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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 7/7/23, 11:29 AM 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 7/7/23, 11:29 AM 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 7/7/23, 11:29 AM 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 7/7/23, 11:29 AM 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 7/7/23, 11:29 AM 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 7/7/23, 11:29 AM 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 7/7/23, 11:29 AM 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. REFERENCES https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 20/33 7/7/23, 11:29 AM Hemorrhagic stroke in children - UpToDate 1. Saver JL, Warach S, Janis S, et al. Standardizing the structure of stroke clinical and epidemiologic research data: the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Common Data Element (CDE) project. Stroke 2012; 43:967. 2. Broderick JP, Phillips SJ, Whisnant JP, et al. Incidence rates of stroke in the eighties: the end of the decline in stroke? Stroke 1989; 20:577. 3. Broderick J, Talbot GT, Prenger E, et al. Stroke in children within a major metropolitan area: the surprising importance of intracerebral hemorrhage. J Child Neurol 1993; 8:250. 4. Fullerton HJ, Wu YW, Zhao S, Johnston SC. Risk of stroke in children: ethnic and gender disparities. Neurology 2003; 61:189. 5. Giroud M, Lemesle M, Gouyon JB, et al. Cerebrovascular disease in children under 16 years of age in the city of Dijon, France: a study of incidence and clinical features from 1985 to 1993. J Clin Epidemiol 1995; 48:1343. 6. Jordan LC, Johnston SC, Wu YW, et al. The importance of cerebral aneurysms in childhood hemorrhagic stroke: a population-based study. Stroke 2009; 40:400. 7. Al-Jarallah A, Al-Rifai MT, Riela AR, Roach ES. Nontraumatic brain hemorrhage in children: etiology and presentation. J Child Neurol 2000; 15:284. 8. Beslow LA, Licht DJ, Smith SE, et al. Predictors of outcome in childhood intracerebral hemorrhage: a prospective consecutive cohort study. Stroke 2010; 41:313. 9. Adil MM, Qureshi AI, Beslow LA, et al. Factors Associated With Increased In-Hospital Mortality Among Children With Intracerebral Hemorrhage. J Child Neurol 2015; 30:1024. 10. Liu J, Wang D, Lei C, et al. Etiology, clinical characteristics and prognosis of spontaneous intracerebral hemorrhage in children: A prospective cohort study in China. J Neurol Sci 2015; 358:367. 11. Al-Shahi R, Warlow C. A systematic review of the frequency and prognosis of arteriovenous malformations of the brain in adults. Brain 2001; 124:1900. 12. Zhao J, Wang S, Li J, et al. Clinical characteristics and surgical results of patients with cerebral arteriovenous malformations. Surg Neurol 2005; 63:156. 13. Di Rocco C, Tamburrini G, Rollo M. Cerebral arteriovenous malformations in children. Acta Neurochir (Wien) 2000; 142:145. 14. Fullerton HJ, Achrol AS, Johnston SC, et al. Long-term hemorrhage risk in children versus adults with brain arteriovenous malformations. Stroke 2005; 36:2099. 15. Chung B, Wong V. Pediatric stroke among Hong Kong Chinese subjects. Pediatrics 2004; 114:e206. https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 21/33 7/7/23, 11:29 AM Hemorrhagic stroke in children - UpToDate 16. Giroud M, Lemesle M, Madinier G, et al. Stroke in children under 16 years of age. Clinical and etiological difference with adults. Acta Neurol Scand 1997; 96:401. 17. Meyer-Heim AD, Boltshauser E. Spontaneous intracranial haemorrhage in children: aetiology, presentation and outcome. Brain Dev 2003; 25:416. 18. Plauchu H, de Chadar vian JP, Bideau A, Robert JM. Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population. Am J Med Genet 1989; 32:291. 19. Saleh M, Carter MT, Latino GA, et al. Brain arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia: clinical presentation and anatomical distribution. Pediatr Neurol 2013; 49:445. 20. Putman CM, Chaloupka JC, Fulbright RK, et al. Exceptional multiplicity of cerebral arteriovenous malformations associated with hereditary hemorrhagic telangiectasia (Osler- Weber-Rendu syndrome). AJNR Am J Neuroradiol 1996; 17:1733. 21. Begbie ME, Wallace GM, Shovlin CL. Hereditary haemorrhagic telangiectasia (Osler-Weber- Rendu syndrome): a view from the 21st century. Postgrad Med J 2003; 79:18. 22. Fulbright RK, Chaloupka JC, Putman CM, et al. MR of hereditary hemorrhagic telangiectasia: prevalence and spectrum of cerebrovascular malformations. AJNR Am J Neuroradiol 1998; 19:477. 23. Morgan T, McDonald J, Anderson C, et al. Intracranial hemorrhage in infants and children with hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome). Pediatrics 2002; 109:E12. 24. Tomlinson FH, R fenacht DA, Sundt TM Jr, et al. Arteriovenous fistulas of the brain and the spinal cord. J Neurosurg 1993; 79:16. 25. Cooke D, Tatum J, Farid H, et al. Transvenous embolization of a pediatric pial arteriovenous fistula. J Neurointerv Surg 2012; 4:e14. 26. Al-Shahi R, Bhattacharya JJ, Currie DG, et al. Prospective, population-based detection of intracranial vascular malformations in adults: the Scottish Intracranial Vascular Malformation Study (SIVMS). Stroke 2003; 34:1163. 27. Gross BA, Smith ER, Goumnerova L, et al. Resection of supratentorial lobar cavernous malformations in children: clinical article J Neurosurg Pediatr 2013; 12:367. 28. Gault J, Sarin H, Awadallah NA, et al. Pathobiology of human cerebrovascular malformations: basic mechanisms and clinical relevance. Neurosurgery 2004; 55:1. 29. Lanthier S, Carmant L, David M, et al. Stroke in children: the coexistence of multiple risk factors predicts poor outcome. Neurology 2000; 54:371. https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 22/33 7/7/23, 11:29 AM Hemorrhagic stroke in children - UpToDate 30. Mottolese C, Hermier M, Stan H, et al. Central nervous system cavernomas in the pediatric age group. Neurosurg Rev 2001; 24:55. 31. Fortuna A, Ferrante L, Mastronardi L, et al. Cerebral cavernous angioma in children. Childs Nerv Syst 1989; 5:201. 32. Gerosa M, Licata C, Fiore DL, Iraci G. Intracranial aneurysms of childhood. Childs Brain 1980; 6:295. 33. Meyer FB, Sundt TM Jr, Fode NC, et al. Cerebral aneurysms in childhood and adolescence. J Neurosurg 1989; 70:420. 34. Patel AN, Richardson AE. Ruptured intracranial aneurysms in the first two decades of life. A study of 58 patients. J Neurosurg 1971; 35:571. 35. Roche JL, Choux M, Czorny A, et al. [Intracranial arterial aneurysm in children. A cooperative study. Apropos of 43 cases]. Neurochirurgie 1988; 34:243. 36. Sedzimir CB, Robinson J. Intracranial hemorrhage in children and adolescents. J Neurosurg 1973; 38:269. 37. Locksley HB, Sahs AL, Knowler L. Report on the cooperative study of intracranial aneurysms and subarachnoid hemorrhage. Section II. General survey of cases in the central registry and characteristics of the sample population. J Neurosurg 1966; 24:922. 38. Locksley HB. Natural history of subarachnoid hemorrhage, intracranial aneurysms and arteriovenous malformations. Based on 6368 cases in the cooperative study. J Neurosurg 1966; 25:219. 39. Gemmete JJ, Toma AK, Davagnanam I, et al. Pediatric cerebral aneurysms. Neuroimaging Clin N Am 2013; 23:771. 40. Alawi A, Edgell RC, Elbabaa SK, et al. Treatment of cerebral aneurysms in children: analysis of the Kids' Inpatient Database. J Neurosurg Pediatr 2014; 14:23. 41. Huang J, McGirt MJ, Gailloud P, Tamargo RJ. Intracranial aneurysms in the pediatric population: case series and literature review. Surg Neurol 2005; 63:424. 42. Jordan LC, Hillis AE. Hemorrhagic stroke in children. Pediatr Neurol 2007; 36:73. 43. Abbas Q, Merchant QU, Nasir B, et al. Spectrum of Intracerebral Hemorrhage in Children: A Report from PICU of a Resource Limited Country. Crit Care Res Pract 2016; 2016:9124245. 44. Wang JJ, Shi KL, Li JW, et al. Risk factors for arterial ischemic and hemorrhagic stroke in childhood. Pediatr Neurol 2009; 40:277. 45. Klinge J, Auberger K, Auerswald G, et al. Prevalence and outcome of intracranial haemorrhage in haemophiliacs a survey of the paediatric group of the German Society of Thrombosis and Haemostasis (GTH). Eur J Pediatr 1999; 158 Suppl 3:S162. https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 23/33 7/7/23, 11:29 AM Hemorrhagic stroke in children - UpToDate 46. Revel-Vilk S, Golomb MR, Achonu C, et al. Effect of intracranial bleeds on the health and quality of life of boys with hemophilia. J Pediatr 2004; 144:490. 47. Yoffe G, Buchanan GR. Intracranial hemorrhage in newborn and young infants with hemophilia. J Pediatr 1988; 113:333. 48. Earley CJ, Kittner SJ, Feeser BR, et al. Stroke in children and sickle-cell disease: Baltimore- Washington Cooperative Young Stroke Study. Neurology 1998; 51:169. 49. Strouse JJ, Hulbert ML, DeBaun MR, et al. Primary hemorrhagic stroke in children with sickle cell disease is associated with recent transfusion and use of corticosteroids. Pediatrics 2006; 118:1916. 50. Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood 1998; 91:288. 51. Dobson SR, Holden KR, Nietert PJ, et al. Moyamoya syndrome in childhood sickle cell disease: a predictive factor for recurrent cerebrovascular events. Blood 2002; 99:3144. 52. Kyrnetskiy EE, Kun LE, Boop FA, et al. Types, causes, and outcome of intracranial hemorrhage in children with cancer. J Neurosurg 2005; 102:31. 53. LaRovere KL, Riggs BJ, Poussaint TY, et al. Neurologic Involvement in Children and Adolescents Hospitalized in the United States for COVID-19 or Multisystem Inflammatory Syndrome. JAMA Neurol 2021; 78:536. 54. Coronado Munoz A, Tasayco J, Morales W, et al. High incidence of stroke and mortality in pediatric critical care patients with COVID-19 in Peru. Pediatr Res 2022; 91:1730. 55. Lo WD, Lee J, Rusin J, et al. Intracranial hemorrhage in children: an evolving spectrum. Arch Neurol 2008; 65:1629. 56. Jordan LC, Kleinman JT, Hillis AE. Intracerebral hemorrhage volume predicts poor neurologic outcome in children. Stroke 2009; 40:1666. 57. Gumer LB, Del Vecchio M, Aronoff S. Strokes in children: a systematic review. Pediatr Emerg Care 2014; 30:660. 58. Beslow LA, Heuer GG, Jordan LC. Nontraumatic Intracerebral Hemorrhage and Subarachnoi d Hemorrhage. In: Pediatric Neurocritical Care, Abend NS, Helfaer MA (Eds), Demos Medical, New York 2012. p.195. 59. Beslow LA, Abend NS, Gindville MC, et al. Pediatric intracerebral hemorrhage: acute symptomatic seizures and epilepsy. JAMA Neurol 2013; 70:448. 60. Abend NS, Beslow LA, Smith SE, et al. Seizures as a presenting symptom of acute arterial ischemic stroke in childhood. J Pediatr 2011; 159:479. https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 24/33 7/7/23, 11:29 AM 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 7/7/23, 11:29 AM 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 7/7/23, 11:29 AM 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 7/7/23, 11:29 AM 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).

ischemic stroke in childhood. J Pediatr 2011; 159:479. https://www.uptodate.com/contents/hemorrhagic-stroke-in-children/print 24/33 7/7/23, 11:29 AM 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 7/7/23, 11:29 AM 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 7/7/23, 11:29 AM 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 7/7/23, 11:29 AM 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 7/7/23, 11:29 AM 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 7/7/23, 11:29 AM 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 7/7/23, 11:29 AM 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 7/7/23, 11:29 AM 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 7/7/23, 11:29 AM 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

7/7/23, 11:32 AM Late recurrence of subarachnoid hemorrhage and intracranial aneurysms - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Late recurrence of subarachnoid hemorrhage and intracranial aneurysms : Robert J Singer, MD, Christopher S Ogilvy, MD, Guy Rordorf, MD : Jos Biller, MD, FACP, FAAN, FAHA : 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: Apr 25, 2023. INTRODUCTION Aneurysmal subarachnoid hemorrhage (SAH) is often a devastating event. However, therapeutic advances have added to the armamentarium for treating this malignant process. As case fatality rates decline, attention is increasingly turned to the management of long-term complications. One of these is the enduring risk of recurrent SAH, which can occur despite successful endovascular or surgical treatment of the ruptured aneurysm. This topic discusses the risk of recurrent aneurysm formation and SAH after a patient has been treated for an initial SAH. Other topics address acute aspects of aneurysmal SAH, as well as the management of patients with unruptured intracranial aneurysms, and aneurysm screening in other high-risk populations. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".) (See "Unruptured intracranial aneurysms".) (See "Screening for intracranial aneurysm".) EPIDEMIOLOGY Cumulative 8- to 10-year incidences of late rebleeding (more than one year after initial SAH) vary from 0.1 to 3.2 percent [1-5]. The risk of SAH recurrence has been estimated to be 15 to 22 times https://www.uptodate.com/contents/late-recurrence-of-subarachnoid-hemorrhage-and-intracranial-aneurysms/print 1/12 7/7/23, 11:32 AM Late recurrence of subarachnoid hemorrhage and intracranial aneurysms - UpToDate higher than the expected rate of a first SAH in a healthy age- and sex-matched cohort [2,4]. Independent risk factors for recurrent SAH in one study were current smoking, younger age, and multiple aneurysms at the time of the initial SAH [2]. Hypertension was an additional important risk factor for aneurysm regrowth or de novo aneurysm formation in another retrospective study [6]. Another long-term follow-up study of 59 patients with childhood aneurysms found that current and previous cigarette smoking was a risk factor for recurrent and de novo aneurysm formation [7]. Cigarette smoking and hypertension are also established risk factors for both unruptured intracranial aneurysms and aneurysmal SAH. (See "Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis", section on 'Risk factors' and "Unruptured intracranial aneurysms", section on 'Aneurysm formation'.) CAUSES Recurrent SAH may result from recurrence of the treated aneurysm, rupture of another preexisting aneurysm in a patient with multiple aneurysms, or rupture of a de novo aneurysm. In the International Subarachnoid Aneurysm Trial (ISAT), 33 rebleeds occurred in 1644 patients followed for 10 to 18.5 years after treatment; 17 were from the treated aneurysm, 6 were from a preexisting, untreated aneurysm, and 9 were from new aneurysms (the preexisting status of one aneurysm was unknown) [1,8]. Recurrence of the treated aneurysm Aneurysms may recur after endovascular or open surgical treatment. Endovascularly treated patients appear to be at somewhat higher risk of rebleeding from the original aneurysm than surgically treated patients [1,3,9]. In systematic reviews of intracranial aneurysms, recurrence after endovascular treatment occurred in 21 to 24 percent [10,11]. Endovascular treatment Among the 2108 patients originally treated in ISAT, late retreatment was more frequent after endovascular coiling than after clipping (8.6 versus 0.9 percent) [12]. The mean time to late retreatment after endovascular coiling was 21 months. Recurrent SAH from the originally treated aneurysm occurred most commonly in the endovascular treatment group (10 of 13) [1]. The mechanism of aneurysm recurrence in this setting may be related to compaction of coils over time and/or to aneurysm sac regrowth [13]. One randomized trial found that the use of hydrogel-coated coils (designed to improve packing and stability) was associated with fewer cases of aneurysm recurrence compared with standard bare platinum coils (24 https://www.uptodate.com/contents/late-recurrence-of-subarachnoid-hemorrhage-and-intracranial-aneurysms/print 2/12 7/7/23, 11:32 AM Late recurrence of subarachnoid hemorrhage and intracranial aneurysms - UpToDate versus 33 percent) [14]. The highest risk for recanalization of a coiled aneurysm appears to be in the first six months and is low after two years [3,15-17]. Most of these aneurysm recurrences are not associated with rupture and SAH; the estimated annual hemorrhage rate after coiling of a ruptured aneurysm is between 0.1 and 3 percent [3,11,15,18-20]. Risk factors for aneurysm recurrence from coil compaction include [9,10,12,17-19,21,22]: Larger lumen size (>10 mm) Larger aneurysm neck size Incomplete occlusion In one predictive model, the Aneurysm Recanalization Stratification Scale, the chance of aneurysm recanalization is stratified based upon aneurysm size (>10 mm versus 10 mm), presence of subarachnoid hemorrhage, presence of intraluminal thrombus, modality of treatment (ie, coils only, stent assistance, or flow diversion), and initial degree of obliteration. Based on these factors, the predicted rate of recurrence can range from 4.9 to 100 percent [21,23]. Surgical clipping Recurrence of an aneurysm that was successfully surgically clipped appears to be relatively rare [1-3,24]. In a study of 112 patients (140 clipped aneurysms) who had agreed to undergo cerebral angiography at a mean of nine years after clipping, four aneurysm regrowths (3 percent) were detected [25]. In another study of 610 patients treated with surgical clipping, follow-up computed tomographic angiography (CTA) 2 to 18 years after the index SAH revealed an aneurysm at the clip site in 24 patients (4 percent) [26]. Recurrent SAH attributed to a previously clipped aneurysm is even less common [1- 3,15,24,26]. As an example, in a cohort of 752 patients with aneurysmal SAH and successful clipping after a mean follow-up of 8 years, only 4 of the 18 subsequent recurrent SAH (0.5 percent) were associated with a recurrent aneurysm at the clip site [2]. In another series of 711 patients, none of the surgically clipped aneurysms were associated with rerupture over a mean of 4.4 years of follow-up [3]. De novo aneurysm formation The incidence of de novo aneurysms after surgical clipping or endovascular treatment may be overestimated, in part because aneurysms may be missed at the time of initial hemorrhage [25,27]. As an example, CTA was used to screen 495 patients who had had prior surgical clipping of a ruptured aneurysm at a mean of 8 years previously (range 4 to 14 years). In 87 patients (18 percent), at least one aneurysm was found at a different location than the clip site [27]. Of these 87 patients, the original digital subtraction angiography (DSA) or CTA was available for 51 patients (with 62 aneurysms on follow-up study). Comparison of the https://www.uptodate.com/contents/late-recurrence-of-subarachnoid-hemorrhage-and-intracranial-aneurysms/print 3/12 7/7/23, 11:32 AM Late recurrence of subarachnoid hemorrhage and intracranial aneurysms - UpToDate original and screening studies revealed that 19 of 62 aneurysms (31 percent) were de novo, and 43 (69 percent) were visible in retrospect. Other cohort studies also find that a significant percentage of "new" aneurysms are present on the original angiogram, when it is available for expert review [2,26]. De novo aneurysm formation probably occurs at a low rate. A meta-analysis of 14,968 total aneurysm patients showed an estimated incidence of 0.3 percent formation of de novo aneurysms per patient-year with no significant difference between patients originally presenting with ruptured versus unruptured aneurysms [28]. In one case series, the five-year cumulative incidence after aneurysm coiling was 0.75 percent [29]. Other studies have reported annual incidence of de novo aneurysm formation of 0.3 to 1.8 percent in patients who have had one aneurysm treated [6,25,30,31]. Multiple aneurysms, smoking, female sex, and older age have been associated with de novo aneurysm formation in some studies [29,32]. In a study of 1601 patients with SAH treated with surgical clipping, the incidence rate of de novo aneurysm formation was 1.42 percent per patient-year [33]. Risk factors for development of a de novo aneurysm included age 50 years, family history of aneurysm, and multiplicity at initial SAH. Risk factors for growth or rupture of de novo aneurysms included female sex, shorter interval from initial SAH to detection of a de novo aneurysm, multiplicity at initial SAH, and de novo aneurysm diameter 4 mm. Growth of preexisting aneurysms Approximately 20 percent of patients with aneurysmal SAH have multiple aneurysms. These may be treated at the same time as the index (ruptured) aneurysm depending on their size, location, and other factors. However, smaller unruptured aneurysms and those less accessible to treatment may be monitored rather than treated. In one study, serial imaging studies were used to follow 87 patients with 111 unruptured aneurysms; 79 patients had ruptured aneurysms clipped at start of follow-up [34]. Unruptured aneurysms increased in size by 1 mm in 45 percent of patients and by 3 mm in 36 percent. Cigarette smoking was a risk factor for 3 mm aneurysm growth. Other follow-up studies in patients after SAH have also documented a significant rate of aneurysm growth in untreated aneurysms [27]. Recurrent SAH occurred in 1.6 percent of patients per year and was significantly predicted by aneurysm growth. Additional risk factors for aneurysm growth are larger aneurysm size, multiple additional aneurysms, and female sex [29]. FOLLOW-UP EVALUATIONS There is no consensus on whether and how to screen for new or recurrent aneurysms after SAH [4]. https://www.uptodate.com/contents/late-recurrence-of-subarachnoid-hemorrhage-and-intracranial-aneurysms/print 4/12 7/7/23, 11:32 AM Late recurrence of subarachnoid hemorrhage and intracranial aneurysms - UpToDate At least two decision models have been used to evaluate the utility of follow-up imaging studies: In the first study, outcomes after SAH were modeled using expected outcome and complications rates obtained from a literature review. It was assumed that patients had successful obliteration of all aneurysms by surgical clipping or endovascular coiling after the index SAH [35]. Patients were screened with computed tomographic angiography (CTA). The expected quality-adjusted life years were virtually the same (approximately 8.3 years) for no screening, screening once at five years, and screening every two years, regardless of the initial type of treatment. Screening prevented new episodes of SAH, but the benefit was offset by the cost of increased morbidity from diagnostic tests and preventive treatment. As an example, with screening every two years after coiling, the expected rate of SAH decreased from 1.9 to 0.5 percent and mortality decreased from 0.9 to 0.6 percent, but the disability rate increased from 0.5 to 1.9 percent due to complications from angiography and retreatment. In a second study, 610 patients with SAH were screened with CTA 2 to 18 years after surgical clipping, and the results of screening were used as input for a decision analysis [26]. Screening every five years (compared with no screening) prevented nearly half of the SAH recurrences, but life expectancy increased only marginally, and these benefits were offset by a negative impact on quality of life and by increased costs. Screening became cost effective but did not increase quality of life in patients when the risks of aneurysm formation and rupture were doubled, and screening was cost effective and improved quality of life in patients with a 4.5-fold increase in both risks. In addition, screening increased quality of life at acceptable costs in patients with fear for a recurrence. In the face of limited and conflicting data, it is our opinion that patients require comprehensive follow-up after SAH. Extra vigilance is warranted for patients with risk factors for recurrent SAH and aneurysm regrowth, such as incomplete occlusion at initial treatment, large aneurysm size, multiple aneurysms, hypertension, and cigarette smoking. For patients treated with endovascular coiling, we obtain immediate evaluation of the coil mass by angiography during the procedure. Follow-up imaging is usually performed at six months, and, if completely occluded, at two years and five years post-procedure. There is variability in longer-term follow-up in terms of type of imaging (CTA, magnetic resonance angiography [MRA], or angiography) and the interval of imaging. Some form of imaging should be conducted for up to 10 years after treatment. In addition, we recommend DSA at three to six months for all patients who have undergone coiling, as angiography remains the gold standard [36]; although some data https://www.uptodate.com/contents/late-recurrence-of-subarachnoid-hemorrhage-and-intracranial-aneurysms/print 5/12 7/7/23, 11:32 AM Late recurrence of subarachnoid hemorrhage and intracranial aneurysms - UpToDate suggest that magnetic resonance angiography (MRA) may be sufficiently accurate for this purpose, it is probably to some extent center specific [37,38]. For patients treated with surgical clipping of aneurysms, we obtain screening with MRA or CTA at three and six months. Additional angiography is performed only if there are worrisome features on the noninvasive studies. Further follow-up imaging studies depend on the appearance and size of the treated and any other aneurysms, the presence of risk factors for aneurysm recurrence, and the patient's functional status and individual preferences. Coil artifacts may interfere with interpretation of CTA in patients treated with coiling, whereas MRA interpretation may be impaired by large artifacts around clipped aneurysms [39,40]. Therefore, CTA is preferred for assessment of patients with clipped aneurysms, and MRA is preferred for patients with coiled aneurysms [41,42]. In one study of 60 patients with 74 coiled aneurysms followed with both angiography and MRA, agreement between the two studies was good. In only four aneurysms was recanalization seen on DSA that was not seen on MRA, with the degree of angiographic recanalization in these patients considered too minor (<3 mm) to indicate further treatment [20,43]. MANAGEMENT The decision to treat de novo aneurysms or enlarging preexisting aneurysms is based on the same factors used for other unruptured aneurysms. (See "Unruptured intracranial aneurysms", section on 'Management'.) Treatment of a recurrent, previously treated aneurysm may not be the same as the initial approach and may involve either endovascular coiling, stent-assisted coiling, or flow diversion [44,45]. Surgical clipping is also a possibility depending upon the aneurysm morphology [3,26,46]. Retreatment is not benign. In one case series, 11 percent of recoiling procedures were associated with potentially life-threatening or disabling events, while 2 of 12 repeated surgical procedures resulted in death [3]. The severity of the functional and neurologic morbidity incurred during the index SAH is also a consideration in determining whether intervention is likely to be of overall benefit to the patient's quality of life. https://www.uptodate.com/contents/late-recurrence-of-subarachnoid-hemorrhage-and-intracranial-aneurysms/print 6/12 7/7/23, 11:32 AM Late recurrence of subarachnoid hemorrhage and intracranial aneurysms - 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: Stroke in adults".) SUMMARY AND RECOMMENDATIONS Epidemiology Patients who have had an aneurysmal subarachnoid hemorrhage (SAH) have a small but enduring risk of an aneurysmal recurrence and rupture relative to the general population, with a cumulative 10-year incidence of SAH as high as 3 percent. Younger age, cigarette smoking, and hypertension appear to be risk factors for recurrence. (See 'Epidemiology' above.) Causes Recurrent SAH may result from recurrence of the treated aneurysm, de novo aneurysm formation, or rupture of another preexisting aneurysm in a patient with multiple aneurysms. (See 'Causes' above.) Recurrence after aneurysm treatment Aneurysms may recur after endovascular or open surgical treatment. The risk of recurrence is higher in patients treated with endovascular techniques (up to 24 percent) than those treated with surgery (up to 4 percent). Incomplete occlusion and larger (>10 mm) aneurysm size are risk factors for recurrence. De novo aneurysms The incidence of de novo aneurysms after surgical clipping or endovascular coiling appears to be up to 1.8 percent of patients per year. The risk is higher in patients with multiple aneurysms and those who smoke. Growth and rupture of preexisting unruptured aneurysms Patients treated for SAH may harbor other unruptured aneurysms. The risk of SAH from these unruptured aneurysm increased with larger aneurysm size, aneurysm growth, multiple additional aneurysms, and female sex. Surveillance imaging after treatment The frequency and type of neuroimaging follow- up depends on many factors including the treatment (endovascular versus surgery) of the index aneurysm, the presence of risk factors for recurrent aneurysmal formation, the number and size of any additional aneurysms, and the neurologic status and preferences of the patient. (See 'Follow-up evaluations' above.) https://www.uptodate.com/contents/late-recurrence-of-subarachnoid-hemorrhage-and-intracranial-aneurysms/print 7/12 7/7/23, 11:32 AM Late recurrence of subarachnoid hemorrhage and intracranial aneurysms - UpToDate Following endovascular treatment For most patients who have undergone endovascular treatment of their aneurysm, we typically obtain a cerebral angiogram approximately six months after the initial repair. Long-term follow-up is typically performed for 5 to 10 years, but the type and frequency of imaging varies between centers and countries. Following surgical clipping For most patients who have undergone surgical clipping of a ruptured aneurysm, we typically obtain computed tomographic angiography (CTA) at three to six months. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Molyneux AJ, Kerr RS, Birks J, et al. Risk of recurrent subarachnoid haemorrhage, death, or dependence and standardised mortality ratios after clipping or coiling of an intracranial aneurysm in the International Subarachnoid Aneurysm Trial (ISAT): long-term follow-up. Lancet Neurol 2009; 8:427. 2. Wermer MJ, Greebe P, Algra A, Rinkel GJ. Incidence of recurrent subarachnoid hemorrhage after clipping for ruptured intracranial aneurysms. Stroke 2005; 36:2394. 3. CARAT Investigators. Rates of delayed rebleeding from intracranial aneurysms are low after surgical and endovascular treatment. Stroke 2006; 37:1437. 4. Rinkel GJ, Algra A. Long-term outcomes of patients with aneurysmal subarachnoid haemorrhage. Lancet Neurol 2011; 10:349. 5. Tsutsumi K, Ueki K, Usui M, et al. Risk of recurrent subarachnoid hemorrhage after complete obliteration of cerebral aneurysms. Stroke 1998; 29:2511. 6. Wermer MJ, van der Schaaf IC, Velthuis BK, et al. Follow-up screening after subarachnoid haemorrhage: frequency and determinants of new aneurysms and enlargement of existing aneurysms. Brain 2005; 128:2421. 7. Koroknay-P l P, Niemel M, Lehto H, et al. De novo and recurrent aneurysms in pediatric patients with cerebral aneurysms. Stroke 2013; 44:1436. 8. Molyneux AJ, Birks J, Clarke A, et al. The durability of endovascular coiling versus neurosurgical clipping of ruptured cerebral aneurysms: 18 year follow-up of the UK cohort of the International Subarachnoid Aneurysm Trial (ISAT). Lancet 2015; 385:691. 9. Johnston SC, Dowd CF, Higashida RT, et al. Predictors of rehemorrhage after treatment of ruptured intracranial aneurysms: the Cerebral Aneurysm Rerupture After Treatment (CARAT) https://www.uptodate.com/contents/late-recurrence-of-subarachnoid-hemorrhage-and-intracranial-aneurysms/print 8/12 7/7/23, 11:32 AM Late recurrence of subarachnoid hemorrhage and intracranial aneurysms - UpToDate study. Stroke 2008; 39:120. 10. Ferns SP, Sprengers ME, van Rooij WJ, et al. Coiling of intracranial aneurysms: a systematic review on initial occlusion and reopening and retreatment rates. Stroke 2009; 40:e523. 11. Naggara ON, White PM, Guilbert F, et al. Endovascular treatment of intracranial unruptured aneurysms: systematic review and meta-analysis of the literature on safety and efficacy. Radiology 2010; 256:887. 12. Campi A, Ramzi N, Molyneux AJ, et al. Retreatment of ruptured cerebral aneurysms in patients randomized by coiling or clipping in the International Subarachnoid Aneurysm Trial (ISAT). Stroke 2007; 38:1538. 13. Hasan DM, Nadareyshvili AI, Hoppe AL, et al. Cerebral aneurysm sac growth as the etiology of recurrence after successful coil embolization. Stroke 2012; 43:866. 14. White PM, Lewis SC, Gholkar A, et al. Hydrogel-coated coils versus bare platinum coils for the endovascular treatment of intracranial aneurysms (HELPS): a randomised controlled trial. Lancet 2011; 377:1655. 15. Schaafsma JD, Sprengers ME, van Rooij WJ, et al. Long-term recurrent subarachnoid hemorrhage after adequate coiling versus clipping of ruptured intracranial aneurysms. Stroke 2009; 40:1758. 16. Sprengers ME, Schaafsma J, van Rooij WJ, et al. Stability of intracranial aneurysms adequately occluded 6 months after coiling: a 3T MR angiography multicenter long-term follow-up study. AJNR Am J Neuroradiol 2008; 29:1768. 17. Ferns SP, Sprengers ME, van Rooij WJ, et al. Late reopening of adequately coiled intracranial aneurysms: frequency and risk factors in 400 patients with 440 aneurysms. Stroke 2011; 42:1331. 18. Raymond J, Guilbert F, Weill A, et al. Long-term angiographic recurrences after selective endovascular treatment of aneurysms with detachable coils. Stroke 2003; 34:1398. 19. Murayama Y, Nien YL, Duckwiler G, et al. Guglielmi detachable coil embolization of cerebral aneurysms: 11 years' experience. J Neurosurg 2003; 98:959. 20. Munich SA, Cress MC, Rangel-Castilla L, et al. Neck Remnants and the Risk of Aneurysm Rupture After Endovascular Treatment With Coiling or Stent-Assisted Coiling: Much Ado About Nothing? Neurosurgery 2019; 84:421. 21. Ogilvy CS, Chua MH, Fusco MR, et al. Stratification of recanalization for patients with endovascular treatment of intracranial aneurysms. Neurosurgery 2015; 76:390. 22. Choi DS, Kim MC, Lee SK, et al. Clinical and angiographic long-term follow-up of completely coiled intracranial aneurysms using endovascular technique. J Neurosurg 2010; 112:575. https://www.uptodate.com/contents/late-recurrence-of-subarachnoid-hemorrhage-and-intracranial-aneurysms/print 9/12 7/7/23, 11:32 AM Late recurrence of subarachnoid hemorrhage and intracranial aneurysms - UpToDate 23. Ogilvy CS, Chua MH, Fusco MR, et al. Validation of a System to Predict Recanalization After Endovascular Treatment of Intracranial Aneurysms. Neurosurgery 2015; 77:168. 24. David CA, Vishteh AG, Spetzler RF, et al. Late angiographic follow-up review of surgically treated aneurysms. J Neurosurg 1999; 91:396. 25. Tsutsumi K, Ueki K, Morita A, et al. Risk of aneurysm recurrence in patients with clipped cerebral aneurysms: results of long-term follow-up angiography. Stroke 2001; 32:1191. 26. Wermer MJ, Koffijberg H, van der Schaaf IC, ASTRA Study Group. Effectiveness and costs of screening for aneurysms every 5 years after subarachnoid hemorrhage. Neurology 2008; 70:2053. 27. van der Schaaf IC, Velthuis BK, Wermer MJ, et al. New detected aneurysms on follow-up screening in patients with previously clipped intracranial aneurysms: comparison with DSA or CTA at the time of SAH. Stroke 2005; 36:1753. 28. Giordan E, Lanzino G, Rangel-Castilla L, et al. Risk of de novo aneurysm formation in patients with a prior diagnosis of ruptured or unruptured aneurysm: systematic review and meta-analysis. J Neurosurg 2018; 131:14. 29. Ferns SP, Sprengers ME, van Rooij WJ, et al. De novo aneurysm formation and growth of untreated aneurysms: a 5-year MRA follow-up in a large cohort of patients with coiled aneurysms and review of the literature. Stroke 2011; 42:313. 30. Sprengers ME, van Rooij WJ, Sluzewski M, et al. MR angiography follow-up 5 years after coiling: frequency of new aneurysms and enlargement of untreated aneurysms. AJNR Am J Neuroradiol 2009; 30:303. 31. Kemp WJ 3rd, Fulkerson DH, Payner TD, et al. Risk of hemorrhage from de novo cerebral aneurysms. J Neurosurg 2013; 118:58. 32. Zuurbier CCM, Bourcier R, Constant Dit Beaufils P, et al. Risk Prediction of New Intracranial Aneurysms at Follow-Up Screening in People With a Positive Family History. Stroke 2023; 54:1015. 33. Han HJ, Lee W, Kim J, et al. Formation, Growth, or Rupture of De Novo Intracranial Aneurysms: Long-Term Follow-up Study of Subarachnoid Hemorrhage Survivors. Neurosurgery 2021; 89:1104. 34. Juvela S, Poussa K, Porras M. Factors affecting formation and growth of intracranial aneurysms: a long-term follow-up study. Stroke 2001; 32:485. 35. Wermer MJ, Buskens E, van der Schaaf IC, et al. Yield of screening for new aneurysms after treatment for subarachnoid hemorrhage. Neurology 2004; 62:369. https://www.uptodate.com/contents/late-recurrence-of-subarachnoid-hemorrhage-and-intracranial-aneurysms/print 10/12 7/7/23, 11:32 AM Late recurrence of subarachnoid hemorrhage and intracranial aneurysms - UpToDate 36. Connolly ES Jr, Rabinstein AA, Carhuapoma JR, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/american Stroke Association. Stroke 2012; 43:1711. 37. Lavoie P, Gari py JL, Milot G, et al. Residual flow after cerebral aneurysm coil occlusion: diagnostic accuracy of MR angiography. Stroke 2012; 43:740. 38. Schaafsma JD, Velthuis BK, van den Berg R, et al. Coil-treated aneurysms: decision making regarding additional treatment based on findings of MR angiography and intraarterial DSA. Radiology 2012; 265:858. 39. Steiger HJ, van Loon JJ. Virtues and drawbacks of titanium alloy aneurysm clips. Acta Neurochir Suppl 1999; 72:81. 40. Masaryk AM, Frayne R, Unal O, et al. Utility of CT angiography and MR angiography for the follow-up of experimental aneurysms treated with stents or Guglielmi detachable coils. AJNR Am J Neuroradiol 2000; 21:1523. 41. Schaafsma JD, Koffijberg H, Buskens E, et al. Cost-effectiveness of magnetic resonance angiography versus intra-arterial digital subtraction angiography to follow-up patients with coiled intracranial aneurysms. Stroke 2010; 41:1736. 42. Farb RI, Nag S, Scott JN, et al. Surveillance of intracranial aneurysms treated with detachable coils: a comparison of MRA techniques. Neuroradiology 2005; 47:507. 43. Cottier JP, Bleuzen-Couthon A, Gallas S, et al. Follow-up of intracranial aneurysms treated with detachable coils: comparison of plain radiographs, 3D time-of-flight MRA and digital subtraction angiography. Neuroradiology 2003; 45:818. 44. Li YD, Li MH, Gao BL, et al. Endovascular treatment of recurrent intracranial aneurysms with re-coiling or covered stents. J Neurol Neurosurg Psychiatry 2010; 81:74. 45. Adeeb N, Griessenauer CJ, Moore J, et al. Pipeline Embolization Device for Recurrent Cerebral Aneurysms after Microsurgical Clipping. World Neurosurg 2016; 93:341. 46. Shi L, Yuan Y, Guo Y, Yu J. Intracranial post-embolization residual or recurrent aneurysms: Current management using surgical clipping. Interv Neuroradiol 2016; 22:413. Topic 16257 Version 12.0 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 https://www.uptodate.com/contents/late-recurrence-of-subarachnoid-hemorrhage-and-intracranial-aneurysms/print 11/12 7/7/23, 11:32 AM Late recurrence of subarachnoid hemorrhage and intracranial aneurysms - UpToDate 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. 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7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Nonaneurysmal subarachnoid hemorrhage : Farhan Siddiq, 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: Feb 13, 2023. INTRODUCTION Subarachnoid hemorrhage (SAH) refers to intracranial bleeding within the subarachnoid space, which lies between the arachnoid and pia mater overlying the brain. Most cases of spontaneous (nontraumatic) SAH are caused by rupture of an intracranial aneurysm. However, approximately 20 percent of SAH cases are not due to a ruptured intracranial aneurysm. The potential causes of nonaneurysmal SAH (NASAH) are diverse; in some cases, the source of bleeding is not identified. This topic will review the etiologies, diagnostic evaluation, and management of NASAH. Aneurysmal SAH is discussed separately. (See "Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis".) (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".) Traumatic SAH and other forms of traumatic brain injury are presented separately. (See "Management of acute moderate and severe traumatic brain injury".) ETIOLOGIES Perimesencephalic nonaneurysmal subarachnoid hemorrhage Perimesencephalic NASAH is a subtype of NASAH identified by a specific pattern of localized blood on computed https://www.uptodate.com/contents/nonaneurysmal-subarachnoid-hemorrhage/print 1/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - UpToDate tomography (CT) of the head and generally characterized by a benign course that distinguishes these patients not only from aneurysmal SAH, but also from other patients with NASAH [1-4]. The head CT findings that define perimesencephalic NASAH include blood isolated to the perimesencephalic cisterns anterior to the brainstem; there may be extension into the ambient cisterns or basal parts of the Sylvian fissures but not into the lateral Sylvian fissure, anterior interhemispheric fissure, or lateral ventricles ( image 1 and image 2) [4,5]. Perimesencephalic NASAH may be caused by spontaneous rupture of a small perforating artery or vein at the surface of the brainstem. However, in most cases, diagnostic testing is unable to definitively identify the cause of bleeding in perimesencephalic NASAH. In some case series, perimesencephalic NASAH accounts for up to two-thirds of patients with NASAH [5]. Perimesencephalic NASAH is discussed in detail separately. (See "Perimesencephalic nonaneurysmal subarachnoid hemorrhage".) Vascular malformations Approximately 10 percent of SAH are caused by vascular malformations [6,7]. Vascular malformations of the brain include arteriovenous malformations, dural arteriovenous fistulas, cavernous malformations, developmental venous anomalies, and capillary telangiectasias. Intracerebral hemorrhage is the most common hemorrhagic presentation, but vascular malformations near the surface of the brain may present with bleeding primarily or exclusively in the subarachnoid space [6,8-11]. Vascular malformations of the brain that most frequently present with SAH are arteriovenous malformations and dural arteriovenous fistulas. Dural arteriovenous fistulas with cortical venous drainage are associated with high risk for early rebleeding [10,12]. Most vascular malformations can be visualized on cerebral angiography [9,13,14]. Angiographically occult vascular malformations such as some cavernous malformations, developmental venous anomalies, and capillary telangiectasias are visualized on magnetic resonance imaging (MRI) but are less likely to be a source of intracranial bleeding, including SAH. Vascular malformations of the brain are discussed in greater detail separately. (See "Brain arteriovenous malformations" and "Vascular malformations of the central nervous system".) Intracranial arterial dissection Dissection of an intracranial artery can produce SAH. Intracranial dissection is usually initiated by a tear in the media, producing an intramural hemorrhage [15]. When the tear extends through (or is initiated in) the intima, a false lumen forms and can lead to narrowing of the (true) lumen with subsequent thrombus formation and https://www.uptodate.com/contents/nonaneurysmal-subarachnoid-hemorrhage/print 2/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - UpToDate thromboembolic ischemic stroke. However, if the dissection tears through the adventitia, SAH may occur. SAH is more common with dissections in the vertebrobasilar circulation than the intracranial carotid circulations. If intracranial dissection causes SAH, bleeding is massive and often devastating [16-18]. Many intracranial dissections are believed to occur in the setting of sudden or unusual stretching of arteries, but such a clinical history is often lacking. While connective tissue diseases such as Ehlers-Danlos syndrome type IV and fibromuscular dysplasia are associated with intracranial arterial dissection, most patients with dissection do not have these conditions. Other risk factors for intracranial dissection include migraine and hypertension. Most cases of intracranial arterial dissection in the setting of SAH are diagnosed by conventional cerebral angiography [1,15,17]. Brain MRI with T1-weighted fat saturation sequences may identify acute intramural hemorrhage as a crescent-shaped hyperdensity adjacent to the arterial lumen on cross-sectional images [15]. The clinical features and diagnosis of intracranial arterial dissections are discussed in greater detail separately. (See "Cerebral and cervical artery dissection: Clinical features and diagnosis".) Intracranial dissections are typically treated surgically or with endovascular interventions due to the high risk of morbidity with rebleeding, but natural history data are limited. (See "Cerebral and cervical artery dissection: Treatment and prognosis", section on 'Subarachnoid hemorrhage due to intracranial dissection'.) Reversible cerebral vasoconstriction syndrome Reversible cerebral vasoconstriction syndrome (RCVS) is a condition characterized by multifocal narrowing of the cerebral arteries and a clinical presentation that typically features recurrent thunderclap headaches with or without neurologic deficits. Patients with severe vasospasm may present with ischemic stroke, cerebral edema, and hemorrhagic complications, including SAH, often within the hemispheric convexities. In case series, convexity SAH was present in 33 percent of patients with RCVS [19]. RCVS is thought to involve vasospasm that may be triggered by vasoactive and other medications, medical conditions, or environmental stimuli, but an associated trigger is frequently not identified. The presence of recurrent thunderclap headaches is a clinical clue used to distinguish RCVS from aneurysmal SAH. Vascular imaging frequently shows widespread, multifocal narrowing of the cerebral arteries. Cerebral angiography is warranted for patients with atypical symptoms such as those presenting with a single instance of a thunderclap headache or those with SAH at the basal cisterns or Sylvian or interhemispheric fissures. Brain imaging in RCVS may show focal SAH https://www.uptodate.com/contents/nonaneurysmal-subarachnoid-hemorrhage/print 3/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - UpToDate typically within the convexities of one or both cerebral hemispheres. Ischemic lesions may be found at border-zone regions of adjacent vascular territories. The management of RCVS is typically supportive, although calcium channel blockers and magnesium sulfate have been used for vasospasm and headaches. Vasoconstriction typically resolves within several weeks. RCVS is discussed in greater detail separately. (See "Reversible cerebral vasoconstriction syndrome".) Cerebral venous thrombosis Cerebral venous thrombosis (CVT) causes increased venous pressure that can lead to the development of cerebral edema, venous infarction, and/or hemorrhage. CVT can also present with SAH as its primary manifestation [6,20-24]. The clinical presentation of CVT commonly includes headache with or without focal neurologic symptoms. Onset is typically less abrupt than with aneurysmal rupture and bleeding on neuroimaging is frequently localized and superficial rather than at the basal cisterns. CVT may be visualized on noninvasive vascular studies such as a CT or magnetic resonance (MR) venogram or on the venous phase of digital subtraction angiography (DSA) and/or on brain MRI. Management typically includes anticoagulation, even for most patients with hemorrhagic presentations. CVT is discussed in detail separately. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis" and "Cerebral venous thrombosis: Treatment and prognosis".) Cerebral amyloid angiopathy Cerebral amyloid angiopathy (CAA) most commonly presents with lobar intracerebral brain hemorrhage (ICH), but isolated convexity SAH may also occur. Subarachnoid bleeding may be focal, often restricted to a single sulcus. Associated imaging findings include chronic cortical microbleeds, superficial siderosis, and bilateral subcortical white matter hyperintensities [25-28]. Clinical symptoms vary by location and extent of acute bleeding. Some patients with convexity SAH may present with transient focal neurologic episodes. CAA is typically diagnosed by characteristic findings on brain MRI that includes T2*- susceptibility-weighted or gradient-echo sequences. Pathologic confirmation is generally reserved for patients with atypical features. The clinical presentation, diagnostic findings, and management of CAA are discussed in detail separately. (See "Cerebral amyloid angiopathy".) Traumatic SAH Trauma is a common cause of intracranial bleeding, including SAH, but is usually identified by the clinical setting. However, the appropriate clinical history may be unavailable for patients who present with confusion or stupor or baseline cognitive impairment, or in the setting of minor trauma not reported or recalled by the patient. In these settings, https://www.uptodate.com/contents/nonaneurysmal-subarachnoid-hemorrhage/print 4/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - UpToDate radiologic clues of a traumatic origin include localized bleeding in superficial sulci, adjacent skull fracture, cerebral contusion, as well as external evidence of traumatic injury [8,29]. Awake patients and any witnesses should be questioned about possible trauma as the cause to SAH. For patients with moderate to severe traumatic brain injury, brain MRI may also show other features typically associated with additional forms of brain injury (eg, intracerebral hemorrhage, diffuse axonal injury) ( image 2). (See "Acute mild traumatic brain injury (concussion) in adults" and "Management of acute moderate and severe traumatic brain injury".) While trauma can be the cause of SAH, SAH may also lead to trauma (eg, fall). Diagnostic evaluation including cerebral DSA may be indicated for some patients with trauma and SAH when history or imaging pattern of SAH suggests that a ruptured intracranial aneurysm or other etiology may have caused the SAH. (See 'Diagnostic evaluation' below.) Spinal lesions Up to 10 percent of patients with spinal vascular malformations present with SAH [8,30,31]. Dural arteriovenous fistulas are the most common type of spinal vascular malformation [32]. Those that cause SAH are usually, but not always, located in the cervical cord or craniocervical junction [33]. Prominent back or neck pain or myelopathic signs at presentation can indicate this source, but these are often absent and the clinical appearance can mimic that of intracranial aneurysm rupture [33-36]. (See "Disorders affecting the spinal cord", section on 'Vascular malformations'.) Ruptured spinal aneurysms are a rare source of bleeding in patients with SAH. These patients usually present with prominent neck or back pain and myelopathic or radicular symptoms that localize to one or more spinal roots [37,38]. Vascular malformations and aneurysms in the spine can be difficult to visualize with cerebral neuroimaging testing [8,33,34]. Cerebral DSA performed to exclude more common intracranial aneurysms may not identify spinal lesions. The diagnosis may be delayed until the patient presents with recurrent SAH. Acute brain imaging may show SAH that predominates in the caudal areas of the brainstem. However, dedicated spinal DSA is typically required to identify these lesions. Spinal vascular malformations and aneurysms are generally managed by neurosurgical and/or endovascular interventions. (See "Disorders affecting the spinal cord", section on 'Vascular malformations'.) Uncommon etiologies Primary and metastatic brain tumors have been reported to produce SAH as the presenting manifestation [6,39,40]. (See "Overview of the clinical features and diagnosis of brain tumors in adults".) https://www.uptodate.com/contents/nonaneurysmal-subarachnoid-hemorrhage/print 5/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - UpToDate Moyamoya disease is associated with cerebral aneurysms that can rupture and produce SAH; however, NASAH may also occur from rupture of the fragile transdural anastomotic vessels [41,42]. (See "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis".) Pituitary apoplexy often presents with sudden onset of headache and vomiting, and there can be prominent subarachnoid blood on head CT, which may obscure visualization of the pituitary adenoma [43-46]. Pituitary apoplexy is usually heralded by vision change and is accompanied by oculomotor nerve palsies. If not identified on the initial CT scan, brain MRI with dedicated pituitary sequences should be performed [47,48]. (See "Causes of hypopituitarism", section on 'Pituitary apoplexy'.) Spontaneous intracranial hypotension may present with orthostatic headache and NASAH, typically in the setting of acute worsening of symptoms [49,50]. Diagnosis of spontaneous intracranial hypotension is typically by brain MRI or myelography. (See "Spontaneous intracranial hypotension: Pathophysiology, clinical features, and diagnosis".) Cerebral vasculitis frequently presents with headache and progressive neurologic symptoms. Acute presentations including ischemic stroke with or without convexity SAH may also occur [51]. (See "Primary angiitis of the central nervous system in adults" and "Overview of and approach to the vasculitides in adults" and "Clinical manifestations and diagnosis of rheumatoid vasculitis", section on 'Neurologic disease'.) Cerebral hyperperfusion syndrome after carotid endarterectomy or angioplasty with or without stenting and reversible posterior leukoencephalopathy syndrome typically presents with neurologic symptoms due to focal cerebral edema and disruption of the blood-brain barrier, the latter of which may produce convexity SAH [25,28,52-55]. (See "Complications of carotid endarterectomy", section on 'Hyperperfusion syndrome' and "Reversible posterior leukoencephalopathy syndrome".) Several infectious agents that may cause meningitis or meningoencephalitis may also present with SAH. These include several bacterial sources (eg, Streptococcus pneumoniae, Staphylococcus aureus, Neisseria meningitidis, Haemophilus in uenzae, Listeria monocytogenes), viruses (eg, herpes zoster), and fungi (eg, Aspergillus and Coccidioides species) [56-60]. Other associated conditions For many patients with NASAH, diagnostic evaluation may not definitively identify the underlying cause. However, some conditions that have been associated with multiple forms of intracranial hemorrhage, including NASAH, may be attributed as the source of bleeding after excluding other causes. (See 'Diagnostic evaluation' below.) https://www.uptodate.com/contents/nonaneurysmal-subarachnoid-hemorrhage/print 6/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - UpToDate Sickle cell disease can be complicated by subarachnoid as well as intracerebral hemorrhage [5,8,61]. Most reported cases occur in children with an established diagnosis. These children are often found to have one or more aneurysms; in some cases, SAH is believed to result from fragile collateral blood vessels. Recent transfusion and treatment with glucocorticoids may be risk factors. (See "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease", section on 'Intracranial hemorrhage management'.) Bleeding disorders can be complicated by NASAH. These include conditions such as disseminated intravascular coagulation or hemophilia and anticoagulant or thrombolytic therapy [3,8,29,62-65]. However, hematologic conditions more frequently present with subdural or intracerebral hemorrhage than with isolated NASAH. Patients with NASAH due to hematologic conditions frequently also present with evidence of systemic bleeding. However, extensive isolated NASAH attributed to reduced platelet activity has been reported in one case series [66]. In general, patients with isolated NASAH and an associated bleeding disorder should be evaluated for an underlying aneurysm or other vascular lesion. (See "Perimesencephalic nonaneurysmal subarachnoid hemorrhage".) Cocaine and other sympathomimetic substances have been associated with both aneurysmal SAH and NASAH [6,8,67-69]. The mechanism of bleeding in NASAH is not known but may be related to acute blood pressure surges and/or an underlying hypertensive or toxic vasculopathy [8,70]. Patients with SAH and cocaine abuse should be assumed to have an underlying aneurysm or other vascular lesion until proven otherwise. (See "Clinical manifestations, diagnosis, and management of the cardiovascular complications of cocaine abuse", section on 'Stroke'.) CLINICAL PRESENTATION The clinical presentation of NASAH varies by location and extent of the subarachnoid bleeding. Diffuse NASAH may mimic clinical features of aneurysmal SAH. Such patients frequently present with a sudden-onset severe (thunderclap) headache, sometimes associated with transient loss of consciousness, vomiting, or neck pain. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Clinical presentation'.) Isolated SAH over the convexity may manifest with transient motor or sensory symptoms corresponding to underlying brain tissue. Symptoms may evolve over seconds to minutes, similar to focal epileptic phenomena and/or seizures [28]. (See "Cerebral amyloid angiopathy", section on 'Transient focal neurologic episodes'.) https://www.uptodate.com/contents/nonaneurysmal-subarachnoid-hemorrhage/print 7/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - UpToDate DIAGNOSTIC EVALUATION SAH should be considered in any patient complaining of a severe headache of sudden onset. Initial evaluation of patients suspected of having SAH includes urgent head CT [29]. If the CT scan fails to show blood in subarachnoid space, a lumbar puncture must be obtained. Additional details on the diagnosis of SAH are discussed separately. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Evaluation and diagnosis'.) Imaging evaluation for underlying causes of bleeding is performed to identify or exclude etiologies that require specific treatment, to prevent complications, and to minimize morbidity. Assess pattern of acute bleeding The selection of initial imaging to identify the cause of bleeding generally varies by the distribution of SAH found on initial head CT ( image 2 and algorithm 1). Aneurysmal SAH pattern Aneurysmal SAH pattern located in the basal cisterns, in the Sylvian or interhemispheric fissures, or diffusely require initial angiographic evaluation to exclude a ruptured cerebral aneurysm as the cause of bleeding. Further testing is performed if angiographic evaluation has not identified an aneurysm or other vascular cause to bleeding. (See 'Evaluation for patients with aneurysmal pattern of bleeding' below.) Convexity SAH SAH that is isolated to the convexities of the cerebral hemispheres may be due to one of several causes; the evaluation will vary by clinical circumstance. (See 'Evaluation for patients with isolated convexity SAH' below.) Evaluation for patients with aneurysmal pattern of bleeding Initial imaging For patients with an aneurysmal SAH pattern, initial angiographic testing is performed to identify patients with a ruptured cerebral aneurysm as the cause of SAH. Patients with aneurysmal SAH typically require surgical or endovascular treatment and intensive medical care; The goal of such treatment is to reduce the risk of rebleeding and treat complications such as cerebral vasospasm and hydrocephalus; all of these are associated with significant morbidity and mortality. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".) Initial angiographic testing may also identify other vascular etiologies such as a vascular malformation or intracranial dissection. (See 'Etiologies' above.) Cerebral angiography Digital subtraction angiography (DSA) is the most sensitive and preferred imaging modality to assess for cerebral aneurysm. DSA should include demonstration https://www.uptodate.com/contents/nonaneurysmal-subarachnoid-hemorrhage/print 8/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - UpToDate of key arterial branch points, including the proximal posterior circulation, to effectively assess for cerebral aneurysms. In addition, injections of the external carotid and vertebral circulations and deep cervical branches may be helpful to identify other vascular causes such as a dural arteriovenous fistula or a vascular malformation in the cervical spine. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) Alternative options Noninvasive testing with CT angiography (CTA) or magnetic resonance angiography (MRA) of the head may be used as an alternative initial angiographic test to identify suspected cerebral aneurysms or other vascular lesions. A major advantage of CTA over DSA is the speed and ease with which it can be obtained, often immediately after the diagnosis of SAH is made by head CT, when the patient is still in the scanner. In this setting, CTA is a more practical approach to acute diagnosis than MRA, given the constraints of acute patient management. Noninvasive testing may avoid the need for conventional angiography in some patients [71-73]. CTA may be more sensitive for aneurysm detection and MRA [74]. However, CTA or MRA has imperfect sensitivity for the detection of cerebral aneurysms, particularly small aneurysms [73]. Even when an aneurysm is identified by noninvasive techniques, DSA may also be performed to exclude multiple aneurysms and to plan surgical intervention [75]. Subsequent testing when cerebral angiography is negative Additional testing to identify nonaneurysmal causes of bleeding should be performed when the underlying cause is uncertain despite initial angiographic evaluation. Patients with perimesencephalic SAH Additional imaging may be unnecessary for stable patients when initial DSA has excluded a cerebral aneurysm and the pattern of bleeding is consistent with a perimesencephalic SAH ( image 3). Patients with a perimesencephalic pattern to SAH and a negative initial DSA have a low likelihood of having an aneurysmal cause of bleeding [2,76]. However, some patients with a perimesencephalic SAH may warrant repeat cerebral DSA or noninvasive CT angiography if the initial study was felt to be technically inadequate or if rebleeding occurs. The imaging evaluation for perimesencephalic SAH is discussed in greater detail separately. (See "Perimesencephalic nonaneurysmal subarachnoid hemorrhage".) Other patients Patients with an aneurysmal SAH pattern that is atypical for perimesencephalic SAH require additional imaging when initial angiography is unrevealing and the cause of bleeding is uncertain. https://www.uptodate.com/contents/nonaneurysmal-subarachnoid-hemorrhage/print 9/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - UpToDate Magnetic resonance imaging We perform gadolinium-enhanced magnetic resonance imaging (MRI) of the brain for patients with an uncertain cause to SAH after angiographic evaluation [6,32,77]. We also perform MRI of the spine for such patients with bleeding concentrated in the cervicomedullary regions. MRI with gadolinium may demonstrate angiographically occult lesions that can cause NASAH, including some vascular malformations in the brain or spinal cord, tumors (eg, pituitary adenoma), and intracranial arterial dissections [36,78]. Head and spinal CT with contrast can be performed as less sensitive alternative tests for patients unable to undergo MRI. Delayed repeat brain MRI may be performed for selected patients after blood has resorbed (eg, six to eight weeks after SAH) if the initial study was limited by the presence and extent of acute bleeding. The role of repeat cerebral angiography For patients with an aneurysmal pattern SAH with an uncertain cause to symptoms despite initial cerebral DSA and MRI, we typically repeat DSA within 4 to 14 days after an initial negative study. However, the optimal timing of this study is unclear and should be individualized according to the patient's condition and presence of other complications. In reported case series, the repeat DSA has been performed at a follow- up interval between four days and four weeks [5,6,8,13,76,79-82]. Some patients with initial negative angiography are found to have an aneurysm on repeat angiography, at rates ranging from 3 to 24 percent in case series [5,6,8,13,76,83,84]. Rates as high as 49 percent have been reported for series of patients that exclude those with perimesencephalic NASAH and others with normal initial head CT [5,76,79]. Reasons for an initial false-negative angiogram include technical or reading errors, small aneurysm size, and obscuration of the aneurysm because of vasospasm, hematoma, or thrombosis within the aneurysm. A repeat study may also reveal an arterial dissection or a vascular malformation not identified on the initial study [33,34,85]. The value of additional angiographic testing to identify a cerebral aneurysm following two negative angiograms is uncertain [1,8,85]. We generally reserve further angiographic testing for patients with technically inadequate initial studies or if rebleeding occurs. Some older case series identified aneurysmal cause to SAH on a third angiogram or by surgical exploration [6,84], but others have reported no additional benefit with a third DSA [85]. While in some cases surgical exploration was prompted by an episode of rebleeding or a suspicious but nondiagnostic finding on angiography, in other cases it is not always certain why surgical exploration was performed. https://www.uptodate.com/contents/nonaneurysmal-subarachnoid-hemorrhage/print 10/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - UpToDate Spinal angiography Spinal angiography may be performed for some patients with NASAH and an unclear cause despite prior imaging [33-36]. This includes those with prominent back or neck pain, radicular or myelopathic features on examination, or abnormal but nondiagnostic findings on other neuroimaging studies. (See "Disorders affecting the spinal cord", section on 'Vascular malformations'.) Evaluation for patients with isolated convexity SAH Nontraumatic convexity SAH is associated with a diverse group of etiologies. These include: Cerebral amyloid angiopathy (see "Cerebral amyloid angiopathy") Reversible cerebral vasoconstriction syndrome (see "Reversible cerebral vasoconstriction syndrome") Cerebral venous thrombosis (see "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis") Mycotic aneurysm from infective endocarditis (see "Overview of infected (mycotic) arterial aneurysm") Hemorrhagic cerebral tumor (see "Overview of the clinical features and diagnosis of brain tumors in adults") Intracranial dissection (see "Cerebral and cervical artery dissection: Clinical features and diagnosis") Vascular malformation (see "Vascular malformations of the central nervous system") Cerebral vasculitis (see "Primary angiitis of the central nervous system in adults") The initial diagnostic imaging test to identify the underlying cause of isolated convexity SAH varies by clinical features ( table 1). As examples, for an 80-year-old patient presenting with transient motor deficit and head CT showing acute convexity SAH, brain MRI with T2*-weighted susceptibility-weighted sequences may be performed as an initial diagnostic test to assess for cerebral amyloid angiopathy (CAA). For a patient presenting with multiple episodes of thunderclap headache over the preceding several days, CTA of the head may be performed to assess for reversible cerebral vasoconstriction syndrome (RCVS). The causes of convexity SAH are typically nonaneurysmal [77,86,87]. However, angiographic evaluation to exclude ruptured cerebral aneurysm is warranted when SAH in the hemispheric convexities is accompanied by bleeding in the basal cisterns or Sylvian or interhemispheric fissures or is diffuse. In addition, angiographic evaluation may be warranted when the initial diagnostic imaging test does not identify the cause of convexity SAH. (See 'Initial imaging' above.) https://www.uptodate.com/contents/nonaneurysmal-subarachnoid-hemorrhage/print 11/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - UpToDate MANAGEMENT AND PROGNOSIS The approach to the general care and initial monitoring of patients with NASAH is the same as that for patients with aneurysmal SAH. Patients with extensive or diffuse NASAH may have a complicated course similar to patients with aneurysmal SAH, including risks of developing hydrocephalus or vasospasm [88]. However, other patients with NASAH presenting with a small amount of focal subarachnoid bleeding and mild symptoms may remain clinically stable and have a more benign course. Supportive care All patients with SAH should be admitted to a facility with neurologic and/or neurosurgical expertise to assess for underlying causes of bleeding and to monitor for complications of SAH. Patients with disabling neurologic symptoms such as hemiparesis or stupor or those with diffuse SAH should be admitted to an intensive care setting at a facility with neurologic and neurosurgical expertise to manage hemodynamic status and monitor for neurologic deterioration. Specific acute supportive care strategies for patients with NASAH include blood pressure control, reversal of anticoagulation, deep venous thrombosis prophylaxis, and pain control. These issues are described in detail separately. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Acute care'.) Complications Patients with NASAH may develop complications associated with aneurysmal SAH [89]. These include: Rebleeding Vasospasm and cerebral ischemia Hydrocephalus Increased intracranial pressure Seizures Hyponatremia Cardiac abnormalities There is little specific information about the incidence or severity of these complications in NASAH in comparison with aneurysmal SAH. The risk of rebleeding depends on the underlying etiology of SAH. The risks of other complications likely vary according to the extent and location of bleeding. Patients with perimesencephalic SAH appear to have lower risk of complications than patients with NASAH due to other etiologies [7,90,91]. https://www.uptodate.com/contents/nonaneurysmal-subarachnoid-hemorrhage/print 12/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - UpToDate In a retrospective single-center review of 138 patients with NASAH, vasospasm occurred in nearly 20 percent of those with diffuse SAH, similar to matched historical controls and higher than those with a perimesencephalic pattern of SAH [89]. Shunt-dependent hydrocephalus occurred in 14 percent of patients with NASAH in one retrospective series [92]. Associated risk factors included acute hydrocephalus, intraventricular hemorrhage, clinical vasospasm, and anticoagulation medication prior to SAH. Patients should receive other interventions to monitor, prevent, and treat complications of SAH. These are discussed separately. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Critical care management' and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Early complications' and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Vasospasm and delayed cerebral ischemia'.) The clinical features and management of complications of SAH are discussed in greater detail separately. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Complications'.) Interventions Interventions to prevent rebleeding and other etiologic-specific complications are individualized to the underlying etiology. (See 'Etiologies' above.) Prognosis In general, the prognosis for patients with NASAH is better than the prognosis for those with aneurysmal hemorrhage; however, NASAH represents a heterogenous group of patients and etiologies, and outcomes are largely dependent on the underlying cause and comorbidities [93,94]. (See 'Etiologies' 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 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/nonaneurysmal-subarachnoid-hemorrhage/print 13/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - 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 topic (see "Patient education: Subarachnoid hemorrhage (The Basics)") SUMMARY AND RECOMMENDATIONS Definition Approximately 20 percent of SAH cases are due to a cause other than a ruptured intracranial aneurysm. There are several potential causes of NASAH, and in some cases, the source of bleeding is not identified. (See 'Introduction' above.) Etiologies Underlying causes of spontaneous NASAH vary by clinical circumstances and location of bleeding. Common causes include (see 'Etiologies' above): Perimesencephalic NASAH Cerebral vascular malformations Intracranial arterial dissection Reversible cerebral vasoconstriction syndrome Cerebral venous thrombosis Cerebral amyloid angiopathy Minor or unsuspected trauma Spinal causes, such as vascular malformation, aneurysm, or tumor Clinical features The clinical presentation of NASAH varies by location and extent of the subarachnoid bleeding. Diffuse NASAH may mimic clinical features of aneurysmal SAH. Isolated SAH over the convexity may manifest with transient motor or sensory symptoms corresponding to underlying brain tissue. (See 'Clinical presentation' above.) Evaluation for underlying cause Imaging evaluation for underlying causes of bleeding is performed to identify or exclude etiologies that require specific treatment, to prevent complications, and to minimize morbidity. The selection of initial imaging testing varies by the distribution of SAH found on initial head CT ( image 2). (See 'Diagnostic evaluation' above.) Evaluation for patients with an aneurysmal SAH pattern Aneurysmal SAH pattern located in the basal cisterns, in the Sylvian or interhemispheric fissures, or diffusely https://www.uptodate.com/contents/nonaneurysmal-subarachnoid-hemorrhage/print 14/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - UpToDate require initial angiographic evaluation to exclude a ruptured cerebral aneurysm as the cause of bleeding ( algorithm 1). (See 'Evaluation for patients with aneurysmal pattern of bleeding' above.) Initial angiographic imaging We prefer digital subtraction angiography (DSA) to assess for cerebral aneurysm because it is more sensitive than noninvasive imaging modalities. Angiography may also identify other vascular etiologies such as a vascular malformation or intracranial dissection. (See 'Initial imaging' above.) Subsequent testing Patients with an aneurysmal SAH pattern that is atypical for perimesencephalic SAH require additional imaging when initial angiography is unrevealing and the cause of bleeding is uncertain. Further diagnostic imaging typically includes MRI of the brain with contrast and repeat cerebral DSA. (See 'Subsequent testing when cerebral angiography is negative' above.) Some patients with a perimesencephalic SAH may warrant repeat cerebral DSA or noninvasive CT angiography if the initial study was felt to be technically inadequate or if rebleeding occurs. (See 'Patients with perimesencephalic SAH' above.) Evaluation for patients with isolated convexity SAH The evaluation of SAH that is isolated to the convexities of the cerebral hemispheres may be due to several causes and varies by clinical circumstances ( table 1). (See 'Evaluation for patients with isolated convexity SAH' above.) Management The approach to the general care and initial monitoring of patients with NASAH is the same as that for patients with aneurysmal SAH. (See 'Management and prognosis' above.) Supportive care All patients with SAH should be admitted to a facility with neurologic and/or neurosurgical expertise. Those with disabling neurologic symptoms or diffuse SAH should be admitted to an intensive care setting with the expertise to manage hemodynamic status and monitor for neurologic deterioration. (See 'Supportive care' above.) Complications Patients with NASAH may develop complications associated with aneurysmal SAH including hydrocephalus, vasospasm and cerebral ischemia, seizures, hyponatremia, and cardiac abnormalities. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".) Interventions Interventions to prevent rebleeding and other etiologic-specific complications are individualized to the underlying etiology. (See 'Interventions' above.) https://www.uptodate.com/contents/nonaneurysmal-subarachnoid-hemorrhage/print 15/32 7/7/23, 11:33 AM

