of a bleeding abnormality or thrombocytopenia, (2) the patient is currently on or has recently received anticoagulants (eg, heparin, warfarin, a direct thrombin inhibitor, or a direct factor Xa inhibitor), or (3) use of anticoagulants is not known. Otherwise, treatment with intravenous tPA can be started before availability of coagulation test results but should be discontinued if the INR, PT, or aPTT exceed the limits stated in the table, or 3 if platelet count is <100,000 mm . With careful consideration and weighting of risk-to-benefit, patients may receive intravenous alteplase despite one or more warnings. Patients who have a persistent neurologic deficit that is potentially disabling, despite improvement of any degree, should be treated with tPA in the absence of other contraindications. Any of the following should be considered disabling deficits: Complete hemianopia: 2 on NIHSS question 3, or Severe aphasia: 2 on NIHSS question 9, or Visual or sensory extinction: 1 on NIHSS question 11, or https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 31/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate Any weakness limiting sustained effort against gravity: 2 on NIHSS question 5 or 6, or Any deficits that lead to a total NIHSS >5, or Any remaining deficit considered potentially disabling in the view of the patient and the treating practitioner using clinical judgment Patients may be treated with intravenous alteplase if glucose level is subsequently normalized. The potential risks of bleeding with alteplase from injuries related to the trauma should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. The increased risk of surgical site bleeding with alteplase should be weighed against the anticipated benefits of reduced stroke-related neurologic deficits. There is a low increased risk of new bleeding with alteplase in the setting of past gastrointestinal or genitourinary bleeding. However, alteplase administration within 21 days of gastrointestinal bleeding is not recommended. Alteplase is reasonable in patients with a seizure at stroke onset if evidence suggests that residual impairments are secondary to acute ischemic stroke and not to a postictal phenomenon. * Alteplase can be given in pregnancy when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding. The safety and efficacy of administering alteplase is uncertain for these relative exclusions. Although these were exclusions in the trial showing benefit in the 3 to 4.5 hour window, intravenous alteplase appears to be safe and may be beneficial for patients with these criteria, including patients taking oral anticoagulants with an INR <1.7. Adapted from: 1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359:1317. 2. Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke Association. Stroke 2009; 40:2945. 3. Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force:, Levine SR, Khatri P, et al. Review, historical context, and clari cations of the NINDS rt-PA stroke trials exclusion criteria: Part 1: rapidly improving stroke symptoms. Stroke 2013; 44:2500. 4. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scienti c rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2016; 47:581. 5. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344. Graphic 71462 Version 26.0 https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 32/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate National Institutes of Health Stroke Scale (NIHSS) Administer stroke scale items in the order listed. Record performance in each category after each subscale exam. Do not go back and change scores. Follow directions provided for each exam technique. Scores should reflect what the patient does, not what the clinician thinks the patient can do. The clinician should record answers while administering the exam and work quickly. Except where indicated, the patient should not be coached (ie, repeated requests to patient to make a special effort). Instructions Scale definition Score 1a. Level of consciousness: The 0 = Alert; keenly responsive. investigator must choose a response if a full 1 = Not alert; but arousable by minor evaluation is prevented by such obstacles as an endotracheal tube, language barrier, stimulation to obey, answer, or respond. 2 = Not alert; requires repeated stimulation orotracheal trauma/bandages. A 3 is scored only if the patient makes no movement to attend, or is obtunded and requires strong or painful stimulation to make _____ (other than reflexive posturing) in response to noxious stimulation. movements (not stereotyped). 3 = Responds only with reflex motor or autonomic effects or totally unresponsive, flaccid, and areflexic. 1b. Level of consciousness questions: The 0 = Answers both questions correctly. patient is asked the month and his/her age. The answer must be correct - there is no 1 = Answers one question correctly. 2 = Answers neither question correctly. partial credit for being close. Aphasic and stuporous patients who do not comprehend the questions will score 2. Patients unable to speak because of endotracheal intubation, _____ orotracheal trauma, severe dysarthria from any cause, language barrier, or any other problem not secondary to aphasia are given a 1. It is important that only the initial answer be graded and that the examiner not "help" the patient with verbal or non-verbal cues. 1c. Level of consciousness commands: The 0 = Performs both tasks correctly. _____ patient is asked to open and close the eyes 1 = Performs one task correctly. and then to grip and release the non-paretic hand. Substitute another one step 2 = Performs neither task correctly. command if the hands cannot be used. Credit is given if an unequivocal attempt is made but not completed due to weakness. If the patient does not respond to command, the task should be demonstrated to him or her (pantomime), and the result scored (ie, https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 33/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate follows none, one or two commands). Patients with trauma, amputation, or other physical impediments should be given suitable one-step commands. Only the first attempt is scored. 2. Best gaze: Only horizontal eye movements will be tested. Voluntary or 0 = Normal. 1 = Partial gaze palsy; gaze is abnormal in one or both eyes, but forced deviation or reflexive (oculocephalic) eye movements will be scored, but caloric testing is not done. If total gaze paresis is not present. the patient has a conjugate deviation of the eyes that can be overcome by voluntary or 2 = Forced deviation, or total gaze paresis not overcome by the oculocephalic reflexive activity, the score will be 1. If a maneuver. patient has an isolated peripheral nerve paresis (cranial nerves III, IV or VI), score a 1. _____ Gaze is testable in all aphasic patients. Patients with ocular trauma, bandages, pre- existing blindness, or other disorder of visual acuity or fields should be tested with reflexive movements, and a choice made by the investigator. Establishing eye contact and then moving about the patient from side to side will occasionally clarify the presence of a partial gaze palsy. 3. Visual: Visual fields (upper and lower 0 = No visual loss. quadrants) are tested by confrontation, using finger counting or visual threat, as 1 = Partial hemianopia. 2 = Complete hemianopia. appropriate. Patients may be encouraged, but if they look at the side of the moving fingers appropriately, this can be scored as 3 = Bilateral hemianopia (blind including cortical blindness). normal. If there is unilateral blindness or enucleation, visual fields in the remaining _____ eye are scored. Score 1 only if a clear-cut asymmetry, including quadrantanopia, is found. If patient is blind from any cause, score 3. Double simultaneous stimulation is performed at this point. If there is extinction, patient receives a 1, and the results are used to respond to item 11. 4. Facial palsy: Ask - or use pantomime to 0 = Normal symmetrical movements. _____ encourage - the patient to show teeth or 1 = Minor paralysis (flattened nasolabial raise eyebrows and close eyes. Score symmetry of grimace in response to noxious fold, asymmetry on smiling). 2 = Partial paralysis (total or near-total stimuli in the poorly responsive or non- comprehending patient. If facial paralysis of lower face). trauma/bandages, orotracheal tube, tape or https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 34/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate other physical barriers obscure the face, these should be removed to the extent 3 = Complete paralysis of one or both sides (absence of facial movement in the upper possible. and lower face). 5. Motor arm: The limb is placed in the appropriate position: extend the arms 0 = No drift; limb holds 90 (or 45) degrees for full 10 seconds. (palms down) 90 degrees (if sitting) or 45 degrees (if supine). Drift is scored if the arm 1 = Drift; limb holds 90 (or 45) degrees, but drifts down before full 10 seconds; does not hit bed or other support. falls before 10 seconds. The aphasic patient is encouraged using urgency in the voice and pantomime, but not noxious 2 = Some effort against gravity; limb cannot get to or maintain (if cued) 90 (or 45) stimulation. Each limb is tested in turn, beginning with the non-paretic arm. Only in degrees, drifts down to bed, but has some effort against gravity. _____ the case of amputation or joint fusion at the shoulder, the examiner should record the 3 = No effort against gravity; limb falls. score as untestable (UN), and clearly write 4 = No movement. the explanation for this choice. UN = Amputation or joint fusion, explain:________________ 5a. Left arm 5b. Right arm 6. Motor leg: The limb is placed in the appropriate position: hold the leg at 30 0 = No drift; leg holds 30-degree position for full 5 seconds. degrees (always tested supine). Drift is 1 = Drift; leg falls by the end of the 5-second period but does not hit bed. scored if the leg falls before 5 seconds. The aphasic patient is encouraged using urgency 2 = Some effort against gravity; leg falls to in the voice and pantomime, but not noxious stimulation. Each limb is tested in bed by 5 seconds, but has some effort against gravity. turn, beginning with the non-paretic leg. _____ Only in the case of amputation or joint fusion at the hip, the examiner should 3 = No effort against gravity; leg falls to bed immediately. record the score as untestable (UN), and clearly write the explanation for this choice. 4 = No movement. UN = Amputation or joint fusion, explain:________________ 6a. Left leg 6b. Right leg 7. Limb ataxia: This item is aimed at finding evidence of a unilateral cerebellar lesion. 0 = Absent. _____ 1 = Present in one limb. Test with eyes open. In case of visual defect, ensure testing is done in intact visual field. 2 = Present in two limbs. The finger-nose-finger and heel-shin tests UN = Amputation or joint fusion, explain:________________ are performed on both sides, and ataxia is scored only if present out of proportion to weakness. Ataxia is absent in the patient https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 35/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate who cannot understand or is paralyzed. Only in the case of amputation or joint fusion, the examiner should record the score as untestable (UN), and clearly write the explanation for this choice. In case of blindness, test by having the patient touch nose from extended arm position. 8. Sensory: Sensation or grimace to pinprick 0 = Normal; no sensory loss. when tested, or withdrawal from noxious stimulus in the obtunded or aphasic patient. 1 = Mild-to-moderate sensory loss; patient feels pinprick is less sharp or is dull on the affected side; or there is a loss of superficial Only sensory loss attributed to stroke is scored as abnormal and the examiner should test as many body areas (arms [not pain with pinprick, but patient is aware of being touched. hands], legs, trunk, face) as needed to accurately check for hemisensory loss. A 2 = Severe to total sensory loss; patient is not aware of being touched in the face, arm, score of 2, "severe or total sensory loss," should only be given when a severe or total and leg. _____ loss of sensation can be clearly demonstrated. Stuporous and aphasic patients will, therefore, probably score 1 or 0. The patient with brainstem stroke who has bilateral loss of sensation is scored 2. If the patient does not respond and is quadriplegic, score 2. Patients in a coma (item 1a=3) are automatically given a 2 on this item. 9. Best language: A great deal of information about comprehension will be 0 = No aphasia; normal. _____ 1 = Mild-to-moderate aphasia; some obvious loss of fluency or facility of obtained during the preceding sections of the examination. For this scale item, the comprehension, without significant limitation on ideas expressed or form of patient is asked to describe what is happening in the attached picture, to name the items on the attached naming sheet and expression. Reduction of speech and/or comprehension, however, makes conversation about provided materials to read from the attached list of sentences. Comprehension is judged from responses difficult or impossible. For example, in conversation about provided materials, here, as well as to all of the commands in the preceding general neurological exam. If examiner can identify picture or naming card content from patient's response. visual loss interferes with the tests, ask the patient to identify objects placed in the hand, repeat, and produce speech. The 2 = Severe aphasia; all communication is through fragmentary expression; great need intubated patient should be asked to write. The patient in a coma (item 1a=3) will for inference, questioning, and guessing by the listener. Range of information that can automatically score 3 on this item. The examiner must choose a score for the be exchanged is limited; listener carries burden of communication. Examiner cannot patient with stupor or limited cooperation, but a score of 3 should be used only if the https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 36/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate patient is mute and follows no one-step identify materials provided from patient commands. response. 3 = Mute, global aphasia; no usable speech or auditory comprehension. 10. Dysarthria: If patient is thought to be 0 = Normal. normal, an adequate sample of speech must be obtained by asking patient to read or 1 = Mild-to-moderate dysarthria; patient slurs at least some words and, at worst, can be understood with some difficulty. repeat words from the attached list. If the patient has severe aphasia, the clarity of articulation of spontaneous speech can be 2 = Severe dysarthria; patient's speech is so _____ slurred as to be unintelligible in the absence rated. Only if the patient is intubated or has other physical barriers to producing speech, of or out of proportion to any dysphasia, or is mute/anarthric. the examiner should record the score as untestable (UN), and clearly write an UN = Intubated or other physical barrier, explanation for this choice. Do not tell the explain:________________ patient why he or she is being tested. 11. Extinction and inattention (formerly neglect): Sufficient information to identify 0 = No abnormality. 1 = Visual, tactile, auditory, spatial, or personal inattention or extinction to neglect may be obtained during the prior testing. If the patient has a severe visual loss bilateral simultaneous stimulation in one of the sensory modalities. preventing visual double simultaneous stimulation, and the cutaneous stimuli are 2 = Profound hemi-inattention or normal, the score is normal. If the patient _____ extinction to more than one modality; has aphasia but does appear to attend to both sides, the score is normal. The does not recognize own hand or orients to only one side of space. presence of visual spatial neglect or anosognosia may also be taken as evidence of abnormality. Since the abnormality is scored only if present, the item is never untestable. _____ Adapted from: Goldstein LB, Samsa GP. Reliability of the National Institutes of Health Stroke Scale. Extension to non- neurologists in the context of a clinical trial. Stroke 1997; 28:307. Graphic 61698 Version 8.0 https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 37/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate Modified Rankin Scale Score Description 0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties and activities 2 Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent, and requiring constant nursing care and attention 6 Dead Reproduced with permission from: Van Swieten JC, Koudstaa PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988; 19:604. Copyright 1988 Lippincott Williams & Wilkins. Graphic 75411 Version 13.0 https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 38/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate ASPECTS study form The ASPECTS value is calculated from two standard axial CT cuts: one at the level of the thalamus and basal ganglia (left), and one just rostral to the basal ganglia (right). A: anterior circulation; P: posterior circulation; C:

in the voice and pantomime, but not noxious stimulation. Each limb is tested in bed by 5 seconds, but has some effort against gravity. turn, beginning with the non-paretic leg. _____ Only in the case of amputation or joint fusion at the hip, the examiner should 3 = No effort against gravity; leg falls to bed immediately. record the score as untestable (UN), and clearly write the explanation for this choice. 4 = No movement. UN = Amputation or joint fusion, explain:________________ 6a. Left leg 6b. Right leg 7. Limb ataxia: This item is aimed at finding evidence of a unilateral cerebellar lesion. 0 = Absent. _____ 1 = Present in one limb. Test with eyes open. In case of visual defect, ensure testing is done in intact visual field. 2 = Present in two limbs. The finger-nose-finger and heel-shin tests UN = Amputation or joint fusion, explain:________________ are performed on both sides, and ataxia is scored only if present out of proportion to weakness. Ataxia is absent in the patient https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 35/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate who cannot understand or is paralyzed. Only in the case of amputation or joint fusion, the examiner should record the score as untestable (UN), and clearly write the explanation for this choice. In case of blindness, test by having the patient touch nose from extended arm position. 8. Sensory: Sensation or grimace to pinprick 0 = Normal; no sensory loss. when tested, or withdrawal from noxious stimulus in the obtunded or aphasic patient. 1 = Mild-to-moderate sensory loss; patient feels pinprick is less sharp or is dull on the affected side; or there is a loss of superficial Only sensory loss attributed to stroke is scored as abnormal and the examiner should test as many body areas (arms [not pain with pinprick, but patient is aware of being touched. hands], legs, trunk, face) as needed to accurately check for hemisensory loss. A 2 = Severe to total sensory loss; patient is not aware of being touched in the face, arm, score of 2, "severe or total sensory loss," should only be given when a severe or total and leg. _____ loss of sensation can be clearly demonstrated. Stuporous and aphasic patients will, therefore, probably score 1 or 0. The patient with brainstem stroke who has bilateral loss of sensation is scored 2. If the patient does not respond and is quadriplegic, score 2. Patients in a coma (item 1a=3) are automatically given a 2 on this item. 9. Best language: A great deal of information about comprehension will be 0 = No aphasia; normal. _____ 1 = Mild-to-moderate aphasia; some obvious loss of fluency or facility of obtained during the preceding sections of the examination. For this scale item, the comprehension, without significant limitation on ideas expressed or form of patient is asked to describe what is happening in the attached picture, to name the items on the attached naming sheet and expression. Reduction of speech and/or comprehension, however, makes conversation about provided materials to read from the attached list of sentences. Comprehension is judged from responses difficult or impossible. For example, in conversation about provided materials, here, as well as to all of the commands in the preceding general neurological exam. If examiner can identify picture or naming card content from patient's response. visual loss interferes with the tests, ask the patient to identify objects placed in the hand, repeat, and produce speech. The 2 = Severe aphasia; all communication is through fragmentary expression; great need intubated patient should be asked to write. The patient in a coma (item 1a=3) will for inference, questioning, and guessing by the listener. Range of information that can automatically score 3 on this item. The examiner must choose a score for the be exchanged is limited; listener carries burden of communication. Examiner cannot patient with stupor or limited cooperation, but a score of 3 should be used only if the https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 36/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate patient is mute and follows no one-step identify materials provided from patient commands. response. 3 = Mute, global aphasia; no usable speech or auditory comprehension. 10. Dysarthria: If patient is thought to be 0 = Normal. normal, an adequate sample of speech must be obtained by asking patient to read or 1 = Mild-to-moderate dysarthria; patient slurs at least some words and, at worst, can be understood with some difficulty. repeat words from the attached list. If the patient has severe aphasia, the clarity of articulation of spontaneous speech can be 2 = Severe dysarthria; patient's speech is so _____ slurred as to be unintelligible in the absence rated. Only if the patient is intubated or has other physical barriers to producing speech, of or out of proportion to any dysphasia, or is mute/anarthric. the examiner should record the score as untestable (UN), and clearly write an UN = Intubated or other physical barrier, explanation for this choice. Do not tell the explain:________________ patient why he or she is being tested. 