NASAH in comparison with aneurysmal SAH. The risk of rebleeding depends on the underlying etiology of SAH. The risks of other complications likely vary according to the extent and location of bleeding. Patients with perimesencephalic SAH appear to have lower risk of complications than patients with NASAH due to other etiologies [7,90,91]. https://www.uptodate.com/contents/nonaneurysmal-subarachnoid-hemorrhage/print 12/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - UpToDate In a retrospective single-center review of 138 patients with NASAH, vasospasm occurred in nearly 20 percent of those with diffuse SAH, similar to matched historical controls and higher than those with a perimesencephalic pattern of SAH [89]. Shunt-dependent hydrocephalus occurred in 14 percent of patients with NASAH in one retrospective series [92]. Associated risk factors included acute hydrocephalus, intraventricular hemorrhage, clinical vasospasm, and anticoagulation medication prior to SAH. Patients should receive other interventions to monitor, prevent, and treat complications of SAH. These are discussed separately. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Critical care management' and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Early complications' and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Vasospasm and delayed cerebral ischemia'.) The clinical features and management of complications of SAH are discussed in greater detail separately. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Complications'.) Interventions Interventions to prevent rebleeding and other etiologic-specific complications are individualized to the underlying etiology. (See 'Etiologies' above.) Prognosis In general, the prognosis for patients with NASAH is better than the prognosis for those with aneurysmal hemorrhage; however, NASAH represents a heterogenous group of patients and etiologies, and outcomes are largely dependent on the underlying cause and comorbidities [93,94]. (See 'Etiologies' 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 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/nonaneurysmal-subarachnoid-hemorrhage/print 13/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - 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 topic (see "Patient education: Subarachnoid hemorrhage (The Basics)") SUMMARY AND RECOMMENDATIONS Definition Approximately 20 percent of SAH cases are due to a cause other than a ruptured intracranial aneurysm. There are several potential causes of NASAH, and in some cases, the source of bleeding is not identified. (See 'Introduction' above.) Etiologies Underlying causes of spontaneous NASAH vary by clinical circumstances and location of bleeding. Common causes include (see 'Etiologies' above): Perimesencephalic NASAH Cerebral vascular malformations Intracranial arterial dissection Reversible cerebral vasoconstriction syndrome Cerebral venous thrombosis Cerebral amyloid angiopathy Minor or unsuspected trauma Spinal causes, such as vascular malformation, aneurysm, or tumor Clinical features The clinical presentation of NASAH varies by location and extent of the subarachnoid bleeding. Diffuse NASAH may mimic clinical features of aneurysmal SAH. Isolated SAH over the convexity may manifest with transient motor or sensory symptoms corresponding to underlying brain tissue. (See 'Clinical presentation' above.) Evaluation for underlying cause Imaging evaluation for underlying causes of bleeding is performed to identify or exclude etiologies that require specific treatment, to prevent complications, and to minimize morbidity. The selection of initial imaging testing varies by the distribution of SAH found on initial head CT ( image 2). (See 'Diagnostic evaluation' above.) Evaluation for patients with an aneurysmal SAH pattern Aneurysmal SAH pattern located in the basal cisterns, in the Sylvian or interhemispheric fissures, or diffusely https://www.uptodate.com/contents/nonaneurysmal-subarachnoid-hemorrhage/print 14/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - UpToDate require initial angiographic evaluation to exclude a ruptured cerebral aneurysm as the cause of bleeding ( algorithm 1). (See 'Evaluation for patients with aneurysmal pattern of bleeding' above.) Initial angiographic imaging We prefer digital subtraction angiography (DSA) to assess for cerebral aneurysm because it is more sensitive than noninvasive imaging modalities. Angiography may also identify other vascular etiologies such as a vascular malformation or intracranial dissection. (See 'Initial imaging' above.) Subsequent testing Patients with an aneurysmal SAH pattern that is atypical for perimesencephalic SAH require additional imaging when initial angiography is unrevealing and the cause of bleeding is uncertain. Further diagnostic imaging typically includes MRI of the brain with contrast and repeat cerebral DSA. (See 'Subsequent testing when cerebral angiography is negative' above.) Some patients with a perimesencephalic SAH may warrant repeat cerebral DSA or noninvasive CT angiography if the initial study was felt to be technically inadequate or if rebleeding occurs. (See 'Patients with perimesencephalic SAH' above.) Evaluation for patients with isolated convexity SAH The evaluation of SAH that is isolated to the convexities of the cerebral hemispheres may be due to several causes and varies by clinical circumstances ( table 1). (See 'Evaluation for patients with isolated convexity SAH' above.) Management The approach to the general care and initial monitoring of patients with NASAH is the same as that for patients with aneurysmal SAH. (See 'Management and prognosis' above.) Supportive care All patients with SAH should be admitted to a facility with neurologic and/or neurosurgical expertise. Those with disabling neurologic symptoms or diffuse SAH should be admitted to an intensive care setting with the expertise to manage hemodynamic status and monitor for neurologic deterioration. (See 'Supportive care' above.) Complications Patients with NASAH may develop complications associated with aneurysmal SAH including hydrocephalus, vasospasm and cerebral ischemia, seizures, hyponatremia, and cardiac abnormalities. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".) Interventions Interventions to prevent rebleeding and other etiologic-specific complications are individualized to the underlying etiology. (See 'Interventions' above.) https://www.uptodate.com/contents/nonaneurysmal-subarachnoid-hemorrhage/print 15/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - UpToDate ACKNOWLEDGMENT The UpToDate editorial staff acknowledges David Brock, MD, CIP, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Rinkel GJ, Wijdicks EF, Hasan D, et al. Outcome in patients with subarachnoid haemorrhage and negative angiography according to pattern of haemorrhage on computed tomography. Lancet 1991; 338:964. 2. van Gijn J, van Dongen KJ, Vermeulen M, Hijdra A. Perimesencephalic hemorrhage: a nonaneurysmal and benign form of subarachnoid hemorrhage. Neurology 1985; 35:493. 3. Canh o P, Ferro JM, Pinto AN, et al. Perimesencephalic and nonperimesencephalic subarachnoid haemorrhages with negative angiograms. Acta Neurochir (Wien) 1995; 132:14. 4. Rinkel GJ, Wijdicks EF, Vermeulen M, et al. Nonaneurysmal perimesencephalic subarachnoid hemorrhage: CT and MR patterns that differ from aneurysmal rupture. AJNR Am J Neuroradiol 1991; 12:829. 5. Schwartz TH, Solomon RA. Perimesencephalic nonaneurysmal subarachnoid hemorrhage: review of the literature. Neurosurgery 1996; 39:433. 6. Tatter SB, Crowell RM, Ogilvy CS. Aneurysmal and microaneurysmal "angiogram-negative" subarachnoid hemorrhage. Neurosurgery 1995; 37:48. 7. Ildan F, Tuna M, Erman T, et al. Prognosis and prognostic factors in nonaneurysmal perimesencephalic hemorrhage: a follow-up study in 29 patients. Surg Neurol 2002; 57:160. 8. Rinkel GJ, van Gijn J, Wijdicks EF. Subarachnoid hemorrhage without detectable aneurysm. A review of the causes. Stroke 1993; 24:1403. 9. Cordonnier C, Al-Shahi Salman R, Bhattacharya JJ, et al. Differences between intracranial vascular malformation types in the characteristics of their presenting haemorrhages: prospective, population-based study. J Neurol Neurosurg Psychiatry 2008; 79:47. 10. Halbach VV, Higashida RT, Hieshima GB, et al. Dural fistulas involving the transverse and sigmoid sinuses: results of treatment in 28 patients. Radiology 1987; 163:443. 11. Bikmaz K, Erdem E, Krisht A. Arteriovenous fistula originating from proximal part of the anterior cerebral artery. Clin Neurol Neurosurg 2007; 109:589. https://www.uptodate.com/contents/nonaneurysmal-subarachnoid-hemorrhage/print 16/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - UpToDate 12. Duffau H, Lopes M, Janosevic V, et al. Early rebleeding from intracranial dural arteriovenous fistulas: report of 20 cases and review of the literature. J Neurosurg 1999; 90:78. 13. du Mesnil de Rochemont R, Heindel W, Wesselmann C, et al. Nontraumatic subarachnoid hemorrhage: value of repeat angiography. Radiology 1997; 202:798. 14. Brown RD Jr, Wiebers DO, Torner JC, O'Fallon WM. Frequency of intracranial hemorrhage as a presenting symptom and subtype analysis: a population-based study of intracranial vascular malformations in Olmsted Country, Minnesota. J Neurosurg 1996; 85:29. 15. Caplan LR. Dissections of brain-supplying arteries. Nat Clin Pract Neurol 2008; 4:34. 16. Sasaki O, Ogawa H, Koike T, et al. A clinicopathological study of dissecting aneurysms of the intracranial vertebral artery. J Neurosurg 1991; 75:874. 17. Santos-Franco JA, Zenteno M, Lee A. Dissecting aneurysms of the vertebrobasilar system. A comprehensive review on natural history and treatment options. Neurosurg Rev 2008; 31:131. 18. Zhao WY, Krings T, Alvarez H, et al. Management of spontaneous haemorrhagic intracranial vertebrobasilar dissection: review of 21 consecutive cases. Acta Neurochir (Wien) 2007; 149:585. 19. Singhal AB, Hajj-Ali RA, Topcuoglu MA, et al. Reversible cerebral vasoconstriction syndromes: analysis of 139 cases. Arch Neurol 2011; 68:1005. 20. Adaletli I, Sirikci A, Kara B, et al. Cerebral venous sinus thrombosis presenting with excessive subarachnoid hemorrhage in a 14-year-old boy. Emerg Radiol 2005; 12:57. 21. Oppenheim C, Domigo V, Gauvrit JY, et al. Subarachnoid hemorrhage as the initial presentation of dural sinus thrombosis. AJNR Am J Neuroradiol 2005; 26:614. 22. Chang R, Friedman DP. Isolated cortical venous thrombosis presenting as subarachnoid hemorrhage: a report of three cases. AJNR Am J Neuroradiol 2004; 25:1676. 23. Sztajzel R, Coeytaux A, Dehdashti AR, et al. Subarachnoid hemorrhage: a rare presentation of cerebral venous thrombosis. Headache 2001; 41:889. 24. Kurosu A, Suzukawa K, Amo M, et al. Perimesencephalic non-aneurysmal subarachnoid hemorrhage caused by cavernous sinus thrombosis: case report. Neurol Med Chir (Tokyo) 2007; 47:258. 25. Kumar S, Goddeau RP Jr, Selim MH, et al. Atraumatic convexal subarachnoid hemorrhage: clinical presentation, imaging patterns, and etiologies. Neurology 2010; 74:893. 26. Katoh M, Yoshino M, Asaoka K, et al. A restricted subarachnoid hemorrhage in the cortical sulcus in cerebral amyloid angiopathy: could it be a warning sign? Surg Neurol 2007; 68:457. https://www.uptodate.com/contents/nonaneurysmal-subarachnoid-hemorrhage/print 17/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - UpToDate 27. Karabatsou K, Lecky BR, Rainov NG, et al. Cerebral amyloid angiopathy with symptomatic or occult subarachnoid haemorrhage. Eur Neurol 2007; 57:103. 28. Beitzke M, Gattringer T, Enzinger C, et al. Clinical presentation, etiology, and long-term prognosis in patients with nontraumatic convexal subarachnoid hemorrhage. Stroke 2011; 42:3055. 29. van Gijn J, Rinkel GJ. Subarachnoid haemorrhage: diagnosis, causes and management. Brain 2001; 124:249. 30. Caroscio JT, Brannan T, Budabin M, et al. Subarachnoid hemorrhage secondary to spinal arteriovenous malformation and aneurysm. Report of a case and review of the literature. Arch Neurol 1980; 37:101. 31. Kandel EI. Complete excision of arteriovenous malformations of the cervical cord. Surg Neurol 1980; 13:135. 32. Koch C. Spinal dural arteriovenous fistula. Curr Opin Neurol 2006; 19:69. 33. van Beijnum J, Straver DC, Rinkel GJ, Klijn CJ. Spinal arteriovenous shunts presenting as intracranial subarachnoid haemorrhage. J Neurol 2007; 254:1044. 34. Aviv RI, Shad A, Tomlinson G, et al. Cervical dural arteriovenous fistulae manifesting as subarachnoid hemorrhage: report of two cases and literature review. AJNR Am J Neuroradiol 2004; 25:854. 35. Kinouchi H, Mizoi K, Takahashi A, et al. Dural arteriovenous shunts at the craniocervical junction. J Neurosurg 1998; 89:755. 36. Rogg JM, Smeaton S, Doberstein C, et al. Assessment of the value of MR imaging for examining patients with angiographically negative subarachnoid hemorrhage. AJR Am J Roentgenol 1999; 172:201. 37. Gonzalez LF, Zabramski JM, Tabrizi P, et al. Spontaneous spinal subarachnoid hemorrhage secondary to spinal aneurysms: diagnosis and treatment paradigm. Neurosurgery 2005; 57:1127. 38. Massand MG, Wallace RC, Gonzalez LF, et al. Subarachnoid hemorrhage due to isolated spinal artery aneurysm in four patients. AJNR Am J Neuroradiol 2005; 26:2415. 39. Scotti G, Filizzolo F, Scialfa G, et al. Repeated subarachnoid hemorrhages from a cervical meningioma. Case report. J Neurosurg 1987; 66:779. 40. Navi BB, Reichman JS, Berlin D, et al. Intracerebral and subarachnoid hemorrhage in patients with cancer. Neurology 2010; 74:494. 41. Marushima A, Yanaka K, Matsuki T, et al. Subarachnoid hemorrhage not due to ruptured aneurysm in moyamoya disease. J Clin Neurosci 2006; 13:146. https://www.uptodate.com/contents/nonaneurysmal-subarachnoid-hemorrhage/print 18/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - UpToDate 42. Wu H, Song S, Zhang X, Jin Y. Nonaneurysmal subarachnoid hemorrhage and cerebral infarction associated with moyamoya disease. J Craniofac Surg 2014; 25:e358. 43. Bjerre P, Videbaek H, Lindholm J. Subarachnoid hemorrhage with normal cerebral angiography: a prospective study on sellar abnormalities and pituitary function. Neurosurgery 1986; 19:1012. 44. Wohaibi MA, Russell NA, Ferayan AA, et al. Pituitary apoplexy presenting as massive subarachnoid hemorrhage. J Neurol Neurosurg Psychiatry 2000; 69:700. 45. Sergides IG, Minhas PS, Anotun N, Pickard JD. Pituitary apoplexy can mimic subarachnoid haemorrhage clinically and radiologically. Emerg Med J 2007; 24:308. 46. Satyarthee GD, Mahapatra AK. Pituitary apoplexy in a child presenting with massive subarachnoid and intraventricular hemorrhage. J Clin Neurosci 2005; 12:94. 47. Inamasu J, Hori S, Sekine K, Aikawa N. Pituitary apoplexy without ocular/visual symptoms. Am J Emerg Med 2001; 19:88. 48. Hernandez A, Angeles Del Real M, Aguirre M, et al. Pituitary apoplexy: a transient benign presentation mimicking mild subarachnoid hemorrhage with negative angiography. Eur J Neurol 1998; 5:499. 49. Cao Y, Na W, Su H, et al. Subarachnoid hemorrhage caused by spontaneous intracranial hypotension: two rare cases report. Int J Neurosci 2023; 133:51. 50. Oppo V, Cossu G, Secci S, Melis M. Widening the spectrum of secondary headache: intracranial hypotension following a non-aneurysmal subarachnoid hemorrhage. Neurol Sci 2019; 40:2179. 51. Andr R, Cottin V, Saraux JL, et al. Central nervous system involvement in eosinophilic granulomatosis with polyangiitis (Churg-Strauss): Report of 26 patients and review of the literature. Autoimmun Rev 2017; 16:963. 52. Ducros A, Boukobza M, Porcher R, et al. The clinical and radiological spectrum of reversible cerebral vasoconstriction syndrome. A prospective series of 67 patients. Brain 2007; 130:3091. 53. Spitzer C, Mull M, Rohde V, Kosinski CM. Non-traumatic cortical subarachnoid haemorrhage: diagnostic work-up and aetiological background. Neuroradiology 2005; 47:525. 54. Muehlschlegel S, Kursun O, Topcuoglu MA, et al. Differentiating reversible cerebral vasoconstriction syndrome with subarachnoid hemorrhage from other causes of subarachnoid hemorrhage. JAMA Neurol 2013; 70:1254. 55. Barboza MA, Maud A, Rodriguez GJ. Reversible cerebral vasoconstriction syndrome and nonaneurysmal subarachnoid hemorrhage. J Vasc Interv Neurol 2014; 7:17. https://www.uptodate.com/contents/nonaneurysmal-subarachnoid-hemorrhage/print 19/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - UpToDate 56. Deliran SS, Brouwer MC, van de Beek D. Subarachnoid Hemorrhage in Bacterial Meningitis Patients. Cerebrovasc Dis 2022; 51:118. 57. Belyamani L, Lakhlit M, Zidouh S. Meningococcus meningitis revealed by a subarachnoid hemorrhage. J Emerg Med 2012; 43:1081. 58. Jain R, Deveikis J, Hickenbottom S, Mukherji SK. Varicella-zoster vasculitis presenting with intracranial hemorrhage. AJNR Am J Neuroradiol 2003; 24:971. 59. Tsuzaki K, Murakata K, Kamei M, et al. A Case of Invasive Aspergillus Rhinosinusitis Presenting with Unilateral Visual Loss and Subsequently Associated with Meningitis, Subarachnoid Hemorrhage, and Cerebral Infarction. Case Rep Neurol Med 2020; 2020:8885166. 60. Singh R, Srinivasan VM, Catapano JS, et al. Coccidioidal meningitis with multiple aneurysms presenting with pseudo-subarachnoid hemorrhage: illustrative case. J Neurosurg Case Lessons 2021; 2:CASE21424. 61. Strouse JJ, Hulbert ML, DeBaun MR, et al. Primary hemorrhagic stroke in children with sickle cell disease is associated with recent transfusion and use of corticosteroids. Pediatrics 2006; 118:1916. 62. Rogers LR. Cerebrovascular complications in cancer patients. Neurol Clin 2003; 21:167. 63. Schwartzman RJ, Hill JB. Neurologic complications of disseminated intravascular coagulation. Neurology 1982; 32:791. 64. Alghamdi MA, Almubarak AO, Alsedrani N, et al. Pretruncal Nonaneurysmal Subarachnoid Hemorrhage with Underlying Hemophilia C. World Neurosurg 2019; 127:109. 65. Das B, Mahajan A, Goel G, Garg A. Tenecteplase-induced Nonaneurysmal Subarachnoid Hemorrhage in a Patient with Acute Ischemic Stroke: A Case Report and Literature Review. Asian J Neurosurg 2020; 15:706. 66. Naidech AM, Rosenberg NF, Maas MB, et al. Predictors of hemorrhage volume and disability after perimesencephalic subarachnoid hemorrhage. Neurology 2012; 78:811. 67. Levine SR, Brust JC, Futrell N, et al. A comparative study of the cerebrovascular complications of cocaine: alkaloidal versus hydrochloride a review. Neurology 1991; 41:1173. 68. Nolte KB, Brass LM, Fletterick CF. Intracranial hemorrhage associated with cocaine abuse: a prospective autopsy study. Neurology 1996; 46:1291. 69. Huang MC, Yang SY, Lin SK, et al. Risk of Cardiovascular Diseases and Stroke Events in Methamphetamine Users: A 10-Year Follow-Up Study. J Clin Psychiatry 2016; 77:1396. https://www.uptodate.com/contents/nonaneurysmal-subarachnoid-hemorrhage/print 20/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - UpToDate 70. Storen EC, Wijdicks EF, Crum BA, Schultz G. Moyamoya-like vasculopathy from cocaine dependency. AJNR Am J Neuroradiol 2000; 21:1008. 71. Madureira S, Canh o P, Guerreiro M, Ferro JM. Cognitive and emotional consequences of perimesencephalic subarachnoid hemorrhage. J Neurol 2000; 247:862. 72. Marquardt G, Niebauer T, Schick U, Lorenz R. Long term follow up after perimesencephalic subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 2000; 69:127. 73. Colen TW, Wang LC, Ghodke BV, et al. Effectiveness of MDCT angiography for the detection of intracranial aneurysms in patients with nontraumatic subarchnoid hemorrhage. AJR Am J Roentgenol 2007; 189:898. 74. Chen X, Liu Y, Tong H, et al. Meta-analysis of computed tomography angiography versus magnetic resonance angiography for intracranial aneurysm. Medicine (Baltimore) 2018; 97:e10771. 75. Hashimoto Y, Kin S, Haraguchi K, Niwa J. Pitfalls in the preoperative evaluation of subarachnoid hemorrhage without digital subtraction angiography: report on 2 cases. Surg Neurol 2007; 68:344. 76. Jung JY, Kim YB, Lee JW, et al. Spontaneous subarachnoid haemorrhage with negative initial angiography: a review of 143 cases. J Clin Neurosci 2006; 13:1011. 77. Larson AS, Brinjikji W. Subarachnoid Hemorrhage of Unknown Cause: Distribution and Role of Imaging. Neuroimaging Clin N Am 2021; 31:167. 78. Wijdicks EF, Schievink WI, Miller GM. MR imaging in pretruncal nonaneurysmal subarachnoid hemorrhage: is it worthwhile? Stroke 1998; 29:2514. 79. Urbach H, Zentner J, Solymosi L. The need for repeat angiography in subarachnoid haemorrhage. Neuroradiology 1998; 40:6. 80. Bradac GB, Bergui M, Ferrio MF, et al. False-negative angiograms in subarachnoid haemorrhage due to intracranial aneurysms. Neuroradiology 1997; 39:772. 81. Duong H, Melan on D, Tampieri D, Ethier R. The negative angiogram in subarachnoid haemorrhage. Neuroradiology 1996; 38:15. 82. Inamasu J, Nakamura Y, Saito R, et al. "Occult" ruptured cerebral aneurysms revealed by repeat angiography: result from a large retrospective study. Clin Neurol Neurosurg 2003; 106:33. 83. Suzuki S, Kayama T, Sakurai Y, et al. Subarachnoid hemorrhage of unknown cause. Neurosurgery 1987; 21:310. 84. Topcuoglu MA, Ogilvy CS, Carter BS, et al. Subarachnoid hemorrhage without evident cause on initial angiography studies: diagnostic yield of subsequent angiography and other https://www.uptodate.com/contents/nonaneurysmal-subarachnoid-hemorrhage/print 21/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - UpToDate neuroimaging tests. J Neurosurg 2003; 98:1235. 85. Hashimoto H, Iida J, Hironaka Y, et al. Use of spiral computerized tomography angiography in patients with subarachnoid hemorrhage in whom subtraction angiography did not reveal cerebral aneurysms. J Neurosurg 2000; 92:278. 86. Forman R, Conners JJ, Song SY, et al. The Spectrum of Nontraumatic Convexity Subarachnoid Hemorrhage. J Stroke Cerebrovasc Dis 2019; 28:104473. 87. Patel KC, Finelli PF. Nonaneurysmal convexity subarachnoid hemorrhage. Neurocrit Care 2006; 4:229. 88. C novas D, Gil A, Jato M, et al. Clinical outcome of spontaneous non-aneurysmal subarachnoid hemorrhage in 108 patients. Eur J Neurol 2012; 19:457. 89. Walcott BP, Stapleton CJ, Koch MJ, Ogilvy CS. Diffuse patterns of nonaneurysmal subarachnoid hemorrhage originating from the Basal cisterns have predictable vasospasm rates similar to aneurysmal subarachnoid hemorrhage. J Stroke Cerebrovasc Dis 2015; 24:795. 90. Coelho LG, Costa JM, Silva EI. Non-aneurysmal spontaneous subarachnoid hemorrhage: perimesencephalic versus non-perimesencephalic. Rev Bras Ter Intensiva 2016; 28:141. 91. Hui FK, Tumial n LM, Tanaka T, et al. Clinical differences between angiographically negative, diffuse subarachnoid hemorrhage and perimesencephalic subarachnoid hemorrhage. Neurocrit Care 2009; 11:64. 92. Schuss P, Hadjiathanasiou A, Brandecker S, et al. Risk factors for shunt dependency in patients suffering from spontaneous, non-aneurysmal subarachnoid hemorrhage. Neurosurg Rev 2019; 42:139. 93. McIntosh AP, Thomas A. Health-Related Quality-of-Life Outcomes: Comparing Patients With Aneurysmal and Nonaneurysmal Subarachnoid Hemorrhage. J Neurosci Nurs 2015; 47:E2. 94. Tsermoulas G, Flett L, Gregson B, Mitchell P. Immediate coma and poor outcome in subarachnoid haemorrhage are independently associated with an aneurysmal origin. Clin Neurol Neurosurg 2013; 115:1362. Topic 1111 Version 23.0 https://www.uptodate.com/contents/nonaneurysmal-subarachnoid-hemorrhage/print 22/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - UpToDate GRAPHICS Perimesencephalic nonaneurysmal subarachnoid hemorrhage Head CT of three different patients demonstrating subarachnoid hemorrhage in the characteristic pattern of perimesencephalic hemorrhage with blood in the interpeduncular and ambient cisterns. CT: computed tomography. Images are courtesy of the Neuroradiology teaching le and the Neurosurgery Department at Thomas Je erson University Hospital. Graphic 76973 Version 5.0 https://www.uptodate.com/contents/nonaneurysmal-subarachnoid-hemorrhage/print 23/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - 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/nonaneurysmal-subarachnoid-hemorrhage/print 24/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - 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/nonaneurysmal-subarachnoid-hemorrhage/print 25/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - UpToDate Diagnostic imaging evaluation to exclude secondary causes of subarachnoid hemorrhage Imaging evaluation is typically performed for patients with spontaneous SAH to identify or exclude a ruptured cerebral aneurysm. Evaluation for nonaneurysmal causes is also warranted for patients with isolated convexity SAH who present with bleeding restricted to the surface of the cerebral hemispheres and for other patients once ruptured aneurysm has been excluded. Further https://www.uptodate.com/contents/nonaneurysmal-subarachnoid-hemorrhage/print 26/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - UpToDate imaging and/or other testing may be indicated for patients with acute SAH to monitor for complications and those who deteriorate clinically. Refer to UpToDate topic for additional details. SAH: subarachnoid hemorrhage; CT: computed tomography; DSA: digital subtraction angiography; CTA: computed tomographic angiography; MRI: magnetic resonance imaging. Refer to UpToDate topics for additional information on management of causes of SAH. Perimesencephalic pattern of acute SAH on head CT performed within 72 hours of onset consists of blood centered anterior to and in contact with the prepontine, interpeduncular, and/or suprasellar cisterns. Extent of blood on head CT should be restricted to the suprasellar, interpeduncular, crural, ambient, quadrigeminal, prepontine, and/or cerebellomedullary cisterns. Additional diagnostic testing is generally performed for patients with atypical features suggestive of a spinal source to bleeding such as those with prominent radicular symptoms and cervicomedullary location of bleeding or if the sensitivity of initial testing is limited by the presence of acute blood or vasospasm. Refer to UpToDate topic for additional details. Graphic 140106 Version 1.0 https://www.uptodate.com/contents/nonaneurysmal-subarachnoid-hemorrhage/print 27/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - UpToDate Radiologic examples of perimesencephalic nonaneurysmal subarachnoid hemorrhage (A-D) CT and CTA of a 47-year-old woman nine hours after ictus demonstrating a PM-NASAH. (E-H) CT and CTA of a 62-year-old man seven hours after ictus demonstrating a PM-NASAH with blood in front of the medulla oblongata (arrow). https://www.uptodate.com/contents/nonaneurysmal-subarachnoid-hemorrhage/print 28/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - UpToDate (I-L) CT and CTA of a 49-year-old woman 14 hours after ictus to illustrate a PM-NASAH with sedimentation of blood in the lateral horns (dashed arrows). (M-P) CT of a 66-year-old man 16 hours after ictus showing a PM-NASAH with the perimesencephalic cisterns filled with blood and associated hydrocephalus (M and N). CT on day seven after ictus showing a spontaneous decrease of hydrocephalus (O). CTA at time of presentation did not show an aneurysm (P). (Q-T) sagittal CT of a 47-year-old man four hours after ictus showing a PM-NASAH with distribution of blood in front of the brain stem and in the ambient cisterns. CT: computed tomography; CTA: computed tomography angiography; PM-NASAH: perimesencephalic subarachnoid hemorrhage From: Mensing LA, Vergouwen MDI, Laban KG, et al. Perimesencephalic Hemorrhage: A Review of Epidemiology, Risk Factors, Presumed Cause, Clinical Course, and Outcome. Stroke 2018; 49:1363. DOI: 10.1161/STROKEAHA.117.019843. Copyright 2018 American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 118108 Version 3.0 https://www.uptodate.com/contents/nonaneurysmal-subarachnoid-hemorrhage/print 29/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - UpToDate Characteristic features and initial diagnostic imaging for common underlying causes of spontaneous isolated convexity subarachnoid hemorrhage Suspected Choice of initial diagnostic Characteristic feature(s) etiology imaging test(s) Age >60 years CAA MRI brain with T2*-weighted SWI or GRE sequences Baseline cognitive impairment Recurrent thunderclap headache (>2 RCVS CTA or MRA of head within 1 week) MRI brain Exposure to vasoactive substance Risk factor for venous thrombosis* CVT CTV or MRV of head Head CT features suggestive of venous thrombosis (eg, hyperdense venous sinus; venous infarction) MRI brain New heart murmur Mycotic aneurysm MRI brain with contrast or cerebral DSA Systemic/cutaneous evidence of embolism Clinical history of active cancer Brain tumor MRI brain with contrast Clinical history of new persistent headaches Head CT features suggestive of tumor (eg, vasogenic edema) Headache prior to neurologic deficits Intracranial dissection CTA of head or cerebral DSA Clinical history of connective tissue disorder Head CT features suggestive of AVM AVM Cerebral DSA (calcification or hypodense flow voids adjacent to SAH) History of minor/occult trauma may be Occult trauma MRI brain elicited Evidence of extracranial bleeding or systemic injuries Clinical history of new persistent headaches Vasculitis MRI brain with contrast Cerebral DSA Progressive cognitive or other neurologic impairments Brain and meningeal biopsy https://www.uptodate.com/contents/nonaneurysmal-subarachnoid-hemorrhage/print 30/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - UpToDate Patients with spontaneous isolated convexity SAH present with bleeding restricted to the surface of the cerebral hemispheres. The suspected underlying cause of convexity SAH may be identified by initial diagnostic imaging test. Additional imaging and/or other testing may be warranted if initial imaging is nondiagnostic. Refer to specific UpToDate topics for additional information on the diagnostic evaluation of conditions that may present with convexity SAH. SAH: subarachnoid hemorrhage; CAA: cerebral amyloid angiopathy; MRI: magnetic resonance imaging; SWI: susceptibility-weighted imaging; GRE: gradient recall echo imaging; RCVS: reversible cerebral vasoconstriction syndrome; CTA: computed tomographic angiography; MRA: magnetic resonance angiography; CT: computed tomography; CVT: cerebral venous thrombosis; CTV: computed tomography venography; MRV: magnetic resonance venography; DSA: digital subtraction angiography; AVM: arteriovenous malformation. Refer to UpToDate topic on the causes of venous thrombosis. Graphic 140108 Version 2.0 https://www.uptodate.com/contents/nonaneurysmal-subarachnoid-hemorrhage/print 31/32 7/7/23, 11:33 AM Nonaneurysmal subarachnoid hemorrhage - UpToDate Contributor Disclosures Farhan Siddiq, 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/nonaneurysmal-subarachnoid-hemorrhage/print 32/32

7/7/23, 11:33 AM Perimesencephalic nonaneurysmal subarachnoid hemorrhage - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Perimesencephalic nonaneurysmal subarachnoid hemorrhage : Farhan Siddiq, MD, Amir S Khan, 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: Mar 06, 2023. INTRODUCTION AND DEFINITION Subarachnoid hemorrhage (SAH) refers to bleeding within the subarachnoid space, which lies between the arachnoid and pia mater and is normally filled with cerebrospinal fluid. Most spontaneous (nontraumatic) cases of SAH are caused by rupture of an intracranial aneurysm, but approximately 20 percent of patients do not have an established vascular lesion on initial four-vessel cerebral angiography [1,2]. The causes of nonaneurysmal SAH (NASAH) are potentially diverse, and often the mechanism of bleeding in these cases is not identified. In 1985, a subtype of NASAH, so-called perimesencephalic NASAH (PM-NASAH), was identified in a case series of 13 patients who had a characteristic pattern of localized blood on computed tomography (CT), normal cerebral angiography, and a benign course that distinguished these patients from both aneurysmal SAH and other patients with NASAH [3]. This observation has subsequently been confirmed by other reports [2,4-7]. It is important to recognize the perimesencephalic pattern of bleeding, because only a small percent will be due to aneurysm rupture; thus, invasive diagnostic testing can be limited in these patients and morbidity thereby reduced. This topic will review the pathogenesis, clinical features, diagnosis, and management of PM- NASAH. Other causes of NASAH are reviewed separately. (See "Nonaneurysmal subarachnoid hemorrhage".) Aneurysmal SAH is reviewed elsewhere. https://www.uptodate.com/contents/perimesencephalic-nonaneurysmal-subarachnoid-hemorrhage/print 1/28 7/7/23, 11:33 AM Perimesencephalic nonaneurysmal subarachnoid hemorrhage - UpToDate (See "Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis".) (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".) EPIDEMIOLOGY The reported proportion of cases of NASAH that are perimesencephalic NASAH varies between 21 and 68 percent [1,2,6,8-11]. In a 2018 systematic review, the annual rate of PM-NASAH was estimated to be 0.5 per 100,000 persons over 18 years of age [12]. The pooled mean age of onset was 53 years, with reported cases ranging in age from 3 to 90 years. In contrast with aneurysmal SAH, there is no clear female predisposition for PM-NASAH; in the systematic review, females accounted for 42 percent of PM-NASAH cases [12]. Case-control studies suggest that hypertension and cigarette smoking are risk factors for PM- NASAH, but these appear to be somewhat less prevalent among patients with PM-NASAH compared with patients with aneurysmal SAH [8,13-15]. In the 2018 systematic review, the pooled odds ratios (compared with controls) for hypertension (1.6) and smoking (1.1) did not reach statistical significance, but there was substantial heterogeneity in the analyses [12]. PM-NASAH is not known to have a genetic predisposition; however, rare cases in first-degree relatives have been described [16]. ETIOLOGY AND PATHOGENESIS Aneurysmal PM-SAH A ruptured saccular aneurysm is the cause of SAH in patients with a perimesencephalic pattern of bleeding in only 2 to 9 percent of patients [1,3,5,17-20]. The aneurysm in these cases arises from the posterior circulation: the basilar tip, the vertebrobasilar junction, or the posterior inferior cerebellar, superior cerebellar, or posterior cerebral artery [5,21-23]. Posterior circulation aneurysms are less common than those arising from the anterior circulation. When posterior circulation aneurysms rupture, a perimesencephalic pattern of SAH results less than 17 percent of the time [19,20,22]. Nonaneurysmal PM-SAH In the majority of cases, PM-SAH is not due to aneurysm rupture (ie, PM-NASAH), and the etiology is not defined, even after extensive evaluation. Theories regarding its origin in some or all cases include [24]: https://www.uptodate.com/contents/perimesencephalic-nonaneurysmal-subarachnoid-hemorrhage/print 2/28 7/7/23, 11:33 AM Perimesencephalic nonaneurysmal subarachnoid hemorrhage - UpToDate Rupture of a perforating artery The perimesencephalic location of the blood clots is consistent with bleeding from a perforating artery arising from the posterior circulation [25]. In one case, this pathogenesis has been substantiated pathologically [26]. In addition, hypertension, a known risk factor for perforating artery disease, is also a risk factor for PM- NASAH. (See 'Epidemiology' above.) In one case series of 25 patients with PM-NASAH, an acute lacunar infarction (usually attributed to occlusive disease of the perforating arteries) was found in four patients [27]. However, the acute lacunar infarctions in this and other reports have been in the distribution of the anterior circulation, and their relationship to the PM-NASAH is not clear [1,28]. Venous origin A venous source for PM-NASAH is suggested by the limited extension of blood and low rate of subsequent rebleeding, both suggesting a low-pressure bleeding source. PM-NASAH often occurs in the setting of physical exertion, which in this paradigm sequentially produces increased intrathoracic pressure, impaired internal jugular venous return, elevated intracranial venous pressure, and leakage of venous blood from susceptible blood vessels [29]. Physical exertion is also believed to increase rupture from arterial pathology, including saccular aneurysms. In multiple case series, a higher incidence of variant forms of venous drainage on conventional or computed tomography (CT) venography was found in patients with PM- NASAH when compared with aneurysmal SAH [30-32]. In these patients, the basal vein of Rosenthal and/or the perimesencephalic veins drain directly into the dural sinuses rather than the vein of Galen, potentially making them more susceptible to venous congestion. Other reported venous anomalies in patients with PM-NASAH include vein of Galen stenosis, venous infarction, and cerebral venous thrombosis [33-37]. Basilar artery wall hematoma In some cases of PM-NASAH, an abnormal contour of the basilar artery has been observed, either a small bulge or luminal narrowing [24,38]. This was interpreted as possible vasospasm in some reports, but others have speculated that an intramural hematoma could account for the abnormal blood vessel appearance and also be the source of bleeding. It is postulated that rupture of the vasa vasorum is the source of the relatively limited bleeding that occurs in PM-NASAH. This is in contrast with an arterial dissection that results from an intimal tear and produces massive SAH. (See "Nonaneurysmal subarachnoid hemorrhage", section on 'Intracranial arterial dissection'.) The role of a putative basilar artery wall hematoma in PM-NASAH remains unproven. In one case series, systematic examination of basilar artery contours in 27 patients with PM- https://www.uptodate.com/contents/perimesencephalic-nonaneurysmal-subarachnoid-hemorrhage/print 3/28 7/7/23, 11:33 AM Perimesencephalic nonaneurysmal subarachnoid hemorrhage - UpToDate NASAH found no variations that suggested this origin of bleeding [9]. This hypothesis awaits further study with high-resolution neuroimaging studies. Other causes Other potential causes of PM-NASAH include rupture of a cryptic vascular malformation, high cervical spinal dural arteriovenous fistula, cavernous angioma, or capillary telangiectasia [39-41]. Some patients with PM-NASAH may have an occult aneurysm; however, the low incidence of rebleeding in these patients suggests that this is rare. (See "Nonaneurysmal subarachnoid hemorrhage".) CLINICAL PRESENTATION The clinical manifestations of PM-NASAH are generally less severe than those of aneurysmal SAH, but the presentation is otherwise similar, with sudden onset of headache, nausea, and vomiting being the most common symptoms [12]. Meningismus and photophobia are also reported [1,7]. Headache onset is instantaneous in approximately 85 percent, and more gradual (beginning in minutes rather than seconds) in the remainder [12]. Transient focal deficits, including as sensory symptoms, weakness, gait impairment, and speech arrest, are reported by approximately 10 percent of patients. Individual patients with PM-NASAH and other forms of SAH cannot be distinguished based upon their clinical symptoms [20]. However, group comparisons of patients with PM-NASAH and aneurysmal SAH find differences in the prevalence of certain clinical features and measures of disease severity. Some examples of these differences, as well as similarities, are: Severity at presentation On initial evaluation in the hospital, over 90 percent of patients with PM-NASAH are categorized in lower Hunt and Hess grades, a measure of the clinical severity of the SAH ( table 1) [1,6,7,42-44]. By contrast, patients with aneurysmal SAH present are likelier to present with more severe symptoms [6,43]. Frequency of cognitive impairment Loss of consciousness at the onset of SAH is reported less frequently in patients with PM-NASAH compared with those with aneurysmal SAH [12]. Amnesia at the onset of bleeding has been reported in up to one-third of patients, possibly due to transient hydrocephalus or a seizure [45]. Headache Sentinel headache, a prodromal feature of up to 40 percent of patients with aneurysmal SAH, is not reported in PM-NASAH [1]. However, patients with PM-NASAH may report severe neck pain prior to acute headache. Headache onset in PM-NASAH may be rapid but typically not instantaneous like in aneurysmal SAH. https://www.uptodate.com/contents/perimesencephalic-nonaneurysmal-subarachnoid-hemorrhage/print 4/28 7/7/23, 11:33 AM Perimesencephalic nonaneurysmal subarachnoid hemorrhage - UpToDate Exertional triggers The clinical setting of physical exertion appears to be as common in PM-NASAH as in aneurysmal SAH [3,7,24,29]. The onset of both PM-NASAH and aneurysmal SAH are more common during daytime and evening hours compared with nighttime [46]. One analysis of the circadian fluctuation found an increased risk of PM-NASAH during the day and late evening hours compared with the hours between 12:00 and 6:00 AM [47]. DIAGNOSTIC EVALUATION SAH should be considered in any patient complaining of severe headache of sudden onset. Urgent CT of the head should immediately follow consideration of the diagnosis. If the suspicion is high and the CT scan fails to show blood in subarachnoid space, a lumbar puncture must be obtained. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Evaluation and diagnosis'.) The diagnosis of PM-NASAH is made in a patient who meets specific computed tomography (CT) criteria described below and in whom at least one angiographic study has failed to demonstrate an aneurysm. (See 'Radiologic criteria' below and 'Initial cerebral angiography' below.) Radiologic criteria The pattern of blood on CT scan identifies a patient with PM-SAH and a low likelihood of an aneurysm ( image 1 and figure 1) [1,5,48-50]. Specific radiographic criteria include the following (all must be true) [12,50]: The diagnostic head CT scan without contrast scan is done within 72 hours after the ictus. The center of the hemorrhage is located immediately anterior to and in contact with brainstem in prepontine, interpeduncular, or suprasellar cistern. Blood is limited to the prepontine, interpeduncular, suprasellar, crural, ambient, and/or quadrigeminal cistern and/or cisterna magna. No extension of blood into sylvian or interhemispheric fissures. Interventricular blood is limited to incomplete filling of the fourth ventricle and occipital horns of the lateral ventricle. No intraparenchymal blood. In some patients, the visualized blood is limited to the quadrigeminal or pretruncal cisterns [48,49,51]. There is high interobserver agreement among radiologists in the identification of PM- SAH (kappa 0.87 to 0.96) [5,50]. https://www.uptodate.com/contents/perimesencephalic-nonaneurysmal-subarachnoid-hemorrhage/print 5/28 7/7/23, 11:33 AM Perimesencephalic nonaneurysmal subarachnoid hemorrhage - UpToDate The timing of the CT scan is critical. A diagnosis of PM-NASAH should not be considered reliable on a CT performed more than 48 to 72 hours after the clinical ictus, as washout and resorption of blood may have taken place and obscured the initial extent of hemorrhage [1,7,52]. Occasionally, an aneurysmal source of bleeding is found to be the cause of a PM-SAH that fulfills all of the above criteria, but an aneurysm is more likely when one or more of the criteria are not fulfilled ( image 2). Thus, angiographic evaluation is essential for all patients with PM-SAH. (See 'Initial cerebral angiography' below.) Evaluation Imaging evaluation is essential for all patients with PM-SAH to exclude an aneurysmal source of bleeding ( algorithm 1). (See 'Initial cerebral angiography' below.) Cerebral venous thrombosis can rarely present with PM-NASAH as its primary manifestation [34- 37]. The thrombosis may be visualized on venous phase of digital subtraction angiography and/or on magnetic resonance imaging venography (MRV) or computed tomography venography (CTV). It is important to exclude the possibility of acute cerebral venous sinus thrombosis when PM-SAH is associated with venous hemorrhagic infarction, and it is reasonable to evaluate for cerebral venous thrombosis if there is a history of prior venous thrombosis or a clinical susceptibility for hypercoagulability. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis".) If discovered, the treatment paradigm for cerebral venous thrombosis would differ significantly than the typical course of management for PM-NASAH. (See "Cerebral venous thrombosis: Treatment and prognosis".) Initial cerebral angiography The likelihood of finding an aneurysm on angiogram in a patient with a PM-SAH has varied from 2 to 9 percent in different reports. (See 'Etiology and pathogenesis' above.) Because of the very high and immediate morbidity and mortality associated with aneurysmal bleeding, every patient with PM-SAH must undergo angiographic evaluation. The commonly used angiographic techniques include computed tomography angiography (CTA), magnetic resonance angiography (MRA), and conventional digital subtraction angiography (DSA). The best modality for evaluation of cerebral vasculature in PM-SAH is controversial. Preference for DSA Digital subtraction angiography (DSA) has the highest resolution for the detection of intracranial aneurysms and remains the gold-standard imaging test. Three- dimensional rotational techniques can further improve the diagnostic yield of DSA by identifying very small aneurysms that may be difficult to visualize with standard two-dimensional angiography [53]. While invasive, DSA has a relatively low morbidity in this setting. In one meta- https://www.uptodate.com/contents/perimesencephalic-nonaneurysmal-subarachnoid-hemorrhage/print 6/28 7/7/23, 11:33 AM Perimesencephalic nonaneurysmal subarachnoid hemorrhage - UpToDate analysis, the combined risk of permanent and transient neurologic complications following DSA was significantly lower in patients with SAH compared with those with a transient ischemic attack (TIA) or stroke (1.8 versus 3.7 percent) [54]. Multidetector CTA as an alternative Of the two noninvasive angiographic techniques, computed tomography angiography (CTA) and magnetic resonance angiography (MRA), CTA has been best studied in the setting of acute SAH. Different meta-analyses have documented sensitivities and specificities of CTA for aneurysm detection to be 83 to 97 and 88 to 97 percent, respectively [55-59]. There is likely to be appreciable interinstitutional variability, stemming from expertise in interpretation and also in the specific technology used. A 2011 meta-analysis of CTA diagnosis of intracranial aneurysms found that, compared with single-detector CTA, use of multidetector CTA was associated with an overall improved sensitivity and specificity for aneurysm detection (both >97 percent) as well as improved detection of smaller aneurysms 4 mm in diameter [57]. Another systematic review and meta-analysis restricted to patients with SAH had similar findings [58]. Multidetector CTA also allows for superior depiction of aneurysm morphology [60]. A decision analysis reported that CTA alone had higher utilities in the setting of PM-SAH compared with other diagnostic strategies including no investigation, DSA alone, and CTA plus DSA [17]. However, certain assumptions in the analysis, including a low prevalence of aneurysm (4 percent), a high complication rate of angiography (2.7 percent morbidity and mortality), and a 97 percent sensitivity and specificity of CTA, favored this outcome and can be disputed. Despite the improvement in CTA technology in accurately identifying small ruptured aneurysms, the specific CTA technology, along with expertise of interpretation, varies at different institutions. As a result, we recommend DSA over CTA as a first test for most patients with PM- SAH. Centers with a high volume of cases of SAH and demonstrated, documented experience with multidetector CTA for this purpose may choose CTA over DSA. The role of repeat angiography For patients with PM-NASAH with initial angiography that was technically difficult, complicated by vasospasm, or associated with severe clinical grade, we repeat imaging with DSA with three-dimensional rotational angiography or multidetector CTA one to two weeks following the onset of PM-SAH. In addition, rebleeding suggests the presence of an occult aneurysm and is an indication for repeat DSA. For other patients with PM-NASAH and negative initial angiography, it is reasonable to avoid repeat testing. When DSA is repeated after an initial first study in patients with SAH, an aneurysm may be revealed in 2 to 24 percent of patients [1,6,10,61]. Reasons for an initial false-negative https://www.uptodate.com/contents/perimesencephalic-nonaneurysmal-subarachnoid-hemorrhage/print 7/28 7/7/23, 11:33 AM Perimesencephalic nonaneurysmal subarachnoid hemorrhage - UpToDate angiogram include technical or reading errors, small aneurysm size, and obscuration of the aneurysm because of vasospasm, hematoma, or thrombosis within the aneurysm [6,23]. A false-negative angiogram in the setting of PM-SAH is a rare but reported event [6,10,23,42,61- 63]. A study of 273 patients with angiogram-negative SAH found that patients with PM-NASAH had a higher rate of variant venous drainage and that the presence of typical venous drainage in such patients was associated with a higher rate of positive findings among those who underwent repeat angiography as well as an increased risk of rebleeding from an arterial source [32]. Given the low yield of repeat angiography, many clinicians do not pursue this unless the initial angiogram is felt to be technically compromised because of vasospasm or other factors [1- 4,64-69]. Others disagree and advocate repeating DSA in all patients [52,59]. A conservative, middle-road approach advocates follow-up imaging with noninvasive CTA [6,63]. Magnetic resonance imaging Magnetic resonance imaging (MRI) has no additional benefit for the detection of a bleeding source compared with CT, CTA, and DSA and is not cost-effective in the evaluation of patients with PM-SAH [12,61,70-72]. However, some centers may continue to perform MRI in selected patients with suspected PM-NASAH if the pattern of bleeding is unusual. Other testing Patients with SAH should undergo basic laboratory testing including complete blood count, serum chemistries, and coagulation studies. A baseline electrocardiogram (ECG) should also be obtained. CLINICAL COURSE AND COMPLICATIONS Most clinical case series report that patients with PM-NASAH have a lower incidence and severity of complications compared with patients with aneurysmal SAH and patients with non-PM-NASAH [2,11,43,73-75]. Rebleeding Rebleeding is rare among patients with PM-SAH after initial negative angiography [76]. In a 2018 systematic review, in-hospital rebleeding was reported in only 3 of over 1220 patients with PM-NASAH [12]. In those patients in whom rebleeding occurs, an occult cerebral aneurysm seems likely because the pattern of recurrent hemorrhage is often not perimesencephalic [6,77]. Rebleeding represents an indication for repeat digital subtraction angiography (DSA). Vasospasm Vasospasm with cerebral ischemia is a leading cause of death and disability after aneurysm rupture, occurring in 20 to 30 percent of patients with aneurysmal SAH [78]. In PM- https://www.uptodate.com/contents/perimesencephalic-nonaneurysmal-subarachnoid-hemorrhage/print 8/28 7/7/23, 11:33 AM Perimesencephalic nonaneurysmal subarachnoid hemorrhage - UpToDate NASAH, vasospasm is less common [79] and typically associated with milder clinical symptoms. In a 2018 systematic review of patients with PM-NASAH, angiographic vasospasm was detected in 9 percent (95% CI 6 to 14 percent) [12]. However, there are reported cases of symptomatic, diffuse, and severe vasospasm affecting the anterior and posterior circulations in patients with PM-NASAH [2,80-85]. Symptomatic vasospasm has been precipitated by DSA in some cases [1,7,73]. The lower incidence of vasospasm in PM-NASAH compared with aneurysmal SAH may be due to the lower volume or less oxyhemoglobin from venous source of bleeding in these patients, although this specific association has not been demonstrated. Transcranial Doppler (TCD) sonography is useful for detecting and monitoring vasospasm in spontaneous SAH [86,87]. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Vasospasm and delayed cerebral ischemia' and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Monitoring'.) Hydrocephalus Hydrocephalus can be an early or delayed complication of SAH. A 2018 systematic review of PM-NASAH found that acute hydrocephalus occurred in 14 percent (95% CI 10 to 18 percent) [12], a rate similar to aneurysmal SAH; symptomatic hydrocephalus, defined as radiographic hydrocephalus with a diminished level of consciousness leading to drainage, was less frequent, occurring in 3 percent (95% CI 2 to 6 percent). One case series found that among their patients with PM-NASAH, filling of all perimesencephalic cisterns was a prerequisite for developing hydrocephalus [88]. In more than half of the cases, hydrocephalus resolved spontaneously without intervention (ventriculostomy and/or shunting), perhaps because of rapid washout of blood limited to the cisterns. Seizures Acute seizures have been described in PM-NASAH, but this is uncommon [12]. PM- NASAH does not appear to be associated with the later development of epilepsy. Hyponatremia Hyponatremia following SAH is due to increased secretion of antidiuretic hormone. In one series, 10 of 35 patients with PM-NASAH developed hyponatremia, only five of whom had sodium levels less than 130 mmol/L [73]. (See "Cerebral salt wasting".) Cardiac and ECG abnormalities Cardiac abnormalities and electrocardiographic (ECG) changes are commonly seen after SAH, ranging in severity from transient ST segment depression to life-threatening cardiac arrhythmias (see "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Cardiopulmonary complications'). In one case series of PM-NASAH, baseline ECG changes were found in 22 percent on admission and transient ECG changes occurred in most [1,73]. No clinically significant cardiac complications have been reported in the setting of PM-NASAH. https://www.uptodate.com/contents/perimesencephalic-nonaneurysmal-subarachnoid-hemorrhage/print 9/28 7/7/23, 11:33 AM Perimesencephalic nonaneurysmal subarachnoid hemorrhage - UpToDate TREATMENT Initial management while aneurysm is being excluded Patients with PM-SAH should be treated as though there is an underlying aneurysm until this has been satisfactorily excluded. Patients are admitted to an intensive care setting for constant hemodynamic and cardiac monitoring, given stool softeners, kept at bed rest, and given analgesia to diminish hemodynamic fluctuations and lower the risk of rebleeding. Anticoagulation and antiplatelet agents should be discontinued. Pneumatic compression stockings to limit risk of deep vein thrombosis should be utilized while patients are immobile. Patients in whom PM-SAH is discovered in the outpatient setting should be transferred to an inpatient setting for further management. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".) Management after exclusion of aneurysm After exclusion of cerebral aneurysm, patients with PM-NASAH should continue to receive symptomatic care with analgesics as needed, cardiac monitoring, serum chemistry monitoring, and monitoring of neurologic status [1]. Blood pressure should be monitored and controlled, but strict bed rest is not required. The risk of epileptic seizures is low and prophylactic antiseizure medications are not recommended [7]. The calcium channel blocker nimodipine has been shown to improve outcomes in patients with aneurysmal SAH [89] (see "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Nimodipine'). The mechanism of its action is uncertain but may involve some type of neuroprotection against vasospasm-induced cerebral ischemia. It is less certain that patients with other mechanisms of SAH also benefit from nimodipine. There are no data as to whether nimodipine provides any benefit for patients with PM-NASAH, who as a group incur little, if any, serious neurologic mortality and morbidity. At the same time, nimodipine is unlikely to be associated with significant adverse effects in this group. We suggest that patients with PM-SAH be treated and monitored as if there is a cerebral aneurysm with nimodipine and transcranial Doppler (TCD) monitoring until imaging evaluation has satisfactorily excluded aneurysmal SAH as the etiology. (See 'The role of repeat angiography' above.) In patients who required anticoagulation prior to the onset of PM-NASAH, there are limited data regarding the optimal time of anticoagulation reinitiation. Early rebleeding has been described with restarting anticoagulation in the immediate posthemorrhagic period [90]. We suggest avoiding therapeutic anticoagulation for the first three to five days following onset of PM-NASAH when possible. While complications following PM-NASAH are less likely than after aneurysmal SAH, they should be managed similarly. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Early complications'.) https://www.uptodate.com/contents/perimesencephalic-nonaneurysmal-subarachnoid-hemorrhage/print 10/28 7/7/23, 11:33 AM Perimesencephalic nonaneurysmal subarachnoid hemorrhage - UpToDate LONG-TERM PROGNOSIS Compared with aneurysmal SAH, patients with PM-NASAH have a good outcome [2,6,73]. Long- term follow-up studies reveal that rebleeding is exceptional and life expectancy is not altered [43,91-93]. With rare exception, patients do not have significant neurologic deficits after PM- NASAH. Some uncontrolled studies suggest that many patients report residual headaches, depression, minor cognitive deficits, and fatigue several years after the PM-NASAH, in some cases affecting employment status [4,91,93,94]. Persistent anosmia is an infrequent (5 percent) complication of PM-NASAH [95]. However, one study found that quality of life two years after PM-NASAH was not significantly different from controls [96]. 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 Definition Perimesencephalic nonaneurysmal subarachnoid hemorrhage (PM-NASAH) refers to a subset of patients with subarachnoid hemorrhage (SAH) who have a characteristic pattern of localized blood on computed tomography (CT), normal cerebral angiography, and a benign course. The annual rate of PM-NASAH was estimated to be 0.5 per 100,000 persons over 18 years of age. (See 'Introduction and definition' above and 'Epidemiology' above.) Clinical features The clinical presentation of PM-NASAH overlaps that of aneurysmal SAH with abrupt onset of headache, meningismus, photophobia, nausea, and vomiting. As a group, patients with PM-NASAH have milder clinical features than those with aneurysmal SAH. (See 'Clinical presentation' above.) Diagnosis The diagnosis of PM-NASAH is made in a patient who meets specific computed tomography (CT) criteria in whom at least one angiographic study has failed to demonstrate an aneurysm. The CT findings that define PM-SAH ( image 3) include blood limited to the prepontine, interpeduncular, suprasellar, crural, ambient, and/or quadrigeminal cistern and/or cisterna magna. There may be extension into the basal parts of the sylvian fissures and small https://www.uptodate.com/contents/perimesencephalic-nonaneurysmal-subarachnoid-hemorrhage/print 11/28 7/7/23, 11:33 AM Perimesencephalic nonaneurysmal subarachnoid hemorrhage - UpToDate amount of spillover in the ventricles but not into the lateral sylvian fissure or anterior interhemispheric fissure. (See 'Radiologic criteria' above.) Evaluation to exclude aneurysm An intracranial aneurysm should be excluded in all patients with PM-SAH ( algorithm 1). We suggest using digital subtraction angiography (DSA). In centers that have a large experience with reliable CT angiography (CTA), this may replace DSA. Repeat imaging with three-dimensional DSA or multidetector CTA should be done in patients with an initial negative study in whom concerns for underlying aneurysm remain because of underlying vasospasm or the technical quality of the initial study. Rare patients who have recurrent hemorrhage should also have a repeat study. (See 'Initial cerebral angiography' above.) Management Patients with PM-SAH who are found to have a cerebral aneurysm should be managed as are other patients with aneurysmal SAH. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".) Patients with PM-NASAH have a lower incidence of complications than patients with aneurysmal SAH. Patients should be clinically monitored for complications including rebleeding, seizures, clinical vasospasm, hydrocephalus, hyponatremia, and cardiac complications. (See 'Clinical course and complications' above.) Aside from monitoring, specific treatments are not required for patients with PM- NASAH. However, until a cerebral aneurysm has been excluded on follow-up imaging, we suggest using prophylactic nimodipine to ameliorate complications of potential vasospasm (Grade 2B). (See 'Treatment' above.) Prognosis The long-term prognosis for patients with PM-NASAH is, in general, excellent. (See 'Long-term prognosis' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges David Brock, MD, CIP, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. https://www.uptodate.com/contents/perimesencephalic-nonaneurysmal-subarachnoid-hemorrhage/print 12/28 7/7/23, 11:33 AM Perimesencephalic nonaneurysmal subarachnoid hemorrhage - UpToDate REFERENCES 1. Schwartz TH, Solomon RA. Perimesencephalic nonaneurysmal subarachnoid hemorrhage: review of the literature. Neurosurgery 1996; 39:433. 2. Rinkel GJ, Wijdicks EF, Hasan D, et al. Outcome in patients with subarachnoid haemorrhage and negative angiography according to pattern of haemorrhage on computed tomography. Lancet 1991; 338:964. 3. van Gijn J, van Dongen KJ, Vermeulen M, Hijdra A. Perimesencephalic hemorrhage: a nonaneurysmal and benign form of subarachnoid hemorrhage. Neurology 1985; 35:493. 4. Canh o P, Ferro JM, Pinto AN, et al. Perimesencephalic and nonperimesencephalic subarachnoid haemorrhages with negative angiograms. Acta Neurochir (Wien) 1995; 132:14. 5. Rinkel GJ, Wijdicks EF, Vermeulen M, et al. Nonaneurysmal perimesencephalic subarachnoid hemorrhage: CT and MR patterns that differ from aneurysmal rupture. AJNR Am J Neuroradiol 1991; 12:829. 6. Jung JY, Kim YB, Lee JW, et al. Spontaneous subarachnoid haemorrhage with negative initial angiography: a review of 143 cases. J Clin Neurosci 2006; 13:1011. 7. Wijdicks EF, Schievink WI, Miller GM. Pretruncal nonaneurysmal subarachnoid hemorrhage. Mayo Clin Proc 1998; 73:745. 8. Flaherty ML, Haverbusch M, Kissela B, et al. Perimesencephalic subarachnoid hemorrhage: incidence, risk factors, and outcome. J Stroke Cerebrovasc Dis 2005; 14:267. 9. Lang EW, Khodair A, Barth H, et al. Subarachnoid hemorrhage of unknown origin and the basilar artery configuration. J Clin Neurosci 2003; 10:74. 10. Urbach H, Zentner J, Solymosi L. The need for repeat angiography in subarachnoid haemorrhage. Neuroradiology 1998; 40:6. 11. Hui FK, Tumial n LM, Tanaka T, et al. Clinical differences between angiographically negative, diffuse subarachnoid hemorrhage and perimesencephalic subarachnoid hemorrhage. Neurocrit Care 2009; 11:64. 12. Mensing LA, Vergouwen MDI, Laban KG, et al. Perimesencephalic Hemorrhage: A Review of Epidemiology, Risk Factors, Presumed Cause, Clinical Course, and Outcome. Stroke 2018; 49:1363. 13. Canh o P, Falc o F, Pinho e Melo T, et al. Vascular risk factors for perimesencephalic nonaneurysmal subarachnoid hemorrhage. J Neurol 1999; 246:492. 14. Kleinpeter G, Lehr S. Characterization of risk factor differences in perimesencephalic subarachnoid hemorrhage. Minim Invasive Neurosurg 2003; 46:142. https://www.uptodate.com/contents/perimesencephalic-nonaneurysmal-subarachnoid-hemorrhage/print 13/28 7/7/23, 11:33 AM Perimesencephalic nonaneurysmal subarachnoid hemorrhage - UpToDate 15. Mensing LA, Ruigrok YM, Greebe P, et al. Risk factors in patients with perimesencephalic hemorrhage. Eur J Neurol 2014; 21:816. 16. Tieleman AA, van der Vliet TA, Vos PE. Two first-degree relatives with perimesencephalic nonaneurysmal hemorrhage. Neurology 2006; 67:535. 17. Ruigrok YM, Rinkel GJ, Buskens E, et al. Perimesencephalic hemorrhage and CT angiography: A decision analysis. Stroke 2000; 31:2976. 18. Velthuis BK, Rinkel GJ, Ramos LM, et al. Perimesencephalic hemorrhage. Exclusion of vertebrobasilar aneurysms with CT angiography. Stroke 1999; 30:1103. 19. Pinto AN, Ferro JM, Canh o P, Campos J. How often is a perimesencephalic subarachnoid haemorrhage CT pattern caused by ruptured aneurysms? Acta Neurochir (Wien) 1993; 124:79. 20. Al n JF, Lagares A, Lobato RD, et al. Comparison between perimesencephalic nonaneurysmal subarachnoid hemorrhage and subarachnoid hemorrhage caused by posterior circulation aneurysms. J Neurosurg 2003; 98:529. 21. Schievink WI, Wijdicks EF, Piepgras DG, et al. Perimesencephalic subarachnoid hemorrhage. Additional perspectives from four cases. Stroke 1994; 25:1507. 22. Kallmes DF, Clark HP, Dix JE, et al. Ruptured vertebrobasilar aneurysms: frequency of the nonaneurysmal perimesencephalic pattern of hemorrhage on CT scans. Radiology 1996; 201:657. 23. White JB, Wijdicks EF, Cloft HJ, Kallmes DF. Vanishing aneurysm in pretruncal nonaneurysmal subarachnoid hemorrhage. Neurology 2008; 71:1375. 24. Schievink WI, Wijdicks EF. Origin of pretruncal nonaneurysmal subarachnoid hemorrhage: ruptured vein, perforating artery, or intramural hematoma? Mayo Clin Proc 2000; 75:1169. 25. Alexander MS, Dias PS, Uttley D. Spontaneous subarachnoid hemorrhage and negative cerebral panangiography. Review of 140 cases. J Neurosurg 1986; 64:537. 26. Hochberg FH, Fisher CM, Roberson GH. Subarachnoid hemorrhage caused by rupture of a small superficial artery. Neurology 1974; 24:319. 27. Rogg JM, Smeaton S, Doberstein C, et al. Assessment of the value of MR imaging for examining patients with angiographically negative subarachnoid hemorrhage. AJR Am J Roentgenol 1999; 172:201. 28. Tatter SB, Buonanno FS, Ogilvy CS. Acute lacunar stroke in association with angiogram- negative subarachnoid hemorrhage. Mechanistic implications of two cases. Stroke 1995; 26:891. https://www.uptodate.com/contents/perimesencephalic-nonaneurysmal-subarachnoid-hemorrhage/print 14/28 7/7/23, 11:33 AM Perimesencephalic nonaneurysmal subarachnoid hemorrhage - UpToDate 29. Matsuyama T, Okuchi K, Seki T, et al. Perimesencephalic nonaneurysmal subarachnoid hemorrhage caused by physical exertion. Neurol Med Chir (Tokyo) 2006; 46:277. 30. Watanabe A, Hirano K, Kamada M, et al. Perimesencephalic nonaneurysmal subarachnoid haemorrhage and variations in the veins. Neuroradiology 2002; 44:319. 31. van der Schaaf IC, Velthuis BK, Gouw A, Rinkel GJ. Venous drainage in perimesencephalic hemorrhage. Stroke 2004; 35:1614. 32. Fang Y, Shao A, Wang X, et al. Deep venous drainage variant rate and degree may be higher in patients with perimesencephalic than in non-perimesencephalic angiogram-negative subarachnoid hemorrhage. Eur Radiol 2021; 31:1290. 33. Mathews MS, Brown D, Brant-Zawadzki M. Perimesencephalic nonaneurysmal hemorrhage associated with vein of Galen stenosis. Neurology 2008; 70:2410. 34. Lee J, Koh EM, Chung CS, et al. Underlying venous pathology causing perimesencephalic subarachnoid hemorrhage. Can J Neurol Sci 2009; 36:638. 35. Fu FW, Rao J, Zheng YY, et al. Perimesencephalic nonaneurysmal subarachnoid hemorrhage caused by transverse sinus thrombosis: A case report and review of literature. Medicine (Baltimore) 2017; 96:e7374. 36. Kurosu A, Suzukawa K, Amo M, et al. Perimesencephalic non-aneurysmal subarachnoid hemorrhage caused by cavernous sinus thrombosis: case report. Neurol Med Chir (Tokyo) 2007; 47:258. 37. Amer RR, Bakhsh EA. Nonaneurysmal Perimesencephalic Subarachnoid Hemorrhage as an Atypical Initial Presentation of Cerebral Venous Sinus Thrombosis: A Case Report. Am J Case Rep 2018; 19:472. 38. Matsumaru Y, Yanaka K, Muroi A, et al. Significance of a small bulge on the basilar artery in patients with perimesencephalic nonaneurysmal subarachnoid hemorrhage. Report of two cases. J Neurosurg 2003; 98:426. 39. Hashimoto H, Iida J, Shin Y, et al. Spinal dural arteriovenous fistula with perimesencephalic subarachnoid haemorrhage. J Clin Neurosci 2000; 7:64. 40. Wijdicks EF, Schievink WI. Perimesencephalic nonaneurysmal subarachnoid hemorrhage: first hint of a cause? Neurology 1997; 49:634. 41. Yaghi S, Oomman S, Keyrouz SG. Non-aneurysmal perimesencephalic subarachnoid hemorrhage caused by a cavernous angioma. Neurocrit Care 2011; 14:84. 42. Franz G, Brenneis C, Kampfl A, et al. Prognostic value of intraventricular blood in perimesencephalic nonaneurysmal subarachnoid hemorrhage. J Comput Assist Tomogr 2001; 25:742. https://www.uptodate.com/contents/perimesencephalic-nonaneurysmal-subarachnoid-hemorrhage/print 15/28 7/7/23, 11:33 AM