11. Extinction and inattention (formerly neglect): Sufficient information to identify 0 = No abnormality. 1 = Visual, tactile, auditory, spatial, or personal inattention or extinction to neglect may be obtained during the prior testing. If the patient has a severe visual loss bilateral simultaneous stimulation in one of the sensory modalities. preventing visual double simultaneous stimulation, and the cutaneous stimuli are 2 = Profound hemi-inattention or normal, the score is normal. If the patient _____ extinction to more than one modality; has aphasia but does appear to attend to both sides, the score is normal. The does not recognize own hand or orients to only one side of space. presence of visual spatial neglect or anosognosia may also be taken as evidence of abnormality. Since the abnormality is scored only if present, the item is never untestable. _____ Adapted from: Goldstein LB, Samsa GP. Reliability of the National Institutes of Health Stroke Scale. Extension to non- neurologists in the context of a clinical trial. Stroke 1997; 28:307. Graphic 61698 Version 8.0 https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 37/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate Modified Rankin Scale Score Description 0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties and activities 2 Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent, and requiring constant nursing care and attention 6 Dead Reproduced with permission from: Van Swieten JC, Koudstaa PJ, Visser MC, et al. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988; 19:604. Copyright 1988 Lippincott Williams & Wilkins. Graphic 75411 Version 13.0 https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 38/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate ASPECTS study form The ASPECTS value is calculated from two standard axial CT cuts: one at the level of the thalamus and basal ganglia (left), and one just rostral to the basal ganglia (right). A: anterior circulation; P: posterior circulation; C: caudate; L: lentiform; IC: internal capsule; I: insular ribbon; MCA: middle cerebral artery; M1: anterior MCA cortex; M2: MCA cortex lateral to insular ribbon; M3: posterior MCA cortex; M4, M5, and M6 are anterior, lateral, and posterior MCA territories immediately superior to M1, M2, and M3, rostral to basal ganglia Reproduced with permission from: Barber, PA, Demchuk, AM, Zhang, J, Buchan, AM. Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. ASPECTS Study Group. Alberta Stroke Programme Early CT Score. Lancet 2000; 355:1670. Copyright 2000 The Lancet. Graphic 72190 Version 1.0 https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 39/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate Visual decision aid depicting the benefits and risks of endovascular thrombectomy added to IV tPA versus IV tPA alone Choice consequence matrix type visual decision aid depicting the benefits and risks of endovascular thrombectomy added to IV tPA versus IV tPA alone. Dark green, attainment of excellent outcome (mRS, 0-1) as a result of thrombectomy; light green, improved disability outcome (other than excellent outcome) as a result of thrombectomy; light red, worse disability outcome (other than severely disabled/dead) as a result of thrombectomy; open rectangle, infarct in new territory as a result of thrombectomy. https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 40/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate tPA: tissue-type plasminogen activator; IV: intravenous; mRS: modified Rankin scale; SICH: symptomatic intracranial hemorrhage. None were severely disabled or dead (mRS, 5-6) as a result of thrombectomy. No differences observed in the rate of SICH due to thrombectomy. From: Tokunboh I, Vales Montero M, Zopelaro Almeida MF, et al. Visual aids for patient, family, and physician decision making about endovascular thrombectomy for acute ischemic stroke. Stroke 2018; 49:90. DOI: 10.1161/STROKEAHA.117.018715. Copyright 2018 American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 116247 Version 3.0 https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 41/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate Visual decision aid depicting the benefits and risks of endovascular thrombectomy for patients ineligible for IV tPA Choice consequence matrix type visual decision aid depicting the benefits and risks of endovascular thrombectomy among tPA-ineligible patients. Dark green, attainment of excellent outcome (mRS, 0-1) as a result of thrombectomy; light green, improved disability outcome (other than excellent outcome) as a result of thrombectomy; light red, worse disability outcome (other than severely disabled/dead) as a result of thrombectomy; open rectangle, infarct in new territory as a result of thrombectomy. https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 42/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate tPA: tissue-type plasminogen activator; IV: intravenous; mRS: modified Rankin scale; SICH: symptomatic intracranial hemorrhage. None were severely disabled or dead (mRS, 5-6) due to thrombectomy. No differences observed in the rate of SICH due to thrombectomy. From: Tokunboh I, Vales Montero M, Zopelaro Almeida MF, et al. Visual aids for patient, family, and physician decision making about endovascular thrombectomy for acute ischemic stroke. Stroke 2018; 49:90. DOI: 10.1161/STROKEAHA.117.018715. Copyright 2018 American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 116248 Version 3.0 https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 43/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate Modified Treatment In Cerebral Ischemia (TICI) scale 0 No reperfusion 1 Flow beyond occlusion without distal branch reperfusion 2a Reperfusion of less than half of the downstream target arterial territory 2b Reperfusion of more than half, yet incomplete, in the downstream target arterial territory 3 Complete reperfusion of the downstream target arterial territory, including distal branches with slow flow This relates to capillary-level reperfusion as measured on catheter angiography. From: Wintermark M, Albers GW, Broderick JP, et al. Acute Stroke Imaging Research Roadmap II. Stroke 2013; 44:2628. DOI: 10.1161/STROKEAHA.113.002015. Copyright 2013 American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 116431 Version 3.0 https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 44/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate Main approaches to managing cervical carotid lesions in patients with tandem occlusions undergoing thrombectomy for acute stroke Schematic summarizing the main approaches to managing cervical carotid lesions in patients with tandem occlusions undergoing thrombectomy for acute stroke. ICA: internal carotid artery; CEA: carotid endarterectomy; CAS: carotid artery stenting; EVT: endovascular therapy. Reprinted with permission of the American Society of Neuroradiology, from: Poppe AY, Jacquin G, Roy D, et al. Tandem Carotid Lesions in Acute Ischemic Stroke: Mechanisms, Therapeutic Challenges, and Future Directions. AJNR Am J Neuroradiol 2020; 41:1142; permission conveyed through Copyright Clearance Center, Inc. Copyright 2020. Graphic 133185 Version 2.0 https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 45/46 7/5/23, 12:13 PM Mechanical thrombectomy for acute ischemic stroke - UpToDate Contributor Disclosures Jamary Oliveira-Filho, MD, MS, PhD No relevant financial relationship(s) with ineligible companies to disclose. Owen B Samuels, MD No relevant financial relationship(s) with ineligible companies to disclose. Jos Biller, MD, FACP, FAAN, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Alejandro A Rabinstein, MD Grant/Research/Clinical Trial Support: Chiesi [Small investigator- initiated project]. Consultant/Advisory Boards: AstraZeneca [Secondary stroke prevention]; Brainomix [AI for stroke diagnostics]; Novo Nordisk [Stroke risk]; Shionogi [Stroke neuroprotection]. Other Financial Interest: Boston Scientific [Adverse event adjudication committee member for stroke risk reduction device in patients with atrial fibrillation]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/mechanical-thrombectomy-for-acute-ischemic-stroke/print 46/46

7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Neuroimaging of acute stroke : Jamary Oliveira-Filho, MD, MS, PhD, Maarten G Lansberg, MD, PhD : Scott E Kasner, MD, Glenn A Tung, MD, FACR : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jan 30, 2023. INTRODUCTION Neuroimaging in the evaluation of acute stroke is used to differentiate hemorrhage from ischemic stroke, to assess the degree of brain injury, and to identify the vascular lesion responsible for the stroke. Multimodal computed tomography (CT) and magnetic resonance imaging (MRI), including perfusion imaging, can distinguish between brain tissue that is irreversibly infarcted and that which is potentially salvageable, thereby allowing selection of patients who are likely to benefit from reperfusion therapy. The use of this technology is dependent upon availability. Neuroimaging during the acute phase (first 24 hours) of stroke will be reviewed here. Other aspects of the acute evaluation of stroke, the clinical diagnosis of various types of stroke, and the subacute and long-term assessment of patients who have had a stroke are discussed separately: Initial assessment and management of acute stroke Clinical diagnosis of stroke subtypes Overview of the evaluation of stroke Approach to reperfusion therapy for acute ischemic stroke Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis Nonaneurysmal subarachnoid hemorrhage Ischemic stroke in children: Clinical presentation, evaluation, and diagnosis https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 1/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate Hemorrhagic stroke in children Stroke in the newborn: Classification, manifestations, and diagnosis APPROACH TO IMAGING Goals of imaging Neuroimaging should be obtained for all patients suspected of having acute stroke or transient ischemic attack (TIA) [1]. Brain and neurovascular imaging plays an essential role in acute stroke by [2,3]: Differentiating ischemia from hemorrhage Excluding stroke mimics, such as tumor Assessing the status of large cervical and intracranial arteries Estimating the volume of brain tissue that is irreversibly infarcted (ie, infarction core) Estimating the extent of potentially salvageable brain tissue that is at risk for infarction (ie, ischemic penumbra) Guiding acute interventions, including patient selection for reperfusion therapies (ie, intravenous thrombolysis and mechanical thrombectomy) Urgency and scope of imaging Because "time is brain" and because imaging provides essential information for selecting treatment, immediate imaging of patients with acute stroke is a priority [4]. Brain imaging is required to exclude the presence of acute hemorrhage, because the management of patients with hemorrhagic stroke is very different from that of patients with acute ischemic stroke. Neurovascular imaging with CT angiography (CTA) or MR angiography (MRA) is necessary for confirming the presence of large artery occlusion in patients who are potential candidates for mechanical thrombectomy. Neurovascular imaging should evaluate the extracranial (internal carotid and vertebral) and intracranial (internal carotid, vertebral, basilar, and Circle of Willis) large vessels. (See "Approach to reperfusion therapy for acute ischemic stroke".) Multimodal CT and MRI can identify acute infarction, large vessel occlusion, infarct core, and salvageable brain tissue and are used to select patients for intravenous thrombolysis and mechanical thrombectomy in later time windows. (See 'Multimodal imaging' below and "Approach to reperfusion therapy for acute ischemic stroke".) Brain imaging should not be considered in isolation but rather as one part of the acute stroke evaluation. The approach to imaging may differ according to individual patient characteristics (eg, time from stroke onset or time last known well, potential candidate for reperfusion therapies) and local availability of stroke expertise and imaging capabilities. https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 2/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate CT or MRI for initial imaging? While CT and MRI can both be used for the initial evaluation of patients suspected of an acute stroke, CT with CTA is the standard imaging modality at most centers. Advantages of CT CT is used more often than MRI in acute stroke because of its widespread availability, the rapid scan times, and lower cost [5,6]. The noncontrast CT has excellent test performance characteristics for differentiating ischemic from hemorrhagic stroke. Disadvantage of CT Although the noncontrast CT can show signs of early acute ischemic stroke, these signs are very subtle and are often absent in the first hours after ischemic stroke onset (see 'Parenchymal changes on CT' below). Because of that, both the sensitivity and interrater agreement for the assessment of early infarct signs on CT are suboptimal. In one report of 786 patients with ischemic stroke, the sensitivity of noncontrast CT during the first six hours of cerebral ischemia was 64 percent, and local investigators reached only a 40 percent sensitivity [7]. Advantages of MRI A major advantage of MRI is that DWI is much more sensitive than noncontrast CT for detection of acute ischemic stroke and the exclusion of some stroke mimics. This can be particularly helpful when the diagnosis of stroke is in doubt. For example, the absence of a lesion on DWI can suggest that symptoms are caused by a stroke mimic. In addition, MRI does not expose the patient to radiation. Standard brain MRI protocols that include conventional T1-weighted, T2-weighted, fluid- attenuated inversion recovery (FLAIR), and T2*-weighted gradient-recalled echo (GRE) sequences along with DWI can reliably diagnose both acute ischemic stroke and acute hemorrhagic stroke in emergency settings. MRI with T2*-weighted GRE and susceptibility- weighted imaging (SWI) is equivalent to noncontrast CT for the detection of acute intraparenchymal hemorrhage and is better than noncontrast CT for the detection of chronic hemorrhage [8-10]. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Brain MRI'.) Disadvantages of MRI Compared with CT, shortcomings of MRI are higher cost, limited availability and access (particularly in the emergency setting), patient intolerance or incompatibility, and longer scan completion time. There are numerous potential contraindications to MRI including metallic or electrical implants, devices, and foreign bodies. This issue is reviewed in detail separately. (See "Patient evaluation for metallic or electrical implants, devices, or foreign bodies before magnetic resonance imaging" and https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 3/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate "Patient evaluation before gadolinium contrast administration for magnetic resonance imaging".) Despite these drawbacks, a trial of patients with a large vessel occlusion found that 88 percent were able to undergo MRI [11], and a few reports have demonstrated that it is possible to use MRI routinely as the sole neuroimaging screening method prior to intravenous thrombolytic therapy [12,13] or endovascular therapy [14]. In one such study of 135 patients screened with MRI and treated with intravenous thrombolysis, quality improvement processes led to reduced door-to-needle times of 60 minutes [12]. These data suggest that MRI can be used as the only imaging method in select centers with sufficient MRI availability for the evaluation of patients with suspected acute ischemic stroke. Multimodal imaging Assessment of ischemic brain injury and brain perfusion can be performed with either multimodal CT or multimodal MRI if results are likely to influence treatment decisions, such as mechanical thrombectomy in the late time window (ie, >6 hours from stroke onset or from the time of last known well). Multimodal CT includes noncontrast head CT with CTA of the head and neck and CT perfusion (CTP). Multimodal CT improves detection of acute ischemic stroke when compared with noncontrast CT alone [15-18]. In addition, multimodal CT can diagnose large vessel occlusion and estimate the core and penumbra of an acute ischemic stroke [19,20]. After endovascular intervention, both hemorrhage and contrast staining of infarcted tissue can occur. Both conditions have the same appearance on standard noncontrast CT. Dual-energy CT can be used to differentiate the two. Multimodal MRI includes MRI of the brain without contrast, high-susceptibility imaging (to exclude hemorrhage), MRA of the head and neck, DWI, and perfusion-weighted imaging (PWI). Multimodal MRI can identify acute infarction, emergent large vessel occlusion, infarct core, and salvageable penumbral brain tissue [21-23]. Time-based selection of imaging It is vitally important to determine the time the patient was last known to be well (ie, at neurologic baseline), because the use of reperfusion therapies for ischemic stroke (intravenous thrombolysis and mechanical thrombectomy) are time- and imaging-dependent. (See "Approach to reperfusion therapy for acute ischemic stroke".) Time last known well <4.5 hours For patients with suspected stroke who present in less than 4.5 hours from time last known well, noncontrast head CT with CTA of the head and neck is the preferred imaging option at most hospitals and is sufficient to exclude hemorrhage and direct treatment with intravenous thrombolysis. The addition of CTA is https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 4/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate required to determine the presence of a large vessel occlusion and eligibility for mechanical thrombectomy [24]. An alternative is MRI with high-susceptibility sequence, DWI, and MRA. Time last known well 4.5 to 24 hours For patients with suspected stroke who present within 4.5 to 24 hours of the time last known well (including patients with wake-up stroke and other patients with unknown time of symptom onset), the most common imaging choice is multimodal CT, including noncontrast CT, CTA, and CTP [24]. An alternative is multimodal MRI, if available urgently. Both approaches can determine eligibility for mechanical thrombectomy in the extended 6- to 24-hour time window. In addition, perfusion-core mismatch can be used to select patients with wake-up stroke or unknown symptom onset time but within 4.5 to 9 hours of time last known well, who may benefit from intravenous thrombolysis. (See 'Mismatch and salvageable brain tissue' below.) Time last known well unknown For patients presenting with an unknown time of stroke symptom onset and unknown time last known well, the first-choice imaging modality is MRI with DWI, FLAIR, and high-susceptibility sequence [24,25]. This can exclude hemorrhage and determine the presence or absence of a DWI-FLAIR mismatch, which is indicative of stroke onset within 4.5 hours and therefore potential benefit with intravenous thrombolysis. (See 'DWI-FLAIR mismatch' below.) IMAGING FINDINGS OF ISCHEMIC STROKE Assessment of early infarct signs Parenchymal changes on CT In the setting of hyperacute ischemic stroke, the initial head CT study may show either no evidence of ischemic change or may show early infarct signs, which include the following [26-30]: Loss of gray-white matter differentiation in the basal ganglia (eg, obscuration of the lentiform nucleus) Loss of insular ribbon or obscuration of Sylvian fissure Cortical hypoattenuation and sulcal effacement Early infarct signs can be subtle ( image 1 and image 2); both under- and overestimation of early infarct signs are common even in a controlled setting [31]. Studies that have examined the ability of neurologists, neuroradiologists, and general practitioners to recognize early infarct signs have shown modest interrater reliability, particularly among clinicians with more limited training [32]. Nevertheless, the importance of a noncontrast CT interpreted by an experienced https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 5/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate reader as not showing signs of acute ischemia should not be underestimated; it excludes a large infarction with high specificity [7]. In a systematic review involving 15 studies where noncontrast CT scans were performed within six hours of stroke onset, the prevalence of early infarction signs was 61 percent (standard deviation 21 percent) [26]. The sensitivity of noncontrast CT for signs of brain infarction increases over time from stroke onset. Note that minor ischemic changes (ie, early infarct signs that involve a relatively small volume of brain tissue) on noncontrast CT are not a contraindication to treatment with intravenous thrombolysis, nor is the presence of a hyperdense artery sign (see 'Hyperdense artery sign on CT' below) [1]. While the presence of early infarct signs has been associated with an increased risk of poor functional outcome (odds ratio 3.11, 95% CI 2.77-3.49) [26], an analysis from the National Institute of Neurological Disorders and Stroke (NINDS) trial found that early noncontrast CT signs of infarction were not associated with reduced efficacy of intravenous thrombolysis (tissue plasminogen activator [tPA]) treatment; patients treated with tPA did better whether or not they had early CT signs [33]. (See "Approach to reperfusion therapy for acute ischemic stroke", section on 'Alteplase'.) ASPECTS method The Alberta Stroke Program Early CT Score (ASPECTS) was developed to provide a simple and reliable method of assessing and communicating the extent of early ischemic changes on noncontrast CT [34]. ASPECTS has been studied mainly in patients