ACKNOWLEDGMENT The UpToDate editorial staff acknowledges David Brock, MD, CIP, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. https://www.uptodate.com/contents/perimesencephalic-nonaneurysmal-subarachnoid-hemorrhage/print 12/28 7/7/23, 11:33 AM Perimesencephalic nonaneurysmal subarachnoid hemorrhage - UpToDate REFERENCES 1. Schwartz TH, Solomon RA. Perimesencephalic nonaneurysmal subarachnoid hemorrhage: review of the literature. Neurosurgery 1996; 39:433. 2. Rinkel GJ, Wijdicks EF, Hasan D, et al. Outcome in patients with subarachnoid haemorrhage and negative angiography according to pattern of haemorrhage on computed tomography. Lancet 1991; 338:964. 3. van Gijn J, van Dongen KJ, Vermeulen M, Hijdra A. Perimesencephalic hemorrhage: a nonaneurysmal and benign form of subarachnoid hemorrhage. Neurology 1985; 35:493. 4. Canh o P, Ferro JM, Pinto AN, et al. Perimesencephalic and nonperimesencephalic subarachnoid haemorrhages with negative angiograms. Acta Neurochir (Wien) 1995; 132:14. 5. Rinkel GJ, Wijdicks EF, Vermeulen M, et al. Nonaneurysmal perimesencephalic subarachnoid hemorrhage: CT and MR patterns that differ from aneurysmal rupture. AJNR Am J Neuroradiol 1991; 12:829. 6. Jung JY, Kim YB, Lee JW, et al. Spontaneous subarachnoid haemorrhage with negative initial angiography: a review of 143 cases. J Clin Neurosci 2006; 13:1011. 7. Wijdicks EF, Schievink WI, Miller GM. Pretruncal nonaneurysmal subarachnoid hemorrhage. Mayo Clin Proc 1998; 73:745. 8. Flaherty ML, Haverbusch M, Kissela B, et al. Perimesencephalic subarachnoid hemorrhage: incidence, risk factors, and outcome. J Stroke Cerebrovasc Dis 2005; 14:267. 9. Lang EW, Khodair A, Barth H, et al. Subarachnoid hemorrhage of unknown origin and the basilar artery configuration. J Clin Neurosci 2003; 10:74. 10. Urbach H, Zentner J, Solymosi L. The need for repeat angiography in subarachnoid haemorrhage. Neuroradiology 1998; 40:6. 11. Hui FK, Tumial n LM, Tanaka T, et al. Clinical differences between angiographically negative, diffuse subarachnoid hemorrhage and perimesencephalic subarachnoid hemorrhage. Neurocrit Care 2009; 11:64. 12. Mensing LA, Vergouwen MDI, Laban KG, et al. Perimesencephalic Hemorrhage: A Review of Epidemiology, Risk Factors, Presumed Cause, Clinical Course, and Outcome. Stroke 2018; 49:1363. 13. Canh o P, Falc o F, Pinho e Melo T, et al. Vascular risk factors for perimesencephalic nonaneurysmal subarachnoid hemorrhage. J Neurol 1999; 246:492. 14. Kleinpeter G, Lehr S. Characterization of risk factor differences in perimesencephalic subarachnoid hemorrhage. Minim Invasive Neurosurg 2003; 46:142. https://www.uptodate.com/contents/perimesencephalic-nonaneurysmal-subarachnoid-hemorrhage/print 13/28 7/7/23, 11:33 AM Perimesencephalic nonaneurysmal subarachnoid hemorrhage - UpToDate 15. Mensing LA, Ruigrok YM, Greebe P, et al. Risk factors in patients with perimesencephalic hemorrhage. Eur J Neurol 2014; 21:816. 16. Tieleman AA, van der Vliet TA, Vos PE. Two first-degree relatives with perimesencephalic nonaneurysmal hemorrhage. Neurology 2006; 67:535. 17. Ruigrok YM, Rinkel GJ, Buskens E, et al. Perimesencephalic hemorrhage and CT angiography: A decision analysis. Stroke 2000; 31:2976. 18. Velthuis BK, Rinkel GJ, Ramos LM, et al. Perimesencephalic hemorrhage. Exclusion of vertebrobasilar aneurysms with CT angiography. Stroke 1999; 30:1103. 19. Pinto AN, Ferro JM, Canh o P, Campos J. How often is a perimesencephalic subarachnoid haemorrhage CT pattern caused by ruptured aneurysms? Acta Neurochir (Wien) 1993; 124:79. 20. Al n JF, Lagares A, Lobato RD, et al. Comparison between perimesencephalic nonaneurysmal subarachnoid hemorrhage and subarachnoid hemorrhage caused by posterior circulation aneurysms. J Neurosurg 2003; 98:529. 21. Schievink WI, Wijdicks EF, Piepgras DG, et al. Perimesencephalic subarachnoid hemorrhage. Additional perspectives from four cases. Stroke 1994; 25:1507. 22. Kallmes DF, Clark HP, Dix JE, et al. Ruptured vertebrobasilar aneurysms: frequency of the nonaneurysmal perimesencephalic pattern of hemorrhage on CT scans. Radiology 1996; 201:657. 23. White JB, Wijdicks EF, Cloft HJ, Kallmes DF. Vanishing aneurysm in pretruncal nonaneurysmal subarachnoid hemorrhage. Neurology 2008; 71:1375. 24. Schievink WI, Wijdicks EF. Origin of pretruncal nonaneurysmal subarachnoid hemorrhage: ruptured vein, perforating artery, or intramural hematoma? Mayo Clin Proc 2000; 75:1169. 25. Alexander MS, Dias PS, Uttley D. Spontaneous subarachnoid hemorrhage and negative cerebral panangiography. Review of 140 cases. J Neurosurg 1986; 64:537. 26. Hochberg FH, Fisher CM, Roberson GH. Subarachnoid hemorrhage caused by rupture of a small superficial artery. Neurology 1974; 24:319. 27. Rogg JM, Smeaton S, Doberstein C, et al. Assessment of the value of MR imaging for examining patients with angiographically negative subarachnoid hemorrhage. AJR Am J Roentgenol 1999; 172:201. 28. Tatter SB, Buonanno FS, Ogilvy CS. Acute lacunar stroke in association with angiogram- negative subarachnoid hemorrhage. Mechanistic implications of two cases. Stroke 1995; 26:891. https://www.uptodate.com/contents/perimesencephalic-nonaneurysmal-subarachnoid-hemorrhage/print 14/28 7/7/23, 11:33 AM Perimesencephalic nonaneurysmal subarachnoid hemorrhage - UpToDate 29. Matsuyama T, Okuchi K, Seki T, et al. Perimesencephalic nonaneurysmal subarachnoid hemorrhage caused by physical exertion. Neurol Med Chir (Tokyo) 2006; 46:277. 30. Watanabe A, Hirano K, Kamada M, et al. Perimesencephalic nonaneurysmal subarachnoid haemorrhage and variations in the veins. Neuroradiology 2002; 44:319. 31. van der Schaaf IC, Velthuis BK, Gouw A, Rinkel GJ. Venous drainage in perimesencephalic hemorrhage. Stroke 2004; 35:1614. 32. Fang Y, Shao A, Wang X, et al. Deep venous drainage variant rate and degree may be higher in patients with perimesencephalic than in non-perimesencephalic angiogram-negative subarachnoid hemorrhage. Eur Radiol 2021; 31:1290. 33. Mathews MS, Brown D, Brant-Zawadzki M. Perimesencephalic nonaneurysmal hemorrhage associated with vein of Galen stenosis. Neurology 2008; 70:2410. 34. Lee J, Koh EM, Chung CS, et al. Underlying venous pathology causing perimesencephalic subarachnoid hemorrhage. Can J Neurol Sci 2009; 36:638. 35. Fu FW, Rao J, Zheng YY, et al. Perimesencephalic nonaneurysmal subarachnoid hemorrhage caused by transverse sinus thrombosis: A case report and review of literature. Medicine (Baltimore) 2017; 96:e7374. 36. Kurosu A, Suzukawa K, Amo M, et al. Perimesencephalic non-aneurysmal subarachnoid hemorrhage caused by cavernous sinus thrombosis: case report. Neurol Med Chir (Tokyo) 2007; 47:258. 37. Amer RR, Bakhsh EA. Nonaneurysmal Perimesencephalic Subarachnoid Hemorrhage as an Atypical Initial Presentation of Cerebral Venous Sinus Thrombosis: A Case Report. Am J Case Rep 2018; 19:472. 38. Matsumaru Y, Yanaka K, Muroi A, et al. Significance of a small bulge on the basilar artery in patients with perimesencephalic nonaneurysmal subarachnoid hemorrhage. Report of two cases. J Neurosurg 2003; 98:426. 39. Hashimoto H, Iida J, Shin Y, et al. Spinal dural arteriovenous fistula with perimesencephalic subarachnoid haemorrhage. J Clin Neurosci 2000; 7:64. 40. Wijdicks EF, Schievink WI. Perimesencephalic nonaneurysmal subarachnoid hemorrhage: first hint of a cause? Neurology 1997; 49:634. 41. Yaghi S, Oomman S, Keyrouz SG. Non-aneurysmal perimesencephalic subarachnoid hemorrhage caused by a cavernous angioma. Neurocrit Care 2011; 14:84. 42. Franz G, Brenneis C, Kampfl A, et al. Prognostic value of intraventricular blood in perimesencephalic nonaneurysmal subarachnoid hemorrhage. J Comput Assist Tomogr 2001; 25:742. https://www.uptodate.com/contents/perimesencephalic-nonaneurysmal-subarachnoid-hemorrhage/print 15/28 7/7/23, 11:33 AM Perimesencephalic nonaneurysmal subarachnoid hemorrhage - UpToDate 43. Ildan F, Tuna M, Erman T, et al. Prognosis and prognostic factors in nonaneurysmal perimesencephalic hemorrhage: a follow-up study in 29 patients. Surg Neurol 2002; 57:160. 44. Report of World Federation of Neurological Surgeons Committee on a Universal Subarachnoid Hemorrhage Grading Scale. J Neurosurg 1988; 68:985. 45. Hop JW, Brilstra EH, Rinkel GJ. Transient amnesia after perimesencephalic haemorrhage: the role of enlarged temporal horns. J Neurol Neurosurg Psychiatry 1998; 65:590. 46. Vermeer SE, Rinkel GJ, Algra A. Circadian fluctuations in onset of subarachnoid hemorrhage. New data on aneurysmal and perimesencephalic hemorrhage and a systematic review. Stroke 1997; 28:805. 47. Mensing LA, Greebe P, Algra A, et al. Circadian fluctuations in onset of perimesencephalic hemorrhage. J Neurol 2013; 260:2638. 48. Schievink WI, Wijdicks EF. Pretruncal subarachnoid hemorrhage: an anatomically correct description of the perimesencephalic subarachnoid hemorrhage. Stroke 1997; 28:2572. 49. Schwartz TH, Mayer SA. Quadrigeminal variant of perimesencephalic nonaneurysmal subarachnoid hemorrhage. Neurosurgery 2000; 46:584. 50. Wallace AN, Vyhmeister R, Dines JN, et al. Evaluation of an anatomic definition of non- aneurysmal perimesencephalic subarachnhoid hemorrhage. J Neurointerv Surg 2016; 8:378. 51. Schwartz TH, Farkas J. Quadrigeminal non-aneurysmal subarachnoid hemorrhage a true variant of perimesencephalic subarachnoid hemorrhage. Case report. Clin Neurol Neurosurg 2003; 105:95. 52. Tatter SB, Crowell RM, Ogilvy CS. Aneurysmal and microaneurysmal "angiogram-negative" subarachnoid hemorrhage. Neurosurgery 1995; 37:48. 53. Ishihara H, Kato S, Akimura T, et al. Angiogram-negative subarachnoid hemorrhage in the era of three dimensional rotational angiography. J Clin Neurosci 2007; 14:252. 54. Cloft HJ, Joseph GJ, Dion JE. Risk of cerebral angiography in patients with subarachnoid hemorrhage, cerebral aneurysm, and arteriovenous malformation: a meta-analysis. Stroke 1999; 30:317. 55. Chappell ET, Moure FC, Good MC. Comparison of computed tomographic angiography with digital subtraction angiography in the diagnosis of cerebral aneurysms: a meta-analysis. Neurosurgery 2003; 52:624. 56. Colen TW, Wang LC, Ghodke BV, et al. Effectiveness of MDCT angiography for the detection of intracranial aneurysms in patients with nontraumatic subarchnoid hemorrhage. AJR Am J Roentgenol 2007; 189:898. https://www.uptodate.com/contents/perimesencephalic-nonaneurysmal-subarachnoid-hemorrhage/print 16/28 7/7/23, 11:33 AM Perimesencephalic nonaneurysmal subarachnoid hemorrhage - UpToDate 57. Menke J, Larsen J, Kallenberg K. Diagnosing cerebral aneurysms by computed tomographic angiography: meta-analysis. Ann Neurol 2011; 69:646. 58. Westerlaan HE, van Dijk JM, Jansen-van der Weide MC, et al. Intracranial aneurysms in patients with subarachnoid hemorrhage: CT angiography as a primary examination tool for diagnosis systematic review and meta-analysis. Radiology 2011; 258:134. 59. Kalra VB, Wu X, Matouk CC, Malhotra A. Use of follow-up imaging in isolated perimesencephalic subarachnoid hemorrhage: a meta-analysis. Stroke 2015; 46:401. 60. Wang H, Li W, He H, et al. 320-detector row CT angiography for detection and evaluation of intracranial aneurysms: comparison with conventional digital subtraction angiography. Clin Radiol 2013; 68:e15. 61. Topcuoglu MA, Ogilvy CS, Carter BS, et al. Subarachnoid hemorrhage without evident cause on initial angiography studies: diagnostic yield of subsequent angiography and other neuroimaging tests. J Neurosurg 2003; 98:1235. 62. Huttner HB, Hartmann M, K hrmann M, et al. Repeated digital substraction angiography after perimesencephalic subarachnoid hemorrhage? J Neuroradiol 2006; 33:87. 63. Hashimoto H, Iida J, Hironaka Y, et al. Use of spiral computerized tomography angiography in patients with subarachnoid hemorrhage in whom subtraction angiography did not reveal cerebral aneurysms. J Neurosurg 2000; 92:278. 64. Rinkel GJ, van Gijn J, Wijdicks EF. Subarachnoid hemorrhage without detectable aneurysm. A review of the causes. Stroke 1993; 24:1403. 65. Yu DW, Jung YJ, Choi BY, Chang CH. Subarachnoid hemorrhage with negative baseline digital subtraction angiography: is repeat digital subtraction angiography necessary? J Cerebrovasc Endovasc Neurosurg 2012; 14:210. 66. Agid R, Andersson T, Almqvist H, et al. Negative CT angiography findings in patients with spontaneous subarachnoid hemorrhage: When is digital subtraction angiography still needed? AJNR Am J Neuroradiol 2010; 31:696. 67. Khan AA, Smith JD, Kirkman MA, et al. Angiogram negative subarachnoid haemorrhage: outcomes and the role of repeat angiography. Clin Neurol Neurosurg 2013; 115:1470. 68. Bashir A, Mikkelsen R, S rensen L, Sunde N. Non-aneurysmal subarachnoid hemorrhage: When is a second angiography indicated? Neuroradiol J 2018; 31:244. 69. Potter CA, Fink KR, Ginn AL, Haynor DR. Perimesencephalic Hemorrhage: Yield of Single versus Multiple DSA Examinations-A Single-Center Study and Meta-Analysis. Radiology 2016; 281:858. https://www.uptodate.com/contents/perimesencephalic-nonaneurysmal-subarachnoid-hemorrhage/print 17/28 7/7/23, 11:33 AM Perimesencephalic nonaneurysmal subarachnoid hemorrhage - UpToDate 70. Wijdicks EF, Schievink WI, Miller GM. MR imaging in pretruncal nonaneurysmal subarachnoid hemorrhage: is it worthwhile? Stroke 1998; 29:2514. 71. Andaluz N, Zuccarello M. Yield of further diagnostic work-up of cryptogenic subarachnoid hemorrhage based on bleeding patterns on computed tomographic scans. Neurosurgery 2008; 62:1040. 72. Maslehaty H, Barth H, Petridis AK, et al. Special features of subarachnoid hemorrhage of unknown origin: a review of a series of 179 cases. Neurol Res 2012; 34:91. 73. Rinkel GJ, Wijdicks EF, Vermeulen M, et al. The clinical course of perimesencephalic nonaneurysmal subarachnoid hemorrhage. Ann Neurol 1991; 29:463. 74. Goergen SK, Barrie D, Sacharias N, Waugh JR. Perimesencephalic subarachnoid haemorrhage: negative angiography and favourable prognosis. Australas Radiol 1993; 37:156. 75. Angermann M, Jablawi F, Angermann M, et al. Clinical Outcome and Prognostic Factors of Patients with Perimesencephalic and Nonperimesencephalic Subarachnoid Hemorrhage. World Neurosurg 2022; 165:e512. 76. Reynolds MR, Blackburn SL, Zipfel GJ. Recurrent idiopathic perimesencephalic subarachnoid hemorrhage. J Neurosurg 2011; 115:612. 77. Caroscio JT, Brannan T, Budabin M, et al. Subarachnoid hemorrhage secondary to spinal arteriovenous malformation and aneurysm. Report of a case and review of the literature. Arch Neurol 1980; 37:101. 78. Kassell NF, Sasaki T, Colohan AR, Nazar G. Cerebral vasospasm following aneurysmal subarachnoid hemorrhage. Stroke 1985; 16:562. 79. Lee SU, Hong EP, Kim BJ, et al. Delayed Cerebral Ischemia and Vasospasm After Spontaneous Angiogram-Negative Subarachnoid Hemorrhage: An Updated Meta-Analysis. World Neurosurg 2018; 115:e558. 80. Sert A, Aydin K, Pirgon O, et al. Arterial spasm following perimesencephalic nonaneurysmal subarachnoid hemorrhage in a pediatric patient. Pediatr Neurol 2005; 32:275. 81. Sheehan JM, Cloft H, Kassell NF. Symptomatic delayed arterial spasm following non- aneurysmal perimesencephalic subarachnoid hemorrhage: a case report and review of the literature. Acta Neurochir (Wien) 2000; 142:709. 82. Schievink WI, Wijdicks EF, Spetzler RF. Diffuse vasospasm after pretruncal nonaneurysmal subarachnoid hemorrhage. AJNR Am J Neuroradiol 2000; 21:521. 83. Goedee SH, Sluzewski M, Tijssen CC. Mesencephalic infarction due to vasospasm after non- aneurysmal perimesencephalic haemorrhage. Pract Neurol 2013; 13:125. https://www.uptodate.com/contents/perimesencephalic-nonaneurysmal-subarachnoid-hemorrhage/print 18/28 7/7/23, 11:33 AM Perimesencephalic nonaneurysmal subarachnoid hemorrhage - UpToDate 84. Fernandez A, Bond RL, Aziz-Sultan MA, et al. Cerebral infarction secondary to vasospasm after perimesencephalic subarachnoid hemorrhage. J Clin Neurosci 2011; 18:994. 85. Samaniego EA, Dabus G, Fuentes K, Linfante I. Endovascular treatment of severe vasospasm in nonaneurysmal perimesencephalic subarachnoid hemorrhage. Neurocrit Care 2011; 15:537. 86. 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. 87. Krejza J, Kochanowicz J, Mariak Z, et al. Middle cerebral artery spasm after subarachnoid hemorrhage: detection with transcranial color-coded duplex US. Radiology 2005; 236:621. 88. Rinkel GJ, Wijdicks EF, Vermeulen M, et al. Acute hydrocephalus in nonaneurysmal perimesencephalic hemorrhage: evidence of CSF block at the tentorial hiatus. Neurology 1992; 42:1805. 89. Dorhout Mees SM, Rinkel GJ, Feigin VL, et al. Calcium antagonists for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev 2007; :CD000277. 90. van der Worp HB, Fonville S, Ramos LM, Rinkel GJ. Recurrent perimesencephalic subarachnoid hemorrhage during antithrombotic therapy. Neurocrit Care 2009; 10:209. 91. Marquardt G, Niebauer T, Schick U, Lorenz R. Long term follow up after perimesencephalic subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 2000; 69:127. 92. Greebe P, Rinkel GJ. Life expectancy after perimesencephalic subarachnoid hemorrhage. Stroke 2007; 38:1222. 93. Rinkel GJ, Wijdicks EF, Vermeulen M, et al. Outcome in perimesencephalic (nonaneurysmal) subarachnoid hemorrhage: a follow-up study in 37 patients. Neurology 1990; 40:1130. 94. Madureira S, Canh o P, Guerreiro M, Ferro JM. Cognitive and emotional consequences of perimesencephalic subarachnoid hemorrhage. J Neurol 2000; 247:862. 95. Greebe P, Rinkel GJ, Algra A. Anosmia after perimesencephalic nonaneurysmal hemorrhage. Stroke 2009; 40:2885. 96. Brilstra EH, Hop JW, Rinkel GJ. Quality of life after perimesencephalic haemorrhage. J Neurol Neurosurg Psychiatry 1997; 63:382. Topic 1114 Version 29.0 https://www.uptodate.com/contents/perimesencephalic-nonaneurysmal-subarachnoid-hemorrhage/print 19/28 7/7/23, 11:33 AM Perimesencephalic nonaneurysmal subarachnoid hemorrhage - UpToDate GRAPHICS 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/perimesencephalic-nonaneurysmal-subarachnoid-hemorrhage/print 20/28 7/7/23, 11:33 AM Perimesencephalic nonaneurysmal subarachnoid hemorrhage - UpToDate Perimesencephalic nonaneurysmal subarachnoid hemorrhage Head CT of three different patients demonstrating subarachnoid hemorrhage in the characteristic pattern of perimesencephalic hemorrhage with blood in the interpeduncular and ambient cisterns. CT: computed tomography. Images are courtesy of the Neuroradiology teaching le and the Neurosurgery Department at Thomas Je erson University Hospital. Graphic 76973 Version 5.0 https://www.uptodate.com/contents/perimesencephalic-nonaneurysmal-subarachnoid-hemorrhage/print 21/28 7/7/23, 11:33 AM Perimesencephalic nonaneurysmal subarachnoid hemorrhage - UpToDate Subarachnoid spaces and cisterns as seen in a median section of the brain The superior cistern (located dorsal to the midbrain) together with the subarachnoid space at the sides of the midbrain are referred to clinically as the cisterna ambiens. The superior cistern is important because it contains internal cerebral veins, which join caudally to form the great cerebral vein (of Galen). It also contains the posterior cerebral and superior cerebellar arteries. The choroid plexuses in the roof of the third and fourth ventricles are shown in red. Graphic 74410 Version 5.0 https://www.uptodate.com/contents/perimesencephalic-nonaneurysmal-subarachnoid-hemorrhage/print 22/28 7/7/23, 11:33 AM Perimesencephalic nonaneurysmal subarachnoid hemorrhage - UpToDate Radiologic examples of perimesencephalic aneurysmal subarachnoid hemorrhage Head CT (A-C) and CTA (D) of a 70-year-old man 21 hours after ictus demonstrating a perimesencephalic bleeding pattern with an aneurysm of the basilar artery. Head CT (E-G) and CTA (H) of a 52-year-old woman 18 hours after ictus showing a nonperimesencephalic bleeding pattern (arrow points at extension to the lateral part of the Sylvian fissure and dashed arrow points to intraventricular hemorrhage) with an aneurysm of the basilar artery. CT: computed tomography; CTA: computed tomography angiography. From: Mensing LA, Vergouwen MDI, Laban KG, et al. Perimesencephalic Hemorrhage: A Review of Epidemiology, Risk Factors, Presumed Cause, Clinical Course, and Outcome. Stroke 2018; 49:1363. DOI: 10.1161/STROKEAHA.117.019843. Copyright 2018 American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 118109 Version 3.0 https://www.uptodate.com/contents/perimesencephalic-nonaneurysmal-subarachnoid-hemorrhage/print 23/28 7/7/23, 11:33 AM Perimesencephalic nonaneurysmal subarachnoid hemorrhage - UpToDate Diagnostic imaging evaluation to exclude secondary causes of subarachnoid hemorrhage Imaging evaluation is typically performed for patients with spontaneous SAH to identify or exclude a ruptured cerebral aneurysm. Evaluation for nonaneurysmal causes is also warranted for patients with isolated convexity SAH who present with bleeding restricted to the surface of the cerebral hemispheres and for other patients once ruptured aneurysm has been excluded. Further https://www.uptodate.com/contents/perimesencephalic-nonaneurysmal-subarachnoid-hemorrhage/print 24/28 7/7/23, 11:33 AM Perimesencephalic nonaneurysmal subarachnoid hemorrhage - UpToDate imaging and/or other testing may be indicated for patients with acute SAH to monitor for complications and those who deteriorate clinically. Refer to UpToDate topic for additional details. SAH: subarachnoid hemorrhage; CT: computed tomography; DSA: digital subtraction angiography; CTA: computed tomographic angiography; MRI: magnetic resonance imaging. Refer to UpToDate topics for additional information on management of causes of SAH. Perimesencephalic pattern of acute SAH on head CT performed within 72 hours of onset consists of blood centered anterior to and in contact with the prepontine, interpeduncular, and/or suprasellar cisterns. Extent of blood on head CT should be restricted to the suprasellar, interpeduncular, crural, ambient, quadrigeminal, prepontine, and/or cerebellomedullary cisterns. Additional diagnostic testing is generally performed for patients with atypical features suggestive of a spinal source to bleeding such as those with prominent radicular symptoms and cervicomedullary location of bleeding or if the sensitivity of initial testing is limited by the presence of acute blood or vasospasm. Refer to UpToDate topic for additional details. Graphic 140106 Version 1.0 https://www.uptodate.com/contents/perimesencephalic-nonaneurysmal-subarachnoid-hemorrhage/print 25/28 7/7/23, 11:33 AM Perimesencephalic nonaneurysmal subarachnoid hemorrhage - UpToDate Radiologic examples of perimesencephalic nonaneurysmal subarachnoid hemorrhage (A-D) CT and CTA of a 47-year-old woman nine hours after ictus demonstrating a PM-NASAH. (E-H) CT and CTA of a 62-year-old man seven hours after ictus demonstrating a PM-NASAH with blood in front of the medulla oblongata (arrow). https://www.uptodate.com/contents/perimesencephalic-nonaneurysmal-subarachnoid-hemorrhage/print 26/28 7/7/23, 11:33 AM Perimesencephalic nonaneurysmal subarachnoid hemorrhage - UpToDate (I-L) CT and CTA of a 49-year-old woman 14 hours after ictus to illustrate a PM-NASAH with sedimentation of blood in the lateral horns (dashed arrows). (M-P) CT of a 66-year-old man 16 hours after ictus showing a PM-NASAH with the perimesencephalic cisterns filled with blood and associated hydrocephalus (M and N). CT on day seven after ictus showing a spontaneous decrease of hydrocephalus (O). CTA at time of presentation did not show an aneurysm (P). (Q-T) sagittal CT of a 47-year-old man four hours after ictus showing a PM-NASAH with distribution of blood in front of the brain stem and in the ambient cisterns. CT: computed tomography; CTA: computed tomography angiography; PM-NASAH: perimesencephalic subarachnoid hemorrhage From: Mensing LA, Vergouwen MDI, Laban KG, et al. Perimesencephalic Hemorrhage: A Review of Epidemiology, Risk Factors, Presumed Cause, Clinical Course, and Outcome. Stroke 2018; 49:1363. DOI: 10.1161/STROKEAHA.117.019843. Copyright 2018 American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 118108 Version 3.0 https://www.uptodate.com/contents/perimesencephalic-nonaneurysmal-subarachnoid-hemorrhage/print 27/28 7/7/23, 11:33 AM Perimesencephalic nonaneurysmal subarachnoid hemorrhage - UpToDate Contributor Disclosures Farhan Siddiq, MD No relevant financial relationship(s) with ineligible companies to disclose. Amir S Khan, 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/perimesencephalic-nonaneurysmal-subarachnoid-hemorrhage/print 28/28

7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Reversal of anticoagulation in intracranial hemorrhage : W David Freeman, MD, Jeffrey I Weitz, MD : Lawrence LK Leung, MD, Scott E Kasner, MD : Richard P Goddeau, Jr, DO, FAHA, Jennifer S Tirnauer, 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 17, 2023. INTRODUCTION Intracranial hemorrhage, which includes intracerebral, intraventricular, subarachnoid, subdural, and epidural bleeding, is a potentially devastating occurrence associated with anticoagulant therapy. Reversal of anticoagulation in patients with anticoagulant-associated intracranial hemorrhage is a medical emergency, as anticoagulation is associated with greater hematoma growth, neurologic deterioration, and increased risk of death and major disability compared with no anticoagulation. This topic discusses the reversal of anticoagulation in patients with anticoagulant-associated intracranial hemorrhage. Other aspects of the management and prevention of intracranial hemorrhage are presented separately. Risks and prevention (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Risk factors'.) (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Intracranial'.) (See "Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis", section on 'Risk of recurrence'.) Management https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 1/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Intracerebral hemorrhage (ICH) (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis".) Intraventricular hemorrhage (IVH) (See "Intraventricular hemorrhage", section on 'Management'.) Subarachnoid hemorrhage (SAH) (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".) Subdural hematoma (SDH) (See "Subdural hematoma in adults: Management and prognosis".) Epidural hematoma (EDH) (See "Intracranial epidural hematoma in adults", section on 'Management'.) TERMINOLOGY The following terms are used herein: Intracranial hemorrhage Intracranial hemorrhage is the broadest term for bleeding; it includes bleeding anywhere inside the skull, including intracerebral, intraventricular, subarachnoid, and subdural hemorrhage. Intracerebral hemorrhage Intracerebral hemorrhage (ICH) is bleeding in the brain parenchyma. Intraventricular hemorrhage Intraventricular hemorrhage refers to bleeding within the ventricular system in the brain. Subarachnoid hemorrhage Subarachnoid hemorrhage is bleeding directly adjacent to the brain in the subarachnoid space (between the pia mater and arachnoid membrane); most of these are caused by ruptured saccular aneurysms. Subdural hematoma Subdural hematoma is bleeding outside the subarachnoid space directly beneath the dura mater. Epidural hematoma Epidural hematoma is bleeding in the potential space between the dura mater and the skull or in the epidural space in the spinal canal. URGENT EVALUATION The goal of the evaluation is to document as rapidly as possible, with brain imaging, whether the patient's symptoms are due to intracranial bleeding rather than another cause, such as https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 2/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate poisoning (related to a suicide attempt or other toxic exposure), encephalopathy, or ischemia; to document that the patient is in fact anticoagulated; and to confirm which anticoagulant is responsible. This information determines whether a reversal agent is needed, and if so, the specific agent. We request urgent evaluation by neurology and/or neurosurgery (and stroke team where available) when a patient presents with a suspected intracranial hemorrhage. Laboratory testing for anticoagulation status and brain imaging should be obtained immediately, notifying the laboratory and the radiology department of the emergency nature of the testing and imaging. Patient history can be obtained while the patient is being examined and blood for laboratory testing is being drawn. Often, the neurologist or stroke team can meet the patient in the radiology department and see the images as they are being obtained or review them immediately after. Rapid clinical assessment We rapidly obtain the relevant history, which includes the onset of symptoms, major neurologic abnormalities, which anticoagulant and dose the patient is taking and for what indication, and when they took the most recent dose. Presenting symptoms Patients with symptomatic intracranial hemorrhage generally present with acute onset of neurologic impairment consistent with stroke, although some patients with subarachnoid hemorrhage (SAH) may be neurologically intact and present with isolated sudden-onset, severe headache (ie, thunderclap headache). Subdural hematoma in the setting of anticoagulation may present with acute neurologic deterioration or milder symptoms initially, depending on the size and acuity. Clinical manifestations of epidural hematoma (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. Symptoms of intracranial hemorrhage may include headache, nausea, vomiting, or neurologic deficit(s). It is important to distinguish between symptomatic hemorrhage and incidentally discovered hemorrhage on neuroimaging; both are potentially clinically serious, but the urgency and aggressiveness needed to manage symptomatic bleeding may be greater than that for an incidentally discovered subdural bleed that may already be stabilized or resolving. (See 'Neuroimaging' below.) https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 3/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Additional details of the presentation and diagnosis of intracranial hemorrhage are reviewed separately by etiology: Intracerebral hemorrhage (see "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Clinical presentation' and "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Evaluation and diagnosis') Intraventricular hemorrhage (see "Intraventricular hemorrhage", section on 'Clinical presentation' and "Intraventricular hemorrhage", section on 'Diagnostic evaluation') Subarachnoid hemorrhage (see "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Clinical presentation' and "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Evaluation and diagnosis') Subdural hematoma (see "Subdural hematoma in adults: Etiology, clinical features, and diagnosis", section on 'Clinical manifestations' and "Subdural hematoma in adults: Etiology, clinical features, and diagnosis", section on 'Diagnosis and evaluation') Epidural hematoma (see "Intracranial epidural hematoma in adults", section on 'Clinical manifestations' and "Intracranial epidural hematoma in adults", section on 'Diagnostic evaluation') Trauma We ask if there was direct trauma to the head. If the patient was injured in a motor vehicle accident or other trauma (eg, a fall), we determine how fast the vehicle was going and whether neurologic deterioration started before or after the accident. If the patient fell, we determine the distance fallen. Anticoagulant and other medications We ask the name of the anticoagulant and confirm that it is the same as that listed in the medical record. We also ask if the patient is taking other medication(s) that could affect hemostasis, such as an antiplatelet agent (eg, aspirin, clopidogrel) or a drug that may affect the metabolism of their anticoagulant. The tables provide examples of drug interactions for warfarin ( table 1) and the direct oral anticoagulants (DOACs) ( table 2). (See "Biology of warfarin and modulators of INR control", section on 'Drug interactions'.) Dose and timing The indication for the anticoagulant should be assessed as this helps in confirming the specific agent, the dose, and the risk of thrombosis if anticoagulation is stopped or reversed. We ask what anticoagulant dose the patient is using and when the last dose was taken. The strength and timing of the last dose taken may impact whether https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 4/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate reversal is necessary and, especially for andexanet alfa, the amount of reversal agent needed. We also assess whether it is possible that the patient may be anticoagulated to a greater degree than expected with routine dosing. This includes questioning about how they are taking the anticoagulant to ascertain possible overdose or incorrect dosing. For patients on warfarin, we ask about the timing and result of the most recent international normalized ratio (INR). Comorbidities We ask if the individual has renal or hepatic disease, which may affect clearance or metabolism of DOACs, as well as any intercurrent infection, which may affect the INR on warfarin. Disorders that alter gastrointestinal absorption of drugs may explain lack of anticoagulant effect in some cases. Concomitant uremia or thrombocytopenia may increase bleeding risk. The underlying condition necessitating anticoagulation may also be a factor in decision-making, especially for those at highest risk of thromboembolic complications (recent pulmonary embolism, mechanical heart valve). Patients with moderate-to-severe neurologic deficits due to acute stroke may be unable to provide a reliable history. In such cases, it is important to review the patient's medical record and ask family members, friends, and caregivers whether the patient is receiving an anticoagulant and if so, when it was last administered. In some cases, it may be reasonable to ask if there was a suspected suicide attempt. If no history is available, we base our assessment on the results of coagulation testing and imaging. Neuroimaging As noted above, neuroimaging is performed in individuals taking an anticoagulant who develop symptoms consistent with intracranial bleeding, including headache, nausea, vomiting, or neurologic defects. The need for intervention may be more urgent in those with symptomatic bleeding than for those with incidentally discovered bleeding. (See 'Rapid clinical assessment' above.) Acute intracranial hemorrhage must be confirmed by neuroimaging, typically with urgent noncontrast computed tomography (CT), or, less frequently, with magnetic resonance imaging (MRI), before undertaking interventions to reverse anticoagulation. It is not possible to distinguish bleeding from ischemia by history and physical examination alone. This is especially true for patients with atrial fibrillation, who are at increased risk for ischemic stroke, but it applies to all individuals. As an example, neurologic symptoms following a motor vehicle accident may be due to traumatic intracranial hemorrhage or due to an ischemic stroke leading to loss of control of the vehicle. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 5/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate In selected cases in which the time delay in obtaining intracranial imaging could be life threatening, the clinicians may decide to treat empirically; this is a challenging decision that weighs the risks and benefits of empiric treatment versus delaying therapy to confirm the diagnosis. As an example, anticoagulant reversal may be reasonable for an individual with head trauma who has papilledema and for whom brain imaging is not available. However, papilledema has causes aside from ICH and by itself (without brain imaging) is not enough evidence for reversal. Laboratory testing We perform the following testing as rapidly as possible: All patients PT with INR, activated partial thromboplastin time (aPTT), and complete blood count (CBC) with platelet count. Patients on dabigatran Thrombin time (TT); diluted thrombin time (dTT) or ecarin clotting time (ECT) may be performed but they are not widely available. Serum creatinine should also be measured, and creatinine clearance calculated, as dabigatran is primarily eliminated by renal clearance. Patients on an oral factor Xa inhibitor or low molecular weight (LMW) heparin Anti- factor Xa activity, creatinine, and calculated creatinine clearance. Selected patients Liver function tests, basic metabolic panel, and other testing to address suspected comorbidities or other causes of neurologic deterioration. TT and anti-factor Xa activity may not be routinely available at all institutions, although most hospitals can perform a TT. Obtaining a platelet count is important to ensure that the patient does not have concomitant thrombocytopenia, which might contribute to bleeding. The usefulness of these coagulation tests varies according to the anticoagulant agent: Warfarin A prolonged PT or INR (eg, INR 1.4) indicates that the patient is anticoagulated. The aPTT is also prolonged with warfarin. In some cases, an individual with a PT or INR at the high end of the normal range may be slightly anticoagulated, especially if the value is higher than his or her baseline before starting warfarin. The PT and INR are monitored daily to determine if the warfarin effect is persistent and additional vitamin K is needed. (See 'Warfarin' below.) Dabigatran High plasma levels of dabigatran may prolong the aPTT. However, the aPTT may be normal or near normal in patients with therapeutic levels of dabigatran. Therefore, https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 6/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate a prolonged aPTT indicates the need for reversal, but normal aPTT values cannot be used to establish the lack of dabigatran effect. The TT, dTT, and ECT are more sensitive to the anticoagulant effects of dabigatran than the aPTT. Therefore, we would not use a reversal agent if the TT, dTT, and/or ECT are normal. If the TT, dTT, or ECT are not available, anticoagulation status is determined from the history of dabigatran ingestion (eg, dose, time since last dose). (See 'Dabigatran' below.) Direct factor Xa inhibitors Direct factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) are detected by anti-factor Xa activity calibrated to the specific agent. In some cases, anti- factor Xa activity calibrated to a different agent may show drug effect, although this is not optimal. The PT and aPTT may be helpful if prolonged but are not considered reliable indicators of anticoagulant effect. An anti-factor Xa activity that indicates a drug level of >30 ng/mL is evidence of anticoagulation. If anti-factor Xa activity is not available and the PT and aPTT are normal, anticoagulation status is determined from the history of anticoagulant ingestion. (See 'Apixaban, edoxaban, and rivaroxaban' below.) Unfractionated heparin Unfractionated heparin prolongs the aPTT and has anti-factor Xa activity. Heparin has a short half-life of approximately one hour after intravenous infusion. A normal aPTT indicates that the anticoagulant effect has resolved. (See 'Unfractionated heparin' below.) LMW heparin LMW heparin has anti-factor Xa activity. The assay should be calibrated to LMW heparin. A detectable LMW heparin level 0.3 international units/mL indicates LMW heparin effect. There is no anticoagulant effect if there is no detectable anti-factor Xa activity or if the anti-factor Xa activity indicates a LMW heparin level less than 0.3 international units/mL. (See 'LMW heparin' below.) The expected effect of anticoagulants on commonly used clotting tests is summarized in the table ( table 3). For warfarin, the extent of INR prolongation at the time of warfarin-associated ICH correlates with initial hematoma size, progressive hematoma enlargement after admission, functional outcome, and mortality [1-6]. Most episodes of warfarin-associated ICH occur in patients with a therapeutic level of anticoagulation (INR 2.0 to 3.5) [1,7-11]. However, even patients with a therapeutic INR can have an increased risk of bleeding, especially those older than 70 years of age. (See "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Mitigating bleeding risk'.) While similar data have not been obtained for all the other anticoagulants, it is likely that the intensity of the anticoagulant effect correlates with the severity of intracerebral bleeding, and https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 7/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate that any level of anticoagulation puts the patient at risk for adverse outcomes of intracranial bleeding compared with no anticoagulation. INDICATIONS FOR REVERSAL AND GOALS OF TREATMENT Acute intracranial hemorrhage Urgent anticoagulant reversal is indicated for patients with acute intracerebral (ICH), intraventricular, subarachnoid, or subdural hemorrhage associated with active anticoagulation. These types of hemorrhage are assumed to be life threating regardless of the extent of hemorrhage visible on initial brain imaging, since ongoing bleeding and hemorrhage enlargement can cause neurologic deterioration, elevation in intracranial pressure, and poor functional outcome or death [12]. An exception is that urgent reversal may not be necessary for a clinically stable patient with a small, chronic subdural hemorrhage and no evidence of elevated intracranial pressure; in such a case, the potential benefit of reversing anticoagulation (reduced risk of hematoma enlargement) must be weighed against the risk of thrombosis related to the underlying need for anticoagulation. As an example, anticoagulation with warfarin dose adjusted to achieve a therapeutic international normalized ratio (INR) may be continued in an individual with a mechanical heart valve and a small subdural hematoma with no signs of increased intracranial pressure, since the risk of valve thrombosis may be a greater concern than hematoma expansion. Another option in such an individual is to switch to heparin anticoagulation, which is easier to reverse quickly, while observing for clinical improvement. This subject is discussed in detail separately. (See "Anticoagulation for prosthetic heart valves: Management of bleeding and invasive procedures" and "Antithrombotic therapy for mechanical heart valves".) As noted above, reversal is only appropriate after intracerebral bleeding has been documented on an imaging study. Empiric treatment for suspected intracranial hemorrhage in the absence of confirmation by one of these methods is not advised unless the patient is in extremis and imaging is not available. This is because reversal agents are potentially prothrombotic, and their use may cause harms without benefit if they are given to an individual who did not actually have a hemorrhage [12]. As noted above, some patients who are receiving an anticoagulant may not actually be anticoagulated, especially if they are on a short-acting agent and took their last dose several half-lives ago. The lack of anticoagulation was demonstrated in some of the trials evaluating reversal agents for the direct oral anticoagulants. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Anticoagulant reversal'.) https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 8/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate The main goals of treatment are to rapidly reverse anticoagulation effects and to maintain reversal for a minimum of 72 hours, thereby limiting hemorrhage enlargement. This is important because hematoma growth, particularly within the first 24 hours after ICH, is an independent predictor of mortality and poor outcome. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis", section on 'Predicting hemorrhage expansion' and "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Clinical risk factors'.) Reversal of anticoagulation, along with blood pressure control, is believed to improve outcomes in warfarin-associated ICH. In one observational study, reduced rates of hematoma enlargement were noted for patients who had reversal of INR <1.3 within four hours of admission (20 versus 42 percent) [13]. The combination of successful reversal of INR <1.3 and blood pressure control <160 mmHg within four hours was associated with lowered rates of hematoma enlargement (18 versus 44 percent) and in-hospital mortality (13 versus 21 percent). Lumbar puncture in suspected subarachnoid hemorrhage When there is strong suspicion for subarachnoid hemorrhage (SAH) despite a normal head computed tomography (CT), lumbar puncture is generally required, except for selected patients with isolated headache, a normal neurologic examination, and high-quality brain imaging performed within six hours of headache onset that is negative for hemorrhage. The sensitivity of CT for detecting SAH decreases over the ensuing hours to days. The evaluation for SAH is discussed in detail separately. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Evaluation and diagnosis'.) Anticoagulation is considered a contraindication to lumbar puncture. Anticoagulation should be reversed for patients who require a lumbar puncture to rule out SAH while anticoagulated, as assessed by criteria described above (eg, INR 1.5 for warfarin; prolonged TT for dabigatran; anti-factor Xa activity assay that indicates a level of apixaban, rivaroxaban, or edoxaban over 30 ng/mL; history of ingestion in the preceding 24 to 48 hours if laboratory testing is inconclusive or unavailable). (See 'Laboratory testing' above.) GENERAL MEASURES FOR ALL ANTICOAGULANTS Discontinue all antithrombotic agents All anticoagulant and antiplatelet therapy should be discontinued. This includes discontinuation of the anticoagulant the patient is taking, and avoidance of other anticoagulants (eg, "routine" orders for heparin or low molecular weight (LMW) heparin administration for venous thromboembolism prophylaxis). These measures must be clearly stipulated in the medical record and ordering system. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 9/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate If an individual has another hemostatic defect such as moderate to severe thrombocytopenia (platelet count <50,000 to 100,000/microL) or use of dual antiplatelet therapy, consideration should be given to concomitant therapy for that defect as well. (See 'Other supportive care' below and 'Limited role of platelet transfusions' below.) Potential exceptions are noted above. (See 'Indications for reversal and goals of treatment' above.) Admit to intensive care Patients with acute anticoagulant-associated intracranial hemorrhage should be managed initially in an intensive care setting where frequent neurologic checks can detect neurologic deterioration, and hemodynamic monitoring can allow tighter blood pressure control and management. Control blood pressure Elevated blood pressure may predispose to hematoma expansion in patients with intracerebral hemorrhage (ICH), as already noted. (See 'Indications for reversal and goals of treatment' above.) We target a systolic blood pressure below 140 mmHg for ICH and below 160 mmHg for subarachnoid hemorrhage. Lower blood pressure targets in the acute setting increase the risk of hypoperfusion and infarction. We generally administer antihypertensive agents for those with a systolic blood pressure above 150 mmHg. Specific antihypertensive agents and the frequency of monitoring are discussed separately. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Blood pressure management' and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Blood pressure control'.) Other supportive care Other interventions include rapid and regular assessment of hemodynamic status and airway, along with optimization of body temperature, pH, and electrolyte balance. Rarely, transfusions may be needed, such as platelet transfusions for thrombocytopenia or red blood cell transfusions for anemia. (See 'Limited role of platelet transfusions' below.) Supportive measures are discussed in more detail separately. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Overview of management'.) Supportive care related to the site of bleeding is presented elsewhere: Intracerebral hemorrhage (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis".) https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 10/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Intraventricular hemorrhage (See "Intraventricular hemorrhage", section on 'Management'.) Subarachnoid hemorrhage (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".) Subdural hematoma (See "Subdural hematoma in adults: Management and prognosis".) Epidural hematoma (See "Intracranial epidural hematoma in adults", section on 'Management'.) Limited role of platelet transfusions Platelet transfusions generally are not indicated in the setting of intracranial bleeding, even for patients on concomitant antiplatelet therapy. Thrombocytopenia Platelet transfusion is appropriate for an individual with platelet counts <100,000/microL or with a known platelet function defect. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Actively bleeding patient' and "Platelet transfusion: Indications, ordering, and associated risks", section on 'Platelet function disorders'.) Antiplatelet agents The available data from trials of patients with spontaneous ICH (eg, the PATCH trial) suggest that empiric platelet transfusions in those without thrombocytopenia may be hazardous and should generally be avoided. (See "Platelet transfusion: Indications, ordering, and associated risks", section on 'Antiplatelet agents'.) Some clinicians use platelet transfusions for patients taking long-acting antiplatelet agents such as clopidogrel or prasugrel, but there is limited evidence to support this approach. Input from the neurologist and hematologist may be helpful in determining an individualized approach. Platelet transfusion is not considered useful for patients taking ticagrelor because ticagrelor is a reversible inhibitor of the adenosine diphosphate (ADP) receptor on the platelet surface and will bind to transfused platelets. REVERSAL STRATEGY FOR SPECIFIC ANTICOAGULANTS The reversal agent depends on which anticoagulant the patient is receiving. This should be confirmed from the history and in some cases, the results of coagulation testing. (See 'Rapid clinical assessment' above and 'Laboratory testing' above.) As noted above, reversal should be done as rapidly as possible but should only be done when intracerebral bleeding is documented (see 'Neuroimaging' above), in order to avoid giving https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 11/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate potentially prothrombotic drugs unnecessarily to a person with an increased thrombosis risk. Our approach for specific anticoagulants (outlined in the following sections) is largely consistent with general guidelines for reversing anticoagulation in the setting of severe bleeding as well as guidelines specific to hemorrhagic stroke [14-19]. A complete listing of society guidelines is presented separately. (See "Society guideline links: Anticoagulation" and "Society guideline links: Stroke in adults".) Warfarin Intracranial bleeding associated with warfarin anticoagulation should be treated with a rapid source of functional clotting factors as well as vitamin K to allow endogenous production of functional vitamin K-dependent factors. Warfarin works by interfering with carboxylation of the vitamin K-dependent clotting factors (factors II [prothrombin], VII, IX, and X). Carboxylation of these factors is essential for their function. The principal means of reversing warfarin rapidly is to replace these fully functional factors. The most rapidly acting source of functional factors is a 4-factor prothrombin complex concentrate (4-factor PCC). Convincing evidence of warfarin anticoagulation is based on a prolonged prothrombin time (PT) and an international normalized ratio (INR) outside the normal range ( 1.4 in most cases). (See 'Laboratory testing' above.) Reversal and monitoring strategy Our approach (described in the following sections) is similar to the 2022 guideline from the American Heart Association (AHA)/American Stroke Association (ASA), the 2018 guideline from the American Society of Hematology (ASH), and the 2012 guideline from the American College of Chest Physicians (ACCP), which recommend the following for serious or life-threatening bleeding associated with warfarin ( table 4) [16,18,19]: Hold warfarin. We also make sure that warfarin has been discontinued and that this is clearly stated in the medical record. Administer a 4-factor PCC; if a PCC is not available, a plasma product such as Fresh Frozen Plasma (FFP) or Thawed Plasma may be used. (See 'Reversal agent' below.) Administer intravenous vitamin K. (See 'Intravenous vitamin K' below.) The effects of these treatments is summarized in the table ( table 5) and an overview of warfarin-associated bleeding and reversal is presented separately. (See "Management of warfarin-associated bleeding or supratherapeutic INR".) https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 12/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate We recheck the PT/INR at approximately 30 minutes following PCC (or plasma) administration and periodically thereafter (eg, INR checked every four to six hours for the first 24 hours, and then checked daily for a few days) to ensure that the INR has become normal (<1.4 in most laboratories) and is maintained in the normal range [11,20]. If the INR remains elevated, additional doses of PCC or plasma may be given [21,22]. Details are presented separately. (See "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Serious/life-threatening bleeding'.) Reversal agent For warfarin-associated ICH, we recommend reversal with 4-factor prothrombin complex concentrate (4-factor PCC) rather than plasma. Options if 4-factor PCC is unavailable include 3-factor PCC supplemented with a source of factor VII, such as recombinant activated factor VII (rFVIIa), or a plasma product such as Fresh Frozen Plasma or Thawed Plasma. However, use of plasma may delay warfarin reversal, leading to a greater risk of complications of hematoma expansion, and may cause a transfusion reaction. We generally do not recommend the use of rFVIIa alone for treatment of warfarin-associated ICH because it does not replace factors II, IX, or X and may give a false sense of security by normalizing the INR without fully reversing warfarin effect. rFVIIa acts rapidly (eg, normalization of the INR within 10 minutes), but the half-life is only two to three hours, and repeated dosing or administration of another product would be required [23,24]. Although the INR is normalized rapidly with rFVIIa, the bleeding risk may persist due to dysfunction of other vitamin K- dependent factors. Thus, the normal INR may give a false sense of security and deprive the patient of other, more effective treatments. Additionally, 4-factor PCC is likely to carry a lower risk of thrombosis than products containing activated factors (rFVIIa or activated PCC, which contains activated factor VII). Prothrombin complex concentrate All four vitamin K-dependent factors are present in 4-factor PCC, which can be administered rapidly in a small volume ( table 6). Thus, 4-factor PCC is the preferred treatment ( table 4). Supporting evidence is summarized below. (See 'Efficacy of PCC versus plasma' below.) All institutions that treat patients with anticoagulant-associated hemorrhage should stock a 4- factor PCC. The available strategies for factor replacement are presented in order of preference; only one of these should be used, along with vitamin K: 4-factor PCC We generally give 4-factor PCC (Kcentra in the United States and Japan; Beriplex or Octaplex in Canada; Octaplex, Cofact, or Proplex in many European countries) https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 13/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate as an initial fixed dose of 1500 to 2000 international units at a rate of 100 units/minute ( table 7). Fixed-dose PCC may be easier logistically to stock and deliver in emergencies, but supplemental PCC doses may be required for those with warfarin-associated ICH who have a higher INR (>3). Alternatively, the initial dose may be calculated by body weight and INR. If weight-based or INR-based dosing is used, institutional protocols should be followed. An example is 25 units/kg for INR 2 to 4; 35 units/kg for INR 4 to 6; and 50 units/kg for INR >6, with a maximum dose of 5000 units [25]. In a randomized trial involving 199 patients with warfarin-associated extracranial bleeding, the rate of effective hemostasis in those assigned to an initial fixed-dose PCC (1000 units) was similar to those assigned a calculated dose that incorporated body weight and INR (87 versus 90 percent) [26]. The median initial dose in the calculated dose group was 1750 units. An additional dose of PCC was given to four patients in the fixed-dose group compared with one in the weight-based group, but the door-to-needle time was shorter in the fixed-dose group (109 versus 142 minutes). The proportion of patients in each group reaching an INR 2.0 within 60 minutes was similar (91 versus 92 percent). 3-factor PCC plus a supplement If a 4-factor PCC is not available, a 3-factor PCC (Profilnine in the United States; Bebulin was discontinued in 2018) can be used. However, 3- factor PCC does not contain factor VII. Therefore, most experts recommend supplementing 3-factor PCC with rFVIIa at a dose of 20 mcg/kg or with plasma (eg, FFP, two units). If rFVIIa is used to supplement 3-factor PCC, we prefer a lower dose (20 mcg/kg) rather than higher doses. This is based on data from a randomized trial in 841 patients with spontaneous intracerebral hemorrhage (ICH; not warfarin-associated) that compared two doses of rFVIIa (80 and 20 mcg/kg) with placebo; PCC was not administered [27]. The primary outcome (severe disability or death) was similar among the three groups, despite less expansion of the hemorrhage in those receiving rFVIIa. Overall, thromboembolic events were similar in the three groups, but severe events (eg, cerebral infarction, myocardial infarction [MI]) were more common in those who received high-dose rFVIIa compared with placebo (8 versus 4 percent). Activated PCC Activated PCC (aPCC) contains factors II, VII, IX, and X; factor VII is mostly present in the activated form (VIIa). The only available aPCC is factor eight inhibitor bypassing activity (FEIBA). FEIBA generally is not used for reversing warfarin anticoagulation, because the activated factor VII is potentially more prothrombotic compared with the factor VII in 4-factor PCC (discussed above) that is not in the activated https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 14/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate state. However, retrospective data suggest that treatment with FEIBA does not increase the risk of thrombotic events compared with plasma products [28]. Plasma products if PCC is unavailable If prothrombin complex concentrate (PCC) is unavailable, a plasma product (eg, FFP, Thawed Plasma) can be used to provide clotting factors. However, plasma requires a much larger volume of administration, often delaying the time to normalization of the INR, during which time hemorrhage expansion can continue. This was illustrated in a series of 45 patients with ICH, in which the median time interval between admission to a neuro-intensive care unit and INR normalization with FFP was 30 hours (range: 14 to 50 hours) [29]. Thus, plasma is not a very effective intervention for reducing the expansion of the hemorrhage [12]. Plasma also carries risks of transfusion reactions. A reasonable approach is to give two units of plasma, recheck the INR, and give additional units if needed. The infusion rate for plasma depends on the patient's ability to tolerate the volume load. FFP and other plasma products such as Thawed Plasma are equally effective in reversing the effects of anticoagulation and are considered interchangeable. Thawed Plasma (FFP that has been stored by refrigeration at 1 to 6 degrees Celsius) has the advantage of being available for immediate use. Eight units (2 liters) of FFP or Thawed Plasma are often required to fully reverse anticoagulation in patients treated with warfarin or other vitamin K antagonists; the total number of units required depends on the extent of INR prolongation. (See "Clinical use of plasma components", section on 'Plasma products'.) Efficacy of PCC versus plasma Prothrombin complex concentrates (PCCs) normalize the INR more rapidly than infusion of plasma or vitamin K alone, often within 10 minutes of administration [11,21,30-33]. However, vitamin K should be administered concomitantly because the effect of PCC is transient (hours) [11]. (See "Plasma derivatives and recombinant DNA- produced coagulation factors", section on 'PCCs'.) Evidence supporting the use of 4-factor PCC in warfarin-associated intracranial bleeding mostly consists of small, randomized trials and observational studies in ICH. As examples: PCC versus plasma Two randomized trials comparing PCC with FFP in intracranial hemorrhage associated with vitamin K antagonists. One trial was stopped early due to safety concerns when the 4-factor PCC group appeared to have a lower rate of death (8 of

INR", section on 'Serious/life-threatening bleeding'.) Reversal agent For warfarin-associated ICH, we recommend reversal with 4-factor prothrombin complex concentrate (4-factor PCC) rather than plasma. Options if 4-factor PCC is unavailable include 3-factor PCC supplemented with a source of factor VII, such as recombinant activated factor VII (rFVIIa), or a plasma product such as Fresh Frozen Plasma or Thawed Plasma. However, use of plasma may delay warfarin reversal, leading to a greater risk of complications of hematoma expansion, and may cause a transfusion reaction. We generally do not recommend the use of rFVIIa alone for treatment of warfarin-associated ICH because it does not replace factors II, IX, or X and may give a false sense of security by normalizing the INR without fully reversing warfarin effect. rFVIIa acts rapidly (eg, normalization of the INR within 10 minutes), but the half-life is only two to three hours, and repeated dosing or administration of another product would be required [23,24]. Although the INR is normalized rapidly with rFVIIa, the bleeding risk may persist due to dysfunction of other vitamin K- dependent factors. Thus, the normal INR may give a false sense of security and deprive the patient of other, more effective treatments. Additionally, 4-factor PCC is likely to carry a lower risk of thrombosis than products containing activated factors (rFVIIa or activated PCC, which contains activated factor VII). Prothrombin complex concentrate All four vitamin K-dependent factors are present in 4-factor PCC, which can be administered rapidly in a small volume ( table 6). Thus, 4-factor PCC is the preferred treatment ( table 4). Supporting evidence is summarized below. (See 'Efficacy of PCC versus plasma' below.) All institutions that treat patients with anticoagulant-associated hemorrhage should stock a 4- factor PCC. The available strategies for factor replacement are presented in order of preference; only one of these should be used, along with vitamin K: 4-factor PCC We generally give 4-factor PCC (Kcentra in the United States and Japan; Beriplex or Octaplex in Canada; Octaplex, Cofact, or Proplex in many European countries) https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 13/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate as an initial fixed dose of 1500 to 2000 international units at a rate of 100 units/minute ( table 7). Fixed-dose PCC may be easier logistically to stock and deliver in emergencies, but supplemental PCC doses may be required for those with warfarin-associated ICH who have a higher INR (>3). Alternatively, the initial dose may be calculated by body weight and INR. If weight-based or INR-based dosing is used, institutional protocols should be followed. An example is 25 units/kg for INR 2 to 4; 35 units/kg for INR 4 to 6; and 50 units/kg for INR >6, with a maximum dose of 5000 units [25]. In a randomized trial involving 199 patients with warfarin-associated extracranial bleeding, the rate of effective hemostasis in those assigned to an initial fixed-dose PCC (1000 units) was similar to those assigned a calculated dose that incorporated body weight and INR (87 versus 90 percent) [26]. The median initial dose in the calculated dose group was 1750 units. An additional dose of PCC was given to four patients in the fixed-dose group compared with one in the weight-based group, but the door-to-needle time was shorter in the fixed-dose group (109 versus 142 minutes). The proportion of patients in each group reaching an INR 2.0 within 60 minutes was similar (91 versus 92 percent). 3-factor PCC plus a supplement If a 4-factor PCC is not available, a 3-factor PCC (Profilnine in the United States; Bebulin was discontinued in 2018) can be used. However, 3- factor PCC does not contain factor VII. Therefore, most experts recommend supplementing 3-factor PCC with rFVIIa at a dose of 20 mcg/kg or with plasma (eg, FFP, two units). If rFVIIa is used to supplement 3-factor PCC, we prefer a lower dose (20 mcg/kg) rather than higher doses. This is based on data from a randomized trial in 841 patients with spontaneous intracerebral hemorrhage (ICH; not warfarin-associated) that compared two doses of rFVIIa (80 and 20 mcg/kg) with placebo; PCC was not administered [27]. The primary outcome (severe disability or death) was similar among the three groups, despite less expansion of the hemorrhage in those receiving rFVIIa. Overall, thromboembolic events were similar in the three groups, but severe events (eg, cerebral infarction, myocardial infarction [MI]) were more common in those who received high-dose rFVIIa compared with placebo (8 versus 4 percent). Activated PCC Activated PCC (aPCC) contains factors II, VII, IX, and X; factor VII is mostly present in the activated form (VIIa). The only available aPCC is factor eight inhibitor bypassing activity (FEIBA). FEIBA generally is not used for reversing warfarin anticoagulation, because the activated factor VII is potentially more prothrombotic compared with the factor VII in 4-factor PCC (discussed above) that is not in the activated https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 14/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate state. However, retrospective data suggest that treatment with FEIBA does not increase the risk of thrombotic events compared with plasma products [28]. Plasma products if PCC is unavailable If prothrombin complex concentrate (PCC) is unavailable, a plasma product (eg, FFP, Thawed Plasma) can be used to provide clotting factors. However, plasma requires a much larger volume of administration, often delaying the time to normalization of the INR, during which time hemorrhage expansion can continue. This was illustrated in a series of 45 patients with ICH, in which the median time interval between admission to a neuro-intensive care unit and INR normalization with FFP was 30 hours (range: 14 to 50 hours) [29]. Thus, plasma is not a very effective intervention for reducing the expansion of the hemorrhage [12]. Plasma also carries risks of transfusion reactions. A reasonable approach is to give two units of plasma, recheck the INR, and give additional units if needed. The infusion rate for plasma depends on the patient's ability to tolerate the volume load. FFP and other plasma products such as Thawed Plasma are equally effective in reversing the effects of anticoagulation and are considered interchangeable. Thawed Plasma (FFP that has been stored by refrigeration at 1 to 6 degrees Celsius) has the advantage of being available for immediate use. Eight units (2 liters) of FFP or Thawed Plasma are often required to fully reverse anticoagulation in patients treated with warfarin or other vitamin K antagonists; the total number of units required depends on the extent of INR prolongation. (See "Clinical use of plasma components", section on 'Plasma products'.) Efficacy of PCC versus plasma Prothrombin complex concentrates (PCCs) normalize the INR more rapidly than infusion of plasma or vitamin K alone, often within 10 minutes of administration [11,21,30-33]. However, vitamin K should be administered concomitantly because the effect of PCC is transient (hours) [11]. (See "Plasma derivatives and recombinant DNA- produced coagulation factors", section on 'PCCs'.) Evidence supporting the use of 4-factor PCC in warfarin-associated intracranial bleeding mostly consists of small, randomized trials and observational studies in ICH. As examples: PCC versus plasma Two randomized trials comparing PCC with FFP in intracranial hemorrhage associated with vitamin K antagonists. One trial was stopped early due to safety concerns when the 4-factor PCC group appeared to have a lower rate of death (8 of 23 [35 percent] receiving FFP versus 5 of 27 [19 percent] receiving PCC) and a lower rate of hematoma expansion [34]. The other trial, which randomly assigned 202 patients who presented with major bleeding associated with a vitamin K antagonist to receive 4-factor PCC or plasma, found that PCC was associated with a trend towards greater hemostatic https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 15/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate efficacy (72 percent with PCC versus 65 percent with plasma) and a greater likelihood of INR correction within the first half hour after the infusion (62 versus 10 percent); serious adverse events were similar [25]. Prospective and retrospective observational studies have consistently shown superior or equivalent outcomes with PCC compared with plasma; in some studies, PCCs were also associated with fewer serious adverse events [22,28,31,35- 39]. Despite the efficacy of PCC in reversing warfarin effect, the mortality of anticoagulant- associated ICH remains high (42 percent in one series) [40]. This is likely due to early hematoma expansion and the delay in anticoagulant reversal during transportation to the hospital, intracranial imaging, and administration of reversal products. 4-factor versus 3-factor PCC These two products have not been compared directly for patients with intracranial bleeding. The rate of INR normalization in patients with systemic bleeding appears higher with 4-factor PCC. (See "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Evidence for efficacy'.) PCC versus rFVIIa or aPCC A case series of 101 patients with warfarin-associated intracranial hemorrhage treated with rFVIIa (mean dose 52 mcg/kg) reported thromboembolic complications in eight patients (seven deep vein thromboses, one stroke) [41]. Similar risks were found in a multicenter randomized trial of rFVIIa in 841 patients with ICH not associated with warfarin [27]. There was no benefit with treatment on the primary clinical outcomes of death and disability, and higher rates of arterial thromboembolic serious adverse events (eg, stroke, MI) were found in patients assigned to the higher dose (80 mcg/kg) treatment group. Other studies have also suggested an association between rFVIIa and serious thromboembolic events. These and other studies are discussed in more detail separately. (See "Recombinant factor VIIa: Administration and adverse effects", section on 'Thromboembolic complications' and "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Reverse anticoagulation'.) In a retrospective study comparing outcomes with 4-factor PCC versus aPCC in 342 patients with ICH, treatment with 4-factor PCC was associated with a higher likelihood of an INR 1.5 [42]. Case reports suggest that incomplete INR correction is associated with clinical worsening in patients treated with PCC. Observational studies show that in some cases ICH can continue to expand, even in patients for whom anticoagulation is reversed, although more rapid reversal with a PCC appears to correlate with a lower risk of expansion [4,11,43]. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 16/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Additional supporting data for PCC are presented separately. (See "Management of warfarin- associated bleeding or supratherapeutic INR", section on 'PCC products'.) Thrombotic events have complicated infusion of PCC, but this risk is difficult to quantify due to varying preparations, doses, and differing patient populations in available reports. Among most series, thrombotic complications occurred in 1.5 to 10 percent of patients [20,31,40,44-46]. The risk may be substantially higher in individuals with prosthetic heart valves or valvular heart disease [43]. Intravenous vitamin K Vitamin K should be given because the half-life of PCC is very short (hours). Vitamin K 10 mg is given by slow intravenous infusion, no faster than 1 mg/min to minimize anaphylactic risk [11,31]. If the INR is 1.5, a lower dose (eg, 5 mg) may be given if desired. The effect of vitamin K on the INR takes approximately 12 to 24 hours; thus, all patients should also receive PCC. (See 'Prothrombin complex concentrate' above.) Intravenous vitamin K administration is preferred over oral or subcutaneous administration because it results in more rapid correction of the INR and because oral administration can be problematic in the setting of neurologic deficits or conditions that affect gastrointestinal absorption. Oral vitamin K may be used in individuals who are awake and have normal gastrointestinal function. Vitamin K administration can be repeated every 12 hours for persistent INR elevation, and daily INR should be obtained to assess for this need [47]. (See 'Laboratory testing' above.) Evidence supporting the efficacy of vitamin K and comparison of the routes of administration are presented separately. (See "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Vitamin K dose, route, formulation'.) Dabigatran Intracranial bleeding associated with dabigatran can be treated with idarucizumab or aPCC. We make sure that dabigatran has been discontinued and that this is clearly stated in the medical record. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Dabigatran reversal'.) Convincing evidence of dabigatran anticoagulation may be based on a clinical history of ingestion within the previous 3.5 days and/or laboratory evidence of dabigatran effect (eg, prolonged activated partial thromboplastin time [aPTT], thrombin time [TT], diluted thrombin time [dTT], or ecarin clotting time [ECT]). An aPTT in the normal range cannot be used to justify withholding of idarucizumab, because drug effect may still be present. However, idarucizumab should not be given to patients who have a normal TT, dTT, and/or ECT. (See "Direct oral https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 17/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Laboratory testing and monitoring (dabigatran)'.) Idarucizumab Idarucizumab is an emergency reversal agent for dabigatran. It is an anti- dabigatran monoclonal antibody fragment. For patients with acute intracranial hemorrhage and convincing evidence of dabigatran anticoagulation, we suggest idarucizumab if available, rather than clotting factor products (aPCC, PCC, or plasma). The dose of idarucizumab is 5 grams (two 2.5-gram vials), administered either as two consecutive infusions or as a bolus (ie, injecting both vials consecutively via syringe). Repeat dosing is generally not required but may be appropriate in selected cases (eg, overdose, persistently prolonged aPTT), although data are limited. We do not combine idarucizumab with other prohemostatic products such as a PCC, aPCC, or rFVIIa. Treatment with idarucizumab may be associated with thrombosis due to the patient's underlying thrombotic risk factors. Evidence for the efficacy and safety of idarucizumab in dabigatran- associated bleeding is presented separately. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Dabigatran reversal'.) Alternative options Activated PCC If idarucizumab is not available, we suggest administering activated prothrombin complex concentrate (aPCC; FEIBA) at a dose of 50 to 80 units/kg. The activated factor VII in this product activates the free factor X and may be sufficient to bypass dabigatran and promote clotting. If aPCC is not available, 4-factor or 3-factor PCC at a dose of 50 units/kg would be reasonable. Three-factor PCC may be supplemented with rFVIIa or plasma. Dosing of these supplements is described above. (See 'Reversal agent' above.) Activated charcoal and dialysis Unabsorbed dabigatran can be removed from the gastrointestinal tract using oral activated charcoal. This is generally appropriate if the last dose was within the previous two hours. Dosing and contraindications are presented separately. (See "Gastrointestinal decontamination of the poisoned patient".) Dabigatran can also be removed by hemodialysis if the consulting specialist believes this would be useful. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 18/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate These interventions are discussed in more detail separately. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Overview of management'.) Apixaban, edoxaban, and rivaroxaban Intracranial bleeding associated with a direct oral factor Xa inhibitor (apixaban, edoxaban, or rivaroxaban) can be treated with andexanet alfa (a reversal agent for factor Xa inhibitors) or 4-factor PCC ( table 8). We make sure that the factor Xa inhibitor has been discontinued and that this is clearly stated in the medical record. Convincing evidence of factor Xa inhibitor anticoagulation may be based on a clinical history of ingestion within a period of five half-lives and/or laboratory evidence of anticoagulant effect (eg, increased anti-factor Xa activity, ideally calibrated for the specific drug). The PT, aPTT, and anti-Xa calibrated for other drugs may be useful if abnormal but are less reliable. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Direct factor Xa inhibitors'.) The half-lives of these agents and the number of days elapsed in five half-lives are listed separately (see "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Interval since last dose'); most are within two to three days. Reversal agent options For patients with acute intracranial hemorrhage and convincing evidence of anticoagulation with a factor Xa inhibitor, we suggest andexanet alfa or 4-factor PCC. These agents have not been directly compared in a randomized trial. We prefer andexanet alfa given the drug's specificity and available data [48,49]. However, some experts consider there to be more equipoise in the choice between andexanet alfa and PCC. In a retrospective chart review of 109 adults with intracranial hemorrhage who were taking either apixaban or rivaroxaban at presentation, the rate of effective hemostasis was similar (71 percent for patients who received andexanet alfa and those who received 4-factor PCC) [50]. At baseline, the mean intracerebral hemorrhage score was 1 and Glasgow Coma Scale score was 14. After treatment, the median change in hematoma volume on repeat brain imaging and the rate of thrombotic complications were also similar between groups, but the total cost of treatment was more than three times higher with andexanet alfa. These results are limited by the relative small sample size, the potential of treatment bias, and uncertain applicability to patients with more severe hemorrhagic events. A randomized trial comparing andexanet versus usual care in patients with intracranial bleeding is ongoing [51]. Further discussion of this subject and evidence for the efficacy and safety of andexanet are reviewed separately. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Andexanet alfa'.) https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 19/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Andexanet alfa Andexanet alfa (andexanet) is an emergency reversal agent for factor Xa inhibitors. It is a recombinantly produced, catalytically inactive form of factor Xa that acts as a "decoy" to bind and sequester the factor Xa inhibitor anticoagulant. Andexanet alfa is given at one of two dose levels based on the dose and timing of the factor Xa inhibitor. The low dose is given as a bolus of 400 mg at 30 mg/min over 15 minutes, followed by an infusion of 480 mg given at 4 mg/min for up to 120 minutes. This is used in patients who received a lower dose of factor Xa inhibitor (eg, rivaroxaban 10 mg, apixaban 5 mg, or edoxaban 30 mg) or if eight hours or more have elapsed since the last dose of factor Xa inhibitor. The high dose is given as a bolus of 800 mg at 30 mg/min over 30 minutes, followed by an infusion at 960 mg given at 8 mg/min for up to 120 minutes. This is used for those who received a higher dose of factor Xa inhibitor (eg, rivaroxaban >10 mg, apixaban >5 mg, edoxaban >30 mg) or unknown dose within the previous eight hours. We do not use anti-factor Xa assays to assess the extent of anticoagulation reversal. Routine anti-factor Xa levels obtained after treatment with andexanet alfa may be falsely elevated due to dilutional effects [52]. We do not combine andexanet with other prohemostatic products such as PCC, aPCC or rFVIIa. 4-factor PCC A 4-factor prothrombin complex concentrate (PCC) is an alternative to andexanet for reversing factor Xa inhibitors. In a retrospective series involving 663 individuals who had an intracranial hemorrhage while receiving apixaban or rivaroxaban, 4-factor PCC was associated with good or excellent hemostasis in 354 of 433 evaluated for efficacy (82 percent) [53]. Thrombosis within 14 days of PCC administration occurred in 22 of the 663 (3.3 percent). These efficacy and safety outcomes are like those seen with andexanet and with 4-factor PCC in other studies of oral factor Xa inhibitor reversal after bleeding in other sites. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Overview of factor Xa inhibitor reversal'.) PCC can be given at a dose of 50 units/kg, or a fixed-dose regimen (2000 or 2500 units) can be used (eg, dosing like that used for warfarin reversal). (See 'Reversal agent' above.) If PCC is used, the patient should not be treated with andexanet. Activated charcoal Unabsorbed anticoagulant can be removed from the gastrointestinal tract using oral activated charcoal. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 20/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate We use the following intervals from the most recent dose to decide if charcoal may be helpful (see "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Factor Xa inhibitors'): Apixaban Within six hours Edoxaban Within two hours Rivaroxaban Within six to eight hours Dosing and contraindications to oral activated charcoal are presented separately. (See "Gastrointestinal decontamination of the poisoned patient".) Direct factor Xa inhibitors cannot be removed by hemodialysis. Unfractionated heparin For patients with intracranial bleeding associated with therapeutic doses of unfractionated heparin, protamine sulfate can be given for heparin reversal. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Unfractionated heparin'.) We make sure that all sources of heparin have been discontinued and that this is clearly stated in the medical record. Protamine sulfate Protamine sulfate (protamine) is an emergency reversal agent for unfractionated heparin. For patients with acute intracranial hemorrhage and convincing evidence of anticoagulation with unfractionated heparin (prolonged aPTT and/or administration within the previous two hours), we recommend protamine. A fixed dose of 50 mg or 25 mg may be given; some experts give 50 mg and others give 25 mg followed by an additional dose of 25 mg if needed (eg, based on a prolonged aPTT). The 50 mg dose would be more appropriate for an individual with a greater aPTT prolongation; however, this dose may be associated with a greater risk for relative hypotension. Alternatively, the dose can be calculated as 1 mg protamine per 100 units of heparin. The number of units of heparin is estimated based on the previous dose and the interval since it was administered, with an estimated half-life of heparin in the range of one to two hours (eg, if a dose of 5000 units was given one hour ago, the number of units would be 2500 and the dose of protamine would be 25 mg). Protamine must be given by slow intravenous infusion, as rapid infusion may cause hypotension, particularly at high doses (eg, 50 mg). The infusion rate should not exceed 20 mg/min and the total dose should not exceed 50 mg in any 10-minute period. Repeat doses may be given for a persistently prolonged aPTT. If heparin had been given by subcutaneous injection, https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 21/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate repeated small doses of protamine may be required because of prolonged heparin absorption from subcutaneous sites. Protamine is derived from fish sperm and may elicit an allergic reaction, especially in previously exposed individuals. In the United States, the protamine sulfate label contains a boxed warning that the drug can cause severe hypotension, cardiovascular collapse, noncardiogenic pulmonary edema, catastrophic pulmonary vasoconstriction, and pulmonary hypertension. Risk factors include high dose or overdose, rapid administration, repeated doses, previous administration of protamine or protamine-containing insulin (eg, neutral protamine hagedorn [NPH] or protamine zinc insulin [PZI]), and certain beta-blockers. Allergy to fish, previous vasectomy, severe left ventricular dysfunction, and abnormal preoperative pulmonary hemodynamics also may be risk factors. Vasopressors and resuscitation equipment should be immediately available in case of a severe reaction to protamine. Evidence for the efficacy and safety of protamine include a number of preclinical and observational studies that demonstrate effective reversal, as summarized in a 2016 guideline [14]. Studies evaluating clinically significant outcomes are lacking, as discussed separately. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Urgent reversal (protamine)'.) LMW heparin Intracranial bleeding associated with low molecular weight (LMW) heparin (eg, enoxaparin, dalteparin, nadroparin, tinzaparin) is uncommon but can occur, particularly in patients with cancer and brain metastases. For intracranial bleeding associated with therapeutic dose LMW heparin, we suggest andexanet alfa rather than protamine sulfate. However, protamine sulfate is a reasonable alternative if andexanet is not available. Evidence of LMW heparin effect may be based on the interval since the last dose and/or anti- factor Xa activity indicating a LMW heparin level of 0.3 international units/mL. (See 'Laboratory testing' above.) We make sure that the LMW heparin has been discontinued and that this is clearly stated in the medical record. Andexanet alfa Despite limited data, andexanet alfa is a reasonable approach for the treatment of intracranial bleeding associated with LMW heparin anticoagulation. Studies evaluating andexanet alfa for reversal of anticoagulation suggested efficacy for achieving hemostasis in a small number of individuals receiving therapeutic dose LMW heparin (16 individuals receiving enoxaparin in the ANNEXA-4 study) [54]. Additional data are needed. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 22/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate For patients with bleeding associated with therapeutic dose LMW heparin, the dosing of andexanet alfa in ANNEXA-4 was the higher dose level, with an 800 mg bolus given at 30 mg/minute over 30 minutes, followed by an infusion of 960 mg given at 8 mg/minute for up to 120 minutes [54]. The lower dose level (400 mg bolus and 480 infusion at 4 mg/minute) may be sufficient in individuals receiving prophylactic dose LMW heparin, although this has not been demonstrated, and it may be safer to use the higher dose level. If andexanet is unavailable, protamine sulfate should be given. (See 'Protamine sulfate if andexanet alfa is unavailable' below.) Protamine sulfate if andexanet alfa is unavailable For patients with acute intracranial hemorrhage and evidence of LMW heparin anticoagulation (increased anti-factor Xa activity [preferred] or administration within the previous 12 hours), protamine sulfate is a reasonable treatment option if andexanet is not available. Unlike its effect with unfractionated heparin, protamine is less effective in reversing the effect of LMW heparin. This is because protamine acts by reversing the inhibitory effect of LMW heparin on thrombin but only reverses approximately 60 percent of the inhibitory effect on factor Xa due to decreased binding to the shorter heparin chains in LMW heparin. Dosing of protamine sulfate in LMW heparin-associated bleeding is discussed separately. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Urgent reversal (protamine)'.) Fondaparinux Fondaparinux is a synthetic pentasaccharide analog of the natural pentasaccharide found in heparin. Fondaparinux acts by binding to and inducing a conformational change in antithrombin that causes selective inhibition of factor Xa. The half-life of fondaparinux is 17 to 21 hours. For patients with intracranial hemorrhage associated with fondaparinux anticoagulation, there is little information to guide management. Andexanet alfa is a reasonable option if it is available. Although data are limited, we would use the higher dose level, with an 800 mg bolus given at 30 mg/minute over 30 minutes, followed by an infusion of 960 mg given at 8 mg/minute for up to 120 minutes. Protamine sulfate is ineffective for fondaparinux reversal. Other options for reversal and additional information about the use of these agents are presented separately. (See "Fondaparinux: Dosing and adverse effects", section on 'Bleeding/emergency surgery'.) https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 23/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate RESUMPTION OF ANTICOAGULATION In many cases, anticoagulation can be resumed after bleeding resolves, provided the patient remains stable and the risk-benefit calculation clearly favors reinitiating anticoagulation. However, the decision must be individualized. Considerations related to this decision and evidence to support the benefit of restarting anticoagulation are presented separately. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Resumption of anticoagulation'.) Likewise, the optimal timing for restarting anticoagulation therapy following an intracranial bleed is unknown. The size and cause of the bleeding (eg, traumatic versus atraumatic) and patient-specific factors that increase bleeding risk may play a role in the calculation. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Prognosis and reinitiation of anticoagulation'.) For individuals treated with high doses of vitamin K, there may be a period of refractoriness after resuming warfarin. The decision process to reinitiate anticoagulation and the timing of reinitiation are discussed separately. (See "Spontaneous intracerebral hemorrhage: Secondary prevention and long-term prognosis", section on 'Management of antithrombotic 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: COVID-19 Anticoagulation" and "Society guideline links: COVID-19 Index of guideline topics".) SUMMARY AND RECOMMENDATIONS Urgent evaluation We perform a rapid clinical assessment to identify important features of the history and neuroimaging to distinguish hemorrhage from ischemia. Lumbar puncture (LP) is generally required when there is strong suspicion for subarachnoid hemorrhage (SAH) despite a normal head computed tomography (CT). All patients should have a complete blood count (CBC) with platelet count, prothrombin time (PT) with international normalized ratio (INR), and activated partial thromboplastin https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 24/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate time (aPTT). Liver function tests and a metabolic panel may also be appropriate. (See 'Urgent evaluation' above.) Additional laboratory evaluation varies by anticoagulant: Dabigatran Thrombin time (TT), creatinine determination, and calculation of the creatinine clearance Factor Xa inhibitors (apixaban, edoxaban, rivaroxaban, low molecular weight [LMW] heparin) Anti-factor Xa activity calibrated to the drug, creatinine, and calculated creatinine clearance TT and anti-factor Xa activity may not be immediately available. General measures for all patients General measures for anticoagulant-associated intracranial hemorrhage (ICH) include discontinuation of all antithrombotic agents, admission with intensive monitoring, and blood pressure control. Other interventions may be needed to treat severe thrombocytopenia, anemia, and metabolic abnormalities. (See 'General measures for all anticoagulants' above.) Indications for anticoagulant reversal Reversal of the anticoagulant effect is indicated in virtually all cases of documented acute ICH and in patients requiring an urgent LP to exclude SAH or infection. A rare exception is an individual for whom the risk of thrombosis is clinically more serious than the risk of hematoma expansion (eg, individual with a mechanical heart valve and a small, stable subdural hematoma). (See 'Indications for reversal and goals of treatment' above.) Specific reversal strategies Reversal should be done as rapidly as possible to limit hemorrhage enlargement, which can be fatal. Warfarin For warfarin-associated ICH, we recommend reversal with 4-factor prothrombin complex concentrate (4-factor PCC) rather than plasma (Grade 1B). PCC is typically given as a fixed dose of 1500 to 2000 international units at a rate of 100 units/minute ( table 7). (See 'Prothrombin complex concentrate' above.) Options if 4-factor PCC is unavailable include 3-factor PCC supplemented with a source of factor VII or a plasma product such as Fresh Frozen Plasma or Thawed Plasma. Use of plasma may delay warfarin reversal, leading to a greater risk of complications of hematoma expansion, and may cause a transfusion reaction. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 25/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Vitamin K is also given to all patients because PCC and plasma act transiently. The dose is 10 mg intravenously (which acts within several hours). Repeat vitamin K dosing may be appropriate if the PT or INR remains elevated. (See 'Intravenous vitamin K' above.) Dabigatran For dabigatran-associated ICH, we suggest idarucizumab (Grade 2C). The dose is 5 g (two 2.5 g vials). If idarucizumab is not available, activated PCC (aPCC; factor eight inhibitor bypassing activity [FEIBA]) may be used. Oral activated charcoal may be given if the patient can take oral medications and the last dose of dabigatran was within the prior two hours. Dabigatran may also be removed by hemodialysis. (See 'Dabigatran' above.) Direct factor Xa inhibitors (eg, apixaban, edoxaban, rivaroxaban) For direct factor Xa inhibitor-associated ICH, we suggest andexanet alfa rather than 4-factor PCC (Grade 2C). 4-factor PCC is a reasonable alternative if andexanet is unavailable. (See 'Apixaban, edoxaban, and rivaroxaban' above.) There are two dose levels for andexanet; the choice between them depends on the anticoagulant being reversed, how much was taken, and the timing of the most recent dose. (See 'Andexanet alfa' above.) The higher dose level uses a bolus of 800 mg at 30 mg/minute followed by an infusion of 960 mg at 8 mg/minute. The lower dose level uses a bolus of 400 mg at 30 mg/minute followed by an infusion of 480 mg at 4 mg/minute. Oral activated charcoal may be given if the patient can take oral medications and the last dose of the anticoagulant was recent (edoxaban within two hours; apixaban within six hours; rivaroxaban within eight hours). The direct factor Xa inhibitors cannot be dialyzed. (See 'Apixaban, edoxaban, and rivaroxaban' above.) UFH Unfractionated heparin (UFH)-associated ICH is treated with protamine sulfate (protamine). The dose is 1 mg protamine per 100 units of heparin; if rapid calculation is not possible, a single intravenous dose of 25 or 50 mg can be given by slow infusion over at least 20 or 30 minutes. Protamine can cause allergic reactions, particularly in individuals previously exposed to protamine sulfate, protamine-containing insulin, or those with a fish allergy. (See 'Unfractionated heparin' above.) LMW heparin (enoxaparin, dalteparin, tinzaparin) For LMW heparin-associated ICH, we suggest andexanet alfa rather than protamine (Grade 2C). The higher dose level (800 mg at 30 mg/minute followed by an infusion of 960 mg at 8 mg/minute) is https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 26/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate appropriate. Protamine sulfate is a reasonable alternative if andexanet is unavailable. (See 'LMW heparin' above.) Fondaparinux Treatment of fondaparinux-associated ICH is individualized. Andexanet alfa at the higher dose level is a reasonable option. (See 'Fondaparinux' above and "Fondaparinux: Dosing and adverse effects", section on 'Bleeding/emergency surgery'.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Maria I Aguilar, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Rosand J, Eckman MH, Knudsen KA, et al. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med 2004; 164:880. 2. Flaherty ML, Tao H, Haverbusch M, et al. Warfarin use leads to larger intracerebral hematomas. Neurology 2008; 71:1084. 3. Berwaerts J, Dijkhuizen RS, Robb OJ, Webster J. Prediction of functional outcome and in- hospital mortality after admission with oral anticoagulant-related intracerebral hemorrhage. Stroke 2000; 31:2558. 4. Yasaka M, Minematsu K, Naritomi H, et al. Predisposing factors for enlargement of intracerebral hemorrhage in patients treated with warfarin. Thromb Haemost 2003; 89:278. 5. Cucchiara B, Messe S, Sansing L, et al. Hematoma growth in oral anticoagulant related intracerebral hemorrhage. Stroke 2008; 39:2993. 6. Flibotte JJ, Hagan N, O'Donnell J, et al. Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage. Neurology 2004; 63:1059. 7. Punthakee X, Doobay J, Anand SS. Oral-anticoagulant-related intracerebral hemorrhage. Thromb Res 2002; 108:31.

prognosis", section on 'Management of antithrombotic 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: COVID-19 Anticoagulation" and "Society guideline links: COVID-19 Index of guideline topics".) SUMMARY AND RECOMMENDATIONS Urgent evaluation We perform a rapid clinical assessment to identify important features of the history and neuroimaging to distinguish hemorrhage from ischemia. Lumbar puncture (LP) is generally required when there is strong suspicion for subarachnoid hemorrhage (SAH) despite a normal head computed tomography (CT). All patients should have a complete blood count (CBC) with platelet count, prothrombin time (PT) with international normalized ratio (INR), and activated partial thromboplastin https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 24/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate time (aPTT). Liver function tests and a metabolic panel may also be appropriate. (See 'Urgent evaluation' above.) Additional laboratory evaluation varies by anticoagulant: Dabigatran Thrombin time (TT), creatinine determination, and calculation of the creatinine clearance Factor Xa inhibitors (apixaban, edoxaban, rivaroxaban, low molecular weight [LMW] heparin) Anti-factor Xa activity calibrated to the drug, creatinine, and calculated creatinine clearance TT and anti-factor Xa activity may not be immediately available. General measures for all patients General measures for anticoagulant-associated intracranial hemorrhage (ICH) include discontinuation of all antithrombotic agents, admission with intensive monitoring, and blood pressure control. Other interventions may be needed to treat severe thrombocytopenia, anemia, and metabolic abnormalities. (See 'General measures for all anticoagulants' above.) Indications for anticoagulant reversal Reversal of the anticoagulant effect is indicated in virtually all cases of documented acute ICH and in patients requiring an urgent LP to exclude SAH or infection. A rare exception is an individual for whom the risk of thrombosis is clinically more serious than the risk of hematoma expansion (eg, individual with a mechanical heart valve and a small, stable subdural hematoma). (See 'Indications for reversal and goals of treatment' above.) Specific reversal strategies Reversal should be done as rapidly as possible to limit hemorrhage enlargement, which can be fatal. Warfarin For warfarin-associated ICH, we recommend reversal with 4-factor prothrombin complex concentrate (4-factor PCC) rather than plasma (Grade 1B). PCC is typically given as a fixed dose of 1500 to 2000 international units at a rate of 100 units/minute ( table 7). (See 'Prothrombin complex concentrate' above.) Options if 4-factor PCC is unavailable include 3-factor PCC supplemented with a source of factor VII or a plasma product such as Fresh Frozen Plasma or Thawed Plasma. Use of plasma may delay warfarin reversal, leading to a greater risk of complications of hematoma expansion, and may cause a transfusion reaction. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 25/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Vitamin K is also given to all patients because PCC and plasma act transiently. The dose is 10 mg intravenously (which acts within several hours). Repeat vitamin K dosing may be appropriate if the PT or INR remains elevated. (See 'Intravenous vitamin K' above.) Dabigatran For dabigatran-associated ICH, we suggest idarucizumab (Grade 2C). The dose is 5 g (two 2.5 g vials). If idarucizumab is not available, activated PCC (aPCC; factor eight inhibitor bypassing activity [FEIBA]) may be used. Oral activated charcoal may be given if the patient can take oral medications and the last dose of dabigatran was within the prior two hours. Dabigatran may also be removed by hemodialysis. (See 'Dabigatran' above.) Direct factor Xa inhibitors (eg, apixaban, edoxaban, rivaroxaban) For direct factor Xa inhibitor-associated ICH, we suggest andexanet alfa rather than 4-factor PCC (Grade 2C). 4-factor PCC is a reasonable alternative if andexanet is unavailable. (See 'Apixaban, edoxaban, and rivaroxaban' above.) There are two dose levels for andexanet; the choice between them depends on the anticoagulant being reversed, how much was taken, and the timing of the most recent dose. (See 'Andexanet alfa' above.) The higher dose level uses a bolus of 800 mg at 30 mg/minute followed by an infusion of 960 mg at 8 mg/minute. The lower dose level uses a bolus of 400 mg at 30 mg/minute followed by an infusion of 480 mg at 4 mg/minute. Oral activated charcoal may be given if the patient can take oral medications and the last dose of the anticoagulant was recent (edoxaban within two hours; apixaban within six hours; rivaroxaban within eight hours). The direct factor Xa inhibitors cannot be dialyzed. (See 'Apixaban, edoxaban, and rivaroxaban' above.) UFH Unfractionated heparin (UFH)-associated ICH is treated with protamine sulfate (protamine). The dose is 1 mg protamine per 100 units of heparin; if rapid calculation is not possible, a single intravenous dose of 25 or 50 mg can be given by slow infusion over at least 20 or 30 minutes. Protamine can cause allergic reactions, particularly in individuals previously exposed to protamine sulfate, protamine-containing insulin, or those with a fish allergy. (See 'Unfractionated heparin' above.) LMW heparin (enoxaparin, dalteparin, tinzaparin) For LMW heparin-associated ICH, we suggest andexanet alfa rather than protamine (Grade 2C). The higher dose level (800 mg at 30 mg/minute followed by an infusion of 960 mg at 8 mg/minute) is https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 26/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate appropriate. Protamine sulfate is a reasonable alternative if andexanet is unavailable. (See 'LMW heparin' above.) Fondaparinux Treatment of fondaparinux-associated ICH is individualized. Andexanet alfa at the higher dose level is a reasonable option. (See 'Fondaparinux' above and "Fondaparinux: Dosing and adverse effects", section on 'Bleeding/emergency surgery'.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Maria I Aguilar, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Rosand J, Eckman MH, Knudsen KA, et al. The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage. Arch Intern Med 2004; 164:880. 2. Flaherty ML, Tao H, Haverbusch M, et al. Warfarin use leads to larger intracerebral hematomas. Neurology 2008; 71:1084. 3. Berwaerts J, Dijkhuizen RS, Robb OJ, Webster J. Prediction of functional outcome and in- hospital mortality after admission with oral anticoagulant-related intracerebral hemorrhage. Stroke 2000; 31:2558. 4. Yasaka M, Minematsu K, Naritomi H, et al. Predisposing factors for enlargement of intracerebral hemorrhage in patients treated with warfarin. Thromb Haemost 2003; 89:278. 5. Cucchiara B, Messe S, Sansing L, et al. Hematoma growth in oral anticoagulant related intracerebral hemorrhage. Stroke 2008; 39:2993. 6. Flibotte JJ, Hagan N, O'Donnell J, et al. Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage. Neurology 2004; 63:1059. 7. Punthakee X, Doobay J, Anand SS. Oral-anticoagulant-related intracerebral hemorrhage. Thromb Res 2002; 108:31. 8. Sj blom L, H rdemark HG, Lindgren A, et al. Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study. Stroke 2001; 32:2567. 9. Neau JP, Couderq C, Ingrand P, et al. Intracranial hemorrhage and oral anticoagulant treatment. Cerebrovasc Dis 2001; 11:195. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 27/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate 10. 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. 11. Yasaka M, Sakata T, Minematsu K, Naritomi H. Correction of INR by prothrombin complex concentrate and vitamin K in patients with warfarin related hemorrhagic complication. Thromb Res 2002; 108:25. 12. Bower MM, Sweidan AJ, Shafie M, et al. Contemporary Reversal of Oral Anticoagulation in Intracerebral Hemorrhage. Stroke 2019; 50:529. 13. Kuramatsu JB, Gerner ST, Schellinger PD, et al. Anticoagulant reversal, blood pressure levels, and anticoagulant resumption in patients with anticoagulation-related intracerebral hemorrhage. JAMA 2015; 313:824. 14. 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. 15. Steiner T, Al-Shahi Salman R, Beer R, et al. European Stroke Organisation (ESO) guidelines for the management of spontaneous intracerebral hemorrhage. Int J Stroke 2014; 9:840. 16. Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence- Based Clinical Practice Guidelines. Chest 2012; 141:e44S. 17. 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). 18. 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. 19. 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. 20. Hellstern P, Halbmayer WM, K hler M, et al. Prothrombin complex concentrates: indications, contraindications, and risks: a task force summary. Thromb Res 1999; 95:S3. 21. Pabinger I, Brenner B, Kalina U, et al. Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial. J Thromb Haemost 2008; 6:622. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 28/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate 22. Evans SJ, Biss TT, Wells RH, Hanley JP. Emergency warfarin reversal with prothrombin complex concentrates: UK wide study. Br J Haematol 2008; 141:268. 23. S rensen B, Johansen P, Nielsen GL, et al. Reversal of the International Normalized Ratio with recombinant activated factor VII in central nervous system bleeding during warfarin thromboprophylaxis: clinical and biochemical aspects. Blood Coagul Fibrinolysis 2003; 14:469. 24. Freeman WD, Brott TG, Barrett KM, et al. Recombinant factor VIIa for rapid reversal of warfarin anticoagulation in acute intracranial hemorrhage. Mayo Clin Proc 2004; 79:1495. 25. Sarode R, Milling TJ Jr, Refaai MA, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation 2013; 128:1234. 26. Abdoellakhan RA, Khorsand N, Ter Avest E, et al. Fixed Versus Variable Dosing of Prothrombin Complex Concentrate for Bleeding Complications of Vitamin K Antagonists-The PROPER3 Randomized Clinical Trial. Ann Emerg Med 2022; 79:20. 27. Mayer SA, Brun NC, Begtrup K, et al. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2008; 358:2127. 28. Yin EB, Tan B, Nguyen T, et al. Safety and Effectiveness of Factor VIII Inhibitor Bypassing Activity (FEIBA) and Fresh Frozen Plasma in Oral Anticoagulant-Associated Intracranial Hemorrhage: A Retrospective Analysis. Neurocrit Care 2017; 27:51. 29. Lee SB, Manno EM, Layton KF, Wijdicks EF. Progression of warfarin-associated intracerebral hemorrhage after INR normalization with FFP. Neurology 2006; 67:1272. 30. Makris M, Greaves M, Phillips WS, et al. Emergency oral anticoagulant reversal: the relative efficacy of infusions of fresh frozen plasma and clotting factor concentrate on correction of the coagulopathy. Thromb Haemost 1997; 77:477. 31. Fredriksson K, Norrving B, Str mblad LG. Emergency reversal of anticoagulation after intracerebral hemorrhage. Stroke 1992; 23:972. 32. Cartmill M, Dolan G, Byrne JL, Byrne PO. Prothrombin complex concentrate for oral anticoagulant reversal in neurosurgical emergencies. Br J Neurosurg 2000; 14:458. 33. Bershad EM, Suarez JI. Prothrombin complex concentrates for oral anticoagulant therapy- related intracranial hemorrhage: a review of the literature. Neurocrit Care 2010; 12:403. 34. Steiner T, Poli S, Griebe M, et al. Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage related to vitamin K antagonists (INCH): a randomised trial. Lancet Neurol 2016; 15:566. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 29/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate 35. Frontera JA, Gordon E, Zach V, et al. Reversal of coagulopathy using prothrombin complex concentrates is associated with improved outcome compared to fresh frozen plasma in warfarin-associated intracranial hemorrhage. Neurocrit Care 2014; 21:397. 36. Hickey M, Gatien M, Taljaard M, et al. Outcomes of urgent warfarin reversal with frozen plasma versus prothrombin complex concentrate in the emergency department. Circulation 2013; 128:360. 37. Hanger HC, Geddes JA, Wilkinson TJ, et al. Warfarin-related intracerebral haemorrhage: better outcomes when reversal includes prothrombin complex concentrates. Intern Med J 2013; 43:308. 38. Huttner HB, Schellinger PD, Hartmann M, et al. Hematoma growth and outcome in treated neurocritical care patients with intracerebral hemorrhage related to oral anticoagulant therapy: comparison of acute treatment strategies using vitamin K, fresh frozen plasma, and prothrombin complex concentrates. Stroke 2006; 37:1465. 39. Boulis NM, Bobek MP, Schmaier A, Hoff JT. Use of factor IX complex in warfarin-related intracranial hemorrhage. Neurosurgery 1999; 45:1113. 40. Dowlatshahi D, Butcher KS, Asdaghi N, et al. Poor prognosis in warfarin-associated intracranial hemorrhage despite anticoagulation reversal. Stroke 2012; 43:1812. 41. Robinson MT, Rabinstein AA, Meschia JF, Freeman WD. Safety of recombinant activated factor VII in patients with warfarin-associated hemorrhages of the central nervous system. Stroke 2010; 41:1459. 42. Peksa GD, Mokszycki RK, Rech MA, et al. Reversal of Warfarin-Associated Major Hemorrhage: Activated Prothrombin Complex Concentrate versus 4-Factor Prothrombin Complex Concentrate. Thromb Haemost 2020; 120:207. 43. Bertram M, Bonsanto M, Hacke W, Schwab S. Managing the therapeutic dilemma: patients with spontaneous intracerebral hemorrhage and urgent need for anticoagulation. J Neurol 2000; 247:209. 44. Hellstern P. Production and composition of prothrombin complex concentrates: correlation between composition and therapeutic efficiency. Thromb Res 1999; 95:S7. 45. Toth P, van Veen JJ, Robinson K, et al. Real world usage of PCC to "rapidly" correct warfarin induced coagulopathy. Blood Transfus 2013; 11:500. 46. Cabral KP, Fraser GL, Duprey J, et al. Prothrombin complex concentrates to reverse warfarin- induced coagulopathy in patients with intracranial bleeding. Clin Neurol Neurosurg 2013; 115:770. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 30/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate 47. Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:160S. 48. Demchuk AM, Yue P, Zotova E, et al. Hemostatic Efficacy and Anti-FXa (Factor Xa) Reversal With Andexanet Alfa in Intracranial Hemorrhage: ANNEXA-4 Substudy. Stroke 2021; 52:2096. 49. Cohen AT, Lewis M, Connor A, et al. Thirty-day mortality with andexanet alfa compared with prothrombin complex concentrate therapy for life-threatening direct oral anticoagulant- related bleeding. J Am Coll Emerg Physicians Open 2022; 3:e12655. 50. Pham H, Medford WG, Horst S, et al. Andexanet alfa versus four-factor prothrombin complex concentrate for the reversal of apixaban- or rivaroxaban-associated intracranial hemorrhages. Am J Emerg Med 2022; 55:38. 51. https://clinicaltrials.gov/ct2/show/NCT03661528 (Accessed on November 18, 2021). 52. Bourdin M, Perrotin D, Mathieu O, et al. Measuring residual anti-Xa activity of direct factor Xa inhibitors after reversal with andexanet alfa. Int J Lab Hematol 2021; 43:795. 53. Panos NG, Cook AM, John S, et al. Factor Xa Inhibitor-Related Intracranial Hemorrhage: Results From a Multicenter, Observational Cohort Receiving Prothrombin Complex Concentrates. Circulation 2020; 141:1681. 54. Connolly SJ, Crowther M, Eikelboom JW, et al. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. N Engl J Med 2019; 380:1326. Topic 1325 Version 51.0 https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 31/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate GRAPHICS Medications that interfere with the effect of warfarin May increase INR May decrease INR Acetaminophen Antibiotics Dicloxacillin Allopurinol Griseofulvin Amiodarone Nafcillin Androgens Rifampin Methyltestosterone Azathioprine Oxandrolone Cholestyramine Testosterone Enzyme-inducing antiseizure medications Antibiotics Carbamazepine Cephalosporins Phenobarbital Doxycycline Phenytoin (mixed effects described) Fluoroquinolones Ciprofloxacin Ritonavir Levofloxacin Saint John's wort Moxifloxacin Sucralfate Norfloxacin Vitamin K Macrolides Azithromycin Clarithromycin Erythromycin Metronidazole Penicillins (exceptions: dicloxacillin and nafcillin may decrease the INR) Amoxicillin Amoxicillin-clavulanate Trimethoprim-sulfamethoxazole Azole antifungals* Fluconazole Miconazole (oral) Voriconazole Cancer therapies Capecitabine Fluorouracil (5-FU) Imatinib https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 32/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Tamoxifen Cholesterol-lowering agents (exception: cholestyramine may decrease the INR) Fenofibrate Fluvastatin Gemfibrozil Lovastatin Rosuvastatin Simvastatin Cimetidine Glucocorticoids Methylprednisolone Prednisone Omeprazole (case reports with other proton pump inhibitors) Serotonin reuptake inhibitors Duloxetine Fluoxetine Fluvoxamine Venlafaxine Sitaxentan (not available in United States) Tramadol This is a partial list of medications that may increase or decrease warfarin effect on the INR. The patient's medications should be analyzed closely for drug interactions with warfarin, especially when initiating or altering therapy. The effect of a drug interaction can be unpredictable; thus, individuals receiving interacting medications are likely to require increased INR monitoring. Additional medications may increase bleeding risk independent of (or in addition to) effects on the INR (eg, NSAIDs, antiplatelet medications). Refer to UpToDate for additional details. Drug interactions may be evaluated using the Lexi-interact program included with UpToDate. INR: international normalized ratio; NSAIDs: nonsteroidal anti-inflammatory drugs. A more moderate effect on INR control may also be seen with posaconazole and itraconazole. In addition to potentially increasing the INR, serotonin reuptake inhibitors may also increase bleeding risk by inhibiting platelet reuptake of serotonin. References: 1. Greenblatt DJ, von Moltke L. Interaction of warfarin with drugs, natural substances, and foods. J Clin Pharmacol 2005; 45:127. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 33/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate 2. Holbrook A, Schulman S, Witt D, et al. Evidenced-based management of anticoagulant therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed. Chest 2012; 141:e152S. 3. Hazlewood KA, Fugate SE, Harrison DL. E ect of oral corticosteroids on chronic warfarin therapy. Ann Pharmacother 2006; 40:2101. 4. Lexi-Interact. Copyright 1978-2023 Lexicomp, Inc. All Rights Reserved. Graphic 62697 Version 15.0 https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 34/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Pharmacokinetics and drug interactions of direct oral anticoagulants Potential for Metabolism pharmacokinetic drug interactions* Anticoagulant Bioavailability and clearance* Half-life Dabigatran (Pradaxa) 3 to 7% bioavailable Over 80% cleared by the 12 to 17 hours P-gp inhibitors can increase kidney dabigatran effect Unaffected by food Prolonged with kidney P-gp P-gp inducers can substrate* impairment and in older decrease dabigatran Capsule must be taken intact adults effect and requires gastric acidity Avoidance of for absorption some combinations or dose adjustment may be needed Apixaban 50% 27% cleared 12 hours Strong dual (Eliquis) bioavailable by the kidney CYP3A4 and P-gp inhibitors can Prolonged in older adults Unaffected by Metabolized, increase food primarily by CYP3A4 apixaban effect 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 (Savaysa, Lixiana) 62% bioavailable 50% cleared by the kidney 10 to 14 hours P-gp inhibitors can increase edoxaban effect Unaffected by food Reduced efficacy in Prolonged 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/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 35/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate and CrCl >95 mL/minute dose adjustment 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% Prolonged to inhibitors can increase bioavailable Metabolized, primarily by 11 to 13 hours in Unaffected rivaroxaban CYP3A4 older adults by food effect P-gp 20 mg dose: Strong CYP3A4 substrate* 66% inducers and/or P-gp inducers can bioavailable if taken when decrease rivaroxaban fasting; increased if effect Avoidance of taken with food 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/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 36/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - 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 [1] mechanism of this interaction is unknown. 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/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 37/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Expected effects of anticoagulant drugs on commonly used coagulation tests Brand Anti-factor Drug class Drug PT aPTT name(s) Xa activity / * Vitamin K Warfarin Jantoven antagonists / * Acenocoumarol Sintrom Heparins Unfractionated heparin / LMW heparins Enoxaparin Lovenox Dalteparin Fragmin Nadroparin Fraxiparine / Fondaparinux Arixtra Direct Argatroban Acova thrombin inhibitors / Dabigatran Pradaxa / / Direct factor Rivaroxaban Xarelto Xa inhibitors / / Apixaban Eliquis Edoxaban Lixiana, Savaysa PT and aPTT are measured in seconds; anti-factor Xa activity is measured in units/mL. Upward arrow ( ) signifies an increase above normal due to the anticoagulant (prolongation of PT or aPTT; increase in anti-factor Xa activity). The effect magnitude will vary depending on the reagent formulation and instrument used. Dash ( ) signifies no appreciable effect. Normal ranges for the PT, aPTT, and anti-factor Xa activity vary among laboratories and should be reported from the testing laboratory along with the patient result. Refer to the UpToDate topic on coagulation testing for details. PT: prothrombin time; aPTT: activated partial thromboplastin time; LMW heparin: low molecular weight heparin. Warfarin has a weak effect on most aPTT reagents. However, warfarin use will increase the sensitivity of the aPTT to heparin effect. While heparin, LMW heparin, and fondaparinux should, in theory, prolong the PT as indirect thrombin inhibitors, in practice most PT reagents contain heparin-binding chemicals that block any heparin effect below a concentration of 1 unit/mL. Above concentrations of 1 unit/mL, heparin effect on the PT may be observed. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 38/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Anti-factor Xa activity testing must be calibrated for the specific anticoagulant; this information should be verified with the clinical laboratory. Some of the data are from: Samuelson BT, Cuker A, Crowther M, Garcia DA. Laboratory assessment of the anticoagulant activity of direct oral anticoagulants: A systematic review. Chest 2017; 151:127. Graphic 91267 Version 9.0 https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 39/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Guideline recommendations for management of warfarin-associated bleeding and/or high INR Clinical setting 2018 ASH guideline 2012 ACCP guideline Serious or life-threatening 4-factor PCC 4-factor PCC* bleeding Vitamin K (intravenous) Vitamin K (intravenous) Any INR Hold warfarin Hold warfarin (No recommendations given) No bleeding Vitamin K (oral) INR >10 Hold warfarin No bleeding Hold warfarin Hold warfarin INR 4.5 to 10 No vitamin K Vitamin K (low dose, oral) is optional Clinical judgment is required to assess the severity of bleeding, urgency of warfarin reversal, and need for other interventions. Refer to UpToDate for details and additional advice such as the duration of warfarin interruption and repeat INR testing. INR: international normalized ratio; ASH: American Society of Hematology; ACCP: American College of Chest Physicians; PCC: prothrombin complex concentrate; FFP: fresh frozen plasma. A plasma product such as thawed plasma or FFP (approximately 10 mL/kg, depending on INR) can be used as an alternative if PCC is not available. References: 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. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e152S. Graphic 119954 Version 2.0 https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 40/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Reversing anticoagulation in warfarin-associated bleeding Management option Time to anticoagulation reversal Comments and cautions Discontinuing warfarin therapy 5 to 14 days Five days is typical for patients with an INR in the therapeutic range Vitamin K* 6 to 24 hours to correct the INR, longer Recovery of factors X and II to fully reverse anticoagulation (prothrombin) takes longer than 24 hours Risk of anaphylaxis with intravenous injection Impaired response to warfarin lasting up to one week may occur after large doses (ie, >5 mg) Fresh frozen Depends on the time it takes to Effect is transient and concomitant plasma complete the infusion; typically 12 to 32 hours for complete reversal vitamin K must be administered Potential for volume overload (2 to 4 L to normalize INR) Potential for TRALI Potential for viral transmission Prothrombin 15 minutes after 10-minute to 1-hour Effect is transient, and concomitant complex infusion vitamin K must be administered; concentrate limited availability Cost Variable factor VII content depending on the product: a 4-factor PCC is preferred Potentially prothrombotic Recombinant factor VIIa 15 minutes after bolus infusion Effect is transient, and concomitant vitamin K must be administered Cost Potentially prothrombotic Please refer to the UpToDate topic on warfarin reversal in intracerebral hemorrhage for further details of management. INR: international normalized ratio; TRALI: transfusion-related acute lung injury; PCC: prothrombin complex concentrate. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 41/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate A total of 10 mg intravenously by slow infusion given over 10 minutes. Adapted with permission from: Aguilar MI, Hart RG, Kase CS, et al. Treatment of warfarin-associated intercerebral hemorrhage: Literature review and expert opinion. Mayo Clin Proc 2007; 82:82. Copyright 2007 Dowden Health Media. Graphic 79151 Version 16.0 https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 42/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate PCC products available in the United States* Unactivated prothrombin complex concentrates (PCCs) 4 factor: Contains inactive forms of 4 factors: Factors II, VII, IX, and X Kcentra Also contains heparin 3 factor: Contains inactive forms of 3 factors: Factors II, IX, and X Profilnine Contains little or no factor VII Does not contain heparin Activated prothrombin complex concentrate (aPCC) 4 factor: Contains 4 factors: Factors II, VII, IX, and X. Of these, only factor VII is mostly the activated form FEIBA Does not contain heparin The table lists 4-factor and 3-factor PCC products available in the United States. Kcentra is available as Beriplex in Canada. Bebulin (a 3-factor PCC) was discontinued in 2018 due to decreased demand for the product. Potency is determined differently for different products; refer to product information. All PCCs are plasma derived and contain other proteins, including anticoagulant proteins (proteins C and S). Unactivated factors are proenzymes (inactive precursor proteins). Activated factors have higher enzymatic activity. Refer to UpToDate topics for use of these products. US: United States; PCC: prothrombin complex concentrate; FEIBA: factor eight inhibitor bypassing activity. Other 4-factor PCCs available outside the US include Octaplex and Cofact Proplex. Single-factor recombinant activated factor VII (rFVIIa) products are also available. Graphic 94210 Version 8.0 https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 43/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - 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/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 44/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - 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/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 45/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Direct oral anticoagulant reversal agents for life-threatening bleeding (imminent risk of death from bleeding) Reversal agent (all are given intravenously) Anticoagulant Dabigatran (Pradaxa; oral thrombin inhibitor) Idarucizumab (Praxbind). Dose: 5 grams* Oral factor Xa inhibitors: Andexanet alfa (AndexXa). Dosing for the Apixaban (Eliquis) initial bolus and subsequent infusion depend 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.