potentially eligible for intravenous thrombolysis or endovascular therapy. The main application of ASPECTS is identifying patients with acute ischemic stroke who have a limited extent of early infarction (eg, an ASPECTS score 6) and who are therefore likely to benefit from mechanical thrombectomy. (See "Mechanical thrombectomy for acute ischemic stroke".) Calculating ASPECTS The original ASPECTS is assessed in the middle cerebral artery (MCA) territory. ASPECTS is calculated from evaluation of two standard axial noncontrast CT images: one at the level of the thalamus and basal ganglia, and one just rostral to the basal ganglia ( figure 1 and figure 2) [34,35]. The score divides the MCA vascular territory into 10 regions of interest that are evaluated on these two axial cuts: Three subcortical regions from the image at the level of the basal ganglia: - - Caudate (C) Lentiform nucleus (L) Internal capsule (IC) Four cortical regions from the image at the level of the basal ganglia: https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 6/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate - - - Anterior MCA cortex (M1) Lateral MCA cortex (M2) Posterior MCA cortex (M3) Insular cortex (I) Three cortical regions from the image just rostral to the basal ganglia: - - Anterior MCA cortex (M4) Lateral MCA cortex (M5) Posterior MCA cortex (M6) ASPECTS is scored on an ordinal scale from 0 to 10, with lower scores indicating more extensive infarction. One point is subtracted for early ischemic change, such as focal swelling or parenchymal hypoattenuation, in each of the 10 defined regions. Therefore, a normal CT has an ASPECTS value of 10 points, while diffuse ischemic change throughout the MCA territory gives a value of zero. Reliability and accuracy The inter- and intra-observer reliability of the ASPECTS in early studies was reported as good to excellent [36]. However, in later studies, the interobserver reliability of the ASPECTS was lower, particularly for less experienced readers [37,38]. One other problem with the ASPECTS may be that parenchymal signs on noncontrast CT considered to represent early ischemic change may have different pathophysiologic mechanisms. In particular, there is evidence suggesting that hypoattenuation represents the irreversible infarction core, whereas focal swelling may represent penumbra [39,40]. Rating of the ASPECTS using automated image analysis software may address some of the issues of limited interrater reliability with "manual" ASPECTS scoring [38,41-45]. The ASPECTS is traditionally interpreted on the noncontrast CT. However, greater accuracy for detection of ischemic change and for identifying final infarct volume may be achieved when it is scored on CTA source images or on the contrast-enhanced CT images obtained as part of the CT perfusion (CTP) acquisition [46,47]. Predicting functional outcome In the initial ASPECTS study, pretreatment noncontrast CT scans from 156 patients with anterior circulation ischemia who were treated with intravenous tPA were prospectively scored [34]. The ASPECTS predicted functional outcome with good sensitivity and specificity (78 and 96 percent, respectively). The prospective Canadian Alteplase for Stroke Effectiveness Study (CASES) observational cohort study of 1135 patients treated with intravenous tPA found that each one-point decrement in the https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 7/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate baseline ASPECTS was associated with a lower probability of independent functional outcome (odds ratio 0.81, 95% CI 0.75-0.87) [48]. Predicting response to thrombolysis The ASPECTS of baseline noncontrast CT scans from the NINDS and European Cooperative Acute Stroke Study (ECASS-II) tPA stroke studies was not associated with a statistically significant modification of tPA treatment effect [49,50]. This finding is in agreement with a report from the NINDS cohort, which found that signs of early ischemic change on noncontrast CT were not independently associated with increased risk of adverse outcome after intravenous tPA treatment [33]. Selection of patients for mechanical thrombectomy Most trials of endovascular therapy have used ASPECTS to exclude patients with extensive early infarct signs. Therefore, guidelines from the American Heart Association/American Stroke Association (AHA/ASA) recommend treatment with mechanical thrombectomy only for patients with an ASPECTS 6 [1]. Further trials are needed to determine if mechanical thrombectomy is also beneficial for patients with low ASPECTS. Calculating posterior circulation ASPECTS The dedicated posterior circulation ASPECTS (pc-ASPECTS), rated on CTA source images, can be used to quantify early infarct signs in patients with posterior circulation stroke. The pc-ASPECTS subtracts one point for each ischemic lesion (right or left) of the thalamus, cerebellar hemisphere, or posterior cerebral artery territory, and two points for each lesion in the mesencephalon or pons [51,52]. A normal pc-ASPECTS has a value of 10 points; lower scores indicate greater extent of infarction. Parenchymal changes on DWI MRI using diffusion-weighted imaging (DWI) is superior to noncontrast CT for the diagnosis of acute ischemic stroke in patients presenting within 12 hours of symptom onset [53]. DWI can detect abnormalities due to infarction within 3 to 30 minutes of onset [54-56], when conventional MRI and CT images would still appear normal. Studies comparing noncontrast CT, DWI, and fluid-attenuated inversion recovery (FLAIR) have shown that abnormal DWI is a sensitive and specific indicator of ischemic stroke in patients presenting within six hours of symptom onset [57-62]. However, occasional patients with acute ischemic deficits may have a normal DWI. In one retrospective report of 565 patients with acute ischemic stroke, a relevant lesion on DWI was apparent in 518 (92 percent), suggesting that DWI alone may miss an acute stroke in 8 percent of patients [62]. In these cases, follow-up MRI or CT may confirm an infarct [63,64]. In some of these patients, the stroke was a small brainstem lacunar infarction, and in others, ischemia was seen on perfusion MRI in regions that had not yet become abnormal on DWI [63]. https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 8/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate Even in patients with subacute ischemic stroke who delay seeking medical attention, DWI may add clinically useful information to standard MRI. In a prospective observational study of 300 patients with suspected stroke or transient ischemic attack (TIA) and a median delay of 17 days from symptom onset, DWI provided additional clinical information compared with T2-weighted imaging for 108 patients (36 percent), such as clarification of diagnosis or definition of involved vascular territory; this was considered likely to change management in 42 patients (14 percent) [65]. In acute ischemic stroke, failure of the energy-dependent Na-K-ATPase pumps leads to translocation of water from the interstitial to the intracellular space [66]. Intracellular water (cytotoxic edema) cannot diffuse as freely as extracellular water, and this diffusion restriction or reduced diffusivity is readily demonstrated on DWI. In addition to reduced diffusivity, increased T2 relaxation due to vasogenic edema can "shine through" on DWI images, making it difficult to distinguish vasogenic from cytotoxic edema. This quandary can be overcome by comparing DWI with map images of the apparent diffusion coefficient (ADC). The ADC map provides a quantitative measure of the contribution of reduced diffusivity to DWI: With acute ischemic stroke associated with cytotoxic edema, decreased water diffusion in infarcted tissue causes increased (hyperintense) signal on DWI and corresponding decreased signal intensity on the ADC map image. With vasogenic edema, increased DWI signal may occur due to T2 shine-through, but since water diffusion is increased, there is also corresponding increased signal on the ADC map image. Acute intravascular thrombus Hyperdense artery sign on CT Hyperdensity of an artery (hyperdense artery sign, also known as hyperdense vessel sign or bright artery sign) on noncontrast CT can indicate the presence of the thrombus inside the artery lumen. This can be visualized on noncontrast CT in 30 to 40 percent of patients with an MCA distribution stroke [29,67]. This finding is highly specific for MCA occlusion and can be observed in proximal MCA occlusions (first branch) as well as in more distal MCA branch occlusions (eg, sylvian dot sign). Similarly, thrombus in the basilar artery can appear as a hyperdensity of that artery on noncontrast CT. Hyperdensity of an artery does not reflect ischemic injury of the brain parenchyma. It is therefore neither time dependent (ie, more prevalent over time) nor directly linked to clinical outcome. This contrasts with early infarct signs, which reflect parenchymal injury and are therefore time dependent and associated with a worse prognosis. (See 'Assessment of early infarct signs' above.) https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 9/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate Susceptibility artery sign on MRI Susceptibility-weighted MRI imaging (eg, T2*-weighted gradient-recalled echo [GRE]) is useful for the early detection of acute thrombosis and occlusion involving the MCA or internal carotid artery (ICA) [68-74]. Acute thrombotic occlusion may appear as focal hypointense signal within the MCA or ICA, often in a focal or curvilinear shape; the diameter of the hypointense signal is larger than that of the contralateral unaffected vessel. This finding is called the "susceptibility sign," and it is analogous to the "hyperdense artery sign" described for noncontrast CT. In a retrospective report of 42 patients with stroke in the MCA territory who underwent MRI at 95 to 360 minutes from stroke onset, a susceptibility sign was found in 30 (71 percent) and its specificity was 100 percent [69]. The overall sensitivity was 83 percent compared with MR angiography (MRA) but varied widely depending on location of the occlusion, from 38 percent for occlusions distal to the MCA bifurcation to 97 percent for occlusions proximal to the MCA trunk. Vessel imaging Neurovascular imaging with CTA or MRA can evaluate the aortic arch and the extracranial (internal carotid and vertebral) and intracranial (internal carotid, vertebral, basilar, and Circle of Willis) large vessels. It is essential for determining if there is a large vessel occlusion for patients with acute stroke who may be eligible for mechanical thrombectomy, as well as for proper evaluation of the stroke mechanism. Presence and location of thrombus The head and neck vessel imaging with CTA or MRA can identify thrombus and large vessel occlusion within the territory of the acute ischemic stroke and thereby determine whether the patient may benefit from reperfusion with mechanical thrombectomy. CTA and MRA are also important tools for detecting other vascular lesions that may cause acute ischemic stroke, including arterial atherosclerosis, plaque, stenosis, dissection, vasculitis, fibromuscular dysplasia, and carotid web [75]. For the detection of intracranial large vessel stenosis and occlusion, CTA had sensitivities of 92 to 100 percent and specificities of 82 to 100 percent when compared with conventional angiography [76]. CTA is more accurate for detection of occlusions in larger proximal arteries (eg, emergent large vessel occlusion) compared with smaller distal arteries. The accuracy of CTA for the diagnosis of extracranial carotid stenosis is discussed separately. (See "Evaluation of carotid artery stenosis", section on 'Computed tomography angiography'.) For the detection of intracranial large vessel stenosis and occlusion, contrast-enhanced MRA in various studies had sensitivities of 86 to 97 percent and specificities of 62 to 91 percent when compared with digital subtraction angiography [76]. The accuracy of MRA for the diagnosis of https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 10/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate extracranial carotid stenosis is discussed separately. (See "Evaluation of carotid artery stenosis", section on 'Magnetic resonance angiography'.) Collateral blood flow Collateral blood flow is important because good collateral flow can preserve ischemic brain tissue when the direct supply of blood is blocked by thromboembolism [75]. Good collateral flow is associated with improved outcomes among patients treated with endovascular therapy [77]. Collaterals on multiphase CTA The pial artery collateral vessels of the brain can be assessed using multiphase CTA ( image 3), which acquires information about cerebral blood flow in three phases after contrast administration: The first phase consists of conventional CTA with image acquisition from the aortic arch to skull vertex during the peak arterial phase; the second and third phases consist of image acquisition from the skull base to vertex during the peak- and late-venous phases [78]. In the ESCAPE trial, the presence of moderate-to-good pial collateral circulation on multiphase CTA was one of the criteria used to select patients for mechanical thrombectomy [79]. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Patient selection'.) Collaterals on FLAIR In 85 percent of patients with acute ischemic stroke and MCA occlusion, linear or serpentine hyperintensities in M2 and M3 vessels distal to the site of the occluded vessel can be identified on FLAIR MR images. The extent of these FLAIR- hyperintense vessels correlates with the volume of hypoperfused tissue and is an independent predictor of perfusion-diffusion mismatch [80,81]. Collaterals on perfusion imaging On MR or CT perfusion-weighted imaging (PWI), collateral blood flow is implied from the size of the core-penumbra mismatch. The larger the mismatch, the better the collaterals. The Tmax hyperintensity ratio is another metric that has been proposed as a measure of collateral status on CT and MR perfusion. It reflects the proportion of tissue that is at risk of infarction, which has an extremely severe delay in contrast [82]. Mismatch and salvageable brain tissue Mismatch is an imaging marker that is used to select patients for mechanical thrombectomy who have salvageable brain tissue. In acute ischemic stroke, the infarct core is considered irreversibly infarcted brain tissue. The surrounding or adjacent ischemic penumbra is brain tissue that is hypoperfused and at risk of infarction and is therefore potentially salvageable with reperfusion treatment. A mismatch exists when the infarct core is relatively small compared with the larger ischemic penumbra. Mismatch is assessed by imaging, with several different paradigms employed. https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 11/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate Perfusion-core mismatch Perfusion-core mismatch can be assessed with CT or MRI techniques. Both require image processing with automated software. Studies of endovascular mechanical thrombectomy in the late time window (6 to 24 hours after stroke onset) have relied on CTP or multimodal MRI with DWI and PWI to identify patients with small ischemic cores and relatively large penumbra. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Patient selection'.) CT perfusion CTP quantifies blood flow through the brain using a series of CT scans that are obtained following the injection of an intravenous bolus of iodinated contrast. With this technique, the passage of the contrast through the brain can be evaluated [83,84]. Using perfusion analysis software, maps showing perfusion of the brain are generated. Specifically, analysis of the kinetics of a bolus of iodinated contrast passing through the brain enables estimation of cerebral blood flow, cerebral blood volume, mean transit time of contrast through brain, time to peak, and time to peak of the residue function [84,85]. These maps are useful to estimate the size of the infarction core and the ischemic penumbra. Using perfusion analysis software, it is possible to estimate the size of the infarction core and the ischemic penumbra: The ischemic core is indirectly defined as the region with the most severe perfusion deficit; it is characterized by severely reduced cerebral blood flow by most perfusion software programs. The core region typically also has an elevated mean transit time and decreased cerebral blood volume [25]. The ischemic field, defined as the territory that has a reduction in blood flow severe enough to eventually lead to infarction if blood flow is not reversed, is characterized by a significant delay in contrast arrival by most perfusion software programs. Commonly used perfusion parameters to identify the ischemic field include prolonged Tmax, prolonged time to peak (TTP), and prolonged mean transit time (MTT). The ischemic penumbra is the difference between the ischemic field and the ischemic core (ie, the part of the ischemic field that is not already infarcted). PWI and DWI PWI can demonstrate ischemic regions of the brain while DWI reveals cytotoxic edema from infarction. The PWI-DWI mismatch refers to the presence of a relatively larger area of ischemia on PWI (ie, the penumbra or territory with critically low perfusion) relative to a smaller area of irreversible ischemic injury (ie, the infarction core) on DWI ( image 4 and image 5 and image 6). PWI quantifies the magnetic susceptibility effect from the passage of intravenously administered gadolinium-based contrast agent. Analysis of the characteristics of the https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 12/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate contrast bolus passage through brain tissue can yield maps of the cerebral perfusion, including cerebral blood flow, cerebral blood volume, mean transit time, time-to-peak of the contrast enhancement, and time-to-peak of the residue function. Aside from PWI, another MRI method to evaluate brain perfusion is arterial spin labeling (ASL). Instead of using an intravascular contrast agent, ASL magnetically labels the blood entering the brain. ASL imaging within 24 hours of stroke symptom onset can depict perfusion defects and mismatches of diffusion and perfusion [86]. In addition, asymmetry of perfusion on ASL appears to correlate with stroke severity and outcome. In the DEFUSE 3 trial, which studied patients with late-window (6 to 16 hours after the time last known to be well) acute ischemic stroke, either CT or MR perfusion imaging was used to select patients for mechanical thrombectomy [87]. The study demonstrated a benefit of endovascular thrombectomy regardless of whether CT or MRI was used for patient selection, but the benefit was greater for patients selected using PWI compared with CTP. (See "Mechanical thrombectomy for acute ischemic stroke".) Clinical-core mismatch Using MRI, a clinical-core mismatch (ie, clinical-DWI mismatch) is based on the concept that the neurologic deficits are an expression of both the core infarct and the ischemic penumbra. A mismatch is present if the severity of the neurologic deficits, as measured by the National Institutes of Health Stroke Scale (NIHSS), is greater than that expected from the core infarct, which corresponds to the DWI lesion [88]. An age-adjusted clinical-core mismatch was used to select patients for mechanical thrombectomy in the DAWN trial. (See "Mechanical thrombectomy for acute ischemic stroke".) Clinical-ASPECTS mismatch Using CT, a clinical-ASPECTS mismatch is present if the severity of the neurologic deficits, as measured by the NIHSS, is greater than expected from the severity of the core infarct, as assessed by ASPECTS [89]. In practice, the mismatch is present for patient with an NIHSS score 10 and an ASPECTS 6. DWI-FLAIR mismatch The DWI-FLAIR mismatch refers to evidence of a hyperintense lesion on DWI consistent with acute infarction but no corresponding signal abnormality on the FLAIR images ( image 7) [90]. This mismatch indicates that the stroke is relatively acute (ie, within 4.5 hours), since insufficient time has passed for development of hyperintense signal on FLAIR, a sign of vasogenic edema. DWI-FLAIR mismatch has been used in clinical trials to select patients for treatment with intravenous thrombolysis when the time of stroke onset is unwitnessed or unknown [91]. (See "Approach to reperfusion therapy for acute ischemic stroke", section on 'Benefit with imaging selection of patients'.) https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 13/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate IMAGING OF HEMORRHAGIC STROKE Acute or subacute hemorrhage on imaging is a contraindication to reperfusion therapy (intravenous thrombolysis and mechanical thrombectomy). Evaluation, diagnosis, and management are reviewed separately according to the location of hemorrhage: Intracerebral (see "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis" and "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis") Intraventricular (see "Intraventricular hemorrhage") Subarachnoid (see "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis" and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis" and "Nonaneurysmal subarachnoid hemorrhage") Subdural (see "Subdural hematoma in adults: Etiology, clinical features, and diagnosis" and "Subdural hematoma in adults: Management and prognosis") Epidural (see "Intracranial epidural hematoma in adults") OTHER IMAGING MODALITIES Digital subtraction angiography Digital subtraction angiography (DSA) is a method of visualizing the cerebral vasculature using selective injections of contrast through a catheter placed in the large arteries of the neck (ie, carotid and vertebral arteries) and head (cerebral arteries). DSA is rarely performed to triage patients in the setting of acute ischemic stroke for two main reasons. First, it is less available compared with CT angiography (CTA) and MR angiography (MRA). Second, DSA is associated with a risk of stroke, albeit low. The risk of stroke is estimated to be 0.14 to 1 percent, and the risk of transient ischemia is estimated to be 0.4 to 3 percent [92- 94]. DSA is an integral part of endovascular therapy procedures (ie, mechanical thrombectomy) for patients with acute ischemic stroke secondary to an occlusion of a large cerebral artery. The increased use of DSA started in 2015 after the publication of five major trials that demonstrated benefit of endovascular therapy up to six hours after stroke onset, and it has further increased since 2018 when two landmark trials were published that demonstrated benefit of mechanical https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 14/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate thrombectomy beyond the initial six-hour time window. (See "Mechanical thrombectomy for acute ischemic stroke".) DSA remains the gold standard for determining the severity of arterial stenosis and the presence of vasculopathy or vascular malformations [76]. In addition, it provides information about collateral flow and perfusion. Ultrasound methods Carotid duplex ultrasound (CDUS) and transcranial Doppler (TCD) ultrasound are noninvasive methods for neurovascular evaluation of the extracranial and intracranial large vessels, respectively. Carotid and vertebral duplex and TCD have traditionally been used independently in a predominantly elective, nonacute fashion to evaluate patients with transient ischemic attack (TIA) and ischemic stroke of possible large artery origin. Carotid and vertebral duplex Color flow guided duplex ultrasound is well established as a noninvasive examination to evaluate extracranial atherosclerotic disease. This topic is discussed separately. (See "Evaluation of carotid artery stenosis", section on 'Carotid duplex ultrasound'.) Transcranial Doppler TCD ultrasound uses low frequency (2 MHz) pulsed sound to penetrate bone and insonate intracranial vessels of the circle of Willis. Its use has gained acceptance as a noninvasive means to assess the patency of intracranial vessels. In patients with acute stroke, TCD is able to detect intracranial stenosis, identify collateral pathways, detect emboli on a real-time basis, and monitor reperfusion after thrombolysis [95-98]. Major drawbacks include operator dependence, poor acoustic windows (ie, inability to insonate flow in 15 percent of cases), and low sensitivity to flow in the vertebrobasilar arteries. Combined duplex and TCD The combination of urgent duplex and TCD has been described in a few small studies. As an example, a study of 150 patients found that the

core (ie, the part of the ischemic field that is not already infarcted). PWI and DWI PWI can demonstrate ischemic regions of the brain while DWI reveals cytotoxic edema from infarction. The PWI-DWI mismatch refers to the presence of a relatively larger area of ischemia on PWI (ie, the penumbra or territory with critically low perfusion) relative to a smaller area of irreversible ischemic injury (ie, the infarction core) on DWI ( image 4 and image 5 and image 6). PWI quantifies the magnetic susceptibility effect from the passage of intravenously administered gadolinium-based contrast agent. Analysis of the characteristics of the https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 12/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate contrast bolus passage through brain tissue can yield maps of the cerebral perfusion, including cerebral blood flow, cerebral blood volume, mean transit time, time-to-peak of the contrast enhancement, and time-to-peak of the residue function. Aside from PWI, another MRI method to evaluate brain perfusion is arterial spin labeling (ASL). Instead of using an intravascular contrast agent, ASL magnetically labels the blood entering the brain. ASL imaging within 24 hours of stroke symptom onset can depict perfusion defects and mismatches of diffusion and perfusion [86]. In addition, asymmetry of perfusion on ASL appears to correlate with stroke severity and outcome. In the DEFUSE 3 trial, which studied patients with late-window (6 to 16 hours after the time last known to be well) acute ischemic stroke, either CT or MR perfusion imaging was used to select patients for mechanical thrombectomy [87]. The study demonstrated a benefit of endovascular thrombectomy regardless of whether CT or MRI was used for patient selection, but the benefit was greater for patients selected using PWI compared with CTP. (See "Mechanical thrombectomy for acute ischemic stroke".) Clinical-core mismatch Using MRI, a clinical-core mismatch (ie, clinical-DWI mismatch) is based on the concept that the neurologic deficits are an expression of both the core infarct and the ischemic penumbra. A mismatch is present if the severity of the neurologic deficits, as measured by the National Institutes of Health Stroke Scale (NIHSS), is greater than that expected from the core infarct, which corresponds to the DWI lesion [88]. An age-adjusted clinical-core mismatch was used to select patients for mechanical thrombectomy in the DAWN trial. (See "Mechanical thrombectomy for acute ischemic stroke".) Clinical-ASPECTS mismatch Using CT, a clinical-ASPECTS mismatch is present if the severity of the neurologic deficits, as measured by the NIHSS, is greater than expected from the severity of the core infarct, as assessed by ASPECTS [89]. In practice, the mismatch is present for patient with an NIHSS score 10 and an ASPECTS 6. DWI-FLAIR mismatch The DWI-FLAIR mismatch refers to evidence of a hyperintense lesion on DWI consistent with acute infarction but no corresponding signal abnormality on the FLAIR images ( image 7) [90]. This mismatch indicates that the stroke is relatively acute (ie, within 4.5 hours), since insufficient time has passed for development of hyperintense signal on FLAIR, a sign of vasogenic edema. DWI-FLAIR mismatch has been used in clinical trials to select patients for treatment with intravenous thrombolysis when the time of stroke onset is unwitnessed or unknown [91]. (See "Approach to reperfusion therapy for acute ischemic stroke", section on 'Benefit with imaging selection of patients'.) https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 13/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate IMAGING OF HEMORRHAGIC STROKE Acute or subacute hemorrhage on imaging is a contraindication to reperfusion therapy (intravenous thrombolysis and mechanical thrombectomy). Evaluation, diagnosis, and management are reviewed separately according to the location of hemorrhage: Intracerebral (see "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis" and "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis") Intraventricular (see "Intraventricular hemorrhage") Subarachnoid (see "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis" and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis" and "Nonaneurysmal subarachnoid hemorrhage") Subdural (see "Subdural hematoma in adults: Etiology, clinical features, and diagnosis" and "Subdural hematoma in adults: Management and prognosis") Epidural (see "Intracranial epidural hematoma in adults") OTHER IMAGING MODALITIES Digital subtraction angiography Digital subtraction angiography (DSA) is a method of visualizing the cerebral vasculature using selective injections of contrast through a catheter placed in the large arteries of the neck (ie, carotid and vertebral arteries) and head (cerebral arteries). DSA is rarely performed to triage patients in the setting of acute ischemic stroke for two main reasons. First, it is less available compared with CT angiography (CTA) and MR angiography (MRA). Second, DSA is associated with a risk of stroke, albeit low. The risk of stroke is estimated to be 0.14 to 1 percent, and the risk of transient ischemia is estimated to be 0.4 to 3 percent [92- 94]. DSA is an integral part of endovascular therapy procedures (ie, mechanical thrombectomy) for patients with acute ischemic stroke secondary to an occlusion of a large cerebral artery. The increased use of DSA started in 2015 after the publication of five major trials that demonstrated benefit of endovascular therapy up to six hours after stroke onset, and it has further increased since 2018 when two landmark trials were published that demonstrated benefit of mechanical https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 14/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate thrombectomy beyond the initial six-hour time window. (See "Mechanical thrombectomy for acute ischemic stroke".) DSA remains the gold standard for determining the severity of arterial stenosis and the presence of vasculopathy or vascular malformations [76]. In addition, it provides information about collateral flow and perfusion. Ultrasound methods Carotid duplex ultrasound (CDUS) and transcranial Doppler (TCD) ultrasound are noninvasive methods for neurovascular evaluation of the extracranial and intracranial large vessels, respectively. Carotid and vertebral duplex and TCD have traditionally been used independently in a predominantly elective, nonacute fashion to evaluate patients with transient ischemic attack (TIA) and ischemic stroke of possible large artery origin. Carotid and vertebral duplex Color flow guided duplex ultrasound is well established as a noninvasive examination to evaluate extracranial atherosclerotic disease. This topic is discussed separately. (See "Evaluation of carotid artery stenosis", section on 'Carotid duplex ultrasound'.) Transcranial Doppler TCD ultrasound uses low frequency (2 MHz) pulsed sound to penetrate bone and insonate intracranial vessels of the circle of Willis. Its use has gained acceptance as a noninvasive means to assess the patency of intracranial vessels. In patients with acute stroke, TCD is able to detect intracranial stenosis, identify collateral pathways, detect emboli on a real-time basis, and monitor reperfusion after thrombolysis [95-98]. Major drawbacks include operator dependence, poor acoustic windows (ie, inability to insonate flow in 15 percent of cases), and low sensitivity to flow in the vertebrobasilar arteries. Combined duplex and TCD The combination of urgent duplex and TCD has been described in a few small studies. As an example, a study of 150 patients found that the combination of duplex and TCD could be used effectively to detect arterial lesions amenable to interventional treatment [99]. A major limitation of this approach is that many centers are unable to perform these examinations emergently because of the lack of experienced sonographers. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 15/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Stroke (The Basics)") SUMMARY AND RECOMMENDATIONS Goals of imaging Immediate imaging of patients with suspected acute stroke is a priority because "time is brain" and because imaging provides essential information for selecting treatment. The goals of early neuroimaging are to distinguish ischemia from hemorrhage, exclude stroke mimics, detect signs of early infarction, depict the infarction core and ischemic penumbra, reveal the status of large cervical and intracranial arteries, and help determine patient eligibility for intravenous thrombolysis and mechanical thrombectomy. (See 'Goals of imaging' above and 'Urgency and scope of imaging' above.) Comparison of CT and MRI Noncontrast CT of the head is the standard imaging study for early acute stroke evaluation at most centers because of widespread availability, rapid scan times, and sensitivity for intracranial hemorrhage. MRI with diffusion-weighted imaging (DWI) is superior to CT for the detection of acute ischemic stroke and the exclusion of stroke mimics. In addition, MRI reliably detects acute intracranial hemorrhage. However, MRI is not as readily available for urgent imaging and is more limited by patient contraindications or intolerance. (See 'CT or MRI for initial imaging?' above.) Choosing initial imaging For patients who may be eligible for intravenous thrombolysis or mechanical thrombectomy ( algorithm 1), multimodal CT or MRI can provide crucial information to guide treatment decisions, including: https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 16/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate Whether there is cervical or intracranial large artery stenosis and occlusion The volume of the infarct core that is irreversibly damaged The volume of the ischemic penumbra that is salvageable with reperfusion The selection of initial neuroimaging studies can be guided by the time the patient was last known to be well and by local availability of advanced imaging with multimodal CT and MRI. Specifics are detailed above. (See 'Time-based selection of imaging' above.) Vessel imaging Neurovascular imaging with CT angiography (CTA) or MR angiography (MRA) is essential for confirming the presence of a large artery occlusion in patients who are candidates for mechanical thrombectomy. It is also important for assessing the potential sources of embolism and low flow in ischemic stroke. (See 'Vessel imaging' above.) Imaging the infarct core and ischemic penumbra Evaluation of the infarct core and ischemic penumbra with either DWI and perfusion-weighted imaging (PWI) or CT perfusion (CTP) imaging should be performed if the findings are likely to influence treatment decisions, such as mechanical thrombectomy in the late window (ie, >6 hours from the time last known to be well). (See 'Mismatch and salvageable brain tissue' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Walter Koroshetz, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. 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Topic 1085 Version 40.0 https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 24/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate GRAPHICS Early ischemic changes on noncontrast head CT scan Findings of EIC in a 59-year-old man who presented with acute left hemiparesis. (A and B) NCCT 3.5 hours after symptom onset shows hypodensity and cortical swelling with sulcal effacement. There is loss of gray- white matter differentiation in the right frontal operculum, right temporal operculum, right insular cortex, and right frontoparietal lobes (arrowheads). CT: computed tomography; EIC: early ischemic changes; NCCT: noncontrast-enhanced computed tomography. From: Prakkamakul S, Yoo AJ. ASPECTS CT in Acute Ischemia: Review of Current Data. Top Magn Reson Imaging 2017; 26:103. DOI: 10.1097/RMR.0000000000000122. Copyright 2017. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 121623 Version 2.0 https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 25/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate Evolution of early ischemic changes on head CT scan Evolution of early ischemic changes over time in a 35-year-old woman who presented with acute aphasia. (A) NCCT at one hour after symptom onset shows loss of gray white matter differentiation in the left frontal and temporal operculum and insular cortex and hypodensity in the lentiform nucleus (ASPECTS was 4 points for involvement of insula, lentiform, M1-3, M5). (B and C) NCCT and CTA-SI at two hours after symptoms onset and IV rtPA administration show more conspicuous hypodensity and mild effacement of cortical sulci compared with https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 26/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate NCCT at one hour after symptoms onset. (D) NCCT at eight hours after symptoms onset shows frank hypodensity in the infarcted areas. The extent of the hypodense areas remains the same but is more conspicuous than prior NCCT studies. CT: computed tomography; NCCT: noncontrast-enhanced computed tomography; ASPECTS: The Alberta Stroke Program Early CT score; CTA-SI: computed tomography angiography source image; IV: intravenous; rtPA: recombinant tissue plasminogen activator. From: Prakkamakul S, Yoo AJ. ASPECTS CT in Acute Ischemia: Review of Current Data. Top Magn Reson Imaging 2017; 26:103. DOI: 10.1097/RMR.0000000000000122. Copyright 2017. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 121624 Version 2.0 https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 27/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate ASPECTS study form The ASPECTS value is calculated from two standard axial CT cuts: one at the level of the thalamus and basal ganglia (left), and one just rostral to the basal ganglia (right). A: anterior circulation; P: posterior circulation; C: caudate; L: lentiform; IC: internal capsule; I: insular ribbon; MCA: middle cerebral artery; M1: anterior MCA cortex; M2: MCA cortex lateral to insular ribbon; M3: posterior MCA cortex; M4, M5, and M6 are anterior, lateral, and posterior MCA territories immediately superior to M1, M2, and M3, rostral to basal ganglia Reproduced with permission from: Barber, PA, Demchuk, AM, Zhang, J, Buchan, AM. Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. ASPECTS Study Group. Alberta Stroke Programme Early CT Score. Lancet 2000; 355:1670. Copyright 2000 The Lancet. Graphic 72190 Version 1.0 https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 28/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate ASPECTS study form and MCA variants (A and B) Right hemisphere, observer variations: lower and upper ASPECTS slices show as shaded areas the minimal and maximal variations in size of the cortical areas of the MCA (M1-M6) chosen by six expert observers. Left hemisphere, ASPECTS study form: A = anterior circulation; P = posterior circulation; C = caudate head; L = lentiform nucleus; IC = internal capsule; I = insular ribbon; MCA = middle cerebral artery; M1 = anterior MCA cortex; M2 = MCA cortex lateral to insular ribbon; M3 = posterior MCA cortex; M4, M5, and M6 are anterior, lateral, and posterior MCA territories, respectively, approximately 2 cm superior to M1, M2, and M3, respectively, rostral to basal ganglia. (C and D) Cortical MCA area variations with change of baseline. In the right hemisphere, the baseline is parallel to the inferior OML; in the left hemisphere, the baseline is the superior OML. OML=orbitomeatal line. (E and F) Normal vascular variations in MCA size on the two ASPECTS slices. The right hemisphere shows the larger normal variations described by van der Zwan* (light https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 29/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate shading). The left hemisphere of each shows the smaller, textbook , variations (dark shading). References van der Zwan, A, Hillen, B, Tulleken, AF, et al. Variability of the territories or the major cerebral arteries. J Neurosurg 1992; 77:927. Osborn, AG. Neuroradiology, Mosby, St. Louis 1995. Reproduced with permission from: Pexman, JH, Barber, PA, Hill, MD, et al. Use of the Alberta Stroke Program Early CT Score (ASPECTS) for assessing CT scans in patients with acute stroke. AJNR Am J Neuroradiol 2001; 22:1534. Copyright 2001 American Society of Neuroradiology. Graphic 63480 Version 1.0 https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 30/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate Multiphase CTA images (A) Images in a patient with a left M1 MCA occlusion (arrow) and good collaterals (backfilling arteries). (B) Images in a patient with a left M1 MCA occlusion (dashed arrow) and intermediate collaterals. (C) Images in a patient with a right M1 MCA occlusion (arrowhead) and poor collaterals (minimal backfilling arteries). CTA: computed tomography angiography. https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 31/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate Reproduced with permission from: Menon BK, d'Esterre CD, Qazi EM, et al. Multiphase CT angiography: A new tool for the imaging tria patients with acute ischemic stroke. Radiology 2015; 275:510. Copyright 2015 RSNA. Graphic 121648 Version 1.0 https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 32/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate Classic pattern of DWI-PWI mismatch Representative case with classic pattern of mismatch. (A) Diffusion weighted-image (DWI). (B) DWI abnormal lesion (shown in red) and hypoperfusion lesion (shown in green) superimposed on DWI. (C) DWI abnormal lesion and hypoperfusion lesion with brain image (DWI) removed. PWI: perfusion-weighted image. Reproduced with permission from: Ogata T, Nagakane Y, Christensen S, et al. A topographic study of the evolution of the MR DWI/PWI mismatch pattern and its clinical impact: a study by the EPITHET and DEFUSE Investigators. Stroke 2011; 42:1596. Copyright 2011 Lippincott Williams & Wilkins. Graphic 82701 Version 5.0 https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 33/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate Brain MRI showing large core-penumbra mismatch on diffusion- and perfusion- weighted sequences in a patient with acute ischemic stroke Diffusion- and perfusion-weighted brain MRI showing a large core-penumbra mismatch in a patient with an acute ischemic stroke. Diffusion-weighted MRI (panel A) indicates the infarction core in red as tissue with apparent diffusion coefficient <620 that measures 17 mL in volume. Perfusion-weighted MRI (panel B) indicates the ischemic penumbra in green as tissue with T volume. The mismatch volume is 122 mL and the mismatch ratio is 8.2. >6.0 seconds that measures 139 mL in max MRI: magnetic resonance imaging. Glenn A Tung, MD, FACR. Graphic 129431 Version 2.0 https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 34/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate Brain MRI showing a small core-penumbra mismatch on diffusion- and perfusio weighted sequences in a patient with acute ischemic stroke Diffusion- and perfusion-weighted brain MRI showing a small core-penumbra mismatch in a patient with an acute ischemic stroke. Diffusion-weighted MRI (panel A) indicates the infarction core in red as tissue with apparent diffusion coefficient <620 that measures 151 mL in volume. Perfusion-weighted MRI (panel B) indicates the ischemic penumbra in green as tissue with Tmax >6.0 seconds that measures 177 mL in volume. The mismatch volume is 26 mL and the mismatch ratio is 1.2.