Discontinuing warfarin therapy 5 to 14 days Five days is typical for patients with an INR in the therapeutic range Vitamin K* 6 to 24 hours to correct the INR, longer Recovery of factors X and II to fully reverse anticoagulation (prothrombin) takes longer than 24 hours Risk of anaphylaxis with intravenous injection Impaired response to warfarin lasting up to one week may occur after large doses (ie, >5 mg) Fresh frozen Depends on the time it takes to Effect is transient and concomitant plasma complete the infusion; typically 12 to 32 hours for complete reversal vitamin K must be administered Potential for volume overload (2 to 4 L to normalize INR) Potential for TRALI Potential for viral transmission Prothrombin 15 minutes after 10-minute to 1-hour Effect is transient, and concomitant complex infusion vitamin K must be administered; concentrate limited availability Cost Variable factor VII content depending on the product: a 4-factor PCC is preferred Potentially prothrombotic Recombinant factor VIIa 15 minutes after bolus infusion Effect is transient, and concomitant vitamin K must be administered Cost Potentially prothrombotic Please refer to the UpToDate topic on warfarin reversal in intracerebral hemorrhage for further details of management. INR: international normalized ratio; TRALI: transfusion-related acute lung injury; PCC: prothrombin complex concentrate. https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 41/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate A total of 10 mg intravenously by slow infusion given over 10 minutes. Adapted with permission from: Aguilar MI, Hart RG, Kase CS, et al. Treatment of warfarin-associated intercerebral hemorrhage: Literature review and expert opinion. Mayo Clin Proc 2007; 82:82. Copyright 2007 Dowden Health Media. Graphic 79151 Version 16.0 https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 42/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate PCC products available in the United States* Unactivated prothrombin complex concentrates (PCCs) 4 factor: Contains inactive forms of 4 factors: Factors II, VII, IX, and X Kcentra Also contains heparin 3 factor: Contains inactive forms of 3 factors: Factors II, IX, and X Profilnine Contains little or no factor VII Does not contain heparin Activated prothrombin complex concentrate (aPCC) 4 factor: Contains 4 factors: Factors II, VII, IX, and X. Of these, only factor VII is mostly the activated form FEIBA Does not contain heparin The table lists 4-factor and 3-factor PCC products available in the United States. Kcentra is available as Beriplex in Canada. Bebulin (a 3-factor PCC) was discontinued in 2018 due to decreased demand for the product. Potency is determined differently for different products; refer to product information. All PCCs are plasma derived and contain other proteins, including anticoagulant proteins (proteins C and S). Unactivated factors are proenzymes (inactive precursor proteins). Activated factors have higher enzymatic activity. Refer to UpToDate topics for use of these products. US: United States; PCC: prothrombin complex concentrate; FEIBA: factor eight inhibitor bypassing activity. Other 4-factor PCCs available outside the US include Octaplex and Cofact Proplex. Single-factor recombinant activated factor VII (rFVIIa) products are also available. Graphic 94210 Version 8.0 https://www.uptodate.com/contents/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 43/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - 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/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 44/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - 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/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 45/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Direct oral anticoagulant reversal agents for life-threatening bleeding (imminent risk of death from bleeding) Reversal agent (all are given intravenously) Anticoagulant Dabigatran (Pradaxa; oral thrombin inhibitor) Idarucizumab (Praxbind). Dose: 5 grams* Oral factor Xa inhibitors: Andexanet alfa (AndexXa). Dosing for the Apixaban (Eliquis) initial bolus and subsequent infusion depend 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/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 46/47 7/7/23, 11:35 AM Reversal of anticoagulation in intracranial hemorrhage - UpToDate Contributor Disclosures W David Freeman, MD Other Financial Interest: Cambridge [Book royalties]; Oxford [Book royalties]. All of the relevant financial relationships listed have been mitigated. Jeffrey I Weitz, MD Consultant/Advisory Boards: Alnylam [Anticoagulation]; Anthos [Anticoagulation]; Bayer/Janssen [Anticoagulation]; Boehringer- Ingelheim [Anticoagulation]; Bristol Myers Squibb/Janssen [Anticoagulation]; Bristol Myers Squibb/Pfizer [Anticoagulation]; Daiichi-Sankyo [Anticoagulation]; Ionis Pharmaceuticals [Anticoagulation]; Merck [Anticoagulation]; Pfizer [Anticoagulation]; PhaseBio [Anti-platelet drug reversal]; Regeneron Pharmaceuticals [Anticoagulation]; Servier [Anticoagulation]; VarmX [Anticoagulant reversal]. All of the relevant financial relationships listed have been mitigated. Lawrence LK Leung, 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. Jennifer S Tirnauer, 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/reversal-of-anticoagulation-in-intracranial-hemorrhage/print 47/47

7/7/23, 11:35 AM Screening for intracranial aneurysm - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Screening for intracranial aneurysm : Robert J Singer, MD, Christopher S Ogilvy, MD, Guy Rordorf, MD : Jos Biller, MD, FACP, FAAN, FAHA : 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: Feb 11, 2020. INTRODUCTION Subarachnoid hemorrhage (SAH) is often a devastating event. Approximately 10 percent of patients die prior to reaching the hospital and, of those who make it in time, only one-third will have a "good result" after treatment [1]. Most SAHs are caused by ruptured saccular aneurysms. Recommendations for screening for aneurysms and methods of screening are discussed here. The epidemiology and pathogenesis of intracranial aneurysms and management of unruptured aneurysms, and screening for new aneurysms after treatment for SAH are discussed separately. (See "Unruptured intracranial aneurysms" and "Treatment of cerebral aneurysms", section on 'Early rebleeding'.) RATIONALE The prevalence of intracranial saccular aneurysms by radiographic and autopsy series is approximately 0.4 to 6.0 percent [2], or between 1 to 18 million people in the United States. In adult patients without risk factors, the best estimate is that approximately 2 percent harbor asymptomatic cerebral aneurysms [3]. Of patients with cerebral aneurysms, 20 to 30 percent have multiple aneurysms [4]. Aneurysmal subarachnoid hemorrhage (SAH) occurs at an estimated rate of 6 to 16 per 100,000 population [4]. In North America, this translates into approximately 30,000 affected persons per year. Thus, most aneurysms do not rupture. The probability of rupture is related to the size of the aneurysm. Small aneurysms (less than 6 mm in diameter) are most commonly identified with screening, and these are at low risk for https://www.uptodate.com/contents/screening-for-intracranial-aneurysm/print 1/15 7/7/23, 11:35 AM Screening for intracranial aneurysm - UpToDate rupture ( figure 1) [5]. In addition, patients with smaller aneurysms (<10 mm) that have ruptured have a better prognosis than larger aneurysm rupture [6]. Aneurysm surgery is associated with significant morbidity and mortality. In an international multicenter report of 1449 patients with unruptured intracranial aneurysms, the rate of surgery- related morbidity and mortality in those without a prior history of bleeding from a different aneurysm was 18 percent at 30 days and 16 percent at one year [5]. The one-year rates were affected by age: 6.5 percent under age 45; 14 percent between the ages of 45 and 64; and 32 percent over the age of 64. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".) These findings suggest that widespread screening for cerebral aneurysm is not warranted. This was also the conclusion in guidelines published by the American Stroke Association [7,8]. However, screening may be considered in some populations at relatively high risk of cerebral aneurysm formation: First-degree relatives of patients with cerebral aneurysm, when two or more family members have been affected. Patients with a heritable disorder associated with the presence of intracranial aneurysm, such as autosomal dominant polycystic kidney disease (ADPKD), glucocorticoid-remediable aldosteronism (GRA), and connective tissue diseases such as Ehlers-Danlos syndrome IV and pseudoxanthoma elasticum [9,10]. RELATIVES OF PATIENTS WITH CEREBRAL ANEURYSM Family members of patients with intracranial aneurysms are at increased risk of having an aneurysm. In one study, for example, the age-adjusted prevalence of incidental aneurysms in first-degree relatives of patients with an aneurysm was 9 percent, a number significantly higher than in the general population [11]. Only a small proportion of these families had an identifiable hereditary syndrome known to be associated with aneurysms. In a second report of patients with mostly sporadic subarachnoid hemorrhage (SAH), intracranial aneurysms were found in 4 percent of first-degree relatives (approximately twice that of the general population) [12]. The mode of inheritance is variable, with autosomal dominant, recessive, and multifactorial transmission evident in different families [13]. In a large population study from Scotland, the estimated 10-year prospective risk of SAH for relatives free of SAH at the time of the index SAH increased in an ascending manner according to https://www.uptodate.com/contents/screening-for-intracranial-aneurysm/print 2/15 7/7/23, 11:35 AM Screening for intracranial aneurysm - UpToDate the relationship to the index case as follows [14]: One second-degree relative, 0.3 percent (95% CI 0.0-0.6) One first-degree relative, 0.8 percent (95% CI 0.2-1.5) Two first-degree relatives, 7.1 percent (95% CI 0.2-14.0) The wide confidence intervals around these risk estimates reflect the small numbers of SAH events that occur in relatives of index cases, even in large population studies. Nonetheless, the risk for first-degree relatives of patients with SAH appears to be much higher than that of the general population, where the 10-year prospective risk of SAH is approximately 0.1 percent [15]. The risk of aneurysm among family members of patients with aneurysm is also influenced by those risk factors (cigarette smoking, hypertension) that affect aneurysm formation in the general population [16]. (See "Unruptured intracranial aneurysms", section on 'Aneurysm formation'.) Familial aneurysms tend to rupture at a smaller size and younger age than sporadic aneurysms [11,17,18]. Siblings often experience rupture in the same decade of life [17]. Families with intracranial aneurysms do not appear to demonstrate the phenomenon of anticipation (ie, subsequent generations are not more likely to develop SAH at younger ages than previous generations) [19]. Multiple cerebral aneurysms are also more common in the familial syndrome than among those with sporadic aneurysms [20]. Most cerebral aneurysms are initially discovered in families after rupture causes SAH. Thus, screening studies have predominantly looked at relatives of patients who have suffered an SAH. Recommendations for screening asymptomatic family members of patients with SAH for the presence of intracranial aneurysms depend upon the number of affected relatives. Two or more affected first-degree relatives Screening of asymptomatic first-degree relatives is generally recommended in families that have two or more individuals with aneurysms [21]. One study that employed this approach found aneurysms by magnetic resonance angiography (MRA) in 37 of 400 (9 percent) asymptomatic individuals among 68 families with a history of aneurysmal SAH [22]. Analytic models have come to different conclusions regarding the efficacy of screening, depending in part on the role of conventional angiography in screening and the choice of aneurysm treatment used in their model. One study suggested that this approach would not be effective in reducing morbidity and mortality unless aneurysm prevalence was substantially https://www.uptodate.com/contents/screening-for-intracranial-aneurysm/print 3/15 7/7/23, 11:35 AM Screening for intracranial aneurysm - UpToDate greater than 10 percent [23]. However, another study found that a screening program could reduce morbidity and mortality in this population in a cost-effective manner [24]. If the decision is made to screen, it is uncertain what screening interval is appropriate. In a study that recommended repeat screening at five-year intervals, 74 patients had one repeat screening and 28 patients had a second repeat screening [25]. Ten new aneurysms were detected in nine patients; two patients had an SAH three years after a negative screening procedure. The American Stroke Association guidelines concluded that while people with two or more first- degree relatives with intracranial aneurysm have an increased incidence of intracranial aneurysms, the cost effectiveness of screening in these populations has not been evaluated. They suggest that screening in these individuals should be considered on an individual basis [7,8,26]. Our usual practice is to screen relatives with MRA yearly for three years and then expand the screening interval to every five years for those who had no aneurysms detected on the initial three scans. One affected first-degree relative The lifetime risk of SAH for individuals with only one affected first-degree relative is relatively small, ranging from 1 to 4.7 percent at age 70 [12,14], although the risk of aneurysm formation may be higher [12]. Some advocate screening in this population as well, but this approach is not generally recommended [21]. In one study, for example, 626 first-degree relatives of 160 patients with sporadic SAH were screened with MRA, followed by conventional angiography in those thought to have aneurysms [27]. Aneurysms were found in 25 first-degree relatives (4 percent), twice the prevalence in the general population, but less than one-half the prevalence of people with two or more first-degree relatives with SAH. Eighteen underwent surgery: five with medium-sized aneurysms (5 to 11 mm in diameter), 11 with small aneurysm (less than 5 mm), and two with both small and medium-sized aneurysms. Outcome was assessed at six months after surgery and was combined with a decision analysis model to estimate the effectiveness of screening: Eleven patients who underwent surgery experienced a decrease in function at six months. Surgery increased life expectancy by 0.9 months/person screened at the expense of 19 years of decreased function per person. The number of relatives who would need to be screened to prevent one SAH during a lifetime was 149; 298 would have to be screened to prevent a fatal SAH. https://www.uptodate.com/contents/screening-for-intracranial-aneurysm/print 4/15 7/7/23, 11:35 AM Screening for intracranial aneurysm - UpToDate Other studies have also found that the quality of life and functional outcome of many patients who undergo screening followed by angiography and surgery are diminished for at least one year [28]. Furthermore, the gain in life expectancy per person screened is considerably lower than the benefits offered by other screening programs. These observations suggest that screening of patients with only one affected first-degree relative is not warranted. Guidelines published by the American Stroke Association in 2012 state that while it might be reasonable to offer noninvasive screening, further study is needed to define the risks and benefits of this approach [26]. HEREDITARY SYNDROMES ASSOCIATED WITH ANEURYSM FORMATION Cerebral aneurysm formation is more common in individuals with certain hereditary syndromes as discussed below. Despite this risk, the American Stroke Association guidelines concluded that screening is not efficacious in these populations [7,8]. Autosomal dominant polycystic kidney disease The incidence of cerebral aneurysm in autosomal dominant polycystic kidney disease (ADPKD) is approximately 5 percent in young adults, increasing with age to as high as 10 percent in older patients [29-33]. Patients with a family history of intracranial aneurysm or subarachnoid hemorrhage (SAH) appear to be at greatest risk [29,33,34]. In one study, for example, asymptomatic intracranial aneurysms were found in 6 of 27 patients (22 percent) with, and only 3 of 56 patients (5 percent) without, a positive family history [33]. (See "Autosomal dominant polycystic kidney disease (ADPKD): Extrarenal manifestations".) It has been estimated that aneurysm rupture occurs in 65 to 75 percent of affected patients with ADPKD, a value higher than that of non-ADPKD patients with an intracerebral aneurysm [32]. Aneurysm rupture in ADPKD most often occurs before the age of 50 and in patients with poorly controlled hypertension [32]. In addition, patients who have already had one aneurysm clipped following a cerebral bleed may be at increased risk of new aneurysm formation for as long as 15 years after the initial surgery [35]. Nevertheless, the role for radiologic screening of asymptomatic patients with ADPKD is unsettled. As mentioned above, the decision is based upon weighing the risks of aneurysm surgery versus the benefits of possibly preventing aneurysm rupture; the risk-benefit ratio in asymptomatic patients with ADPKD is uncertain. At present, routine screening is recommended only for high-risk patients, such as those with a previous rupture, a positive family history of an intracerebral bleed, warning symptoms, a high-risk occupation in which loss of consciousness would place the patient or others at extreme risk, and prior to surgery that is likely to be https://www.uptodate.com/contents/screening-for-intracranial-aneurysm/print 5/15 7/7/23, 11:35 AM Screening for intracranial aneurysm - UpToDate associated with hemodynamic instability with hypertension [29,34]. (See "Autosomal dominant polycystic kidney disease (ADPKD): Extrarenal manifestations", section on 'Screening'.) Other hereditary disorders Patients with glucocorticoid-remediable aldosteronism (GRA) are at increased risk of hemorrhagic stroke, in part due to a relatively high frequency of cerebral aneurysm rupture [36] (see "Familial hyperaldosteronism"). It has been suggested that all patients with genetically proven GRA should undergo screening for cerebral aneurysm at puberty and every five years thereafter [36]. However, the benefit of such an approach has not been proven and, as in all patients, must be weighed against the risk of prophylactic surgery for small aneurysms that might not rupture. Connective tissue diseases such as Ehlers-Danlos syndrome and pseudoxanthoma elasticum are associated with an increased risk of cerebral aneurysm formation [13,17], but no studies have specifically addressed the issue of screening. Bicuspid aortic valve is a congenital condition with familial clustering in some cases. In one case- control study, the frequency of intracranial aneurysm was higher in this population compared with a control group (9.8 versus 1.1 percent) [37]. However, the benefit of an aneurysm screening program in individuals with bicuspid aortic valve has not been evaluated. PATIENTS WITH PRIOR ANEURYSMAL SUBARACHNOID HEMORRHAGE Survivors of an aneurysmal subarachnoid hemorrhage (SAH) are at risk for recurrent SAH, which may result from recurrence of the treated aneurysm, rupture of another preexisting aneurysm in a patient with multiple aneurysms, and de novo aneurysm formation. The monitoring of such patients is discussed in detail separately. (See "Late recurrence of subarachnoid hemorrhage and intracranial aneurysms".) CHOICE OF SCREENING TEST If the decision is made to screen, magnetic resonance angiography (MRA) or computed tomography angiography (CTA) of the head with intravenous contrast are reasonable choices [31,33,38,39]. MRA can identify aneurysms 3 to 5 mm or larger [40]. In one cohort study of 138 patients with suspected intracranial aneurysm, volume-rendering, 3D-time-of-flight MRA at 3 Tesla had a greater than 95 percent sensitivity and accuracy for detection of aneurysms [41]. https://www.uptodate.com/contents/screening-for-intracranial-aneurysm/print 6/15 7/7/23, 11:35 AM Screening for intracranial aneurysm - UpToDate CTA identifies small unruptured aneurysms with high diagnostic accuracy and reader agreement [42,43]. In one retrospective cohort study of 579 patients with 711 aneurysms, CTA demonstrated a sensitivity of 95 to 97 percent and a specificity of 100 percent for detection of unruptured aneurysms measuring 3 to 5 mm. For detecting aneurysms <3 mm in diameter, sensitivity was lower (84 to 86 percent) without loss of specificity ( figure 2A-B) [42]. Conventional cerebral angiography is a more invasive test that is associated with a higher risk of complications. Furthermore, the benefits of finding smaller aneurysms with angiography are unlikely to be of benefit for screening purposes. 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: Brain aneurysm (The Basics)") SUMMARY AND RECOMMENDATIONS Screening for asymptomatic intracranial aneurysms in the general population is not indicated. Aneurysms have a baseline prevalence of 0.2 to 6 percent in adults; these have a https://www.uptodate.com/contents/screening-for-intracranial-aneurysm/print 7/15 7/7/23, 11:35 AM Screening for intracranial aneurysm - UpToDate low risk of rupture; interventions to treat aneurysms have an associated risk of complications. (See 'Rationale' above.) Family members of patients with intracranial aneurysms are at increased risk of having an aneurysm. The risk increases with the degree of association and the number of family members affected. (See 'Relatives of patients with cerebral aneurysm' above.) Genetic syndromes associated with a higher risk of cerebral aneurysm formation include autosomal dominant polycystic kidney disease (ADPKD), Ehlers-Danlos syndrome, pseudoxanthoma elasticum, glucocorticoid-remediable aldosteronism (GRA), and bicuspid aortic valve. (See 'Hereditary syndromes associated with aneurysm formation' above.) In populations with two or more first-degree relatives with intracranial aneurysm, screening programs have demonstrated an increased incidence of intracranial aneurysms, but the cost effectiveness of screening in these populations has not been evaluated. Screening in these individuals should be considered on an individual basis. Our usual practice is to screen relatives with magnetic resonance yearly for three years and then expand the screening interval to every five years for those who had no aneurysms detected on the initial three scans. (See 'Two or more affected first-degree relatives' above.) Theoretical modeling suggests that screening is not efficacious in populations with genetic syndromes associated with cerebral aneurysm formation or in family members with a single first-degree relative with aneurysmal subarachnoid hemorrhage (SAH) or an intracranial aneurysm. (See 'One affected first-degree relative' above and 'Hereditary syndromes associated with aneurysm formation' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Tidswell P, Dias PS, Sagar HJ, et al. Cognitive outcome after aneurysm rupture: relationship to aneurysm site and perioperative complications. Neurology 1995; 45:875. 2. Rinkel GJ, Djibuti M, Algra A, van Gijn J. Prevalence and risk of rupture of intracranial aneurysms: a systematic review. Stroke 1998; 29:251. 3. Vernooij MW, Ikram MA, Tanghe HL, et al. Incidental findings on brain MRI in the general population. N Engl J Med 2007; 357:1821. 4. STEHBENS WE. ANEURYSMS AND ANATOMICAL VARIATION OF CEREBRAL ARTERIES. Arch Pathol 1963; 75:45. https://www.uptodate.com/contents/screening-for-intracranial-aneurysm/print 8/15 7/7/23, 11:35 AM Screening for intracranial aneurysm - UpToDate 5. International Study of Unruptured Intracranial Aneurysms Investigators. Unruptured intracranial aneurysms risk of rupture and risks of surgical intervention. N Engl J Med 1998; 339:1725. 6. Roos EJ, Rinkel GJ, Velthuis BK, Algra A. The relation between aneurysm size and outcome in patients with subarachnoid hemorrhage. Neurology 2000; 54:2334. 7. Bederson JB, Awad IA, Wiebers DO, et al. Recommendations for the management of patients with unruptured intracranial aneurysms: A statement for healthcare professionals from the Stroke Council of the American Heart Association. Circulation 2000; 102:2300. 8. Bederson JB, Connolly ES Jr, Batjer HH, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke 2009; 40:994. 9. Neil-Dwyer G, Bartlett JR, Nicholls AC, et al. Collagen deficiency and ruptured cerebral aneurysms. A clinical and biochemical study. J Neurosurg 1983; 59:16. 10. Pepin M, Schwarze U, Superti-Furga A, Byers PH. Clinical and genetic features of Ehlers- Danlos syndrome type IV, the vascular type. N Engl J Med 2000; 342:673. 11. Ronkainen A, Hernesniemi J, Puranen M, et al. Familial intracranial aneurysms. Lancet 1997; 349:380. 12. Raaymakers TW. Aneurysms in relatives of patients with subarachnoid hemorrhage: frequency and risk factors. MARS Study Group. Magnetic Resonance Angiography in Relatives of patients with Subarachnoid hemorrhage. Neurology 1999; 53:982. 13. Bromberg JE, Rinkel GJ, Algra A, et al. Familial subarachnoid hemorrhage: distinctive features and patterns of inheritance. Ann Neurol 1995; 38:929. 14. Teasdale GM, Wardlaw JM, White PM, et al. The familial risk of subarachnoid haemorrhage. Brain 2005; 128:1677. 15. Linn FH, Rinkel GJ, Algra A, van Gijn J. Incidence of subarachnoid hemorrhage: role of region, year, and rate of computed tomography: a meta-analysis. Stroke 1996; 27:625. 16. Rasing I, Nieuwkamp DJ, Algra A, Rinkel GJ. Additional risk of hypertension and smoking for aneurysms in people with a family history of subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 2012; 83:541. 17. St Jean P, Hart B, Webster M, et al. Alpha-1-antitrypsin deficiency in aneurysmal disease. Hum Hered 1996; 46:92. 18. Broderick JP, Brown RD Jr, Sauerbeck L, et al. Greater rupture risk for familial as compared to sporadic unruptured intracranial aneurysms. Stroke 2009; 40:1952. https://www.uptodate.com/contents/screening-for-intracranial-aneurysm/print 9/15 7/7/23, 11:35 AM Screening for intracranial aneurysm - UpToDate 19. Woo D, Hornung R, Sauerbeck L, et al. Age at intracranial aneurysm rupture among generations: Familial Intracranial Aneurysm Study. Neurology 2009; 72:695. 20. Raaymakers TW, Rinkel GJ, Ramos LM. Initial and follow-up screening for aneurysms in families with familial subarachnoid hemorrhage. Neurology 1998; 51:1125. 21. Schievink WI. Intracranial aneurysms. N Engl J Med 1997; 336:28. 22. Ronkainen A, Puranen MI, Hernesniemi JA, et al. Intracranial aneurysms: MR angiographic screening in 400 asymptomatic individuals with increased familial risk. Radiology 1995; 195:35. 23. Crawley F, Clifton A, Brown MM. Should we screen for familial intracranial aneurysm? Stroke 1999; 30:312. 24. Bor AS, Koffijberg H, Wermer MJ, Rinkel GJ. Optimal screening strategy for familial intracranial aneurysms: a cost-effectiveness analysis. Neurology 2010; 74:1671. 25. Wermer MJ, Rinkel GJ, van Gijn J. Repeated screening for intracranial aneurysms in familial subarachnoid hemorrhage. Stroke 2003; 34:2788. 26. Connolly ES Jr, Rabinstein AA, Carhuapoma JR, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/american Stroke Association. Stroke 2012; 43:1711. 27. Magnetic Resonance Angiography in Relatives of Patients with Subarachnoid Hemorrhage Study Group. Risks and benefits of screening for intracranial aneurysms in first-degree relatives of patients with sporadic subarachnoid hemorrhage. N Engl J Med 1999; 341:1344. 28. Raaymakers TW. Functional outcome and quality of life after angiography and operation for unruptured intracranial aneurysms. On behalf of the MARS Study Group. J Neurol Neurosurg Psychiatry 2000; 68:571. 29. Fick GM, Gabow PA. Hereditary and acquired cystic disease of the kidney. Kidney Int 1994; 46:951. 30. Watson ML. Complications of polycystic kidney disease. Kidney Int 1997; 51:353. 31. Chapman AB, Rubinstein D, Hughes R, et al. Intracranial aneurysms in autosomal dominant polycystic kidney disease. N Engl J Med 1992; 327:916. 32. Schievink WI, Torres VE, Piepgras DG, Wiebers DO. Saccular intracranial aneurysms in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 1992; 3:88. 33. Huston J 3rd, Torres VE, Sulivan PP, et al. Value of magnetic resonance angiography for the detection of intracranial aneurysms in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 1993; 3:1871. https://www.uptodate.com/contents/screening-for-intracranial-aneurysm/print 10/15 7/7/23, 11:35 AM Screening for intracranial aneurysm - UpToDate 34. Chauveau D, Pirson Y, Verellen-Dumoulin C, et al. Intracranial aneurysms in autosomal dominant polycystic kidney disease. Kidney Int 1994; 45:1140. 35. Chauveau D, Sirieix ME, Schillinger F, et al. Recurrent rupture of intracranial aneurysms in autosomal dominant polycystic kidney disease. BMJ 1990; 301:966. 36. Litchfield WR, Anderson BF, Weiss RJ, et al. Intracranial aneurysm and hemorrhagic stroke in glucocorticoid-remediable aldosteronism. Hypertension 1998; 31:445. 37. Schievink WI, Raissi SS, Maya MM, Velebir A. Screening for intracranial aneurysms in patients with bicuspid aortic valve. Neurology 2010; 74:1430. 38. Raaymakers TW, Buys PC, Verbeeten B Jr, et al. MR angiography as a screening tool for intracranial aneurysms: feasibility, test characteristics, and interobserver agreement. AJR Am J Roentgenol 1999; 173:1469. 39. Wiebers DO, Torres VE. Screening for unruptured intracranial aneurysms in autosomal dominant polycystic kidney disease. N Engl J Med 1992; 327:953. 40. Huston J 3rd, Nichols DA, Luetmer PH, et al. Blinded prospective evaluation of sensitivity of MR angiography to known intracranial aneurysms: importance of aneurysm size. AJNR Am J Neuroradiol 1994; 15:1607. 41. Li MH, Cheng YS, Li YD, et al. Large-cohort comparison between three-dimensional time-of- flight magnetic resonance and rotational digital subtraction angiographies in intracranial aneurysm detection. Stroke 2009; 40:3127. 42. Yang ZL, Ni QQ, Schoepf UJ, et al. Small Intracranial Aneurysms: Diagnostic Accuracy of CT Angiography. Radiology 2017; 285:941. 43. Lu L, Zhang LJ, Poon CS, et al. Digital subtraction CT angiography for detection of intracranial aneurysms: comparison with three-dimensional digital subtraction angiography. Radiology 2012; 262:605. Topic 1135 Version 16.0 https://www.uptodate.com/contents/screening-for-intracranial-aneurysm/print 11/15 7/7/23, 11:35 AM Screening for intracranial aneurysm - UpToDate GRAPHICS Graph showing risk of rupture of intracranial aneurysms among patients with and without history of prior subarachnoid hemorrhage Retrospective analysis of the probability of subarachnoid hemorrhage (SAH) over time in patients with an unruptured intracranial aneurysm: 446 without (top panel) and 438 with (bottom panel) a history of SAH from a different aneurysm. The results are shown according to the size of the aneurysm. The risk is clearly related to the size of the aneurysm in patients with no prior history of SAH, with aneurysms <10 mm in size having a very low incidence of rupture. Such a relationship was not apparent in those with a prior history of SAH; the values are not shown for aneurysms 25 mm in this group because of the small number of patients. Data from: The International Study of Unruptured Intracranial Aneurysms Investigators, N Engl J Med 1998; 339:1725. Graphic 63534 Version 4.0 https://www.uptodate.com/contents/screening-for-intracranial-aneurysm/print 12/15 7/7/23, 11:35 AM Screening for intracranial aneurysm - UpToDate Sensitivity of CTA for intracranial aneurysms The graph shows the increasing sensitivity of CTA with increasing aneurysm size. Points represent the median, and error bars represent the 95 percent confidence limits. Aneurysms greater than 10 mm have been pooled. Data from: van Gelder, JM. Computed tomographic angiography for detecting cerebral aneurysms: implications of aneurysm size distribution for the sensitivity, speci city, and likelihood ratios. Neurosurgery 2003; 53:597. Graphic 81565 Version 2.0 https://www.uptodate.com/contents/screening-for-intracranial-aneurysm/print 13/15 7/7/23, 11:35 AM Screening for intracranial aneurysm - UpToDate False-positive intracranial aneurysms reported by CTA Bars represent the number of reported aneurysms of each size from 199 false-positive reports of aneurysms. Data from: van Gelder, JM. Computed tomographic angiography for detecting cerebral aneurysms: implications of aneurysm size distribution for the sensitivity, speci city, and likelihood ratios. Neurosurgery 2003; 53:597. Graphic 69728 Version 1.0 https://www.uptodate.com/contents/screening-for-intracranial-aneurysm/print 14/15 7/7/23, 11:35 AM Screening for intracranial aneurysm - 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. 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/screening-for-intracranial-aneurysm/print 15/15

7/7/23, 11:36 AM 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 7/7/23, 11:36 AM 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 7/7/23, 11:36 AM 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 7/7/23, 11:36 AM 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 7/7/23, 11:36 AM 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 7/7/23, 11:36 AM 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 7/7/23, 11:36 AM 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 7/7/23, 11:36 AM 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 7/7/23, 11:36 AM 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 7/7/23, 11:36 AM 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 7/7/23, 11:36 AM 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 7/7/23, 11:36 AM 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 7/7/23, 11:36 AM 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 7/7/23, 11:36 AM 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 7/7/23, 11:36 AM 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 7/7/23, 11:36 AM 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 7/7/23, 11:36 AM 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

7/7/23, 11:36 AM Treatment of cerebral aneurysms - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Treatment of cerebral aneurysms : Robert J Singer, MD, Christopher S Ogilvy, MD, Guy Rordorf, MD : Jos Biller, MD, FACP, FAAN, FAHA : 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: Aug 12, 2022. INTRODUCTION Cerebral aneurysms are thin-walled protrusions in the intracranial arteries that may rupture to cause a subarachnoid hemorrhage (SAH), often a devastating event with a high mortality and morbidity. Unruptured cerebral aneurysms may also manifest clinically by their mass effect on adjacent neurologic structures, or they may be discovered incidentally when a patient has a neuroimaging study for another indication. Unruptured aneurysms have a future risk of rupture and SAH that varies in part by size and location. Endovascular or surgical repair is the only effective treatment for aneurysmal SAH to prevent rebleeding and further morbidity and is also used for some patients with unruptured cerebral aneurysms to prevent SAH. The treatment of cerebral aneurysms is discussed in this topic. Other aspects of the clinical features, diagnosis, and management of cerebral aneurysms and aneurysmal SAH are discussed separately. (See "Screening for intracranial aneurysm".) (See "Unruptured intracranial aneurysms".) (See "Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis".) (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".) PATIENTS WITH SUBARACHNOID HEMORRHAGE https://www.uptodate.com/contents/treatment-of-cerebral-aneurysms/print 1/19 7/7/23, 11:36 AM Treatment of cerebral aneurysms - UpToDate Early rebleeding Rebleeding occurs in 8 to 23 percent of patients with aneurysmal subarachnoid hemorrhage (SAH). Most studies have found that the risk of rebleeding is highest in the first 24 hours after SAH, particularly within six hours of the initial hemorrhage [1-4]. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Rebleeding'.) Aneurysmal rebleeding is associated with a poor prognosis. In a prospective study involving 574 hospitalized patients admitted within 14 days of SAH, rebleeding was associated with a 12-fold reduction in the probability of survival with functional independence at three months (odds ratio [OR] 0.08, 95% CI 0.02-0.34) after correction for admission Hunt and Hess grade and aneurysm size [3]. Another prospective study found similar results [5]. In one case series, half of hemorrhage expansions were related to rerupture of the aneurysm [6]. Other mechanisms of hemorrhage expansion or rebleeding may be similar to those for intracerebral hemorrhage. (See "Spontaneous intracerebral hemorrhage: Acute treatment and prognosis", section on 'Managing hemorrhagic expansion'.) Only aneurysm treatment is effective in preventing rebleeding. In one analysis of neurosurgical aneurysm clipping, the authors estimated the absolute reduction in the risk of a poor outcome was 10 percent (ie, 10 surgeries would prevent a poor outcome in one patient) [7]. Patients in whom aneurysm treatment is not possible or is unavoidably delayed may be candidates for antifibrinolytic therapy. Timing and choice of therapy Decisions regarding the timing and choice of therapy for a rupture intracranial aneurysm are ideally made by a team of experienced clinicians. The timing of surgery following intracranial aneurysm rupture is an area of controversy. The potential benefits of early surgery (within 24 to 72 hours of the hemorrhage) include prevention of rebleeding and management of vasospasm. In addition, the usual methods of treating vasospasm (hypervolemia, induced hypertension, intraarterial vasodilators, and balloon angioplasty) are dangerous in the presence of an untreated aneurysm. (See 'Early rebleeding' above and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Vasospasm and delayed cerebral ischemia'.) Decisions regarding the choice of therapy in the treatment of a ruptured intracranial aneurysm are made by a team of experienced surgeons and endovascular practitioners. Factors important to consider include the neurologic grade and clinical status of the patient, the availability of expertise in surgical and endovascular techniques, as well as the anatomic characteristics of the aneurysm, including the location and the size of the aneurysm and its neck [8,9]. (See 'Anatomic considerations' below.) https://www.uptodate.com/contents/treatment-of-cerebral-aneurysms/print 2/19 7/7/23, 11:36 AM Treatment of cerebral aneurysms - UpToDate Good-grade SAH Early aneurysm repair (within 24 to 72 hours) in patients with good-grade aneurysmal SAH (Hunt and Hess grades I to III) ( table 1) is a generally accepted treatment with a satisfactory outcome in the large majority of patients. Approximately 70 to 90 percent of patients have a good neurologic recovery, with a mortality rate of 1.7 percent to 8 percent [10]. Limited clinical trial evidence suggests that early aneurysm surgery may be associated with a lower risk of rebleeding and better outcome than later surgery, but the results did not achieve statistical significance [11,12]. Observational studies, which are limited by selection bias, suggest that early intervention is associated with better outcomes [13]. A subset of patients with good-grade aneurysmal SAH may do as well, or even better, with endovascular coiling [14,15]. In the largest of the randomized trials to examine this question, the International Subarachnoid Aneurysm Trial (ISAT), 2143 patients with ruptured intracranial aneurysms were randomly assigned to neurosurgical clipping or endovascular coiling [16,17]. The patients in this study represented a selected subgroup in which 88 percent were of good clinical status, and aneurysms 3 mm were excluded; 90 percent of the target aneurysms were smaller than 10 mm in diameter, and 95 percent of aneurysms were in the anterior circulation [17]. Outcomes included: Lower rates of combined death and disability at one year in the endovascular group (23.5 versus 30.9 percent), with an absolute risk reduction of 7.4 percent (95% CI 3.6-11.2) [17]. At 10 years, the endovascular group continued to have somewhat lower rates of both mortality and combined death and dependency (OR 1.35, 95% CI 1.06-1.73, and OR 1.34, 95% CI 1.07-1.67, respectively) [18]. Similar mortality at one year, 8.0 percent (95% CI 6.4-9.8) and 9.9 percent (95% CI 8.2-11.9), in the endovascular and neurosurgical groups, respectively [17]. Higher rates of post-treatment rebleeding from the target aneurysm in the endovascular therapy group during the first year (2.6 versus 1.0 percent). Few rebleeding events occurred in either treatment group after one year but again were more common in the endovascular therapy group [19]. However, within eight years rebleeding rates become similar [20]. (See "Late recurrence of subarachnoid hemorrhage and intracranial aneurysms".) Lower rates of post-treatment seizures in the endovascular group (relative risk 0.52, 95% CI 0.37-0.74) [17]. At one year, the prevalence of epilepsy and cognitive impairment were less common in patients treated by endovascular coiling than surgical clipping [21]. These results can only be applied to patients who fit the characteristics of patients selected to participate in the ISAT, which is a small percentage of patients presenting with SAH [16]. For such https://www.uptodate.com/contents/treatment-of-cerebral-aneurysms/print 3/19 7/7/23, 11:36 AM Treatment of cerebral aneurysms - UpToDate patients, endovascular coiling appears to have somewhat more favorable outcomes and is probably the favored treatment for aneurysm repair if anatomic and morphologic features of the aneurysm are deemed appropriate for endovascular treatment. Poor-grade SAH The prognosis for patients with aneurysmal SAH and with poor clinical grade (Hunt and Hess IV and V) ( table 1) is poor, particularly in those patients with a Glasgow Coma Scale motor score ( table 2) less than 4 [22]. Treatment decisions need to be individualized with consultation with family members. Some data suggest that aneurysm occlusion in such patients (particularly if associated with advanced age and medical comorbidity) may not improve their overall prognosis [23]. Nonetheless, we favor early treatment, with endovascular therapy when possible for patients with poor-grade SAH. Early surgery may be more complicated than a procedure delayed for 10 to 14 days in patients with poor clinical grade. The presence of cerebral edema (which may prevent brain retraction and relaxation) and clot around the aneurysm increases the technical difficulty of surgery. Early surgery may be associated with an increased risk of ischemic complications [24]. However, early rebleeding is also more common in patients with poor clinical grade [25]. One large retrospective study of 2106 patients found that delayed surgery was associated with a small, nonsignificant reduction in delayed cerebral ischemia, but a significant increase in poor outcomes [26]. Endovascular techniques also may offer a less invasive and often definitive mode of therapy for this group [27]; the concerns regarding the increased difficulty of early surgery do not apply to intraluminal therapy. In addition, although not substantiated by any large series, the use of intravascular embolization of aneurysms in the acute setting may facilitate aggressive medical management algorithms for proactive treatment of cerebral vasospasm. A systematic review and meta-analysis that included the ISAT as well as other smaller randomized trials and observational studies found that while outcomes at one-year were more favorable in patient treated with endovascular coiling, the choice of treatment modality did not seem to have a significant impact on outcome in patients with poor preoperative grade [28]. In a subsequently performed randomized trial of 571 patients with SAH that included patients with a broader spectrum of disease severity than were included in ISAT, patients assigned to endovascular treatment were more likely to have a better outcome at one year as measured by the modified Rankin Scale; the difference no longer reached statistical significant at year 3 [29,30]. It is noteworthy that 38 percent of those assigned to endovascular treatment crossed over to surgical clipping (usually because the endovascular treatment was judged to be technically difficult); such patients had a worse outcome than those who received the assigned endovascular treatment and was similar to those who were assigned to and received clipping. https://www.uptodate.com/contents/treatment-of-cerebral-aneurysms/print 4/19 7/7/23, 11:36 AM Treatment of cerebral aneurysms - UpToDate Post-treatment management Patients are managed in the intensive care unit after aneurysm therapy. Continuous cardiodynamic and neurologic monitoring is critical. Postoperative angiography is used at the surgeons' discretion. Patients should have monitoring and treatment for vasospasm. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis", section on 'Vasospasm and delayed cerebral ischemia'.) PATIENTS WITH UNRUPTURED ANEURYSMS The management of unruptured intracranial aneurysms is controversial [31]. There are no randomized trials on which to base recommendations. Decisions about therapy need to weigh the natural history of the aneurysm, the risks of intervention, and patient preferences. While these are discussed in detail separately, in general, asymptomatic aneurysms 7 to 10 mm in diameter warrant strong consideration for treatment, taking into account patient age, existing medical and neurologic conditions, and relative risks for treatment [32]. (See "Unruptured intracranial aneurysms", section on 'Risk factors for aneurysm rupture' and "Unruptured intracranial aneurysms", section on 'Risk of intervention'.) Surgical treatment of unruptured aneurysms has been the most common procedure used in patients who undergo definitive therapy. In clinical studies, which are typically in centers with high case volumes, endovascular techniques appear to be associated with lower morbidity and mortality than surgical clipping and are playing an increasing role in the treatment of unruptured aneurysms [33-40]. New technologies, such as flow diversion, may advance the safety of endovascular treatment and allow aneurysms, previously considered to be inaccessible or technologically difficult for such treatment [41]. (See 'Newer techniques' below.) TECHNIQUES Surgical and endovascular techniques are available for aneurysm treatment. In many cases, anatomic considerations, such as size and location, along with other morphological features, determine which treatment is most appropriate for the patient. Surgery Surgical management of cerebral aneurysms, in which a clip is placed across the neck of the aneurysm, is an effective and safe procedure with the evolution of microsurgical techniques in the hands of an experienced surgeon ( image 1). This applies to patients with unruptured cerebral aneurysms and those with subarachnoid hemorrhage (SAH) [7]. Treatment at specialized neurosurgical centers performing high volumes of cerebral aneurysm procedures is associated with better outcome compared with treatment at lower-volume centers https://www.uptodate.com/contents/treatment-of-cerebral-aneurysms/print 5/19 7/7/23, 11:36 AM Treatment of cerebral aneurysms - UpToDate [42]. Temporary clip occlusion may be achieved via traditional extraluminal clip placement or with an intravascular balloon but does not clearly prevent complications [43]. Intraoperative angiography is useful to facilitate accurate clip placement and to confirm parent vessel patency after clip occlusion and occlusion of the aneurysm; this allows immediate clip revision when necessary, which is estimated to occur in approximately 10 percent of patients [44-48]. Intraoperative hypothermia does not appear to improve neurologic outcome after surgery for intracranial aneurysm clipping [49-51]. Prolonged hypotension should be avoided during surgery [44]. Risks associated with surgical aneurysm treatment include new or worsened neurologic deficits caused by brain retraction, temporary arterial occlusion, and intraoperative hemorrhage [52-54]. Intraprocedural aneurysmal rupture occurred in 19 percent of 711 patients treated with surgical clipping in the Cerebral Aneurysm Rerupture After Treatment (CARAT) study and was associated with periprocedural death and disability [55]. Procedure-related surgical complications occurred in 29 (20 percent) of 143 patients in a retrospective series [56], although functional outcome was good in 22 (76 percent) of those patients. Endovascular therapy Coil embolism The Guglielmi electrolytically detachable coil system was introduced in the early 1990s [57]. Platinum coils are inserted into the lumen of the aneurysm ( image 2). A local thrombus then forms around the coils, obliterating the aneurysmal sac [58]. The procedure is often, but not invariably, performed under general anesthesia [44]. Complications of endovascular coiling include thromboembolism and intraprocedural aneurysm rupture. Both of these complications are somewhat more common in the setting of SAH than for unruptured aneurysms [59,60]. Thromboembolism occurred in 12.5 percent of endovascularly treated aneurysms in one series [61]. Aneurysm size >10 mm and neck size >4 mm were risk factors for this complication. While of unproven benefit, some combination of heparin and/or antiplatelet therapy is used in most centers to minimize sequelae [62]. In one large series, 9.3 percent of patients experienced a thromboembolic event during coiling despite use of heparin and aspirin [63]. In one series, GIIB/IIIa inhibitors appeared to be safer for this indication than thrombolytic agents [64]. Intraprocedural aneurysmal rupture occurred in 5 percent of 299 patients with aneurysmal SAH treated with coil embolization in the CARAT study [55]. Periprocedural death or https://www.uptodate.com/contents/treatment-of-cerebral-aneurysms/print 6/19 7/7/23, 11:36 AM Treatment of cerebral aneurysms - UpToDate disability was more likely in those with this complication compared with those without rupture (34 versus 17 percent). Other studies have shown similar rates of intraprocedural rupture during endovascular coiling of 4 to 5 percent [60,61,65]. Among different series, risk factors for this complication have been variably noted to include small aneurysm size, middle cerebral artery location, ruptured versus unruptured status, and hypertension [61,66,67]. Patients treated with anticoagulation or antiplatelet therapy may require reversal of these therapies if intraprocedural rupture occurs [44]. Coiled aneurysms also appear to be more likely than clipped aneurysms to recur and require additional intervention. (See "Late recurrence of subarachnoid hemorrhage and intracranial aneurysms", section on 'Recurrence of the treated aneurysm'.) Newer techniques Endovascular therapy for cerebral aneurysms is evolving. New techniques under investigation including stent-assisted coiling, balloon-assisted coiling, flow diverters and disruptors, and new embolic material including liquids offer promise that aneurysms previously considered not amenable to therapy will be treatable in the future [59,68]. Anatomic considerations Aneurysms in distal arterial segments are often not amenable to endovascular therapy [69]; surgical therapy may be preferred in these circumstances. Endovascular treatment is often the preferred technique for proximal intracranial carotid and posterior circulation aneurysms, which are accessible by angiogram but harder to get to surgically [70]. In contrast, aneurysms at the middle cerebral artery trifurcation are difficult to coil without complication, and surgery may be preferred for these lesions. Combined endovascular and surgical techniques may be required with some very large or complex aneurysms [71]. Some aneurysms remain challenging to treat by any technique; these include giant aneurysms, fusiform aneurysms, and those with very broad necks and a low fundus-to-neck ratio [59]. ANEURYSM RECURRENCE AND LATE REBLEEDING Patients who survive aneurysmal subarachnoid hemorrhage (SAH) and those with unruptured intracranial aneurysms have a small but enduring risk of subsequent SAH, which can occur despite successful endovascular or surgical treatment of the aneurysm. SAH may result from recurrence of the treated aneurysm, rupture of another pre-existing aneurysm in a patient with multiple aneurysms, and de novo aneurysm formation. The risk of these events and recommendations for monitoring and treatment are discussed separately. (See "Late recurrence of subarachnoid hemorrhage and intracranial aneurysms".) https://www.uptodate.com/contents/treatment-of-cerebral-aneurysms/print 7/19 7/7/23, 11:36 AM Treatment of cerebral aneurysms - 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: Stroke in adults".) SUMMARY AND RECOMMENDATIONS Patients with subarachnoid hemorrhage Patients with ruptured cerebral aneurysms present with aneurysmal subarachnoid hemorrhage (SAH). Decisions regarding the timing and choice of therapy for ruptured intracranial aneurysms are ideally made by a team of experienced clinicians who consider the neurologic grade and clinical status of the patient, the availability of expertise in surgical and endovascular techniques, as well as the anatomic characteristics of the aneurysm. (See 'Timing and choice of therapy' above.) For patients with good-grade aneurysmal SAH (Hunt and Hess grades I to III) ( table 1), we suggest early aneurysm repair (within 24 to 72 hours) (Grade 2C). In centers with available expertise and in patients with endovascularly accessible lesions, short-term outcomes appear to be improved with endovascular coiling compared with surgical clipping. (See 'Good-grade SAH' above.) The optimal timing and choice of therapy in patients with more severe aneurysmal SAH (Hunt and Hess grades IV and V) is uncertain. Their overall prognosis is poor, particularly for older patients. Treatment decisions need to be individualized in consultation with family members. (See 'Poor-grade SAH' above.) Patients with unruptured cerebral aneurysms Asymptomatic aneurysms 7 to 10 mm in diameter warrant strong consideration for treatment, taking into account patient age, existing medical and neurologic conditions, and relative risks for treatment. (See "Unruptured intracranial aneurysms".) Treatment techniques Surgical clipping and endovascular coiling are the most commonly used techniques for aneurysm treatment. In many cases, anatomic considerations, such as size, location, and other morphological features determine which treatment is most appropriate for the patient. (See 'Techniques' above.) Surgical management of cerebral aneurysms involves placing a clip across the neck of the aneurysm to secure the lesion ( image 1). Distal aneurysms and aneurysms at the middle cerebral artery trifurcation can be difficult to treat with endovascular techniques and are frequently treated with surgery. (See 'Surgery' above.) https://www.uptodate.com/contents/treatment-of-cerebral-aneurysms/print 8/19 7/7/23, 11:36 AM Treatment of cerebral aneurysms - UpToDate Endovascular techniques include placing coils into the lumen of the aneurysm ( image 2). A local thrombus then forms around the coils, obliterating the aneurysmal sac. Other options include stent-assisted coiling, balloon-assisted coiling, and flow diverters and disruptors. Endovascular treatment is often the preferred technique for proximal intracranial carotid and posterior circulation aneurysms, which are accessible by angiogram but can be difficult to access surgically. (See 'Endovascular therapy' above.) Combined endovascular and surgical techniques may be required with some very large or complex aneurysms. (See 'Newer techniques' above.) Management of late recurrence Patients with aneurysmal SAH are at enduring risk of recurrent SAH despite aneurysm treatment and may require follow-up evaluations. (See "Late recurrence of subarachnoid hemorrhage and intracranial aneurysms".) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. 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. 2. Inagawa T, Kamiya K, Ogasawara H, Yano T. Rebleeding of ruptured intracranial aneurysms in the acute stage. Surg Neurol 1987; 28:93. 3. Naidech AM, Janjua N, Kreiter KT, et al. Predictors and impact of aneurysm rebleeding after subarachnoid hemorrhage. Arch Neurol 2005; 62:410. 4. Larsen CC, Astrup J. Rebleeding after aneurysmal subarachnoid hemorrhage: a literature review. World Neurosurg 2013; 79:307. 5. Lord AS, Fernandez L, Schmidt JM, et al. Effect of rebleeding on the course and incidence of vasospasm after subarachnoid hemorrhage. Neurology 2012; 78:31. 6. van Asch CJ, Oudendijk JF, Rinkel GJ, Klijn CJ. Early intracerebral hematoma expansion after aneurysmal rupture. Stroke 2010; 41:2592. 7. Brilstra EH, Algra A, Rinkel GJ, et al. Effectiveness of neurosurgical clip application in patients with aneurysmal subarachnoid hemorrhage. J Neurosurg 2002; 97:1036. 8. Bederson JB, Connolly ES Jr, Batjer HH, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke 2009; 40:994. https://www.uptodate.com/contents/treatment-of-cerebral-aneurysms/print 9/19 7/7/23, 11:36 AM Treatment of cerebral aneurysms - UpToDate 9. Sherif C, Gruber A, Dorfer C, et al. Ruptured carotid artery aneurysms of the ophthalmic (C6) segment: clinical and angiographic long term follow-up of a multidisciplinary management strategy. J Neurol Neurosurg Psychiatry 2009; 80:1261. 10. Le Roux PD, Elliott JP, Downey L, et al. Improved outcome after rupture of anterior circulation aneurysms: a retrospective 10-year review of 224 good-grade patients. J Neurosurg 1995; 83:394. 11. Whitfield PC, Kirkpatrick PJ. Timing of surgery for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev 2001; :CD001697. 12. Ohman J, Heiskanen O. Timing of operation for ruptured supratentorial aneurysms: a prospective randomized study. J Neurosurg 1989; 70:55. 13. Phillips TJ, Dowling RJ, Yan B, et al. Does treatment of ruptured intracranial aneurysms within 24 hours improve clinical outcome? Stroke 2011; 42:1936. 14. Koivisto T, Vanninen R, Hurskainen H, et al. Outcomes of early endovascular versus surgical treatment of ruptured cerebral aneurysms. A prospective randomized study. Stroke 2000; 31:2369. 15. Lindgren A, Vergouwen MD, van der Schaaf I, et al. Endovascular coiling versus neurosurgical clipping for people with aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev 2018; 8:CD003085. 16. Molyneux A, Kerr R, Stratton I, et al. International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial. Lancet 2002; 360:1267. 17. Molyneux AJ, Kerr RS, Yu LM, et al. International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion. Lancet 2005; 366:809. 18. Molyneux AJ, Birks J, Clarke A, et al. The durability of endovascular coiling versus neurosurgical clipping of ruptured cerebral aneurysms: 18 year follow-up of the UK cohort of the International Subarachnoid Aneurysm Trial (ISAT). Lancet 2015; 385:691. 19. Molyneux AJ, Kerr RS, Birks J, et al. Risk of recurrent subarachnoid haemorrhage, death, or dependence and standardised mortality ratios after clipping or coiling of an intracranial aneurysm in the International Subarachnoid Aneurysm Trial (ISAT): long-term follow-up. Lancet Neurol 2009; 8:427. 20. Schaafsma JD, Sprengers ME, van Rooij WJ, et al. Long-term recurrent subarachnoid hemorrhage after adequate coiling versus clipping of ruptured intracranial aneurysms. Stroke 2009; 40:1758. https://www.uptodate.com/contents/treatment-of-cerebral-aneurysms/print 10/19 7/7/23, 11:36 AM Treatment of cerebral aneurysms - UpToDate 21. Scott RB, Eccles F, Molyneux AJ, et al. Improved cognitive outcomes with endovascular coiling of ruptured intracranial aneurysms: neuropsychological outcomes from the International Subarachnoid Aneurysm Trial (ISAT). Stroke 2010; 41:1743. 22. van den Berg R, Foumani M, Schr der RD, et al. Predictors of outcome in World Federation of Neurologic Surgeons grade V aneurysmal subarachnoid hemorrhage patients. Crit Care Med 2011; 39:2722. 23. Koffijberg H, Buskens E, Rinkel GJ. Aneurysm occlusion in elderly patients with aneurysmal subarachnoid haemorrhage: a cost-utility analysis. J Neurol Neurosurg Psychiatry 2011; 82:718. 24. Brilstra EH, Rinkel GJ, Algra A, van Gijn J. Rebleeding, secondary ischemia, and timing of operation in patients with subarachnoid hemorrhage. Neurology 2000; 55:1656. 25. Laidlaw JD, Siu KH. Ultra-early surgery for aneurysmal subarachnoid hemorrhage: outcomes for a consecutive series of 391 patients not selected by grade or age. J Neurosurg 2002; 97:250. 26. Dorhout Mees SM, Molyneux AJ, Kerr RS, et al. Timing of aneurysm treatment after subarachnoid hemorrhage: relationship with delayed cerebral ischemia and poor outcome. Stroke 2012; 43:2126. 27. Gonzalez NR, Dusick JR, Duckwiler G, et al. Endovascular coiling of intracranial aneurysms in elderly patients: report of 205 treated aneurysms. Neurosurgery 2010; 66:714. 28. Li H, Pan R, Wang H, et al. Clipping versus coiling for ruptured intracranial aneurysms: a systematic review and meta-analysis. Stroke 2013; 44:29. 29. McDougall CG, Spetzler RF, Zabramski JM, et al. The Barrow Ruptured Aneurysm Trial. J Neurosurg 2012; 116:135. 30. Spetzler RF, McDougall CG, Albuquerque FC, et al. The Barrow Ruptured Aneurysm Trial: 3- year results. J Neurosurg 2013; 119:146. 31. Johnston SC, Wilson CB, Halbach VV, et al. Endovascular and surgical treatment of unruptured cerebral aneurysms: comparison of risks. Ann Neurol 2000; 48:11. 32. Greving JP, Rinkel GJ, Buskens E, Algra A. Cost-effectiveness of preventive treatment of intracranial aneurysms: new data and uncertainties. Neurology 2009; 73:258. 33. Pouratian N, Oskouian RJ Jr, Jensen ME, et al. Endovascular management of unruptured intracranial aneurysms. J Neurol Neurosurg Psychiatry 2006; 77:572. 34. Qureshi AI, Janardhan V, Hanel RA, Lanzino G. Comparison of endovascular and surgical treatments for intracranial aneurysms: an evidence-based review. Lancet Neurol 2007; 6:816. https://www.uptodate.com/contents/treatment-of-cerebral-aneurysms/print 11/19 7/7/23, 11:36 AM Treatment of cerebral aneurysms - UpToDate 35. Johnston SC, Zhao S, Dudley RA, et al. Treatment of unruptured cerebral aneurysms in California. Stroke 2001; 32:597. 36. Vallee JN, Aymard A, Vicaut E, et al. Endovascular treatment of basilar tip aneurysms with Guglielmi detachable coils: predictors of immediate and long-term results with multivariate analysis 6-year experience. Radiology 2003; 226:867. 37. Raftopoulos C, Goffette P, Vaz G, et al. Surgical clipping may lead to better results than coil embolization: results from a series of 101 consecutive unruptured intracranial aneurysms. Neurosurgery 2003; 52:1280. 38. Zacharia BE, Ducruet AF, Hickman ZL, et al. Technological advances in the management of unruptured intracranial aneurysms fail to improve outcome in New York state. Stroke 2011; 42:2844. 39. McDonald JS, McDonald RJ, Fan J, et al. Comparative effectiveness of unruptured cerebral aneurysm therapies: propensity score analysis of clipping versus coiling. Stroke 2013; 44:988. 40. Hwang JS, Hyun MK, Lee HJ, et al. Endovascular coiling versus neurosurgical clipping in patients with unruptured intracranial aneurysm: a systematic review. BMC Neurol 2012; 12:99. 41. De Vries J, Boogaarts J, Van Norden A, Wakhloo AK. New generation of Flow Diverter (surpass) for unruptured intracranial aneurysms: a prospective single-center study in 37 patients. Stroke 2013; 44:1567. 42. Berman MF, Solomon RA, Mayer SA, et al. Impact of hospital-related factors on outcome after treatment of cerebral aneurysms. Stroke 2003; 34:2200. 43. Jabre A, Symon L. Temporary vascular occlusion during aneurysm surgery. Surg Neurol 1987; 27:47. 44. Connolly ES Jr, Rabinstein AA, Carhuapoma JR, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/american Stroke Association. Stroke 2012; 43:1711. 45. Tang G, Cawley CM, Dion JE, Barrow DL. Intraoperative angiography during aneurysm surgery: a prospective evaluation of efficacy. J Neurosurg 2002; 96:993. 46. Chiang VL, Gailloud P, Murphy KJ, et al. Routine intraoperative angiography during aneurysm surgery. J Neurosurg 2002; 96:988. 47. Klopfenstein JD, Spetzler RF, Kim LJ, et al. Comparison of routine and selective use of intraoperative angiography during aneurysm surgery: a prospective assessment. J Neurosurg 2004; 100:230. https://www.uptodate.com/contents/treatment-of-cerebral-aneurysms/print 12/19 7/7/23, 11:36 AM Treatment of cerebral aneurysms - UpToDate 48. Kumar R, Friedman JA. Intraoperative angiography during cerebral aneurysm surgery. Neurocrit Care 2009; 11:299. 49. Todd MM, Hindman BJ, Clarke WR, et al. Mild intraoperative hypothermia during surgery for intracranial aneurysm. N Engl J Med 2005; 352:135. 50. Zhao ZX, Wu C, He M. A systematic review of clinical outcomes, perioperative data and selective adverse events related to mild hypothermia in intracranial aneurysm surgery. Clin Neurol Neurosurg 2012; 114:827. 51. Li LR, You C, Chaudhary B. Intraoperative mild hypothermia for postoperative neurological deficits in intracranial aneurysm patients. Cochrane Database Syst Rev 2012; :CD008445. 52. Andrews RJ, Bringas JR. A review of brain retraction and recommendations for minimizing intraoperative brain injury. Neurosurgery 1993; 33:1052. 53. Samson D, Batjer HH, Bowman G, et al. A clinical study of the parameters and effects of temporary arterial occlusion in the management of intracranial aneurysms. Neurosurgery 1994; 34:22. 54. Fridriksson S, S veland H, Jakobsson KE, et al. Intraoperative complications in aneurysm surgery: a prospective national study. J Neurosurg 2002; 96:515. 55. Elijovich L, Higashida RT, Lawton MT, et al. Predictors and outcomes of intraprocedural rupture in patients treated for ruptured intracranial aneurysms: the CARAT study. Stroke 2008; 39:1501. 56. McLaughlin N, Bojanowski MW. Early surgery-related complications after aneurysm clip placement: an analysis of causes and patient outcomes. J Neurosurg 2004; 101:600. 57. Dovey Z, Misra M, Thornton J, et al. Guglielmi detachable coiling for intracranial aneurysms: the story so far. Arch Neurol 2001; 58:559. 58. Guglielmi G, Vi uela F, Sepetka I, Macellari V. Electrothrombosis of saccular aneurysms via endovascular approach. Part 1: Electrochemical basis, technique, and experimental results. J Neurosurg 1991; 75:1. 59. Pierot L, Wakhloo AK. Endovascular treatment of intracranial aneurysms: current status. Stroke 2013; 44:2046. 60. Sturiale CL, Brinjikji W, Murad MH, Lanzino G. Endovascular treatment of intracranial aneurysms in elderly patients: a systematic review and meta-analysis. Stroke 2013; 44:1897. 61. Pierot L, Cognard C, Anxionnat R, et al. Ruptured intracranial aneurysms: factors affecting the rate and outcome of endovascular treatment complications in a series of 782 patients (CLARITY study). Radiology 2010; 256:916. https://www.uptodate.com/contents/treatment-of-cerebral-aneurysms/print 13/19 7/7/23, 11:36 AM Treatment of cerebral aneurysms - UpToDate 62. van den Bergh WM, Kerr RS, Algra A, et al. Effect of antiplatelet therapy for endovascular coiling in aneurysmal subarachnoid hemorrhage. Stroke 2009; 40:1969. 63. Ries T, Siemonsen S, Grzyska U, et al. Abciximab is a safe rescue therapy in thromboembolic events complicating cerebral aneurysm coil embolization: single center experience in 42 cases and review of the literature. Stroke 2009; 40:1750. 64. Brinjikji W, McDonald JS, Kallmes DF, Cloft HJ. Rescue treatment of thromboembolic complications during endovascular treatment of cerebral aneurysms. Stroke 2013; 44:1343. 65. Renowden SA, Benes V, Bradley M, Molyneux AJ. Detachable coil embolisation of ruptured intracranial aneurysms: a single center study, a decade experience. Clin Neurol Neurosurg 2009; 111:179. 66. Nguyen TN, Raymond J, Guilbert F, et al. Association of endovascular therapy of very small ruptured aneurysms with higher rates of procedure-related rupture. J Neurosurg 2008; 108:1088. 67. Chalouhi N, Penn DL, Tjoumakaris S, et al. Treatment of small ruptured intracranial aneurysms: comparison of surgical and endovascular options. J Am Heart Assoc 2012; 1:e002865. 68. Chua MMJ, Silveira L, Moore J, et al. Flow diversion for treatment of intracranial aneurysms: Mechanism and implications. Ann Neurol 2019; 85:793. 69. Fernandez Zubillaga A, Guglielmi G, Vi uela F, Duckwiler GR. Endovascular occlusion of intracranial aneurysms with electrically detachable coils: correlation of aneurysm neck size and treatment results. AJNR Am J Neuroradiol 1994; 15:815. 70. Tateshima S, Murayama Y, Gobin YP, et al. Endovascular treatment of basilar tip aneurysms using Guglielmi detachable coils: anatomic and clinical outcomes in 73 patients from a single institution. Neurosurgery 2000; 47:1332. 71. Suzuki S, Tateshima S, Jahan R, et al. Endovascular treatment of middle cerebral artery aneurysms with detachable coils: angiographic and clinical outcomes in 115 consecutive patients. Neurosurgery 2009; 64:876. Topic 90190 Version 13.0 https://www.uptodate.com/contents/treatment-of-cerebral-aneurysms/print 14/19 7/7/23, 11:36 AM Treatment of cerebral aneurysms - UpToDate GRAPHICS 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/treatment-of-cerebral-aneurysms/print 15/19 7/7/23, 11:37 AM Treatment of cerebral aneurysms - 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/treatment-of-cerebral-aneurysms/print 16/19 7/7/23, 11:37 AM Treatment of cerebral aneurysms - UpToDate Clip ligation of cerebral aneurysm Left panel: Anteroposterior cerebral angiogram demonstrating a basilar summit aneurysm. Right panel: Postoperative cerebral angiogram demonstrating clip ligation of the lesion with preserved parent vessel patency. Courtesy of Guy Rordorf, MD. Graphic 68084 Version 3.0 https://www.uptodate.com/contents/treatment-of-cerebral-aneurysms/print 17/19 7/7/23, 11:37 AM Treatment of cerebral aneurysms - UpToDate Aneurysm before and after therapy Towne projection of an aneurysm of the right posterior cerebral artery before (left panel) and after (right panel) successful coil embolization. Courtesy of Guy Rordorf, MD. Graphic 80064 Version 3.0 https://www.uptodate.com/contents/treatment-of-cerebral-aneurysms/print 18/19 7/7/23, 11:37 AM Treatment of cerebral aneurysms - UpToDate