25/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate Evolution of early ischemic changes on head CT scan Evolution of early ischemic changes over time in a 35-year-old woman who presented with acute aphasia. (A) NCCT at one hour after symptom onset shows loss of gray white matter differentiation in the left frontal and temporal operculum and insular cortex and hypodensity in the lentiform nucleus (ASPECTS was 4 points for involvement of insula, lentiform, M1-3, M5). (B and C) NCCT and CTA-SI at two hours after symptoms onset and IV rtPA administration show more conspicuous hypodensity and mild effacement of cortical sulci compared with https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 26/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate NCCT at one hour after symptoms onset. (D) NCCT at eight hours after symptoms onset shows frank hypodensity in the infarcted areas. The extent of the hypodense areas remains the same but is more conspicuous than prior NCCT studies. CT: computed tomography; NCCT: noncontrast-enhanced computed tomography; ASPECTS: The Alberta Stroke Program Early CT score; CTA-SI: computed tomography angiography source image; IV: intravenous; rtPA: recombinant tissue plasminogen activator. From: Prakkamakul S, Yoo AJ. ASPECTS CT in Acute Ischemia: Review of Current Data. Top Magn Reson Imaging 2017; 26:103. DOI: 10.1097/RMR.0000000000000122. Copyright 2017. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 121624 Version 2.0 https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 27/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate ASPECTS study form The ASPECTS value is calculated from two standard axial CT cuts: one at the level of the thalamus and basal ganglia (left), and one just rostral to the basal ganglia (right). A: anterior circulation; P: posterior circulation; C: caudate; L: lentiform; IC: internal capsule; I: insular ribbon; MCA: middle cerebral artery; M1: anterior MCA cortex; M2: MCA cortex lateral to insular ribbon; M3: posterior MCA cortex; M4, M5, and M6 are anterior, lateral, and posterior MCA territories immediately superior to M1, M2, and M3, rostral to basal ganglia Reproduced with permission from: Barber, PA, Demchuk, AM, Zhang, J, Buchan, AM. Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. ASPECTS Study Group. Alberta Stroke Programme Early CT Score. Lancet 2000; 355:1670. Copyright 2000 The Lancet. Graphic 72190 Version 1.0 https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 28/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate ASPECTS study form and MCA variants (A and B) Right hemisphere, observer variations: lower and upper ASPECTS slices show as shaded areas the minimal and maximal variations in size of the cortical areas of the MCA (M1-M6) chosen by six expert observers. Left hemisphere, ASPECTS study form: A = anterior circulation; P = posterior circulation; C = caudate head; L = lentiform nucleus; IC = internal capsule; I = insular ribbon; MCA = middle cerebral artery; M1 = anterior MCA cortex; M2 = MCA cortex lateral to insular ribbon; M3 = posterior MCA cortex; M4, M5, and M6 are anterior, lateral, and posterior MCA territories, respectively, approximately 2 cm superior to M1, M2, and M3, respectively, rostral to basal ganglia. (C and D) Cortical MCA area variations with change of baseline. In the right hemisphere, the baseline is parallel to the inferior OML; in the left hemisphere, the baseline is the superior OML. OML=orbitomeatal line. (E and F) Normal vascular variations in MCA size on the two ASPECTS slices. The right hemisphere shows the larger normal variations described by van der Zwan* (light https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 29/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate shading). The left hemisphere of each shows the smaller, textbook , variations (dark shading). References van der Zwan, A, Hillen, B, Tulleken, AF, et al. Variability of the territories or the major cerebral arteries. J Neurosurg 1992; 77:927. Osborn, AG. Neuroradiology, Mosby, St. Louis 1995. Reproduced with permission from: Pexman, JH, Barber, PA, Hill, MD, et al. Use of the Alberta Stroke Program Early CT Score (ASPECTS) for assessing CT scans in patients with acute stroke. AJNR Am J Neuroradiol 2001; 22:1534. Copyright 2001 American Society of Neuroradiology. Graphic 63480 Version 1.0 https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 30/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate Multiphase CTA images (A) Images in a patient with a left M1 MCA occlusion (arrow) and good collaterals (backfilling arteries). (B) Images in a patient with a left M1 MCA occlusion (dashed arrow) and intermediate collaterals. (C) Images in a patient with a right M1 MCA occlusion (arrowhead) and poor collaterals (minimal backfilling arteries). CTA: computed tomography angiography. https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 31/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate Reproduced with permission from: Menon BK, d'Esterre CD, Qazi EM, et al. Multiphase CT angiography: A new tool for the imaging tria patients with acute ischemic stroke. Radiology 2015; 275:510. Copyright 2015 RSNA. Graphic 121648 Version 1.0 https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 32/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate Classic pattern of DWI-PWI mismatch Representative case with classic pattern of mismatch. (A) Diffusion weighted-image (DWI). (B) DWI abnormal lesion (shown in red) and hypoperfusion lesion (shown in green) superimposed on DWI. (C) DWI abnormal lesion and hypoperfusion lesion with brain image (DWI) removed. PWI: perfusion-weighted image. Reproduced with permission from: Ogata T, Nagakane Y, Christensen S, et al. A topographic study of the evolution of the MR DWI/PWI mismatch pattern and its clinical impact: a study by the EPITHET and DEFUSE Investigators. Stroke 2011; 42:1596. Copyright 2011 Lippincott Williams & Wilkins. Graphic 82701 Version 5.0 https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 33/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate Brain MRI showing large core-penumbra mismatch on diffusion- and perfusion- weighted sequences in a patient with acute ischemic stroke Diffusion- and perfusion-weighted brain MRI showing a large core-penumbra mismatch in a patient with an acute ischemic stroke. Diffusion-weighted MRI (panel A) indicates the infarction core in red as tissue with apparent diffusion coefficient <620 that measures 17 mL in volume. Perfusion-weighted MRI (panel B) indicates the ischemic penumbra in green as tissue with T volume. The mismatch volume is 122 mL and the mismatch ratio is 8.2. >6.0 seconds that measures 139 mL in max MRI: magnetic resonance imaging. Glenn A Tung, MD, FACR. Graphic 129431 Version 2.0 https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 34/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate Brain MRI showing a small core-penumbra mismatch on diffusion- and perfusio weighted sequences in a patient with acute ischemic stroke Diffusion- and perfusion-weighted brain MRI showing a small core-penumbra mismatch in a patient with an acute ischemic stroke. Diffusion-weighted MRI (panel A) indicates the infarction core in red as tissue with apparent diffusion coefficient <620 that measures 151 mL in volume. Perfusion-weighted MRI (panel B) indicates the ischemic penumbra in green as tissue with Tmax >6.0 seconds that measures 177 mL in volume. The mismatch volume is 26 mL and the mismatch ratio is 1.2. MRI: magnetic resonance imaging. Glenn A Tung, MD, FACR. Graphic 129434 Version 2.0 https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 35/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate MRI showing DWI-FLAIR mismatch in acute ischemic stroke due to left middle cerebral artery occlusion A 49-year-old woman presented with right hemiplegia and dysarthria. The patient arrived at the emergency department 72 minutes after symptom detection. Her initial NIHSS score was 13. Brain MRI showed an acute ischemic lesion in the left MCA territory on DWI (A and B) without parenchymal signal changes on FLAIR (C and D). MRA showed occlusion of the M1 segment of the left MCA with collateral blood flow in the distal cerebral artery territory (E). Intravenous thrombolysis was started 140 minutes after symptom detection. On DSA, the left MCA was still occluded on the M1 segment (F) and was recanalized after mechanical thrombectomy with a TICI score of 3 (G). Time from symptom detection to recanalization was 189 minutes (3 hours and 9 minutes). The mRS score at three months was 0. NIHSS: National Institutes of Health Stroke Scale; MRI: magnetic resonance imaging; MCA: middle cerebral artery; DWI: diffusion-weighted imaging; FLAIR: fluid-attenuated inversion recovery; MRA: magnetic resonance angiography; DSA: digital subtraction angiography; TICI: thrombolysis in cerebral infarction; mRS: modified Rankin scale. https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 36/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate Used with permission of the American Society of Neuroradiology, from: Mourand I, Milhaud D, Arquizan C, et al. Favorable bridging therapy based on DWI-FLAIR mismatch in patients with unclear-onset stroke. AJNR Am J Neuroradiol 2016; 37:88; permission conveyed through Copyright Clearance Center, Inc. Copyright 2016. Graphic 129421 Version 1.0 https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 37/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate Indications for mechanical thrombectomy to treat patients with acute ischemic IV: intravenous; tPA: tissue plasminogen activator (alteplase or tenecteplase); CTA: computed tomography an artery occlusion; MT: mechanical thrombectomy; ASPECTS: Alberta Stroke Program Early CT Score; NIHSS: Na tomography; MRI: magnetic resonance imaging; mRS: modified Rankin Scale; MCA: middle cerebral artery; IC recovery. Patients are not ordinarily eligible for IV tPA unless the time last known to be well is <4.5 hours. However, im that is diffusion positive and FLAIR negative) is an option at expert stroke centers to select patients with wake associated UpToDate topics for details. Usually assessed with MRA or CTA, less often with digital subtraction angiography. There is intracranial arterial occlusion of the distal ICA, middle cerebral (M1/M2), or anterior cerebral (A1/A2 MT may be a treatment option for patients with acute ischemic stroke caused by occlusion of the basilar ar stroke centers, but benefit is uncertain. [1] Based upon data from the Aurora study . Reference: https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 38/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate 1. Albers GW, Lansberg MG, Brown S, et al. Assessment of Optimal Patient Selection for Endovascular Thrombectomy Beyond 6 Hou Neurol 2021; 78:1064. Graphic 117086 Version 3.0 https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 39/40 7/5/23, 12:16 PM Neuroimaging of acute stroke - UpToDate Contributor Disclosures Jamary Oliveira-Filho, MD, MS, PhD No relevant financial relationship(s) with ineligible companies to disclose. Maarten G Lansberg, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. Glenn A Tung, MD, FACR No relevant financial relationship(s) with ineligible companies to disclose. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/neuroimaging-of-acute-stroke/print 40/40

7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Overview of the evaluation of stroke : Louis R Caplan, MD : Scott E Kasner, MD : John F Dashe, MD, PhD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Mar 23, 2023. INTRODUCTION The symptoms of brain ischemia may be transient, lasting seconds to minutes, or may persist for longer periods of time. Symptoms and signs remain indefinitely if the brain becomes irreversibly damaged and infarction occurs. Unfortunately, neurologic symptoms do not accurately reflect the presence or absence of infarction, and the tempo of the symptoms does not indicate the cause of the ischemia [1,2]. This is a critical issue because treatment depends upon accurately identifying the cause of symptoms. An overview of the evaluation of patients who present with neurologic symptoms that may be consistent with stroke is discussed here. This evaluation includes the following: Understanding the classification of stroke An initial quick evaluation to stabilize vital signs, determine if intracranial hemorrhage is present, and, in patients with ischemic stroke, decide if reperfusion therapy is warranted (see "Initial assessment and management of acute stroke") Forming a hypothesis of the stroke etiology based upon the history, physical examination, and initial brain imaging study (usually a noncontrast head CT scan) Confirming the precise pathophysiologic process with more directed diagnostic testing The approach to patients with transient brain ischemia is reviewed separately. (See "Initial evaluation and management of transient ischemic attack and minor ischemic stroke".) https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 1/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate CLASSIFICATION Cerebrovascular disease is caused by one of several pathophysiologic processes ( table 1) involving the blood vessels of the brain: Intrinsic vessel abnormality The process may be intrinsic to the vessel, as in atherosclerosis, lipohyalinosis, inflammation, amyloid deposition, arterial dissection, developmental malformation, aneurysmal dilation, or venous thrombosis. Embolism The process may originate remotely, as occurs when an embolus from the heart or extracranial circulation lodges in an intracranial vessel. Inadequate blood flow The process may result from inadequate cerebral blood flow due to decreased perfusion pressure or increased blood viscosity. Vessel rupture The process may result from rupture of a vessel in the subarachnoid space or intracerebral tissue. The first three processes can lead to transient brain ischemia (transient ischemic attack [TIA]) or permanent brain infarction (ischemic stroke), while the fourth results in either subarachnoid hemorrhage or an intracerebral hemorrhage (primary hemorrhagic stroke). Approximately 80 percent of strokes are due to ischemic cerebral infarction and 20 percent to brain hemorrhage. Transient brain ischemia TIA is now defined as a transient episode of neurologic dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction. This tissue-based definition of TIA relies on the absence of end-organ injury as assessed by imaging or other techniques. The proposed advantages of the tissue-based definition are that the defined end point is biological (tissue injury) rather than arbitrary (24 hours). (See "Definition, etiology, and clinical manifestations of transient ischemic attack", section on 'Definition of TIA'.) The approach to patients with TIA is reviewed separately. (See "Initial evaluation and management of transient ischemic attack and minor ischemic stroke".) Intracerebral hemorrhage Bleeding in intracerebral hemorrhage (ICH) is usually derived from arterioles or small arteries. The bleeding is directly into the brain, forming a localized hematoma which spreads along white matter pathways. Accumulation of blood occurs over minutes or hours; the hematoma gradually enlarges by adding blood at its periphery like a snowball rolling downhill. The most common causes of ICH are hypertension, trauma, bleeding diatheses, amyloid angiopathy, illicit drug use (mostly amphetamines and cocaine), and vascular malformations. Less frequent causes include bleeding into tumors, aneurysmal rupture, and https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 2/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate vasculitis. Neurologic symptoms usually increase gradually over minutes or a few hours. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis" and "Clinical diagnosis of stroke subtypes".) Subarachnoid hemorrhage Rupture of arterial aneurysms is the major cause of subarachnoid hemorrhage (SAH). Aneurysm rupture releases blood directly into the cerebrospinal fluid (CSF) under arterial pressure. The blood spreads quickly within the CSF, rapidly increasing intracranial pressure. Death or deep coma ensues if the bleeding continues. The bleeding usually lasts only a few seconds but rebleeding is common. With causes of SAH other than aneurysm rupture (eg, vascular malformations, bleeding diatheses, trauma, amyloid angiopathy, and illicit drug use), the bleeding is less abrupt and may continue over a longer period of time. Symptoms of SAH begin abruptly, occurring at night in 30 percent of cases. The primary symptom is a sudden, severe headache (97 percent of cases) classically described as the "worst headache of my life." The headache is lateralized in 30 percent of patients, predominantly to the side of the aneurysm. The onset of the headache may or may not be associated with a brief loss of consciousness, seizure, nausea, vomiting, focal neurologic deficit, or stiff neck ( figure 1) [3]. There are usually no important focal neurologic signs at presentation unless bleeding occurs into the brain and CSF at the same time (meningocerebral hemorrhage). (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) Ischemia There are three main subtypes of brain ischemia: Thrombosis Embolism Systemic hypoperfusion Thrombotic stroke Thrombotic strokes are those in which the pathologic process giving rise to thrombus formation in an artery produces a stroke either by reduced blood flow distally (low flow) or by an embolic fragment that breaks off and travels to a more distant vessel (artery-to- artery embolism). All thrombotic strokes can be divided into either large or small vessel disease ( table 2). Large vessel disease includes both the extracranial and intracranial arterial system; atherothrombosis is by far the most common pathologic process. (See "Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis".) Small vessel disease refers specifically to penetrating arteries that arise from the distal vertebral artery, the basilar artery, the middle cerebral artery stem, and the arteries of the https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 3/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate circle of Willis. These arteries thrombose due to atheroma formation at their origin or in the parent large artery, or due to lipohyalinosis (a lipid hyaline build-up distally secondary to hypertension). Penetrating artery (small vessel) disease can result in small deep infarcts usually referred to as lacunes. (See "Lacunar infarcts".) Embolic stroke Embolism refers to particles of debris originating elsewhere that block arterial access to a particular brain region. Since the process is not local (as with thrombosis), local therapy only temporarily solves the problem; further events may occur if the source of embolism is not identified and treated. Embolic strokes are divided into four categories ( table 2). (See "Stroke: Etiology, classification, and epidemiology".) Those with a known source that is cardiac Those with a possible cardiac or aortic source based upon transthoracic and/or transesophageal echocardiographic findings Those with an arterial source Those with a truly unknown source in which these tests are negative or inconclusive Systemic hypoperfusion Systemic hypoperfusion is a more general circulatory problem, manifesting itself in the brain and perhaps other organs. Reduced perfusion can be due to cardiac pump failure caused by cardiac arrest or arrhythmia, or to reduced cardiac output related to acute myocardial ischemia, pulmonary embolism, pericardial effusion, or bleeding. Hypoxemia may further reduce the amount of oxygen carried to the brain. (See "Clinical diagnosis of stroke subtypes".) INITIAL GENERAL ASSESSMENT Sudden loss of focal brain function is the core feature of the onset of ischemic stroke. However, patients with conditions other than brain ischemia can present in a similar fashion ( table 3). In addition, patients who have an ischemic stroke may present with other serious medical conditions. Thus, the initial evaluation requires a rapid but broad assessment. The goals in this initial phase include: Ensuring medical stability Quickly reversing any conditions that are contributing to the patient's problem Moving toward uncovering the pathophysiologic basis of the patient's neurologic symptoms https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 4/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Diagnosing an intracerebral or subarachnoid hemorrhage as soon as possible can be lifesaving and prevent or minimize permanent neurologic damage. The history may provide clues to these diagnoses, but early triage of the patient to CT scan or MRI is critical. However, it is important to assess and optimize vital physiologic function before sending the patient for an imaging study. (See "Initial assessment and management of acute stroke".) Vital signs Parameters of particular concern in patients with stroke include blood pressure, breathing, and temperature. Blood pressure The mean arterial blood pressure (MAP) is usually elevated in patients with an acute stroke. This may be due to chronic hypertension, which is a major risk factor for ischemic stroke. However, an acute elevation in blood pressure often represents an appropriate response to maintain brain perfusion. The decision to treat requires a balance between the potential danger of severe increases in blood pressure, and a possible decline in neurologic functioning when blood pressure is lowered. (See "Initial assessment and management of acute stroke", section on 'Blood pressure management'.) Breathing Patients with increased intracranial pressure (ICP) due to hemorrhage, vertebrobasilar ischemia, or bihemispheric ischemia can present with a decreased respiratory drive or muscular airway obstruction. Hypoventilation, with a resulting increase in the partial pressure of carbon dioxide, may lead to cerebral vasodilation which further elevates ICP. Intubation may be necessary to restore adequate ventilation and to protect the airway. This is especially important in the presence of vomiting, which occurs commonly with increased ICP, vertebrobasilar ischemia, and intracranial hemorrhage. Fever Fever may occur in patients with an acute stroke and can worsen brain ischemia [4]. Normothermia should be maintained for at least the first several days after an acute stroke. (See "Initial assessment and management of acute stroke", section on 'Fever'.) History and physical examination The history and physical examination should be used to distinguish between other disorders in the differential diagnosis of stroke ( table 3). As examples, seizures, syncope, migraine, and hypoglycemia can mimic acute ischemia. The most difficult cases involve patients with focal signs and altered level of consciousness. It is important to ask the patient or a relative whether the patient takes insulin or oral hypoglycemic agents, has a history of a seizure disorder or drug overdose or abuse, medications on admission, recent trauma, or hysteria (see "Differential diagnosis of transient ischemic attack and acute stroke"). The history is also important in separating ischemia from hemorrhage and distinguishing between subtypes of ischemia and hemorrhage. https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 5/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Ischemia versus hemorrhage Noncontrast computed tomography (CT) is typically the first diagnostic study in patients with suspected stroke. The main advantages of CT are widespread access and speed of acquisition. CT is highly sensitive for the diagnosis of hemorrhage in the acute setting [5]. Intracerebral hemorrhages are evident almost instantly after onset as focal white hyperdense lesions within the brain parenchyma. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Head CT'.) Intracerebral hemorrhages can also be defined by MRI; the use of susceptibility sequences improves the sensitivity of MRI for early detection of hemorrhage. Gradient-echo images can also show the presence of old hemorrhages since this technique is very sensitive to hemosiderin, which can remain in old hemorrhages indefinitely. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Brain MRI'.) Small subarachnoid hemorrhages can be missed by either CT or MRI. Lumbar puncture may be needed to make the diagnosis in such patients. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Lumbar puncture'.) MRI is more sensitive than CT for the early diagnosis of brain infarction, although CT may identify subtle indicators of infarction within six hours of stroke onset in a significant number of patients (see "Neuroimaging of acute stroke", section on 'Assessment of early infarct signs'). Fluid-attenuated inversion recovery (FLAIR) MRI sequences and diffusion-weighted images (DWI- MRI) are especially useful in showing infarcts early after the onset of symptoms. In patients with ischemia who do not yet have brain infarction, both CT and MRI may be normal. (See "Neuroimaging of acute stroke", section on 'Assessment of early infarct signs'.) Is the patient a candidate for reperfusion? Timely restoration of blood flow is the most effective maneuver for salvaging ischemic brain tissue that is not already infarcted. Removal of occlusive intracranial thrombi must be accomplished quickly, since the benefit of reperfusion therapy for ischemic stroke decreases in a continuous fashion over time. An important aspect of the hyperacute phase of stroke assessment is to determine if the patient is eligible for intravenous thrombolysis and/or mechanical thrombectomy: Intravenous thrombolytic therapy with alteplase (recombinant tissue-type plasminogen activator or rt-PA) improves outcomes in patients with acute ischemic stroke who can be treated within 3 to 4.5 hours from stroke onset and meet additional eligibility criteria ( table 4). This issue is discussed in detail separately. (See "Approach to reperfusion therapy for acute ischemic stroke", section on 'Alteplase'.) Intra-arterial mechanical thrombectomy using a second-generation stent retriever device can improve outcomes for well-selected patients with ischemic stroke caused by a large https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 6/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate artery occlusion in the proximal anterior circulation when started up to 24 hours from the time last seen. This therapy is reviewed in detail elsewhere. (See "Mechanical thrombectomy for acute ischemic stroke".) DETERMINING A PRESUMPTIVE DIAGNOSIS OF STROKE SUBTYPE After completing the initial assessment, the goal of the subsequent evaluation is to determine the underlying pathophysiology of the stroke in order to guide therapy ( table 1). This part of the discussion assumes that patients with subarachnoid hemorrhage have already been identified by the initial history and physical examination and noncontrast head CT (with or without lumbar puncture). A review of the clinical features and diagnosis of subarachnoid hemorrhage is found separately. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) In addition, the presence of intracerebral hemorrhage should already be evident by this phase of the evaluation; the diagnostic evaluation in these patients is reviewed elsewhere. (See 'Evaluation of patients with intracerebral hemorrhage' below.) In practice, then, this second stage of evaluation is focused upon distinguishing between embolic and thrombotic strokes; in patients with the latter, it is worth differentiating between large vessel and small vessel (penetrating artery or lacunar) infarcts since the causes, outcomes, and treatments are different. Some patients will have more than one potential etiology for stroke, although the majority will have only one predominant cause [6]. (See "Stroke: Etiology, classification, and epidemiology" and "Clinical diagnosis of stroke subtypes".) A presumptive diagnosis of the stroke subtype can be made following a thorough history, physical examination, and imaging study such as CT or MRI. However, confirmation of the diagnosis requires more extensive testing. A history of carotid stenosis is a significant risk factor for large artery thrombotic stroke, but these patients need to have other stroke subtypes considered in the differential diagnosis. In the North American Symptomatic Carotid Endarterectomy Trial (NASCET), of patients with 70 to 99 percent stenosis who subsequently had an ischemic stroke, 20 and 45 percent of strokes that occurred in the territory of symptomatic and asymptomatic carotid arteries, respectively, were unrelated to carotid stenosis [7]. History A number of features in the clinical history may be useful in determining the type of stroke: https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 7/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Clinical course Ecology Previous transient ischemic attack (TIA) Activity at the onset or just before the stroke Associated symptoms Clinical course The most important historical item for differentiating stroke subtypes is the pace and course of the symptoms and signs and their clearing [8]. Each subtype has a characteristic course. Embolic strokes most often occur suddenly ( figure 2). The deficits indicate focal loss of brain function that is usually maximal at onset. Rapid recovery also favors embolism. Thrombosis-related symptoms often fluctuate, varying between normal and abnormal or progressing in a stepwise or stuttering fashion with some periods of improvement ( figure 3). Penetrating artery occlusions usually cause symptoms that develop during a period of hours or at most a few days ( figure 4), compared with large artery-related brain ischemia, which can evolve over a longer period. Intracerebral hemorrhage (ICH) does not improve during the early period; it progresses gradually during minutes or a few hours ( figure 5). Aneurysmal subarachnoid hemorrhage (SAH) develops in an instant. Focal brain dysfunction is less common. Patients often do not give a specific history regarding the course of neurologic symptoms. I may ask if the patient could walk, talk, use the phone, use the hand, etc, as the events developed after the first symptoms occurred [8]. Ecology Ecology refers to known demographic and historical features that provide probabilities of the patient having one or more of the stroke subtypes. Age, sex, and race are important demographic variables generally known to the clinician before taking the history [9]. Most thrombotic and embolic strokes related to atherosclerosis occur in older patients. Individuals under age 40 rarely have severe atherosclerosis unless they also have major risk factors such as diabetes, hypertension, hyperlipidemia, smoking, or a strong family history. By contrast, cardiac-origin embolism is common in young people who are known to have heart disease. https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 8/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Hypertensive ICH is more common among Black individuals and individuals of Asian descent (eg, Chinese and Japanese) compared with White individuals. Premenopausal women have a lower frequency of atherosclerosis than men of similar age unless they have major stroke risk factors. Even after adjusting for age, the incidence of atherosclerotic stroke is four times higher in men [10]. Black and Asian individuals have a lower incidence of occlusive disease of the extracranial carotid and vertebral arteries than White men. Hypertension is the most common and most important stroke risk factor, including isolated systolic hypertension (see "Overview of secondary prevention of ischemic stroke", section on 'Hypertension'). Epidemiologic studies show that there is a gradually increasing incidence of both coronary disease and stroke as the blood pressure rises above 110/75 mmHg ( figure 6) [11,12]. However, these observations do not prove a causal relationship, since increasing blood pressure could be a marker for other risk factors such as increasing body weight, which is associated with dyslipidemia, glucose intolerance, and the metabolic syndrome. The best evidence for a causal role of increasing blood pressure in cardiovascular complications is an improvement in outcome with antihypertensive therapy. This evidence is reviewed elsewhere. Chronic hypertension is a risk factor for both thrombotic extracranial and intracranial large artery disease and penetrating artery disease. Conversely, the absence of a history of hypertension or of present hypertension reduces the likelihood of penetrating artery disease. Smoking increases the likelihood of extracranial occlusive vascular disease, more than doubling the risk of stroke [13]. The risk of ischemic stroke decreases over time after smoking cessation. In one series of middle-aged women, for example, the excess risk among former smokers largely disappeared two to four years after cessation [13]. (See "Cardiovascular risk of smoking and benefits of smoking cessation".) Several other risk factors for stroke have been identified: Diabetes increases the likelihood of large and small artery occlusive disease. The use of amphetamines increases the likelihood of both ICH and SAH but not brain ischemia. Cocaine-related strokes are often hemorrhagic (ICH and SAH), due to aneurysms and vascular malformations [14]. Cocaine is also associated with brain ischemia, especially involving the posterior circulation intracranial arteries; this is probably due to vasoconstriction. https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 9/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Heart disease, including cardiac valvular disease, prior myocardial infarction, atrial fibrillation, and endocarditis, increases the probability of a stroke due to embolism. Stroke during the puerperium has an increased likelihood of being related to venous or arterial thrombosis. The presence of a known bleeding disorder or prescription of warfarin or other anticoagulants predisposes to hemorrhage, into either the brain or the cerebrospinal fluid (CSF). The link between stroke and oral contraceptive use has been a controversial issue. Initial studies suggesting this association were performed with oral contraceptives containing higher doses of estrogen; the risk may not be as great with current low dose oral contraceptives. (See "Combined estrogen-progestin contraception: Side effects and health concerns", section on 'Cardiovascular effects'.) The presence of these risk factors increases the odds that a stroke is due to a particular mechanism, but the clinician cannot make a firm diagnosis simply on the basis of probability. As examples: some conditions such as hypertension predispose to more than one subtype (thrombosis, intracranial hemorrhage); the presence of a prior myocardial infarction increases the likelihood of cardiac origin embolism, but also increases the likelihood of carotid and vertebral artery neck occlusive disease (thrombosis); and an older patient with severe atherosclerosis may also harbor an unexpected cerebral aneurysm. Previous transient ischemic attack A history of TIA (especially more than one) in the same territory as the stroke strongly favors the presence of a local vascular lesion (thrombosis). Attacks in more than one vascular territory suggest brain embolism from the heart or aorta. TIAs are not a feature of brain hemorrhage. Patients often will not volunteer a prior history of symptoms consistent with a TIA. Many patients, for example, do not relate prior hand or eye problems to subsequent leg problems. Thus, the physician must ask directly about specific symptoms. "Did your arm, hand, or leg ever transiently go numb?" "Did you ever have difficulty speaking?" "Did you ever lose vision? If so, in which part of your vision? Was it in one eye and, if so, which one?" Activity at the onset or just before the stroke Hemorrhages (ICH and SAH) can be precipitated by sex or other physical activity, while thrombotic strokes are unusual under these circumstances. Trauma before the stroke suggests traumatic dissection or occlusion of arteries or traumatic brain hemorrhage. Sudden coughing and sneezing sometimes precipitates brain https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 10/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate embolism. Similarly, getting up during the night to urinate seems to promote brain embolism (a matutinal embolus). Associated symptoms The presence of certain associated symptoms is suggestive of specific stroke subtypes. Fever raises the suspicion of endocarditis and resulting embolic stroke. Infections activate acute phase blood reactants, thereby predisposing to thrombosis. Headache is typically a feature of hemorrhagic strokes, but some patients have headaches in the prodromal period before thrombotic strokes. Vomiting is common in patients with ICH, SAH, and posterior circulation large artery ischemia ( figure 1). Seizures are most often seen in patients with lobar ICH or brain embolism; they are rare in patients with acute thrombosis [15]. Reduced alertness favors the presence of hemorrhage. Accompanying neurologic signs are suggestive of ICH, while the absence of focal signs suggests SAH. Loss of consciousness is also common in patients with thrombotic and embolic strokes that are large or involve the posterior circulation large arteries. Physical examination Important clues in the general physical examination include the following: Absent pulses (inferior extremity, radial, or carotid) favors a diagnosis of atherosclerosis with thrombosis, although the sudden onset of a cold, blue limb favors embolism. The internal carotid arteries in the neck cannot be reliably palpated but, in some patients, occlusion of the common carotid artery in the neck can be diagnosed by the absence of a carotid pulse. The presence of a neck bruit suggests the presence of occlusive extracranial disease, especially if the bruit is long, focal, and high pitched. Palpating the facial pulses is helpful in diagnosing common carotid and internal carotid artery occlusions and temporal arteritis. The facial pulses on the side of the occlusion are often lost with common carotid artery occlusions. By contrast, some patients with internal carotid artery occlusion will have increased facial pulses on the side of the occlusion because collateral channels develop between the external carotid artery facial branches https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 11/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate and the carotid arteries intracranially. In patients with temporal arteritis, the temporal arteries are often irregular and have sausage-shaped areas of dilatation, may be tender, and are often pulseless. Cardiac findings, especially atrial fibrillation, murmurs, and cardiac enlargement, favor cardiac-origin embolism. (See "Auscultation of cardiac murmurs in adults".) Careful examination of the optic fundus may reveal a cholesterol crystal, white platelet- fibrin, or red clot emboli. Subhyaloid hemorrhages in the eye suggest a suddenly developing brain or subarachnoid hemorrhage. When the carotid artery is occluded, the iris may appear speckled and the ipsilateral pupil can become dilated and poorly reactive. The retina in that circumstance may also show evidence of chronic ischemia (venous stasis retinopathy). Neurologic examination The patient's account of his or her neurologic symptoms and the neurologic signs found on examination tell more about the location of the process in the brain than the particular stroke subtype. The blood supply to various parts of the brain and associated neurologic findings are shown in the figures ( figure 7A-G). Nevertheless, some constellations of symptoms and signs occasionally suggest a specific process ( table 5). Weakness of the face, arm, and leg on one side of the body unaccompanied by sensory, visual, or cognitive abnormalities (pure motor stroke) favors the presence of a thrombotic stroke involving penetrating arteries or a small ICH. Large focal neurologic deficits that begin abruptly or progress quickly are characteristic of embolism or ICH. Abnormalities of language suggest anterior circulation disease, as does the presence of motor and sensory signs on the same side of the body ( figure 8). Vertigo, staggering, diplopia, deafness, crossed symptoms (one side of the face and other side of the body), bilateral motor and/or sensory signs, and hemianopia or bilateral visual field loss suggest involvement of the posterior circulation. (See "Posterior circulation cerebrovascular syndromes".) The sudden onset of impaired consciousness in the absence of focal neurologic signs is characteristic of SAH. https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 12/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Imaging studies Brain imaging and a comprehensive neurovascular evaluation should be obtained for most patients suspected of having acute ischemic stroke or transient ischemic attack. Neurovascular imaging is important to determine the potential sources of embolism or low flow in ischemic stroke and to detect possible aneurysms or vessel malformations in hemorrhagic stroke. (See "Neuroimaging of acute stroke".) The location and size of a brain infarct on CT or MRI may further aid in distinguishing between stroke subtypes. Small subcortical (deep) infarcts are most commonly located in the basal ganglia, internal capsule, thalamus, and pons. They are potentially within the blood supply of a single penetrating artery. The most common cause of a small deep infarct is lacunar infarction due to degenerative changes in the penetrating arteries. Rostral brainstem (midbrain and thalamus), occipital lobe, and cerebellar infarcts are most commonly caused by brain embolism. (See "Posterior circulation cerebrovascular syndromes".) On the other hand, large subcortical infarcts, infarcts that are limited to the cerebral cortex, and infarcts that are both cortical and subcortical are commonly caused by thrombosis or embolism. CONFIRMING THE DIAGNOSIS The previous assessment should allow the formation of a presumptive diagnosis of the underlying stroke pathophysiology. The next phase of the evaluation is to confirm this hypothesis with diagnostic tests. Embolic stroke Embolism is especially likely in the following circumstances: The onset is sudden and the neurologic deficit is maximal from the beginning The infarct and deficit are large There is a known cardiac or large artery lesion present The infarct is or becomes hemorrhagic on CT or MRI There are multiple cortical or cortical/subcortical infarcts in different vascular territories Clinical findings improve quickly (so-called "spectacular shrinking deficit") [16] In addition, embolic stroke is common in patients who have had a posterior circulation stroke; in a registry of 361 patients who had vertebrobasilar strokes or transient ischemic attacks (TIAs) and were admitted to a university hospital, 41 percent had an embolic event [17]. https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 13/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate A possible cardiac source should be considered in all patients with suspected embolic stroke, particularly in patients under age 45, whether or not they have clinical evidence of heart disease. This issue is discussed below. (See 'Cardiac evaluation' below.) Vascular studies The extracranial and intracranial arteries are also common sources of brain embolism and should be studied. (See "Stroke: Etiology, classification, and epidemiology".) If the infarct and brain symptoms are within the anterior circulation (carotid artery supply), then the extracranial and intracranial carotid arteries, and the middle and anterior cerebral artery branches should be the focus of the examinations. When the infarct is within the posterior circulation (vertebrobasilar system), the extracranial and intracranial vertebral arteries, the basilar artery, and the posterior cerebral arteries should be the focus of the vascular investigations. The anterior circulation can be studied using duplex ultrasound of the neck and transcranial Doppler (TCD) of the intracranial arteries [18,19]. B-mode images of the carotid artery also demonstrate the degree of stenosis and irregularities or ulcerations within plaques. Alternatively, CT angiography (CTA) or MR angiography (MRA) of the neck and head arteries may be sufficient. Conventional angiography is performed when the screening tests do not fully define the lesion and more characterization is warranted, and when surgery or interventional treatment through an arterial catheter (angioplasty or intra-arterial thrombolysis) may be indicated. Within the posterior circulation, duplex and color-flow Doppler investigation of the origins of the vertebral arteries [20] and ultrasound of the subclavian arteries (especially when the radial pulse or blood pressure on one side is lower than the other) can detect lesions of the proximal portion of the vertebral arteries. Atherosclerosis most often affects this proximal region. The ultrasonographer can then insonate over the rest of the vertebral artery in the neck using a continuous-wave Doppler to detect the direction of flow within the artery (craniad as would be normal, or reversed or to-and-fro flow suggesting proximal obstruction). CTA and MRA of the neck vertebral arteries are also helpful, but these tests may not adequately show the origins of the vertebral arteries [21]. The clinician must be certain that the films are adequate to see the complete extracranial and intracranial vertebrobasilar system. An important advance in the detection of brain embolism is monitoring by TCD [22]. Emboli that pass under ultrasound probes make a high-pitched chirp and are recorded as high-intensity transient signals (HITS). The location and pattern of these emboli can help define the presence https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 14/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate of embolism and give clues as to the source. TCD monitoring can also help to assess the effectiveness of treatment. Artery-to-artery versus cardiac sources of embolism The distinction between artery-to- artery and non-artery-to-artery sources of embolism can be difficult. Suspicion of the former typically arises once vascular pathology in a large vessel has been identified (eg, with noninvasive testing). Repetitive spells within a single vascular territory are also suggestive of an artery-to-artery source, as is a normal echocardiogram. However, caution must be used in interpreting the results of a transthoracic echocardiogram. As previously mentioned, this study can exclude a cardiomyopathy and most atrial and mitral valve pathology, but may miss other potential embolic sources such as clot in the atrial appendage, a patent foramen ovale, mitral valve lesions, and aortic atherosclerosis. Transesophageal echocardiography (TEE) is better for identifying these lesions. However, transthoracic echocardiography (TTE) is generally superior to TEE for identifying left ventricular apical thrombus. (See 'Echocardiography' below.) Small vessel (lacunar) stroke Most patients with lacunar infarcts have risk factors for penetrating artery disease (eg, hypertension, diabetes mellitus, or polycythemia). The clinical findings typically conform to one of the well-recognized lacunar syndromes: pure motor hemiparesis, pure sensory stroke, dysarthria-clumsy hand, or ataxic hemiparesis. (See "Lacunar infarcts".) Further testing is of low yield in patients suspected of having a lacunar infarction who have the typical risk factors, clinical neurologic findings, and characteristic brain imaging (eg, small subcortical infarct). On the other hand, some patients seen within the first few hours after symptom onset with clinical findings suggestive of lacunar infarction are found to have large artery disease; this has been particularly true for patients of Asian descent. (See "Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis", section on 'Racial and ethnic differences'.) Vascular imaging (CTA or MRA) can be performed at the same time as brain imaging (CT or MRI) to exclude occlusion of the parent feeding artery, a condition that can mimic a lacunar infarct. (See "Lacunar infarcts", section on 'Evaluation and diagnosis'.) It is particularly important to perform intracranial vascular imaging in Black patients and patients of Asian descent, since intracranial large artery occlusive disease is common in these patients. An alternative diagnostic test to exclude intracranial occlusive disease is TCD, a technique that measures the blood flow velocities in the large intracranial arteries using an ultrasound probe placed over the orbit, temporal bone, and foramen magnum [18]. (See "Neuroimaging of acute stroke", section on 'Ultrasound methods'.) https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 15/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Large vessel atherothrombotic stroke Large vessel atherothrombotic strokes are often preceded by TIAs, and the onset may or may not be abrupt. The course of neurologic symptoms and signs fluctuates or is progressive in development. Infarcts that are large and subcortical are usually caused by occlusion of intracranial arteries.