surgery: a prospective evaluation of efficacy. J Neurosurg 2002; 96:993. 46. Chiang VL, Gailloud P, Murphy KJ, et al. Routine intraoperative angiography during aneurysm surgery. J Neurosurg 2002; 96:988. 47. Klopfenstein JD, Spetzler RF, Kim LJ, et al. Comparison of routine and selective use of intraoperative angiography during aneurysm surgery: a prospective assessment. J Neurosurg 2004; 100:230. https://www.uptodate.com/contents/treatment-of-cerebral-aneurysms/print 12/19 7/7/23, 11:36 AM Treatment of cerebral aneurysms - UpToDate 48. Kumar R, Friedman JA. Intraoperative angiography during cerebral aneurysm surgery. Neurocrit Care 2009; 11:299. 49. Todd MM, Hindman BJ, Clarke WR, et al. Mild intraoperative hypothermia during surgery for intracranial aneurysm. N Engl J Med 2005; 352:135. 50. Zhao ZX, Wu C, He M. A systematic review of clinical outcomes, perioperative data and selective adverse events related to mild hypothermia in intracranial aneurysm surgery. Clin Neurol Neurosurg 2012; 114:827. 51. Li LR, You C, Chaudhary B. Intraoperative mild hypothermia for postoperative neurological deficits in intracranial aneurysm patients. Cochrane Database Syst Rev 2012; :CD008445. 52. Andrews RJ, Bringas JR. A review of brain retraction and recommendations for minimizing intraoperative brain injury. Neurosurgery 1993; 33:1052. 53. Samson D, Batjer HH, Bowman G, et al. A clinical study of the parameters and effects of temporary arterial occlusion in the management of intracranial aneurysms. Neurosurgery 1994; 34:22. 54. Fridriksson S, S veland H, Jakobsson KE, et al. Intraoperative complications in aneurysm surgery: a prospective national study. J Neurosurg 2002; 96:515. 55. Elijovich L, Higashida RT, Lawton MT, et al. Predictors and outcomes of intraprocedural rupture in patients treated for ruptured intracranial aneurysms: the CARAT study. Stroke 2008; 39:1501. 56. McLaughlin N, Bojanowski MW. Early surgery-related complications after aneurysm clip placement: an analysis of causes and patient outcomes. J Neurosurg 2004; 101:600. 57. Dovey Z, Misra M, Thornton J, et al. Guglielmi detachable coiling for intracranial aneurysms: the story so far. Arch Neurol 2001; 58:559. 58. Guglielmi G, Vi uela F, Sepetka I, Macellari V. Electrothrombosis of saccular aneurysms via endovascular approach. Part 1: Electrochemical basis, technique, and experimental results. J Neurosurg 1991; 75:1. 59. Pierot L, Wakhloo AK. Endovascular treatment of intracranial aneurysms: current status. Stroke 2013; 44:2046. 60. Sturiale CL, Brinjikji W, Murad MH, Lanzino G. Endovascular treatment of intracranial aneurysms in elderly patients: a systematic review and meta-analysis. Stroke 2013; 44:1897. 61. Pierot L, Cognard C, Anxionnat R, et al. Ruptured intracranial aneurysms: factors affecting the rate and outcome of endovascular treatment complications in a series of 782 patients (CLARITY study). Radiology 2010; 256:916. https://www.uptodate.com/contents/treatment-of-cerebral-aneurysms/print 13/19 7/7/23, 11:36 AM Treatment of cerebral aneurysms - UpToDate 62. van den Bergh WM, Kerr RS, Algra A, et al. Effect of antiplatelet therapy for endovascular coiling in aneurysmal subarachnoid hemorrhage. Stroke 2009; 40:1969. 63. Ries T, Siemonsen S, Grzyska U, et al. Abciximab is a safe rescue therapy in thromboembolic events complicating cerebral aneurysm coil embolization: single center experience in 42 cases and review of the literature. Stroke 2009; 40:1750. 64. Brinjikji W, McDonald JS, Kallmes DF, Cloft HJ. Rescue treatment of thromboembolic complications during endovascular treatment of cerebral aneurysms. Stroke 2013; 44:1343. 65. Renowden SA, Benes V, Bradley M, Molyneux AJ. Detachable coil embolisation of ruptured intracranial aneurysms: a single center study, a decade experience. Clin Neurol Neurosurg 2009; 111:179. 66. Nguyen TN, Raymond J, Guilbert F, et al. Association of endovascular therapy of very small ruptured aneurysms with higher rates of procedure-related rupture. J Neurosurg 2008; 108:1088. 67. Chalouhi N, Penn DL, Tjoumakaris S, et al. Treatment of small ruptured intracranial aneurysms: comparison of surgical and endovascular options. J Am Heart Assoc 2012; 1:e002865. 68. Chua MMJ, Silveira L, Moore J, et al. Flow diversion for treatment of intracranial aneurysms: Mechanism and implications. Ann Neurol 2019; 85:793. 69. Fernandez Zubillaga A, Guglielmi G, Vi uela F, Duckwiler GR. Endovascular occlusion of intracranial aneurysms with electrically detachable coils: correlation of aneurysm neck size and treatment results. AJNR Am J Neuroradiol 1994; 15:815. 70. Tateshima S, Murayama Y, Gobin YP, et al. Endovascular treatment of basilar tip aneurysms using Guglielmi detachable coils: anatomic and clinical outcomes in 73 patients from a single institution. Neurosurgery 2000; 47:1332. 71. Suzuki S, Tateshima S, Jahan R, et al. Endovascular treatment of middle cerebral artery aneurysms with detachable coils: angiographic and clinical outcomes in 115 consecutive patients. Neurosurgery 2009; 64:876. Topic 90190 Version 13.0 https://www.uptodate.com/contents/treatment-of-cerebral-aneurysms/print 14/19 7/7/23, 11:36 AM Treatment of cerebral aneurysms - UpToDate GRAPHICS 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/treatment-of-cerebral-aneurysms/print 15/19 7/7/23, 11:37 AM Treatment of cerebral aneurysms - 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/treatment-of-cerebral-aneurysms/print 16/19 7/7/23, 11:37 AM Treatment of cerebral aneurysms - UpToDate Clip ligation of cerebral aneurysm Left panel: Anteroposterior cerebral angiogram demonstrating a basilar summit aneurysm. Right panel: Postoperative cerebral angiogram demonstrating clip ligation of the lesion with preserved parent vessel patency. Courtesy of Guy Rordorf, MD. Graphic 68084 Version 3.0 https://www.uptodate.com/contents/treatment-of-cerebral-aneurysms/print 17/19 7/7/23, 11:37 AM Treatment of cerebral aneurysms - UpToDate Aneurysm before and after therapy Towne projection of an aneurysm of the right posterior cerebral artery before (left panel) and after (right panel) successful coil embolization. Courtesy of Guy Rordorf, MD. Graphic 80064 Version 3.0 https://www.uptodate.com/contents/treatment-of-cerebral-aneurysms/print 18/19 7/7/23, 11:37 AM Treatment of cerebral aneurysms - 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. 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/treatment-of-cerebral-aneurysms/print 19/19

7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Unruptured intracranial aneurysms : Robert J Singer, MD, Christopher S Ogilvy, MD, Guy Rordorf, MD : Jos Biller, MD, FACP, FAAN, FAHA : 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: Feb 11, 2020. INTRODUCTION Most subarachnoid hemorrhages (SAHs) are caused by ruptured intracranial saccular (berry) aneurysms [1-5]. The epidemiology and pathogenesis of intracranial aneurysms and the management of unruptured aneurysms are discussed here. The epidemiology, etiology, clinical manifestations, diagnosis, and treatment of SAH, and issues related to screening for aneurysms, are discussed separately. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis" and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis" and "Screening for intracranial aneurysm".) EPIDEMIOLOGY The prevalence of intracranial saccular aneurysms by radiographic and autopsy series is estimated to be 3.2 percent in a population without comorbidity, a mean age of 50 years, and a 1:1 gender ratio [1,6,7]. Of patients with cerebral aneurysms, 20 to 30 percent have multiple aneurysms [8]. Aneurysmal subarachnoid hemorrhage (SAH) occurs at an estimated rate of 6 to 16 per 100,000 population [9]. In North America, this translates into approximately 30,000 affected persons per year. Thus, most aneurysms, particularly small aneurysms, do not rupture. (See 'Risk factors for aneurysm rupture' below.) Rupture of an intracranial aneurysm is believed to account for 0.4 to 0.6 percent of all deaths. Approximately 10 percent of patients die prior to reaching the hospital, and only one-third have https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 1/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate a "good result" after treatment. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".) Most intracranial aneurysms (approximately 85 percent) are located in the anterior circulation, predominantly on the circle of Willis. Common sites include the junction of the anterior communicating artery with the anterior cerebral artery, the junction of the posterior communicating artery with the internal carotid artery, and the bifurcation of the middle cerebral artery. Posterior circulation sites often include the top of the basilar artery, the junction of the basilar artery and the superior or anterior inferior cerebellar arteries, and the junction of the vertebral artery and the posterior inferior cerebellar artery [10]. There is a female preponderance for aneurysms ranging from 54 to 61 percent [7,9]. In populations older than 50 years, the increased prevalence in women may approach a 2:1 ratio or greater. RISK FACTORS FOR ANEURYSM FORMATION Genetic factors The role for genetic factors in the pathogenesis of intracranial aneurysm formation is supported by studies that have found an increased risk in patients with some known hereditary syndromes and by the occurrence of aneurysms in families. A systematic review and meta-analysis confirmed a substantial genetic contribution to the occurrence of intracranial aneurysms that involve multiple pathophysiologic pathways, while noting that large- scale replication studies in a full spectrum of populations are needed with investigation on how specific genetic factors relate to aneurysm size, location, and risk of rupture [11]. Hereditary syndromes A known hereditary syndrome is often present when aneurysms are diagnosed in more than one family member. Heritable disorders associated with the presence of intracranial aneurysm include: Connective tissue diseases such as Ehlers-Danlos syndrome and pseudoxanthoma elasticum are associated with intracranial aneurysms [12,13], but probably not Marfan syndrome [14]. The mechanism by which connective tissue diseases predispose to aneurysm formation presumably involves an inherent weakness of the arterial wall exposed to the nonlaminar flow pattern of blood, which is then exposed to shear stresses. Aneurysm formation in glucocorticoid-remediable hyperaldosteronism may result in part from congenital hypertension during the early stages of cerebrovascular development [15]. Concurrent hypertension also may contribute in polycystic kidney disease (PKD), although the precise mechanism is unclear. It is uncertain whether patients with these disorders should undergo routine screening for intracranial https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 2/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate aneurysm. (See "Screening for intracranial aneurysm", section on 'Other hereditary disorders'.) Autosomal dominant PKD is associated with a 6.9 times higher risk of intracranial aneurysm [7]. Autosomal recessive PKD may also be a risk factor [16]. (See "Autosomal dominant polycystic kidney disease (ADPKD): Extrarenal manifestations".) The role of aneurysm screening in patients with PKD is discussed separately. (See "Screening for intracranial aneurysm", section on 'Autosomal dominant polycystic kidney disease'.) Glucocorticoid-remediable aldosteronism (familial aldosteronism type I). (See "Familial hyperaldosteronism".) Screening in these patients is described separately. (See "Screening for intracranial aneurysm", section on 'Other hereditary disorders'.) Moyamoya syndrome is also associated with an increased frequency of intracranial aneurysms. Although most cases of moyamoya are sporadic, there is probably a genetic susceptibility underlying the disease, and familial occurrence is known to occur. (See "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis".) Familial aneurysms Family members of patients with intracranial aneurysms are at increased risk of having an aneurysm, even in the absence of a known hereditary syndrome. In one study, for example, the age-adjusted prevalence of incidental aneurysms in first-degree relatives of patients with an aneurysm was 9 percent, a number significantly higher than the general population [17]. Only a small proportion of these families had an identifiable hereditary syndrome known to be associated with aneurysms. In a second report of patients with mostly sporadic subarachnoid hemorrhage (SAH), intracranial aneurysms were found in 4 percent of first-degree relatives (approximately twice that of the general population) [18]. Other studies have estimated that a family history of aneurysm or SAH confers a 3.6 times greater risk [7]. The mode of inheritance is variable, with autosomal dominant, recessive, and multifactorial transmission evident in different families [19,20]. Familial aneurysms have been linked to multiple chromosomal loci [11,20-26]. Familial aneurysms tend to rupture at a smaller size and younger age than sporadic aneurysms [17,27,28]. Siblings often experience rupture in the same decade of life [27]. https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 3/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate Aneurysms tend to occur at similar locations within families, suggesting that a specific anatomic vulnerability may be inherited [29]. Other factors Because intracranial aneurysms are the major etiology of SAH, risk factors for SAH may also be risk factors for intracranial aneurysms. Risk factors for SAH include hypertension, cigarette smoking, and alcohol consumption [30-32]. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) Hypercholesterolemia and regular physical exercise appear to decrease the risk of aneurysm formation [33]. Known and possible risk factors for aneurysm formation include: Cigarette smoking The importance of cigarette smoking was illustrated in a case-control analysis of 45 men and 70 women with SAH between the ages of 35 and 64 [34]. Cigarette smokers had a significantly increased risk of SAH compared with a control population; the relative risk for men and women was 3.0 and 4.7, respectively, and the risk increased with the number of cigarettes smoked. Those who both smoked and had hypertension had an almost 15-fold increase in risk of SAH compared with normotensive nonsmokers; this additive effect of hypertension and smoking on aneurysm formation has been noticed in other studies as well [33]. In a study of familial intracranial aneurysms, the risk of intracranial aneurysm within affected families was increased by cigarette smoking [24]. The mechanism by which cigarette smoking predisposes to aneurysm formation may involve decreasing the effectiveness of alpha-1 antitrypsin, an important inhibitor of proteases such as elastase [10]. Support for this hypothesis is derived from studies, which suggest that patients with alpha-1 antitrypsin deficiency are at increased risk of aneurysm formation [27]. Hypertension The association between hypertension and aneurysm formation and rupture has been controversial, although the balance of evidence suggests that hypertension is a risk factor [33]. One report, for example, compared 113 patients with SAH and angiographically verified aneurysms with 63 patients with SAH but no aneurysm [35]. Blood pressure greater than 160/95 was present in 62 percent of patients with aneurysms compared with 37 percent without. In another study in which over 20,000 Medicare patients were followed, there was an increased prevalence of hypertension in patients with aneurysms compared with a control population (43 versus 35 percent) [36]. Estrogen deficiency There is a female preponderance for aneurysms ranging from 54 to 61 percent [9]. The estrogen deficiency of menopause causes a reduction in the collagen https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 4/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate content of tissues. (See "Clinical manifestations and diagnosis of menopause".) This collagen wasting may contribute to aneurysm development in postmenopausal women, analogous to the situation in patients with connective tissue diseases. In one case- control study, premenopausal women without a history of smoking or hypertension were at reduced risk of SAH compared with age-matched postmenopausal women (odds ratio 0.24) [37]. Furthermore, the use of estrogen replacement therapy was associated with a reduced risk of SAH in postmenopausal women (odds ratio 0.47). This protective effect of estrogen replacement therapy has been seen in other studies as well [38]. Coarctation of the aorta Patients with coarctation of the aorta are at increased risk for aneurysm formation [39-41]. This may result from secondary hypertension or from shared morphologic or genetic risk factors. (See "Clinical manifestations and diagnosis of coarctation of the aorta".) PATHOGENESIS Aneurysm formation Saccular aneurysms are responsible for most subarachnoid hemorrhages (SAHs), although fusiform and mycotic aneurysms can be identified in selected patients. Saccular aneurysms are thin-walled protrusions from the intracranial arteries that are composed of a very thin or absent tunica media, and an absent or severely fragmented internal elastic lamina [42]. Fusiform aneurysms consist of enlargement or dilatation of the entire circumference of the involved vessel that may in part be formed due to atherosclerosis. Mycotic aneurysms usually result from infected emboli due to infective endocarditis [43]. Intracranial saccular aneurysms are acquired lesions, not congenital. The pathogenesis of saccular aneurysm formation is multifactorial [44]. Hemodynamic stress causes excessive wear and tear and breakdown of the internal elastic lamina. Turbulent blood flow produces vibrations that may coincide with the resonant frequency of the vessel wall, resulting in structural fatigue. Patients with hyperdynamic flow patterns as a result of anomalous collateral pathways or other high-flow states are predisposed to accelerated degenerative changes in the vessel wall and subsequent aneurysm development. Hypertension, cigarette smoking, and connective tissue disease probably play a contributory rather than causal role in this process (see 'Other factors' https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 5/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate above). There is some evidence that inflammation plays a role in the pathogenesis and growth of intracranial aneurysms [45-48]. In a study that examined 66 saccular aneurysm samples (42 ruptured and 24 unruptured), four histologic types of aneurysm walls were identified that may reflect consecutive stages of degeneration leading to rupture [49]: Endothelialized wall with linearly organized smooth muscle cells (Type A); 7 of 17 (41 percent) ruptured. Thickened wall with disorganized smooth muscle cells (Type B); 11 of 20 (55 percent) ruptured. Hypocellular wall with either intimal hyperplasia or organizing luminal thrombosis (Type C); 9 of 14 (64 percent) ruptured. Extremely thin thrombosis-lined hypocellular wall (Type D); all 15 (100 percent) ruptured. Lack of elastic lamina was a common feature of both ruptured and unruptured aneurysms. Ruptured aneurysm walls were more likely to have complete absence of endothelial lining and evidence of inflammation, characterized by T cell and macrophage infiltration, compared with unruptured walls. Subsequent pathologic studies identified odontogenic bacterial DNA in the walls of both ruptured and unruptured aneurysms, suggesting that infection may play a role in the formation or rupture of saccular aneurysms [50,51]. Aneurysm growth and rupture It is believed that most intracranial aneurysms develop over a short period of hours, days, or weeks, attaining a size allowed by the elasticity limits of the aneurysmal wall; at this point, the aneurysm either ruptures or undergoes stabilization and hardening [44,52,53]. Those aneurysms that do not rupture gain significant tensile strength due to compensatory hardening with formation of excessive collagen. Therefore, the likelihood of rupture decreases unless the size of the aneurysm is fairly large at the time of initial stabilization. Aneurysms 1 cm or larger at initial stabilization are considerably more likely to undergo subsequent growth and rupture because wall stress increases with the square of the diameter (Laplace's law). (See 'Size' below.) This theory of aneurysm growth and rupture is believed to explain the apparent discrepancy between data that show a low rate of rupture for aneurysms 7 to 10 mm and smaller [52,54-56] and the observation that a large percentage of patients that present with SAH appear to have had rupture of aneurysms that were smaller than 10 mm in diameter [57], and a majority appear smaller than 7 mm in diameter [58]. Thus, the critical size for aneurysmal rupture is smaller for aneurysms that rupture soon after formation, as would appear to be true for the vast majority of https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 6/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate small aneurysms that rupture [44,53]. This hypothesis is based on data derived from patients with unruptured aneurysms and no history of prior SAH, and may not be applicable to patients who have an unruptured aneurysm and prior SAH from another aneurysm. CLINICAL MANIFESTATIONS Most intracranial aneurysms are asymptomatic unless they rupture, and so they are usually found either incidentally or when a patient presents with subarachnoid hemorrhage (SAH). (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) Some unruptured aneurysms can become symptomatic [59,60]. Symptoms include headache (which may be severe and comparable to the headache of SAH [59]), visual acuity loss, cranial neuropathies (particularly third nerve palsy), pyramidal tract dysfunction, and facial pain; they are felt to be due to the mass effect of the aneurysm. (See "Third cranial nerve (oculomotor nerve) palsy in adults".) Ischemia can occur as a result of emboli originating from within an aneurysm. Treatment of the aneurysm may lead to resolution of symptoms [60]. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".) DIAGNOSIS Most intracranial aneurysms present as subarachnoid hemorrhage (SAH) or are found incidentally or on screening. (See "Screening for intracranial aneurysm".) Because symptomatic unruptured aneurysms are unusual, there are few data on the best diagnostic strategy in the presence of symptoms that could be due to an aneurysm. One exception is the clinical setting of a non-pupil sparing third nerve palsy, the evaluation of which is discussed separately. (See "Third cranial nerve (oculomotor nerve) palsy in adults", section on 'Evaluation for intracranial aneurysm'.) Magnetic resonance angiography (MRA) and computed tomography angiography (CTA) appear to be able to detect aneurysms 5 mm or larger; smaller aneurysms (down to 2 mm) are less reliably detected or may be seen in retrospect when compared with cerebral angiography ( image 1) [61-64]. A systematic review of studies of CTA concluded that the sensitivity of CTA ranged from 53 percent for 2 mm aneurysms to 95 percent for 7 mm aneurysms, and that specificity was also higher for larger aneurysms ( figure 1A-B) [64]. As technology improves, the sensitivity and specificity of noninvasive imaging is also likely to improve. A 2011 meta- https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 7/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate analysis of CTA diagnosis of intracranial aneurysms found that, compared with single-detector CTA, use of multidetector CTA was associated with an overall improved sensitivity and specificity for aneurysm detection (both >97 percent) as well as improved detection of smaller aneurysms 4 mm in diameter [65]. Another study examining 307 aneurysm in 246 patients found that three-dimensional time-of-flight MRA with volume rendering at 3.0 Tesla had a sensitivity and specificity of 99 and 97 percent, respectively, that was irrespective of aneurysm size (range <3 to >10 mm) [66]. Pretest probability should affect the interpretations of CTA results: in the presence of SAH, an aneurysm is likely, and a positive CTA finding of any size can generally be trusted, while a negative result should lead to further testing; in the absence of SAH, a CTA finding of a large aneurysm (>7 mm) can be trusted, but findings of small or medium aneurysms have a higher likelihood of being false positives and may require confirmation, if felt to be clinically important [64]. Angiography is a more invasive test that is associated with a higher risk of complications, and it should only be performed if there is a high clinical suspicion for an aneurysm despite negative noninvasive studies. Very small aneurysms (below the practical limit of detection of MRA and CTA) can occasionally present with symptoms such as third nerve palsy [60]. RISK FACTORS FOR ANEURYSM RUPTURE Two large prospective studies have reported on the natural history of unruptured intracranial aneurysms, the International Study of Unruptured Intracranial Aneurysms (ISUIA), which prospectively assessed 1692 patients with 2686 unruptured, untreated aneurysms (6544 patient- years) in the United States, Canada, and Europe [54], and the Unruptured Cerebral Aneurysms Study (UCAS), a Japanese cohort that followed 6697 aneurysms in 5720 patients (11,660 aneurysm-years) [67]. Both of these studies noted that aneurysm size and location were associated with the risk of rupture. The PHASES score, developed from the pooled analysis of six prospective cohort studies, incorporates age, hypertension, the maximum diameter of the aneurysm, a previous history of subarachnoid hemorrhage (SAH), and the site of the aneurysm as the main predictors of rupture [68] and provides a useful summary for individualization of management decisions [69]. Size The ISUIA and UCAS confirmed results from previous studies showing that the rates of aneurysmal rupture were lower in smaller aneurysms [52,54-56,67]. The size cutpoint in both studies for defining low risk of rupture was 7 mm [54,67]. With increasing size over 7 mm, the risk of aneurysmal SAH increases correspondingly. In the ISUIA, for anterior circulation https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 8/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate aneurysms, five-year rates of rupture for those 7 to 12 mm was 2.6 percent; for those 13 to 24 mm, 14.5 percent; and for those >25 mm, 40 percent. Another prospective cohort study followed 374 patients with 448 aneurysms that were <5 mm in size; the average annual rupture rate was 0.54 percent overall, 0.34 percent for single aneurysms, and 0.95 percent for multiple aneurysms [70]. In this group, aneurysm rupture risk was also somewhat higher in those <50 years of age and those with aneurysms >4 mm in size. Hazard ratios reported in the UCAS, using aneurysms 3 to 4 mm as the reference, were 3.3 for aneurysms 7 to 9 mm, 9.1 for aneurysms 10 to 24 mm, and 76.3 for aneurysms 25 mm [67]. Aneurysm growth is more likely to occur in larger than smaller aneurysm [71,72]. Among 165 patients with 191 unruptured aneurysms, the frequency of enlargement over 47 months was 7, 25, and 83 percent for aneurysms <8 mm, 8 to 12 mm, and >13 mm, respectively [72]. One study also found that internal carotid and basilar artery aneurysms were more likely to grow than those located in other regions [71]. The results of one study suggest that risks of rupture in smaller, <5 mm aneurysms can be further stratified by the aneurysm-to-vessel size ratio; a ratio of 3.1 was the threshold identified for a higher risk of rupture (odds ratio 9.10) [73,74]. This finding requires independent verification. Aneurysm growth Based in part upon the theory of aneurysm growth and rupture discussed above as well as the data that associated aneurysm size and risk of rupture, it is believed that aneurysms that grow in size are also at high risk of rupture and that untreated aneurysms should be monitored for growth. (See 'Monitoring' below.) The data supporting this are expectedly somewhat limited. One study followed 165 patients with 258 unruptured aneurysms with serial computed tomography angiography (CTA) [75]. Eighteen percent of aneurysms were observed to grow larger and were associated with a higher rate of rupture than those that did not grow (2.4 versus 0.2 percent per year). Site Both the ISUIA and the UCAS, as well as other studies, have found that the risk of aneurysm rupture varied according to its location [54,67,76]. In the ISUIA, three aneurysm site groupings were associated with different rates of rupture [54]. The three groupings of aneurysm site were based on the parent artery: Cavernous carotid artery aneurysms had the lowest rates of rupture. Anterior circulation aneurysms, involving the anterior communicating, anterior cerebral, or internal carotid arteries, had intermediate rates of rupture. https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 9/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate Posterior circulation aneurysms, involving the vertebrobasilar, posterior cerebral arterial system, or posterior communicating arteries, had the highest rates of rupture. The cumulative five-year rate of rupture according to aneurysm site and size at diagnosis were as follows: For 7 to 12 mm aneurysms, rupture rates for cavernous carotid, anterior circulation, and posterior circulation aneurysms were 0, 2.6, and 14.5 percent. For 13 to 24 mm aneurysms, rupture rates for cavernous carotid, anterior circulation, and posterior circulation aneurysms were 3.0, 14.5, and 18.4 percent. For 25 mm or larger aneurysms, rupture rates for cavernous carotid, anterior circulation, and posterior circulation aneurysms were 6.4, 40, and 50 percent. In the UCAS, aneurysms in the anterior and posterior communicating arteries were more likely to rupture than those in the middle cerebral artery [67]. Using the latter group as a reference, the hazard ratios associated with rupture in the posterior and anterior communicating arteries were 1.9 and 2.0, respectively. Racial differences It is unclear whether racial or genetic background has a substantial impact upon the natural history of unruptured intracranial aneurysms. The prospective ISUIA data were obtained primarily from white populations in North America and Europe, but no similar large prospective study has been published in other populations. However, predisposition to aneurysm formation is clearly influenced by genetic makeup (see 'Genetic factors' above), and there is epidemiologic evidence of wide variations in the rate of SAH worldwide [77]. Although not directly comparable, data from a systematic review of 13 retrospective studies of unruptured intracranial aneurysms in Japan [78] found a much higher overall rupture rate than that reported in the ISUIA study [54]. Similar to the ISUIA data, the risk of rupture in Japan was significantly increased for large, posterior circulation and symptomatic aneurysms [78]. Most of the studies in the Japanese review included a mix of patients with and without prior SAH, populations that appear to have different risks in the prospective ISUIA study. Prospective studies underway in Japan may address these issues [79,80]. Precipitating events An acute trigger event such as physical exertion appears to occur in some cases of aneurysm rupture but not all. Emotionally stressful life events have not been convincingly shown to be a trigger for aneurysm rupture. (See "Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis", section on 'Pathogenesis'.) https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 10/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate Prior hemorrhage If an individual has had a previous aneurysmal SAH, the risk of rupture of a separate aneurysm is probably higher than if the individual did not have that history. In the ISUIA, unruptured aneurysms less than 7 mm in a patient with a history of aneurysmal SAH ruptured at a rate of 0.5 percent per year compared with 0.1 percent per year in those with no prior aneurysmal SAH [54]. A higher risk for those with prior SAH was not noted for larger aneurysm categories in the ISUIA, but the number of patients with large unruptured aneurysms and prior SAH was relatively small. Family history Familial aneurysms tend to rupture at a smaller size and younger age than sporadic aneurysms [17,27,28]. In one study, the observed rupture rate of 1.2 percent per year was almost 17 times higher than the rupture rate of aneurysms matched for size and location in the ISUIA [28]. Others In the UCAS, the presence of a daughter sac (an irregular protrusion of the aneurysm wall) was associated with an increased risk of rupture (hazard ratio = 1.6), while the presence of thrombus or calcification did not appear to influence the risk of rupture [67]. One study found that multiple aneurysms were more likely to grow than single lesions [76]. Studies of advanced imaging techniques hold the promise that new technologies will be able to identify other characteristics of aneurysms at high risk of rupture, such as inflammation within the aneurysm wall [81]. In both the ISUIA and UCAS, the effect of patient's age, gender, hypertension, and tobacco smoking were not significant predictors of SAH in a multivariate analysis [54,67]. By contrast, a case-control study comparing patients with ruptured and unruptured cerebral aneurysm found that smoking and a migraine history appeared to increase the risk of rupture, while hypercholesterolemia (or possibly its treatment with statins) appeared to be protective [82]. In this study, the prevalence of hypertension, age, and gender was not different between the groups. Other prospective follow-up studies in patients with unruptured aneurysms have found that aneurysm rupture was associated with cigarette smoking and younger patient age [75,83]. MANAGEMENT The management of unruptured intracranial aneurysms is controversial [84]. There are no randomized trials on which to base recommendations. Decisions about therapy need to weigh the natural history of the aneurysm, the risks of intervention, and patient preferences. Risk of intervention A systematic review and meta-analysis of the available observational studies included 60 studies, 9845 patients, and 10,845 aneurysms. The overall mortality https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 11/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate associated with surgical clipping of unruptured aneurysms was 1.7 percent; unfavorable outcomes occurred in 6.7 percent [85]. Observational studies that compared the risks of surgical versus endovascular repair in general found lower rates of poor outcomes in patients treated with endovascular repair. In the International Study of Unruptured Intracranial Aneurysms (ISUIA), rates of poor neurologic outcome at one year were 12.6 and 9.8 percent for those treated surgically and endovascularly, respectively [54]. In another cohort study, endovascular repair was associated with lower mortality (0.6 versus 1.6 percent) and lower rates of stroke (4.3 versus 9.0 percent) [86]. Risk factors for poor outcomes include advanced age, larger aneurysm size, and location in the posterior circulation; these are more consistently observed in surgically rather than endovascularly treated patients [54,87]. Age is a crucial element in deciding whether to treat an unruptured aneurysm [44]. Morbidity and mortality are increased with open surgery in patients 50 years and older and with endovascular procedures in patients 70 years and older. However, age has relatively little effect on the natural history of unruptured aneurysms. Benefit of intervention The ISUIA investigators concluded that in patients without a history of previous subarachnoid hemorrhage (SAH), it is unlikely that any therapy would be able to improve upon the untreated natural history of aneurysms that are smaller than 7 mm, and they also suggested that in patients with larger asymptomatic unruptured aneurysms, patient preference for immediate risk versus risk over time might determine the appropriate course of action. The investigators also point to specific groups from their data that appear to have the largest benefit from intervention, such as open surgery for patients younger than 50 years with aneurysms of the posterior communicating artery that are 7 to 24 mm. Although it may be appropriate to take these subgroup data into account when making recommendations for individual patients, it is important to recognize that such subgroup analyses are vulnerable to statistical problems and need to be confirmed prospectively. The management of unruptured intracranial aneurysms has also been evaluated by studies performing cost-effectiveness analyses. One such study, published prior to the prospective 2003 ISUIA report [54], found that treatment of asymptomatic aneurysms <10 mm in diameter in patients with no history of SAH from another aneurysm worsened clinical outcomes; treatment of unruptured aneurysms that were larger, symptomatic, or in patients with a history of SAH was cost effective [88]. Aneurysm location was not considered in this analysis. https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 12/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate A later decision and cost-effectiveness analysis used the 2003 ISUIA data and compared surgical or endovascular treatment with no treatment for unruptured intracranial aneurysms [89]. The following observations were reported: For 50-year-old patients, treatment was ineffective or not cost effective for aneurysms with the following characteristics: Small (<7 mm), due to the low risk of rupture Located in the cavernous carotid artery Large (>25 mm) and located in the posterior circulation, due to the high risk of complications from treatment For 40-year-old patients, treatment was ineffective or not cost effective for aneurysms with the following characteristics: Small (<12 mm) or large (>25 mm) and located in the cavernous carotid artery Small (<7 mm) and located in the anterior circulation Indications for intervention The available studies emphasize the need to examine each case individually, considering factors such as comorbid medical illness, patient age, aneurysm size and location, and risks of treatment. The sum of these data supports expectant management of very small saccular aneurysms, particularly when such aneurysms are located in the anterior circulation or when they are detected in older patients. A task force of the Stroke Council of the American Heart Association published recommendations (also prior to the 2003 ISUIA data) for the management of patients with an unruptured intracranial aneurysm that are similar to the above recommendations [90]: The treatment of small incidental intracavernous internal carotid artery aneurysms is generally not indicated. For large symptomatic intracavernous aneurysms, treatment decisions should be individualized on the basis of patient age, severity and progression of symptoms, and treatment alternatives. The higher risk of treatment and shorter life expectancy in older individuals must be considered in all patients, and it favors observation in older patients with asymptomatic aneurysms. Symptomatic intradural aneurysms of all sizes should be considered for treatment with relative urgency. https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 13/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate Coexisting or remaining aneurysms of all sizes in patients with an SAH due to another treated aneurysm warrant consideration for treatment. Aneurysms located at the basilar apex carry a relatively high risk of rupture. Treatment decisions must take into account the patient's age, existing medical and neurologic condition, and relative risks of repair. If a decision is made for observation, reevaluation on a periodic basis with computed tomography angiography (CTA)/magnetic resonance angiography (MRA) or selective contrast angiography should be considered, with changes in aneurysmal size sought, although careful attention to technical factors will be required to optimize the reliability of these measures. Given the apparent low risk of hemorrhage from incidental, small (<7 mm) aneurysms in patients without previous SAH, observation rather than intervention is generally advocated. However, special consideration for treatment should be given to young (<50 years) patients in this group. Asymptomatic aneurysms 7 to 10 mm in diameter warrant strong consideration for treatment, taking into account patient age, existing medical and neurologic conditions, and relative risks for treatment [91]. Choice of procedure Surgical treatment of unruptured aneurysms has been the most common procedure used in patients who undergo definitive therapy. In clinical studies, which are typically in centers with high case volumes, endovascular techniques appear to be associated with lower morbidity and mortality than surgical clipping and are playing an increasing role in the treatment of unruptured aneurysms [92-96]. (See "Treatment of cerebral aneurysms", section on 'Patients with unruptured aneurysms'.) New technologies, such as flow diversion, may advance the safety of endovascular treatment and allow aneurysms, previously considered to be inaccessible or technologically difficult for such treatment, to undergo treatment [97]. Special situations With AVM Rare patients have an intracranial aneurysm associated with an intracranial arteriovenous malformation (AVM). These aneurysms are more likely to be associated with growth and rupture than aneurysms in general [98]. Therefore, repairing the aneurysm prior to treating the AVM is recommended. Carotid stenosis One study found that intracranial aneurysms appeared to be more common than expected in a population of patients with symptomatic carotid artery disease, perhaps because of shared risk factors [99]. Aneurysms distal to a symptomatic cervical internal https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 14/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate carotid artery stenosis may be susceptible to sudden hemodynamic changes with carotid endarterectomy (CEA) that could lead to aneurysmal rupture [44]. On the other hand, surgical clipping of an aneurysm distal to a severe internal carotid stenosis may increase the risk of ischemic stroke. Unfortunately, data for this situation are too sparse to allow firm conclusions as to which problem should be tackled first. However, caution is advised if CEA is performed in this setting, especially if the unruptured ipsilateral aneurysm is 7 mm or larger in diameter or if there is a history of SAH from another aneurysm. Use of antithrombotic therapy Patients with intracranial aneurysms may require antithrombotic therapy for the management of other conditions such as atrial fibrillation. The available data are limited, somewhat conflicting, and not sufficient to determine whether anticoagulant (eg, warfarin) or antiplatelet therapy increases the risk of aneurysm rupture. [100]. Anticoagulant therapy does appear to increase the severity of rupture should it occur. The available data regarding the risks of antithrombotic therapy in patients with unruptured aneurysm are discussed in detail separately. (See "Anticoagulant and antiplatelet therapy in patients with an unruptured intracranial aneurysm".) Monitoring For patients with unruptured intracranial aneurysms that are not treated with open surgery or endovascular methods, the following recommendations are made for monitoring [44]: We suggest that unruptured intracranial aneurysms be monitored with CTA or MRA annually for two to three years, and every two to five years thereafter if the aneurysm is clinically and radiographically stable [44]. However, it is not unreasonable to obtain the first reimaging study of newly detected small aneurysms at six months, since there is evidence that newly formed small aneurysms may be at higher risk of rupture than older, more stable aneurysms (see 'Aneurysm growth and rupture' above). Longer reimaging intervals are certainly appropriate if the six-month study shows no significant change. Patients should be instructed to avoid smoking, heavy alcohol consumption, stimulant medications, illicit drugs, and excessive straining and Valsalva maneuvers. Patients whose aneurysm is treated are at risk for recurrent aneurysm formation and require monitoring. This is discussed in detail separately. (See "Late recurrence of subarachnoid hemorrhage and intracranial aneurysms".) https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 15/28 7/7/23, 11:37 AM