due to degenerative changes in the penetrating arteries. Rostral brainstem (midbrain and thalamus), occipital lobe, and cerebellar infarcts are most commonly caused by brain embolism. (See "Posterior circulation cerebrovascular syndromes".) On the other hand, large subcortical infarcts, infarcts that are limited to the cerebral cortex, and infarcts that are both cortical and subcortical are commonly caused by thrombosis or embolism. CONFIRMING THE DIAGNOSIS The previous assessment should allow the formation of a presumptive diagnosis of the underlying stroke pathophysiology. The next phase of the evaluation is to confirm this hypothesis with diagnostic tests. Embolic stroke Embolism is especially likely in the following circumstances: The onset is sudden and the neurologic deficit is maximal from the beginning The infarct and deficit are large There is a known cardiac or large artery lesion present The infarct is or becomes hemorrhagic on CT or MRI There are multiple cortical or cortical/subcortical infarcts in different vascular territories Clinical findings improve quickly (so-called "spectacular shrinking deficit") [16] In addition, embolic stroke is common in patients who have had a posterior circulation stroke; in a registry of 361 patients who had vertebrobasilar strokes or transient ischemic attacks (TIAs) and were admitted to a university hospital, 41 percent had an embolic event [17]. https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 13/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate A possible cardiac source should be considered in all patients with suspected embolic stroke, particularly in patients under age 45, whether or not they have clinical evidence of heart disease. This issue is discussed below. (See 'Cardiac evaluation' below.) Vascular studies The extracranial and intracranial arteries are also common sources of brain embolism and should be studied. (See "Stroke: Etiology, classification, and epidemiology".) If the infarct and brain symptoms are within the anterior circulation (carotid artery supply), then the extracranial and intracranial carotid arteries, and the middle and anterior cerebral artery branches should be the focus of the examinations. When the infarct is within the posterior circulation (vertebrobasilar system), the extracranial and intracranial vertebral arteries, the basilar artery, and the posterior cerebral arteries should be the focus of the vascular investigations. The anterior circulation can be studied using duplex ultrasound of the neck and transcranial Doppler (TCD) of the intracranial arteries [18,19]. B-mode images of the carotid artery also demonstrate the degree of stenosis and irregularities or ulcerations within plaques. Alternatively, CT angiography (CTA) or MR angiography (MRA) of the neck and head arteries may be sufficient. Conventional angiography is performed when the screening tests do not fully define the lesion and more characterization is warranted, and when surgery or interventional treatment through an arterial catheter (angioplasty or intra-arterial thrombolysis) may be indicated. Within the posterior circulation, duplex and color-flow Doppler investigation of the origins of the vertebral arteries [20] and ultrasound of the subclavian arteries (especially when the radial pulse or blood pressure on one side is lower than the other) can detect lesions of the proximal portion of the vertebral arteries. Atherosclerosis most often affects this proximal region. The ultrasonographer can then insonate over the rest of the vertebral artery in the neck using a continuous-wave Doppler to detect the direction of flow within the artery (craniad as would be normal, or reversed or to-and-fro flow suggesting proximal obstruction). CTA and MRA of the neck vertebral arteries are also helpful, but these tests may not adequately show the origins of the vertebral arteries [21]. The clinician must be certain that the films are adequate to see the complete extracranial and intracranial vertebrobasilar system. An important advance in the detection of brain embolism is monitoring by TCD [22]. Emboli that pass under ultrasound probes make a high-pitched chirp and are recorded as high-intensity transient signals (HITS). The location and pattern of these emboli can help define the presence https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 14/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate of embolism and give clues as to the source. TCD monitoring can also help to assess the effectiveness of treatment. Artery-to-artery versus cardiac sources of embolism The distinction between artery-to- artery and non-artery-to-artery sources of embolism can be difficult. Suspicion of the former typically arises once vascular pathology in a large vessel has been identified (eg, with noninvasive testing). Repetitive spells within a single vascular territory are also suggestive of an artery-to-artery source, as is a normal echocardiogram. However, caution must be used in interpreting the results of a transthoracic echocardiogram. As previously mentioned, this study can exclude a cardiomyopathy and most atrial and mitral valve pathology, but may miss other potential embolic sources such as clot in the atrial appendage, a patent foramen ovale, mitral valve lesions, and aortic atherosclerosis. Transesophageal echocardiography (TEE) is better for identifying these lesions. However, transthoracic echocardiography (TTE) is generally superior to TEE for identifying left ventricular apical thrombus. (See 'Echocardiography' below.) Small vessel (lacunar) stroke Most patients with lacunar infarcts have risk factors for penetrating artery disease (eg, hypertension, diabetes mellitus, or polycythemia). The clinical findings typically conform to one of the well-recognized lacunar syndromes: pure motor hemiparesis, pure sensory stroke, dysarthria-clumsy hand, or ataxic hemiparesis. (See "Lacunar infarcts".) Further testing is of low yield in patients suspected of having a lacunar infarction who have the typical risk factors, clinical neurologic findings, and characteristic brain imaging (eg, small subcortical infarct). On the other hand, some patients seen within the first few hours after symptom onset with clinical findings suggestive of lacunar infarction are found to have large artery disease; this has been particularly true for patients of Asian descent. (See "Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis", section on 'Racial and ethnic differences'.) Vascular imaging (CTA or MRA) can be performed at the same time as brain imaging (CT or MRI) to exclude occlusion of the parent feeding artery, a condition that can mimic a lacunar infarct. (See "Lacunar infarcts", section on 'Evaluation and diagnosis'.) It is particularly important to perform intracranial vascular imaging in Black patients and patients of Asian descent, since intracranial large artery occlusive disease is common in these patients. An alternative diagnostic test to exclude intracranial occlusive disease is TCD, a technique that measures the blood flow velocities in the large intracranial arteries using an ultrasound probe placed over the orbit, temporal bone, and foramen magnum [18]. (See "Neuroimaging of acute stroke", section on 'Ultrasound methods'.) https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 15/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Large vessel atherothrombotic stroke Large vessel atherothrombotic strokes are often preceded by TIAs, and the onset may or may not be abrupt. The course of neurologic symptoms and signs fluctuates or is progressive in development. Infarcts that are large and subcortical are usually caused by occlusion of intracranial arteries. Patients with suspected large vessel atherothrombotic strokes need to have both intracranial and extracranial vascular testing. Extracranial vascular testing can be performed with MRA, CTA, or duplex carotid ultrasound. All are reliable and specific for detecting important severe occlusive lesions in the extracranial carotid arteries. Ultrasound devices such as color-flow Doppler imaging and power Doppler improve the resolution and quantification of carotid artery lesions. (See "Evaluation of carotid artery stenosis".) One approach to patients with suspected carotid artery stenosis is to first perform carotid duplex ultrasound. Patients with stenoses less than 50 percent are followed with serial examinations, usually on an annual basis to determine if there is progression. Transcranial Doppler and either MRA or CTA should be performed if the carotid stenosis is greater than 50 percent on the duplex ultrasound. Both MRA and CTA accurately define abnormalities within the carotid and vertebral arteries in the neck and their intracranial branches. MRI can be performed at the same time as MRA; the presence or absence of a brain infarct can help determine treatment. (See "Evaluation of carotid artery stenosis".) Head CT and CTA are acceptable alternatives to MRI and MRA and may be more available than MR in some centers. Head CT and CTA should be done if MRI and MRA are contraindicated or impractical. Conventional angiography is rarely performed; indications include patients who cannot tolerate an MRA or CTA, patients with discrepant CTA/MRA and ultrasound findings, and patients with suspected nonatherosclerotic disease (eg, dissection, fibromuscular dysplasia). Patients with carotid artery stenosis who have had nondisabling strokes may be candidates for carotid endarterectomy or carotid artery stenting. (See "Management of symptomatic carotid atherosclerotic disease".) CARDIAC EVALUATION A cardiac evaluation is important in most patients with brain ischemia [23]. Not only are cardiac and aortic origin emboli common, but many patients with cerebrovascular occlusive disease have concurrent coronary heart disease that can lead to significant morbidity and mortality [24- https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 16/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate 27]. The basic evaluation includes a thorough history focusing on the presence of cardiac ischemia and arrhythmias, a careful cardiac examination, and an electrocardiogram. Monitoring for subclinical atrial fibrillation All patients with ischemic stroke should have cardiac monitoring for at least the first 24 hours after stroke onset to look for subclinical atrial fibrillation (AF) [28]. In addition, we suggest ambulatory cardiac monitoring for several weeks (eg, 30 days) for patients with a cryptogenic ischemic stroke or transient ischemic attack (TIA). These patients are characterized by brain ischemia not attributable to a definite source of cardioembolism, large artery atherosclerosis, or small artery disease despite extensive vascular and cardiac evaluation, including no evidence of AF on standard 12-lead electrocardiogram (ECG) and 24-hour cardiac monitoring (see "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)"). Prolonged cardiac event monitoring increase the detection of subclinical AF in patients with TIA or acute ischemic stroke who present with sinus rhythm [29-34]. By contrast, subclinical AF, if transient, infrequent, and largely asymptomatic, may be undetected on standard cardiac monitoring such as continuous telemetry and 24- or 48-hour Holter monitors. This issue is illustrated by the following observations among trials of patients without an identified mechanism for stroke or TIA: In The CRYSTAL AF trial, 441 patients with cryptogenic stroke and no evidence of AF during at least 24 hours of ECG monitoring were randomly assigned to prolonged ambulatory cardiac monitoring with a subcutaneous insertable cardiac monitor (also sometimes referred to as implantable cardiac monitor or implantable loop recorder) recorder or to a control group with conventional follow-up [29]. At six months, AF detection was significantly higher in the monitored group (8.9 percent, versus 1.4 percent in the control group, hazard ratio [HR] 6.4, 95% CI 1.9-21.7). In the EMBRACE trial, 572 patients who had a cryptogenic stroke or TIA (with no AF after 24-hour cardiac monitoring) in the previous six months were randomly assigned to additional ambulatory monitoring with a 30-day external loop recorder (intervention group) or a 24-hour Holter monitor (control group) [30]. At study end, the rate of AF detection was significantly greater in the intervention group (16.1 percent, versus 3.2 percent in the control group, 95% CI 8.0-17.6). The PER DIEM trial randomly assigned 300 patients within six months of ischemic stroke and no known AF (66 percent had a cryptogenic stroke) in a 1:1 ratio to monitoring with either an insertable cardiac monitor (placed for one year) or an external loop recorder (worn for four weeks) [33]. At 12 months, detection of new AF lasting more than two https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 17/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate minutes was observed in a greater number of patients in the insertable cardiac monitor group compared with the external loop recorder group (15.3 versus 4.7 percent, absolute difference 10.7 percent, 95% CI 4.0-17.3 percent). Long-term cardiac monitoring can detect subclinical AF even among patients with a known mechanism for ischemic stroke. The STROKE-AF trial randomly assigned 492 patients with ischemic stroke attributed to large vessel or small vessel disease in a 1:1 ratio to monitoring with an insertable cardiac monitor or to site-specific usual care (external cardiac monitoring with ECG, Holter, telemetry, or event recorders) [34]. At 12 months, detection of AF lasting more than 30 seconds was higher in the insertable cardiac monitor group compared with the usual care group (12.1 versus 1.8 percent, absolute difference approximately 10.3 percent, HR 7.4, 95% CI 2.6- 21.3). These results parallel other data showing that prolonged cardiac event monitoring increases the detection of subclinical AF [31,35-39]. Such monitoring may then reduce the risk of recurrent ischemic stroke by prompting the appropriate use of long-term anticoagulation [40]. However, rigorous evidence is lacking that anticoagulation of subclinical AF improves outcomes for patients initially diagnosed with cryptogenic stroke [41]. The approach to treatment of subclinical AF detected on monitoring is reviewed separately. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Occult or subclinical atrial fibrillation on monitoring'.) In addition, the minimum duration of time (in minutes) of the episodes of AF that increases the risk of thrombus formation in the atria and thereby increases the risk of cardioembolic stroke has not been firmly established. (See "Stroke in patients with atrial fibrillation", section on 'Long- term anticoagulation'.) The optimal cardiac monitoring method (ie, continuous telemetry, ambulatory electrocardiography, serial electrocardiography, transtelephonic ECG monitoring, or insertable cardiac monitor) is uncertain. (See "Ambulatory ECG monitoring".) Other potential indicators that may predict which patients have or are likely to develop atrial fibrillation include determination of the left atrial appendage ejection fraction by transesophageal echocardiography [42] and demonstration of an atrial fibrillation phenotype on left atrial appendage pulse wave Doppler even when the surface ECG shows normal sinus rhythm [43]. In addition, measurements of B-type (brain) natriuretic protein (BNP) and the N- terminal fragment of BNP indicate that these values are elevated in patients with atrial fibrillation who have cardiogenic embolism, even in those with normal ventricular function, when compared with patients who have noncardiogenic stroke (see "Blood biomarkers for https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 18/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate stroke", section on 'Cardioembolic stroke'). These measurements in patients with normal cardiac ventricular function might identify those who have intermittent atrial fibrillation or are prone to develop it. Further research is needed to confirm whether these indicators are clinically useful. Atrial cardiopathy characterized by a large left atrium and abnormal function and morphology of the left atrium and left atrial appendage can predispose to thrombus formation even without atrial fibrillation. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Atrial cardiopathies'.) Echocardiography All patients with suspected embolic stroke should have an echocardiogram. The choice between transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) as the initial imaging test to identify a source of embolism should be individualized on a case-by-case basis. (See "Echocardiography in detection of cardiac and aortic sources of systemic embolism".) TTE is the preferred initial test for the majority of patients with a suspected cardiac or aortic source of emboli, including: Patients 45 years with a neurologic event and no identified disease on neurovascular imaging studies Patients with a high suspicion of left ventricular thrombus Patients in whom TEE is contraindicated (eg, esophageal stricture, unstable hemodynamic status) or who refuse TEE TEE is the preferred initial test to localize the source of embolism in the following circumstances: Patients <45 years without known cardiovascular disease (ie, absence of myocardial infarction or valvular disease history) Patients with a high pretest probability of a cardiac embolic source in whom a negative TTE would be likely to be falsely negative Patients with atrial fibrillation (a situation where left atrial or left atrial appendage thrombus is a likely cause of ischemic stroke), but only if the TEE would impact management Patients with a mechanical or bioprosthetic heart valve; although the long-term risk of thrombus is higher with mechanical valve than with bioprosthetic valve, both can develop thrombus Patients with suspected aortic pathology Transesophageal versus transthoracic echo While TTE and TEE have advantages and disadvantages, both are effective diagnostic tests with a role in the evaluation of suspected https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 19/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate cardioaortic source of embolism. In most patients, TEE yields higher quality images and has a greater sensitivity and specificity than TTE, but a few conditions (eg, left ventricular thrombus) are better seen on TTE. However, TEE is an uncomfortable invasive procedure that may not be tolerated by very ill patients. Because it is less invasive and readily available in most institutions, TTE is often reasonable as the initial test of choice. A TEE is often performed to examine the atria, atrial septal region, and the aorta if the TTE and preliminary cardiac and vascular imaging tests do not clarify the cause of brain ischemia [44,45]. (See "Initial evaluation and management of transient ischemic attack and minor ischemic stroke".) A TEE is the best test to exclude significant ascending aortic atheromatous disease. It is also the best test to look for evidence of patent foramen ovale (PFO), atrial septal aneurysm, or atrial septal defect, conditions that can cause otherwise cryptogenic stroke. (See "Thromboembolism from aortic plaque" and "Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism)" and "Atrial septal abnormalities (PFO, ASD, and ASA) and risk of cerebral emboli in adults".) TEE is also the best way to identify clot in the left atrial appendage. These emboli are 3 mm or less in diameter and are usually beyond the resolution of the transthoracic echocardiographic ultrasound probe. By contrast, left ventricular thrombi in patients with heart failure or a previous myocardial infarction are best seen with TTE since the true left ventricular apex is not well seen on TEE. (See "Echocardiography in detection of cardiac and aortic sources of systemic embolism".) BLOOD TESTS A number of blood tests may be indicated in select patients with brain ischemia or hemorrhage, including [28,46]: Blood glucose Complete blood count, including hemoglobin, hematocrit, white blood cell count, and platelet count Prothrombin time, international normalized ratio (INR), and activated partial thromboplastin time Thrombin time and/or ecarin clotting time if patient is known or suspected to be taking a direct thrombin inhibitor or a direct factor Xa inhibitor Blood lipids, including total, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol, and triglycerides https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 20/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate D-dimer and fibrinogen levels may be helpful in detecting patients whose brain ischemia can be related to cancer or inflammatory disease. (See "Blood biomarkers for stroke".) Hypercoagulable studies While hypercoagulable states are sometimes found in patients who have had an ischemic stroke, widespread testing for these disorders is limited by a number of factors including a relatively low prevalence of thrombophilias and alteration of the sensitivity and specificity of the tests involved in the setting of an acute ischemic event and in patients taking heparin or warfarin [47]. Furthermore, it remains unclear if the inherited thrombophilias directly predispose to stroke as they do to venous thrombosis. A case-control study found that one in seven patients with a first ever acute ischemic stroke tested positive for one of the inherited thrombophilias, but that the relationship was likely to be coincidental rather than causal in almost all cases [48]. In a systematic review, the prevalence of inherited deficiencies of protein C, protein S, antithrombin III, or plasminogen was low in unselected patients with ischemic stroke [49]. The pretest probabilities of other coagulation defects in these patients were as follows: Lupus anticoagulant 3 percent (8 percent in patients 50 years) Anticardiolipin antibodies 17 percent (21 percent in patients 50 years) Activated protein C resistance/factor V Leiden mutation 7 percent (11 percent in patients 50 years) Prothrombin mutation 5 percent (6 percent in patients 50 years) The posttest probabilities of these abnormalities increased with increasing pretest probability and features of the patients' history and clinical presentation suggestive of coagulopathy (eg, cerebral or venous thrombosis without precipitating factors). In the absence of definitive data, it is my practice to obtain testing for hypercoagulable conditions in patients who have: A personal or family history of systemic thromboses No clear etiology for ischemic stroke or transient ischemic attack (TIA), despite cardiac and vascular imaging, especially when involving young patients Clinical findings that suggest systemic lupus erythematosus or the antiphospholipid antibody syndrome Antiphospholipid antibodies The role of antiphospholipid antibodies (aPL) in the pathogenesis of ischemic stroke remains unclear. Transient elevations of aPL or lupus anticoagulants can be seen in the setting of acute stroke. Thus, elevated levels may simply be a https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 21/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate sequel to stroke and not related to its cause. On the other hand, aPL may be associated with thrombosis or a cardiac valve abnormality that is the cause of stroke. The evidence is conflicting as to how to interpret positive aPL assays among the full complement of ischemic stroke patients, as illustrated by the following reports [50,51]: A large, prospective, cohort study (APASS) of 1770 patients with ischemic stroke found that the presence of aPL, either LA or aCL, did not predict increased risk for subsequent vascular ischemic events, including ischemic stroke; did not confer increased risk for subgroups of patients younger than 55 years or those with cryptogenic stroke; and did not predict a differential response to aspirin or warfarin therapy [50]. A small subgroup (120) positive for both LA and ACL had a tendency toward higher risk of vascular occlusive events at two years than those without aPL (31.7 versus 24 percent). (See "Clinical manifestations of antiphospholipid syndrome", section on 'Neurologic involvement'.) In patients with systemic lupus erythematosus, one study found that the levels of both aCL binding to beta 2 glycoprotein I, and anti-phosphatidylserine antibodies binding to prothrombin were significantly higher in patients with a history of cerebral infarction compared with those who had no history of cerebral infarction [52]. Furthermore, lupus patients who were positive for both of these antibodies had a 77 percent prevalence of cerebral infarction (odds ratio 30.0, 95% CI 11-86). The presence of either antibody alone was not associated with a significantly increased stroke risk. In 2712 women and 2262 men in the Framingham Heart Study cohort who were free of stroke or TIA at the time of their baseline examination and were followed for 11 years, elevated serum concentrations of ACL independently and significantly predicted the risk of first ischemic stroke or TIA in women but not men [51]. In the absence of definitive data, we recommend obtaining antiphospholipid antibody testing in patients who have: A history of lupus or symptoms compatible with lupus Features that suggest the antiphospholipid syndrome such as miscarriages, venous thrombosis, or migraine headaches Cryptogenic stroke or TIA at a young age Others Plasma fibrinogen levels are risk factors for coronary heart disease and stroke [53,54]. However, the routine use of fibrinogen as a cardiovascular risk marker is limited by measurement variability. (See "Blood biomarkers for stroke" and "Overview of possible risk factors for cardiovascular disease".) https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 22/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Other studies may include hemoglobin electrophoresis in patients suspected of having a hemoglobinopathy, and an erythrocyte sedimentation rate, tests for Lyme disease, syphilis, and HIV infection in selected patients. EVALUATION OF PATIENTS WITH INTRACEREBRAL HEMORRHAGE CT scans usually define the size and location of intracerebral hemorrhage (ICH) and the presence of intraventricular blood [55]. Mass effect caused by the intracerebral mass, shift of midline structures, herniation of brain contents from one compartment to another, and the presence of hydrocephalus are also easily seen on CT. MRI with echo-planar T2*-weighted (susceptibility) images can also show hemorrhages soon after the onset of symptoms. Microbleeds (tiny older hemorrhages) are shown using this technique and can be clues to the presence of cerebral amyloid angiopathy. It is not necessary to perform both CT and MRI to exclude hemorrhage if echo-planar MRI scanning is available. A detailed description of the MRI characteristics of hyperacute ICH is found separately. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Brain MRI'.) Vascular malformations and brain tumor are better visualized on MRI. Echo-planar MRI can also show old hemorrhages not visible on CT scans. The location and appearance of the lesion as well as the history of the patient (eg, race, blood pressure, presence of known bleeding disorder, use of drugs) help determine the choice of additional diagnostic studies. Hypertensive ICH No further diagnostic tests are necessary in the severely hypertensive patient with a well circumscribed and homogeneous hematoma that is located in a typical location for hypertensive ICH (eg, putamen/internal capsule, caudate nucleus, thalamus, pons, or cerebellum); the clinician can be confident that the patient has a hypertensive hemorrhage in this circumstance (see "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis"). Similarly, a traumatic etiology can be diagnosed with confidence in the patient who has had recent trauma and lesions in the appropriate location and with the appearance of contusion and traumatic hemorrhages (eg, anterior and/or orbital frontal lobes and anterior-medial temporal lobes). Bleeding disorder Evaluation for a bleeding disorder (platelet count, prothrombin time, international normalized ratio (INR), activated partial thromboplastin time for all patients, and thrombin time and/or ecarin clotting time if the patient is known or suspected to be taking a direct thrombin inhibitor or a direct factor Xa inhibitor) should be performed in every patient with an intracranial hemorrhage, especially if the cause is not immediately https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 23/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate clear. A bleeding tendency can cause or contribute to bleeding initiated by other etiologies. (See "Approach to the adult with a suspected bleeding disorder".) Iatrogenic prescription of anticoagulants is the most common bleeding disorder contributing to brain hemorrhages. Oral anticoagulant-related intracerebral hemorrhage is often lobar [56]. Compared with spontaneous intracerebral hemorrhages, anticoagulant- related hemorrhages are larger and associated with greater hematoma expansion and mortality [56,57]. (See "Risks and prevention of bleeding with oral anticoagulants".) Lobar or atypical hemorrhage Amyloid angiopathy, bleeding into a tumor, and vascular malformations are likely etiologies of hemorrhages that are lobar or atypical in appearance. Cerebral amyloid angiopathy Hemorrhages related to amyloid angiopathy are usually lobar and have a predilection to cluster in posterior brain regions, including the parietal and occipital lobes. The hemorrhages are usually multiple. T2* weighted (susceptibility) MRI images may show the presence of old small hemorrhages ("microbleeds"). Patients with amyloid angiopathy are typically over the age of 60 years. (See "Cerebral amyloid angiopathy".) Vascular malformation or brain tumor Other bleeding lesions should be excluded in patients under the age of 60 if the blood pressure is not sufficiently elevated to make a firm diagnosis of hypertensive lobar hemorrhage. A repeat MRI after the blood has been reabsorbed (four to eight weeks) may show residual vascular malformations or a brain tumor. Vascular imaging using CT angiography (CTA) or MR angiography (MRA) of the intracranial circulation is useful as a screening test for vascular malformations and aneurysms. Contrast angiography by arterial catheterization may be necessary in patients with a CTA or MRA suggestive of vascular malformation. (See "Vascular malformations of the central nervous system" and "Brain arteriovenous malformations".) Cocaine use Patients with intracerebral hemorrhage after cocaine use (but not amphetamines) have a relatively high incidence of underlying aneurysms and vascular malformations. They require vascular imaging tests (eg, CTA, MRA, and/or conventional angiography). SOCIETY GUIDELINE LINKS https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 24/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Hemorrhagic stroke (The Basics)" and "Patient education: Stroke (The Basics)") Beyond the Basics topics (see "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Classification Cerebrovascular disease is caused by one of several pathophysiologic processes ( table 1 and table 2) involving the blood vessels of the brain. (See 'Classification' above.) Initial evaluation Sudden loss of focal brain function is the core feature of the onset of ischemic stroke. However, patients with conditions other than stroke can present in a similar fashion ( table 3). The initial evaluation requires a rapid but broad assessment to stabilize vital signs, determine if intracranial hemorrhage is present, and decide if reperfusion therapy with intravenous thrombolysis ( table 4) or mechanical thrombectomy is warranted for patients with ischemic stroke. (See 'Initial general assessment' above and 'Is the patient a candidate for reperfusion?' above.) https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 25/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate Determining the type of stroke After completing the initial assessment, the goal of the subsequent evaluation is to determine the underlying pathophysiology of the stroke based upon the history, physical examination, and initial neuroimaging findings ( table 1). Certain constellations of symptoms and signs can suggest a specific ischemic process ( table 5). (See 'Determining a presumptive diagnosis of stroke subtype' above.) Confirming the diagnosis Confirming the precise pathophysiologic process is aided by more directed diagnostic testing, including cardiac studies and neurovascular imaging. (See 'Confirming the diagnosis' above.) Cardiac monitoring Cardiac monitoring for at least the first 24 hours after the onset of ischemic stroke is useful to look for arrhythmias. For patients with a cryptogenic ischemic stroke or transient ischemic attack (TIA) and no evidence of atrial fibrillation on electrocardiogram (ECG) and 24-hour cardiac monitoring, we suggest ambulatory cardiac monitoring for several weeks. All patients with suspected embolic stroke should have an echocardiogram. (See 'Cardiac evaluation' above and 'Echocardiography' above.) Blood tests A number of blood tests are indicated in patients with brain ischemia, including a complete blood count, platelet count, prothrombin time and partial thromboplastin time, and serum lipids. However, indications to test for hypercoagulable disorders are limited. Furthermore, it remains unclear if the inherited thrombophilias directly predispose to arterial stroke as they do to venous thrombosis. (See 'Blood tests' above.) Evaluation for a bleeding disorder in patients with hemorrhagic stroke In this setting, all patients require platelet count, prothrombin time, activated partial thromboplastin time, and thrombin time and/or ecarin clotting time if the patient is known or suspected to be taking a direct thrombin inhibitor or a direct factor Xa inhibitor. (See 'Evaluation of patients with intracerebral hemorrhage' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Caplan LR. Terms describing brain ischemia by tempo are no longer useful: a polemic (with apologies to Shakespeare). Surg Neurol 1993; 40:91. 2. Caplan LR. TIAs: we need to return to the question, 'What is wrong with Mr. Jones?'. Neurology 1988; 38:791. https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 26/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate 3. Gorelick PB, Hier DB, Caplan LR, Langenberg P. Headache in acute cerebrovascular disease. Neurology 1986; 36:1445. 4. Ginsberg MD, Busto R. Combating hyperthermia in acute stroke: a significant clinical concern. Stroke 1998; 29:529. 5. Caplan LR. Imaging and laboratory diagnosis. In: Caplan's Stroke: A Clinical Approach, 4th, S aunders, Philadelphia 2009. p.87. 6. Moncayo J, Devuyst G, Van Melle G, Bogousslavsky J. Coexisting causes of ischemic stroke. Arch Neurol 2000; 57:1139. 7. Barnett HJ, Gunton RW, Eliasziw M, et al. Causes and severity of ischemic stroke in patients with internal carotid artery stenosis. JAMA 2000; 283:1429. 8. Caplan LR. Diagnosis and the clinical encounter. In: Caplan's Stroke: A Clinical Approach, 4th, Saunders, Philadelphia 2009. p.64. 9. Caplan LR, Gorelick PB, Hier DB. Race, sex and occlusive cerebrovascular disease: a review. Stroke 1986; 17:648. 10. Petty GW, Brown RD Jr, Whisnant JP, et al. Ischemic stroke subtypes: a population-based study of incidence and risk factors. Stroke 1999; 30:2513. 11. MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke, and coronary heart disease. Part 1, Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990; 335:765. 12. Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360:1903. 13. Kawachi I, Colditz GA, Stampfer MJ, et al. Smoking cessation and decreased risk of stroke in women. JAMA 1993; 269:232. 14. Kase CS, Caplan LR. Intracerebral Hemorrhage, Butterworth-Heinemann, Boston 1996. 15. Labovitz DL, Hauser WA, Sacco RL. Prevalence and predictors of early seizure and status epilepticus after first stroke. Neurology 2001; 57:200. 16. Caplan LR. Brain embolism. In: Practical Clinical Neurocardiology, Caplan LR, Chimowitz M, Hurst JW (Eds), Marcel Dekker, New York 1999. 17. Glass TA, Hennessey PM, Pazdera L, et al. Outcome at 30 days in the New England Medical Center Posterior Circulation Registry. Arch Neurol 2002; 59:369. 18. Sarkar S, Ghosh S, Ghosh SK, Collier A. Role of transcranial Doppler ultrasonography in stroke. Postgrad Med J 2007; 83:683. https://www.uptodate.com/contents/overview-of-the-evaluation-of-stroke/print 27/53 7/5/23, 12:17 PM Overview of the evaluation of stroke - UpToDate 19. Mart nez-S nchez P, Serena J, Alexandrov AV, et al. Update on ultrasound techniques for the diagnosis of cerebral ischemia. Cerebrovasc Dis 2009; 27 Suppl 1:9. 20. Saito K, Kimura K, Nagatsuka K, et al. Vertebral artery occlusion in duplex color-coded ultrasonography. Stroke 2004; 35:1068.