patients with no history of SAH from another aneurysm worsened clinical outcomes; treatment of unruptured aneurysms that were larger, symptomatic, or in patients with a history of SAH was cost effective [88]. Aneurysm location was not considered in this analysis. https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 12/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate A later decision and cost-effectiveness analysis used the 2003 ISUIA data and compared surgical or endovascular treatment with no treatment for unruptured intracranial aneurysms [89]. The following observations were reported: For 50-year-old patients, treatment was ineffective or not cost effective for aneurysms with the following characteristics: Small (<7 mm), due to the low risk of rupture Located in the cavernous carotid artery Large (>25 mm) and located in the posterior circulation, due to the high risk of complications from treatment For 40-year-old patients, treatment was ineffective or not cost effective for aneurysms with the following characteristics: Small (<12 mm) or large (>25 mm) and located in the cavernous carotid artery Small (<7 mm) and located in the anterior circulation Indications for intervention The available studies emphasize the need to examine each case individually, considering factors such as comorbid medical illness, patient age, aneurysm size and location, and risks of treatment. The sum of these data supports expectant management of very small saccular aneurysms, particularly when such aneurysms are located in the anterior circulation or when they are detected in older patients. A task force of the Stroke Council of the American Heart Association published recommendations (also prior to the 2003 ISUIA data) for the management of patients with an unruptured intracranial aneurysm that are similar to the above recommendations [90]: The treatment of small incidental intracavernous internal carotid artery aneurysms is generally not indicated. For large symptomatic intracavernous aneurysms, treatment decisions should be individualized on the basis of patient age, severity and progression of symptoms, and treatment alternatives. The higher risk of treatment and shorter life expectancy in older individuals must be considered in all patients, and it favors observation in older patients with asymptomatic aneurysms. Symptomatic intradural aneurysms of all sizes should be considered for treatment with relative urgency. https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 13/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate Coexisting or remaining aneurysms of all sizes in patients with an SAH due to another treated aneurysm warrant consideration for treatment. Aneurysms located at the basilar apex carry a relatively high risk of rupture. Treatment decisions must take into account the patient's age, existing medical and neurologic condition, and relative risks of repair. If a decision is made for observation, reevaluation on a periodic basis with computed tomography angiography (CTA)/magnetic resonance angiography (MRA) or selective contrast angiography should be considered, with changes in aneurysmal size sought, although careful attention to technical factors will be required to optimize the reliability of these measures. Given the apparent low risk of hemorrhage from incidental, small (<7 mm) aneurysms in patients without previous SAH, observation rather than intervention is generally advocated. However, special consideration for treatment should be given to young (<50 years) patients in this group. Asymptomatic aneurysms 7 to 10 mm in diameter warrant strong consideration for treatment, taking into account patient age, existing medical and neurologic conditions, and relative risks for treatment [91]. Choice of procedure Surgical treatment of unruptured aneurysms has been the most common procedure used in patients who undergo definitive therapy. In clinical studies, which are typically in centers with high case volumes, endovascular techniques appear to be associated with lower morbidity and mortality than surgical clipping and are playing an increasing role in the treatment of unruptured aneurysms [92-96]. (See "Treatment of cerebral aneurysms", section on 'Patients with unruptured aneurysms'.) New technologies, such as flow diversion, may advance the safety of endovascular treatment and allow aneurysms, previously considered to be inaccessible or technologically difficult for such treatment, to undergo treatment [97]. Special situations With AVM Rare patients have an intracranial aneurysm associated with an intracranial arteriovenous malformation (AVM). These aneurysms are more likely to be associated with growth and rupture than aneurysms in general [98]. Therefore, repairing the aneurysm prior to treating the AVM is recommended. Carotid stenosis One study found that intracranial aneurysms appeared to be more common than expected in a population of patients with symptomatic carotid artery disease, perhaps because of shared risk factors [99]. Aneurysms distal to a symptomatic cervical internal https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 14/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate carotid artery stenosis may be susceptible to sudden hemodynamic changes with carotid endarterectomy (CEA) that could lead to aneurysmal rupture [44]. On the other hand, surgical clipping of an aneurysm distal to a severe internal carotid stenosis may increase the risk of ischemic stroke. Unfortunately, data for this situation are too sparse to allow firm conclusions as to which problem should be tackled first. However, caution is advised if CEA is performed in this setting, especially if the unruptured ipsilateral aneurysm is 7 mm or larger in diameter or if there is a history of SAH from another aneurysm. Use of antithrombotic therapy Patients with intracranial aneurysms may require antithrombotic therapy for the management of other conditions such as atrial fibrillation. The available data are limited, somewhat conflicting, and not sufficient to determine whether anticoagulant (eg, warfarin) or antiplatelet therapy increases the risk of aneurysm rupture. [100]. Anticoagulant therapy does appear to increase the severity of rupture should it occur. The available data regarding the risks of antithrombotic therapy in patients with unruptured aneurysm are discussed in detail separately. (See "Anticoagulant and antiplatelet therapy in patients with an unruptured intracranial aneurysm".) Monitoring For patients with unruptured intracranial aneurysms that are not treated with open surgery or endovascular methods, the following recommendations are made for monitoring [44]: We suggest that unruptured intracranial aneurysms be monitored with CTA or MRA annually for two to three years, and every two to five years thereafter if the aneurysm is clinically and radiographically stable [44]. However, it is not unreasonable to obtain the first reimaging study of newly detected small aneurysms at six months, since there is evidence that newly formed small aneurysms may be at higher risk of rupture than older, more stable aneurysms (see 'Aneurysm growth and rupture' above). Longer reimaging intervals are certainly appropriate if the six-month study shows no significant change. Patients should be instructed to avoid smoking, heavy alcohol consumption, stimulant medications, illicit drugs, and excessive straining and Valsalva maneuvers. Patients whose aneurysm is treated are at risk for recurrent aneurysm formation and require monitoring. This is discussed in detail separately. (See "Late recurrence of subarachnoid hemorrhage and intracranial aneurysms".) https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 15/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - 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 topic (see "Patient education: Brain aneurysm (The Basics)") SUMMARY AND RECOMMENDATIONS In the general population, the prevalence of unruptured intracranial aneurysms is estimated to be approximately 3 percent. A higher risk of intracranial aneurysm formation occurs in certain genetic syndromes including Ehlers-Danlos syndrome, polycystic kidney disease (PKD), and others. Apart from these genetic syndromes, a family history of intracranial aneurysm is also a risk factor. Nongenetic risk factors include hypertension and cigarette smoking. Most unruptured aneurysms present as an incidental finding on a neuroimaging study or in screening. Occasionally, aneurysms can produce compressive symptoms such as a third cranial nerve palsy. Magnetic resonance angiography (MRA) and computed tomography angiography (CTA) appear to be able to detect aneurysms 5 mm or larger. Conventional angiography is more sensitive, but carries procedural risks. The most common treatments for aneurysms are surgical clipping and endovascular coiling. Indications for intervention take into account the risk of aneurysm rupture. In general, we suggest treatment of most nonintracavernous intracranial aneurysms that are greater than https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 16/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate 7 to 10 mm in size, while observation and monitoring is suggested for smaller aneurysms. Patients with an intracranial aneurysm should be monitored for aneurysm growth, aneurysm recurrence, and new aneurysm formation. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Etminan N, Rinkel GJ. Unruptured intracranial aneurysms: development, rupture and preventive management. Nat Rev Neurol 2016; 12:699. 2. Brown RD Jr, Broderick JP. Unruptured intracranial aneurysms: epidemiology, natural history, management options, and familial screening. Lancet Neurol 2014; 13:393. 3. Rinkel GJE. Management of patients with unruptured intracranial aneurysms. Curr Opin Neurol 2019; 32:49. 4. Hackenberg KAM, H nggi D, Etminan N. Unruptured Intracranial Aneurysms. Stroke 2018; 49:2268. 5. Ellis JA, Nossek E, Kronenburg A, et al. Intracranial Aneurysm: Diagnostic Monitoring, Current Interventional Practices, and Advances. Curr Treat Options Cardiovasc Med 2018; 20:94. 6. Vernooij MW, Ikram MA, Tanghe HL, et al. Incidental findings on brain MRI in the general population. N Engl J Med 2007; 357:1821. 7. Vlak MH, Algra A, Brandenburg R, Rinkel GJ. Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country, and time period: a systematic review and meta-analysis. Lancet Neurol 2011; 10:626. 8. STEHBENS WE. ANEURYSMS AND ANATOMICAL VARIATION OF CEREBRAL ARTERIES. Arch Pathol 1963; 75:45. 9. Sarti C, Tuomilehto J, Salomaa V, et al. Epidemiology of subarachnoid hemorrhage in Finland from 1983 to 1985. Stroke 1991; 22:848. 10. Schievink WI. Intracranial aneurysms. N Engl J Med 1997; 336:28. 11. Alg VS, Sofat R, Houlden H, Werring DJ. Genetic risk factors for intracranial aneurysms: a meta-analysis in more than 116,000 individuals. Neurology 2013; 80:2154. 12. Neil-Dwyer G, Bartlett JR, Nicholls AC, et al. Collagen deficiency and ruptured cerebral aneurysms. A clinical and biochemical study. J Neurosurg 1983; 59:16. https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 17/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate 13. Pepin M, Schwarze U, Superti-Furga A, Byers PH. Clinical and genetic features of Ehlers- Danlos syndrome type IV, the vascular type. N Engl J Med 2000; 342:673. 14. Conway JE, Hutchins GM, Tamargo RJ. Marfan syndrome is not associated with intracranial aneurysms. Stroke 1999; 30:1632. 15. Litchfield WR, Anderson BF, Weiss RJ, et al. Intracranial aneurysm and hemorrhagic stroke in glucocorticoid-remediable aldosteronism. Hypertension 1998; 31:445. 16. Chalhoub V, Abi-Rafeh L, Hachem K, et al. Intracranial aneurysm and recessive polycystic kidney disease: the third reported case. JAMA Neurol 2013; 70:114. 17. Ronkainen A, Hernesniemi J, Puranen M, et al. Familial intracranial aneurysms. Lancet 1997; 349:380. 18. Raaymakers TW. Aneurysms in relatives of patients with subarachnoid hemorrhage: frequency and risk factors. MARS Study Group. Magnetic Resonance Angiography in Relatives of patients with Subarachnoid hemorrhage. Neurology 1999; 53:982. 19. Bromberg JE, Rinkel GJ, Algra A, et al. Familial subarachnoid hemorrhage: distinctive features and patterns of inheritance. Ann Neurol 1995; 38:929. 20. Wills S, Ronkainen A, van der Voet M, et al. Familial intracranial aneurysms: an analysis of 346 multiplex Finnish families. Stroke 2003; 34:1370. 21. Onda H, Kasuya H, Yoneyama T, et al. Genomewide-linkage and haplotype-association studies map intracranial aneurysm to chromosome 7q11. Am J Hum Genet 2001; 69:804. 22. Hashikata H, Liu W, Inoue K, et al. Confirmation of an association of single-nucleotide polymorphism rs1333040 on 9p21 with familial and sporadic intracranial aneurysms in Japanese patients. Stroke 2010; 41:1138. 23. van der Voet M, Olson JM, Kuivaniemi H, et al. Intracranial aneurysms in Finnish families: confirmation of linkage and refinement of the interval to chromosome 19q13.3. Am J Hum Genet 2004; 74:564. 24. Deka R, Koller DL, Lai D, et al. The relationship between smoking and replicated sequence variants on chromosomes 8 and 9 with familial intracranial aneurysm. Stroke 2010; 41:1132. 25. Foroud T, Koller DL, Lai D, et al. Genome-wide association study of intracranial aneurysms confirms role of Anril and SOX17 in disease risk. Stroke 2012; 43:2846. 26. Hussain I, Duffis EJ, Gandhi CD, Prestigiacomo CJ. Genome-wide association studies of intracranial aneurysms: an update. Stroke 2013; 44:2670. 27. St Jean P, Hart B, Webster M, et al. Alpha-1-antitrypsin deficiency in aneurysmal disease. Hum Hered 1996; 46:92. https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 18/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate 28. Broderick JP, Brown RD Jr, Sauerbeck L, et al. Greater rupture risk for familial as compared to sporadic unruptured intracranial aneurysms. Stroke 2009; 40:1952. 29. Mackey J, Brown RD Jr, Moomaw CJ, et al. Familial intracranial aneurysms: is anatomic vulnerability heritable? Stroke 2013; 44:38. 30. Teunissen LL, Rinkel GJ, Algra A, van Gijn J. Risk factors for subarachnoid hemorrhage: a systematic review. Stroke 1996; 27:544. 31. Knekt P, Reunanen A, Aho K, et al. Risk factors for subarachnoid hemorrhage in a longitudinal population study. J Clin Epidemiol 1991; 44:933. 32. Lepp l JM, Paunio M, Virtamo J, et al. Alcohol consumption and stroke incidence in male smokers. Circulation 1999; 100:1209. 33. Vlak MH, Rinkel GJ, Greebe P, Algra A. Independent risk factors for intracranial aneurysms and their joint effect: a case-control study. Stroke 2013; 44:984. 34. Bonita R. Cigarette smoking, hypertension and the risk of subarachnoid hemorrhage: a population-based case-control study. Stroke 1986; 17:831. 35. Stober T, Sen S, Anst tt T, et al. Direct evidence of hypertension and the possible role of post-menopause oestrogen deficiency in the pathogenesis of berry aneurysms. J Neurol 1985; 232:67. 36. Taylor CL, Yuan Z, Selman WR, et al. Cerebral arterial aneurysm formation and rupture in 20,767 elderly patients: hypertension and other risk factors. J Neurosurg 1995; 83:812. 37. Longstreth WT, Nelson LM, Koepsell TD, van Belle G. Subarachnoid hemorrhage and hormonal factors in women. A population-based case-control study. Ann Intern Med 1994; 121:168. 38. Mhurchu CN, Anderson C, Jamrozik K, et al. Hormonal factors and risk of aneurysmal subarachnoid hemorrhage: an international population-based, case-control study. Stroke 2001; 32:606. 39. Perloff JK. The Clinical Recognition of Congenital Heart Disease, 4th ed, WB Saunders, Philad elphia 1994. 40. HODES HL, STEINFELD L, BLUMENTHAL S. Congenital cerebral aneurysms and coarctation of the aorta. Arch Pediatr 1959; 76:28. 41. Connolly HM, Huston J 3rd, Brown RD Jr, et al. Intracranial aneurysms in patients with coarctation of the aorta: a prospective magnetic resonance angiographic study of 100 patients. Mayo Clin Proc 2003; 78:1491. 42. Austin G, Fisher S, Dickson D, et al. The significance of the extracellular matrix in intracranial aneurysms. Ann Clin Lab Sci 1993; 23:97. https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 19/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate 43. Patel RL, Richards P, Chambers DJ, Venn G. Infective endocarditis complicated by ruptured cerebral mycotic aneurysm. J R Soc Med 1991; 84:746. 44. Wiebers DO, Piepgras DG, Meyer FB, et al. Pathogenesis, natural history, and treatment of unruptured intracranial aneurysms. Mayo Clin Proc 2004; 79:1572. 45. Starke RM, Chalouhi N, Ali MS, et al. The role of oxidative stress in cerebral aneurysm formation and rupture. Curr Neurovasc Res 2013; 10:247. 46. Chalouhi N, Ali MS, Starke RM, et al. Cigarette smoke and inflammation: role in cerebral aneurysm formation and rupture. Mediators Inflamm 2012; 2012:271582. 47. Aoki T, Nishimura M. Targeting chronic inflammation in cerebral aneurysms: focusing on NF-kappaB as a putative target of medical therapy. Expert Opin Ther Targets 2010; 14:265. 48. Chalouhi N, Points L, Pierce GL, et al. Localized increase of chemokines in the lumen of human cerebral aneurysms. Stroke 2013; 44:2594. 49. Fr sen J, Piippo A, Paetau A, et al. Remodeling of saccular cerebral artery aneurysm wall is associated with rupture: histological analysis of 24 unruptured and 42 ruptured cases. Stroke 2004; 35:2287. 50. Pyysalo MJ, Pyysalo LM, Pessi T, et al. The connection between ruptured cerebral aneurysms and odontogenic bacteria. J Neurol Neurosurg Psychiatry 2013; 84:1214. 51. Hallikainen J, Ker nen S, Savolainen J, et al. Role of oral pathogens in the pathogenesis of intracranial aneurysm: review of existing evidence and potential mechanisms. Neurosurg Rev 2021; 44:239. 52. Wiebers DO, Whisnant JP, Sundt TM Jr, O'Fallon WM. The significance of unruptured intracranial saccular aneurysms. J Neurosurg 1987; 66:23. 53. Sato K, Yoshimoto Y. Risk profile of intracranial aneurysms: rupture rate is not constant after formation. Stroke 2011; 42:3376. 54. Wiebers DO, Whisnant JP, Huston J 3rd, et al. Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet 2003; 362:103. 55. International Study of Unruptured Intracranial Aneurysms Investigators. Unruptured intracranial aneurysms risk of rupture and risks of surgical intervention. N Engl J Med 1998; 339:1725. 56. Wiebers DO, Whisnant JP, O'Fallon WM. The natural history of unruptured intracranial aneurysms. N Engl J Med 1981; 304:696. 57. Forget TR Jr, Benitez R, Veznedaroglu E, et al. A review of size and location of ruptured intracranial aneurysms. Neurosurgery 2001; 49:1322. https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 20/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate 58. White PM, Wardlaw J. Unruptured intracranial aneurysms: prospective data have arrived. Lancet 2003; 362:90. 59. Raps EC, Rogers JD, Galetta SL, et al. The clinical spectrum of unruptured intracranial aneurysms. Arch Neurol 1993; 50:265. 60. Friedman JA, Piepgras DG, Pichelmann MA, et al. Small cerebral aneurysms presenting with symptoms other than rupture. Neurology 2001; 57:1212. 61. Huston J 3rd, Nichols DA, Luetmer PH, et al. Blinded prospective evaluation of sensitivity of MR angiography to known intracranial aneurysms: importance of aneurysm size. AJNR Am J Neuroradiol 1994; 15:1607. 62. Schwartz RB, Tice HM, Hooten SM, et al. Evaluation of cerebral aneurysms with helical CT: correlation with conventional angiography and MR angiography. Radiology 1994; 192:717. 63. White PM, Teadsale E, Wardlaw JM, Easton V. What is the most sensitive non-invasive imaging strategy for the diagnosis of intracranial aneurysms? J Neurol Neurosurg Psychiatry 2001; 71:322. 64. van Gelder JM. Computed tomographic angiography for detecting cerebral aneurysms: implications of aneurysm size distribution for the sensitivity, specificity, and likelihood ratios. Neurosurgery 2003; 53:597. 65. Menke J, Larsen J, Kallenberg K. Diagnosing cerebral aneurysms by computed tomographic angiography: meta-analysis. Ann Neurol 2011; 69:646. 66. Li MH, Li YD, Tan HQ, et al. Contrast-free MRA at 3.0 T for the detection of intracranial aneurysms. Neurology 2011; 77:667. 67. UCAS Japan Investigators, Morita A, Kirino T, et al. The natural course of unruptured cerebral aneurysms in a Japanese cohort. N Engl J Med 2012; 366:2474. 68. Greving JP, Wermer MJ, Brown RD Jr, et al. Development of the PHASES score for prediction of risk of rupture of intracranial aneurysms: a pooled analysis of six prospective cohort studies. Lancet Neurol 2014; 13:59. 69. Rabinstein AA. Intracranial aneurysms: individualising the risk of rupture. Lancet Neurol 2014; 13:25. 70. Sonobe M, Yamazaki T, Yonekura M, Kikuchi H. Small unruptured intracranial aneurysm verification study: SUAVe study, Japan. Stroke 2010; 41:1969. 71. Matsubara S, Hadeishi H, Suzuki A, et al. Incidence and risk factors for the growth of unruptured cerebral aneurysms: observation using serial computerized tomography angiography. J Neurosurg 2004; 101:908. https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 21/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate 72. Burns JD, Huston J 3rd, Layton KF, et al. Intracranial aneurysm enlargement on serial magnetic resonance angiography: frequency and risk factors. Stroke 2009; 40:406. 73. Kashiwazaki D, Kuroda S, Sapporo SAH Study Group. Size ratio can highly predict rupture risk in intracranial small (<5 mm) aneurysms. Stroke 2013; 44:2169. 74. Mocco J, Brown RD Jr, Torner JC, et al. Aneurysm Morphology and Prediction of Rupture: An International Study of Unruptured Intracranial Aneurysms Analysis. Neurosurgery 2018; 82:491. 75. Villablanca JP, Duckwiler GR, Jahan R, et al. Natural history of asymptomatic unruptured cerebral aneurysms evaluated at CT angiography: growth and rupture incidence and correlation with epidemiologic risk factors. Radiology 2013; 269:258. 76. Chien A, Liang F, Sayre J, et al. Enlargement of small, asymptomatic, unruptured intracranial aneurysms in patients with no history of subarachnoid hemorrhage: the different factors related to the growth of single and multiple aneurysms. J Neurosurg 2013; 119:190. 77. Ingall T, Asplund K, M h nen M, Bonita R. A multinational comparison of subarachnoid hemorrhage epidemiology in the WHO MONICA stroke study. Stroke 2000; 31:1054. 78. Morita A, Fujiwara S, Hashi K, et al. Risk of rupture associated with intact cerebral aneurysms in the Japanese population: a systematic review of the literature from Japan. J Neurosurg 2005; 102:601. 79. Morita A. [On-line outcome study of unruptured cerebral aneurysm in Japan (UCAS Japan)]. Rinsho Shinkeigaku 2002; 42:1188. 80. Yonekura M. Small unruptured aneurysm verification (SUAVe Study, Japan) interim report. Neurol Med Chir (Tokyo) 2004; 44:213. 81. Hasan D, Chalouhi N, Jabbour P, et al. Early change in ferumoxytol-enhanced magnetic resonance imaging signal suggests unstable human cerebral aneurysm: a pilot study. Stroke 2012; 43:3258. 82. Vlak MH, Rinkel GJ, Greebe P, Algra A. Risk of rupture of an intracranial aneurysm based on patient characteristics: a case-control study. Stroke 2013; 44:1256. 83. Juvela S, Poussa K, Lehto H, Porras M. Natural history of unruptured intracranial aneurysms: a long-term follow-up study. Stroke 2013; 44:2414. 84. Johnston SC, Wilson CB, Halbach VV, et al. Endovascular and surgical treatment of unruptured cerebral aneurysms: comparison of risks. Ann Neurol 2000; 48:11. 85. Kotowski M, Naggara O, Darsaut TE, et al. Safety and occlusion rates of surgical treatment of unruptured intracranial aneurysms: a systematic review and meta-analysis of the literature from 1990 to 2011. J Neurol Neurosurg Psychiatry 2013; 84:42. https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 22/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate 86. Alshekhlee A, Mehta S, Edgell RC, et al. Hospital mortality and complications of electively clipped or coiled unruptured intracranial aneurysm. Stroke 2010; 41:1471. 87. Ogilvy CS, Carter BS. Stratification of outcome for surgically treated unruptured intracranial aneurysms. Neurosurgery 2003; 52:82. 88. Johnston SC, Gress DR, Kahn JG. Which unruptured cerebral aneurysms should be treated? A cost-utility analysis. Neurology 1999; 52:1806. 89. Takao H, Nojo T. Treatment of unruptured intracranial aneurysms: decision and cost- effectiveness analysis. Radiology 2007; 244:755. 90. Bederson JB, Awad IA, Wiebers DO, et al. Recommendations for the management of patients with unruptured intracranial aneurysms: A statement for healthcare professionals from the Stroke Council of the American Heart Association. Circulation 2000; 102:2300. 91. Greving JP, Rinkel GJ, Buskens E, Algra A. Cost-effectiveness of preventive treatment of intracranial aneurysms: new data and uncertainties. Neurology 2009; 73:258. 92. Johnston SC, Zhao S, Dudley RA, et al. Treatment of unruptured cerebral aneurysms in California. Stroke 2001; 32:597. 93. Vallee JN, Aymard A, Vicaut E, et al. Endovascular treatment of basilar tip aneurysms with Guglielmi detachable coils: predictors of immediate and long-term results with multivariate analysis 6-year experience. Radiology 2003; 226:867. 94. Raftopoulos C, Goffette P, Vaz G, et al. Surgical clipping may lead to better results than coil embolization: results from a series of 101 consecutive unruptured intracranial aneurysms. Neurosurgery 2003; 52:1280. 95. Zacharia BE, Ducruet AF, Hickman ZL, et al. Technological advances in the management of unruptured intracranial aneurysms fail to improve outcome in New York state. Stroke 2011; 42:2844. 96. McDonald JS, McDonald RJ, Fan J, et al. Comparative effectiveness of unruptured cerebral aneurysm therapies: propensity score analysis of clipping versus coiling. Stroke 2013; 44:988. 97. De Vries J, Boogaarts J, Van Norden A, Wakhloo AK. New generation of Flow Diverter (surpass) for unruptured intracranial aneurysms: a prospective single-center study in 37 patients. Stroke 2013; 44:1567. 98. Wiebers DO, Torres VE. Screening for unruptured intracranial aneurysms in autosomal dominant polycystic kidney disease. N Engl J Med 1992; 327:953. 99. H man LM, Jongen LM, van der Worp HB, et al. Incidental intracranial aneurysms in patients with internal carotid artery stenosis: a CT angiography study and a metaanalysis. Stroke https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 23/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate 2009; 40:1341. 100. Hasan DM, Mahaney KB, Brown RD Jr, et al. Aspirin as a promising agent for decreasing incidence of cerebral aneurysm rupture. Stroke 2011; 42:3156. Topic 1132 Version 14.0 https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 24/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate GRAPHICS Unruptured small basilar tip aneurysm on MRA A 3D time of flight MRA, shows a 4 mm basilar tip aneurysm (arrow). Image B is a magnified view and shows the small unruptured aneurysm (arrow). MRA: magnetic resonance angiogram. Graphic 93978 Version 1.0 https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 25/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate Sensitivity of CTA for intracranial aneurysms The graph shows the increasing sensitivity of CTA with increasing aneurysm size. Points represent the median, and error bars represent the 95 percent confidence limits. Aneurysms greater than 10 mm have been pooled. Data from: van Gelder, JM. Computed tomographic angiography for detecting cerebral aneurysms: implications of aneurysm size distribution for the sensitivity, speci city, and likelihood ratios. Neurosurgery 2003; 53:597. Graphic 81565 Version 2.0 https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 26/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate False-positive intracranial aneurysms reported by CTA Bars represent the number of reported aneurysms of each size from 199 false-positive reports of aneurysms. Data from: van Gelder, JM. Computed tomographic angiography for detecting cerebral aneurysms: implications of aneurysm size distribution for the sensitivity, speci city, and likelihood ratios. Neurosurgery 2003; 53:597. Graphic 69728 Version 1.0 https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 27/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - 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. 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/unruptured-intracranial-aneurysms/print 28/28

7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Definition, etiology, and clinical manifestations of transient ischemic attack : Natalia S Rost, MD, MPH, Erica Camargo Faye, 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 23, 2022. INTRODUCTION Stroke and transient ischemic attack (TIA) are caused by one of several pathophysiologic processes involving the blood flow of the brain: The process may be intrinsic to the vessel, as in atherosclerosis, lipohyalinosis, inflammation, amyloid deposition, arterial dissection, developmental malformation, aneurysmal dilation, or venous thrombosis. The process may originate remotely, as occurs when an embolus from the heart or extracranial circulation lodges in an intracranial vessel. The process may result from inadequate cerebral blood flow due to decreased perfusion pressure or increased blood viscosity. The process may result from rupture of a vessel in the subarachnoid space or intracerebral tissue. The first three processes can lead to transient cerebral ischemia (transient cerebral ischemic attack or TIA) or permanent cerebral infarction (ischemic stroke), while the fourth results in either subarachnoid hemorrhage or an intracerebral hemorrhage (primary hemorrhagic stroke). This topic will discuss the definition, etiology, and clinical manifestations of TIA. The clinical diagnosis, evaluation, and treatment of TIA are discussed separately. (See "Initial evaluation and https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 1/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate management of transient ischemic attack and minor ischemic stroke" and "Differential diagnosis of transient ischemic attack and acute stroke" and "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack".) DEFINITION OF TIA Traditional time-based definition of TIA TIA was originally defined as a sudden onset of a focal neurologic symptom and/or sign lasting less than 24 hours, brought on by a transient decrease in blood flow, which renders the brain ischemic in the area producing the symptom. The time limit was intended to separate ischemia without infarction from infarction. However, this classic, time-based definition of TIA is 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. Tissue-based definition of TIA In the tissue-based definition, TIA is a transient episode of neurologic dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction [1]. In keeping with this definition of TIA, ischemic stroke is defined as an infarction of central nervous system tissue (brain, spinal cord, or retinal cells) attributable to ischemia, based on neuropathologic, neuroimaging, and/or clinical evidence (ie, persistence of symptoms or findings) of permanent tissue injury [2]. Thus, the benign connotation of "TIA" has been replaced by an understanding that even relatively brief ischemia can cause permanent neurologic or retinal injury. (See 'Symptom duration and infarction' below.) The advantages of tissue-based definitions of TIA and stroke include the following [1,3]: The end point is biologic (tissue injury, as confirmed or excluded by neuroimaging) rather than arbitrary (24 hours) The definition encourages use of neurodiagnostic tests to identify brain injury and its cause, which furthers earlier therapeutic interventions The presence or absence of ischemic brain is more accurately reflected The shortcomings of tissue-based definitions of TIA/stroke include the following: Dependency on the sensitivity and availability of neuroimaging Infarctions associated with classically-defined TIA are often very small; most are less than 1 mL in volume [4]. Imaging methods that have low sensitivity for small infarcts, such as computed tomography (CT) or conventional magnetic resonance imaging (MRI), would result in some https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 2/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate transient events being inappropriately classified as TIA without acute infarction. Conversely, imaging with diffusion-weighted MRI (DWI), with its higher sensitivity for acute infarction, would increase the proportion of transient events classified as ischemic stroke [5]. High variance in practice for imaging in patients with suspected TIA would reduce the ability to compare studies from different institutions as well as from different time periods. Dependency on population and case-mix The diagnosis of TIA without acute infarction depends not only on the sensitivity of imaging but also on clinical judgment as to whether the signs and symptoms are consistent with an ischemic syndrome and therefore warrant an imaging study. Hence, the prevalence of TIA without acute infarction depends on the population characteristics and the case mix, particularly the mixture of typical and atypical transient spells (see 'Typical TIA' below and 'Atypical TIA' below). There is a high variance in the prevalence of brain infarcts for TIA defined by time (ie, transient symptoms lasting <24 hours), with infarct rates ranging from 4 to 34 percent by CT and 21 to 67 percent by diffusion-weighted MRI [6]. Symptom duration and infarction The duration of ischemic symptoms does not reliably distinguish whether a symptomatic ischemic event will result in ischemic infarction [1]. A classically defined TIA with symptoms lasting for as little as a few minutes can be associated with infarction on DWI, whereas a spell lasting for many hours may show no signs of infarction on DWI. In patients with prolonged symptoms without development of infarction, concern for a nonischemic etiology of the spell should be raised [7]. Some reports suggest that increased duration of classically defined TIA (<24 hours in duration) is associated with a higher probability of infarction on DWI, but the association is not absolute [4,8- 11]. A systematic analysis of patients with classically defined TIA found that symptom duration was not a reliable predictor for the presence of infarction ( figure 1), even though the mean duration tended to be significantly longer in patients with infarction than in those without infarction [4]. One potential caveat is that abnormalities on initial imaging, such as DWI obtained during or soon after symptoms, may actually be reversible injuries. However, most patients with TIA seek medical attention after their symptoms fully resolve; a low proportion ( 7 percent) of patients with classically defined TIA are admitted and scanned at the height of their symptoms [8-10,12]. Therefore, infarcts observed in patients with classically defined TIA most likely represent permanent brain injury, as the probability of DWI reversibility decreases as the time from symptom onset to imaging increases. https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 3/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate EPIDEMIOLOGY TIA is a common neurologic problem [13]. In a population-based cohort study from 1948 to 2017 of over 14,000 predominantly White participants from the Framingham Heart Study, the estimated overall incidence of TIA was 1.19 per 1000 person-years [14]. The incidence increased with age; for the age group 45 to 54 years, the incidence was 0.22 per 1000 person-years, while for the age group 85 to 94 years, the incidence was 4.88 per 1000 person-years. In a community-based registry study from Italy, the annual incidence of TIA from 2007 to 2009 was 0.52 per 1000 population [15]. In the Cincinnati and Northern Kentucky region of the United States, where the ethnic and socioeconomic demographics are similar to that of the United States as a whole, another population-based study found that the adjusted annual incidence rate for TIA from 1993 to 1994 was 0.83 per 1000 population, and that Black individuals and men had significantly higher rates of TIA than White individuals and women [16]. From these data, it was estimated that 240,000 TIAs occurred in the United States in 2002. The estimated overall prevalence of TIA among adults in the United States is approximately 2 percent [17]. This number is felt to under-represent the true prevalence of TIA. Poor awareness by lay-persons of the signs and symptoms of cerebral or ocular ischemia and the risk of subsequent stroke, combined with a high rate of failure to seek medical attention after a TIA, may account for this finding [18]. Use of the tissue-based definition of TIA in epidemiologic studies is likely to modestly alter the incidence and prevalence rates of TIA and stroke, but these changes are encouraged because they should reflect more accurate diagnosis [1]. Data from several reports suggest that defining TIA by the absence of infarction on imaging will decrease the annual rate of TIA by approximately 30 percent and increase the annual incidence of stroke by 7 percent [19-21]. MECHANISMS AND CLINICAL MANIFESTATIONS A TIA should be considered a syndrome. The symptoms of a TIA depend in part upon the pathophysiologic subtype, which are divided into three main mechanisms: Embolic TIA, which may be artery-to-artery, or due to a cardioaortic or unknown source Lacunar or small penetrating vessel TIA Large artery, low-flow TIA Embolic TIA Embolic TIAs are characterized by discrete, usually single (and not stereotyped if multiple), more prolonged episodes of focal neurologic symptoms. The embolus may arise from https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 4/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate a pathologic process in an artery, usually extracranial, or from the heart (eg, atrial fibrillation or left ventricular thrombus) or aorta. A diligent search for a potential embolic source is necessary in all cases of TIA. (See "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack".) Embolic TIAs may last hours rather than minutes as in low-flow TIAs. As an example, in one study that divided patients with TIAs into those with symptoms of short duration (less than 60 minutes) or long duration (60 minutes or greater), the latter group was more likely to have an embolic source (86 versus 46 percent) [22]. Embolic TIAs also may less likely be repetitive compared with low-flow TIAs since they are the result of emboli from a specific source (eg, a one-, two-, or three-time phenomenon). When the source of the embolus is in a proximal vessel, recurrent emboli can lodge in different branches of the parent vessel giving different symptoms. Emboli are subject to natural thrombolysis and migration since they typically break off of fresh thrombus. They may produce transient ischemia on many occasions, but an element of silent infarction remains. Embolic TIAs are best divided into those in the anterior cerebral circulation (carotid, anterior cerebral artery, middle cerebral artery territory) and those in the posterior cerebral circulation (vertebrobasilar, posterior cerebral artery territory). Symptoms in both circulations depend upon the size of the embolic fragment in relation to the size of the artery occluded. Anterior circulation embolic TIAs Embolic TIAs in the anterior circulation may be large enough to occlude the middle cerebral artery stem, producing a contralateral hemiplegia secondary to ischemia in the deep white matter and basal ganglion/internal capsule lenticulostriate territory ( figure 2). In addition, they may produce cortical surface symptoms. These include aphasic and dysexecutive syndromes in the dominant hemisphere and anosognosia or neglect in the nondominant hemisphere. Smaller emboli that occlude branches of the middle cerebral artery stem result in more focal symptoms, including hand alone or arm and hand numbness, weakness, and/or heaviness induced by ischemia to the frontal area of the contralateral frontal lobe motor system ( figure 3). Rarely, the symptoms also may be as specific as thumb or hand numbness or a swollen feeling, suggesting focal ischemia in the hand area of the sensory strip or parietal association cortex. Isolated upper limb weakness may implicate cervical carotid atherosclerosis as the cause of cerebral ischemic symptoms [23]. Transient monocular visual loss often signifies atherothrombotic disease in the internal carotid artery proximal to the ophthalmic artery origin (see "Amaurosis fugax (transient monocular or binocular visual loss)"). Atherothrombotic disease is most often responsible https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 5/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate for these syndromes, although carotid dissection and embolism from the aorta, heart, or an unknown source also should be considered. In a report of 129 patients with monocular visual loss of presumed ischemic origin, diffusion-weighted MRI of the brain revealed concurrent acute brain infarcts in 24 percent [24]. These infarcts were typically small, often multiple, frequently ipsilateral to the involved eye, and usually asymptomatic. The finding of concurrent acute brain infarction in a patient with transient monocular visual loss suggests a proximal source of embolic particles that travel to both the retinal and hemispheric circulations. Posterior circulation embolic TIAs Posterior circulation territory embolic TIAs are generally produced by emboli arising from atherothrombotic disease at the origin or distal segment of one of the vertebral arteries or of the proximal basilar artery. Emboli arising from the aortic arch, the heart, an unknown source, or from a dissecting lesion in the vertebral artery should also be considered. Symptoms vary according to the vertebral or basilar artery branch in which the embolus lodges ( figure 4). Emboli can produce transient ataxia, dizziness, diplopia, dysarthria, quadrantanopsia, hemianopsia, numbness, crossed face and body numbness, and unilateral hearing loss. When the top of the basilar artery is embolized, sudden, overwhelming stupor or coma may ensue due to bilateral medial thalamic, subthalamus, and medial rostral midbrain reticular activating system ischemia. Emboli in the more distal branches of the posterior cerebral artery may result in a homonymous field defect or in memory loss (inferior medial temporal lobe ischemia). Lacunar or small vessel TIA Lacunar or penetrating or small vessel TIAs are due to transient cerebral ischemia induced by stenosis of one of the intracerebral penetrating vessels arising from the middle cerebral artery stem, the basilar artery, the vertebral artery ( figure 5), or the circle of Willis ( figure 6 and figure 7). Occasionally, recurrent stereotyped TIAs occur; in this setting, the term lacunar or small vessel TIAs seems appropriate. Most often, lacunar or small vessel TIAs are thought to be caused either by atherothrombotic obstructive lesions at the origin of the penetrating vessel or by lipohyalinosis distally within the penetrating vessel. Less commonly, embolism may cause lacunar or small vessel TIAs. (See "Lacunar infarcts", section on 'Etiology'.) These small vessel TIAs cause symptoms similar to the lacunar strokes that are likely to follow. Thus, face, arm, and leg weakness or numbness due to ischemia in the internal capsule, pons, or thalamus may occur, similar to the symptoms due to ischemia from embolism or large vessel https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 6/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate atherothrombotic disease or dissection. As a result, serious disease in the parent vessel must be excluded before the diagnosis of lacunar or small vessel TIA can be established with confidence. Lacunar infarcts may be preceded by lacunar TIAs consisting of brief repetitive stereotyped clinical symptoms and signs, and lacunar stroke onset may be stepwise and progressive rather than abrupt [25-27]. Such a pattern of TIAs, or non-sudden onset in association with a lacunar syndrome, is highly suggestive of small vessel lipohyalinotic etiology [28]. (See "Lacunar infarcts".) Low-flow TIA Large artery low-flow TIAs are often associated with a tightly stenotic atherosclerotic lesion at the internal carotid artery origin or in the intracranial portion of the internal carotid artery (siphon) when collateral flow from the circle of Willis to the ipsilateral middle or anterior cerebral artery is impaired ( figure 6 and figure 7). Other important causes include atherosclerotic stenotic lesions in the middle cerebral artery stem ( figure 3) or at the junction of the vertebral and basilar artery. Any obstructive vascular process in the extracranial or intracranial arteries can cause a low-flow TIA syndrome if collateral flow to the potentially ischemic brain also is diminished. Low-flow TIAs usually are brief (minutes) and often recurrent. They may occur as little as several times per year but typically occur more often (once per week or up to several times per day). Anterior circulation low-flow TIAs Low-flow TIAs are generally stereotyped, especially when they are due to hemodynamically significant stenotic lesions at the origin of the internal carotid artery, at the siphon portion of the internal carotid artery where collateral flow to the circle of Willis is inadequate, or in the middle cerebral artery stem. Symptoms due to ischemia from these lesions often include weakness or numbness of the hand, arm, leg, face, tongue, and/or cheek. Recurrent aphasic syndromes appear when there is focal ischemia in the dominant hemisphere, and recurrent neglect occurs in the presence of focal ischemia in the nondominant hemisphere ischemia. Limb-shaking TIAs are a rare, but classic, hypoperfusion syndrome of repetitive jerking movements of the arm or leg due to a severe stenosis or occlusion of the contralateral internal carotid or middle cerebral artery [29-31]. Posterior circulation low-flow TIAs In contrast, recurrent symptoms are often not stereotyped when the stenotic lesion that obstructs flow involves the vertebrobasilar junction or the basilar artery. The many closely packed neuronal structures in the brainstem preclude consistent manifestations of recurrent focal ischemia in this area. Nevertheless, certain generalizations about recurrent low-flow TIA symptoms in the posterior circulation can be made. https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 7/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Obstructive lesions in the distal vertebral artery or at the vertebrobasilar junction usually cause dizziness that may or may not include spinning or vertigo. The patient may complain that the room is tilting or that the floor is coming up at them, rather than spinning dizziness. Patients may use the word dizziness to describe a myriad of symptoms, not necessarily spinning. Other symptoms can include numbness of one side of the body or face, dysarthria, or diplopia. Ischemia in the pons from stenotic lesions in the proximal to mid-basilar artery can cause bilateral leg and arm weakness or numbness and a feeling of heaviness in addition to dizziness. Ischemia in the territory of the top of the basilar artery or proximal posterior cerebral artery may present with all of the above recurrent symptoms as well as overwhelming drowsiness, vertical diplopia, eyelid drooping, and an inability to look up. Transient ischemia at the top of the basilar artery is usually due to embolism rather than low-flow TIA. URGENCY OF EVALUATION TIA is a neurologic emergency ( table 1). Patients with TIA and minor, nondisabling stroke have a high early risk of recurrent stroke (see 'Risk of recurrent stroke' below). Recognition of TIAs can identify patients who may benefit from preventive therapy. Therefore, the initial management of suspected TIA and minor ischemic stroke includes immediate antiplatelet treatment and urgent evaluation ( algorithm 1). This is reviewed in detail separately. (See "Initial evaluation and management of transient ischemic attack and minor ischemic stroke".) DIAGNOSIS The diagnosis of TIA is based upon the clinical features of the transient attack and the neuroimaging findings [6]. Since few patients with suspected TIA present when fully symptomatic [32], determining the likelihood of ischemia as the cause of the event often depends upon the history as reported by the patient and witnesses. Typical TIA Typical TIAs are characterized by transient, focal neurologic symptoms, generally with sudden onset, that can be localized to a single vascular territory within the brain, including one or more of the following: Transient monocular blindness (amaurosis fugax) https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 8/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Aphasia or dysarthria Hemianopia Hemiparesis and/or hemisensory loss In such cases, the likelihood of ischemia is relatively high. However, events consistent with typical TIA may sometimes occur due to nonischemic mechanisms such as seizure, migraine, intracerebral hemorrhage, and others. (See "Differential diagnosis of transient ischemic attack and acute stroke".) A key problem with the diagnosis of TIA is how to determine if symptoms are caused by ischemia when brain imaging is normal. Although clinical features are not definitive for etiology, an ischemic insult is the most likely cause when the attack is consistent with a typical TIA (ie, one with transient, focal neurologic symptoms localizing to a single vascular territory). Atypical TIA The clinical characteristics of transient symptoms considered to be atypical of an ischemic attack include the following [33-35]: Gradual build-up of symptoms (more than five minutes) March of symptoms from one body part to another (without passing the midline) Progression of symptoms from one type to another Isolated disturbance of vision in both eyes characterized by the occurrence of positive phenomena (eg, flashing lights) Isolated sensory symptoms with remarkably focal distribution, such as in a finger, chin, or tongue Very brief spells (less than 30 seconds) Identical spells occurring over a period of more than one year Isolated brainstem symptoms, such as dysarthria, diplopia, or hearing loss Amnesia, confusion Incoordination of limbs With atypical attacks as defined above, the likelihood of an ischemic cause may be relatively low. In several reports, the proportion of patients with atypical attacks who had acute brain infarction on diffusion weighted magnetic resonance imaging (MRI) was approximately 10 percent, suggesting that a minority of atypical spells have an ischemic cause and are therefore TIAs [6,36,37]. Alternatively, it may be the case that the sensitivity of MRI is not sufficient to reveal the ischemic lesions associated with atypical spells. One report that evaluated 275 patients with definite vertebrobasilar territory infarction found that preceding transient isolated brainstem symptoms occurred in 16 percent, suggesting that isolated brainstem symptoms can sometimes signify an ischemic attack [38]. https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 9/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate However, there is evidence that patients with atypical TIAs characterized by negative focal symptoms (where "negative" indicates a loss of some neurologic function) have similar short- and long-term risks of subsequent ischemic stroke as do patients with typical TIAs and should therefore be investigated and treated as true TIAs. A population-based longitudinal cohort study from the United Kingdom prospectively evaluated patients with minor ischemic stroke (n = 1287), classic TIA (n = 1021), or nonconsensus TIA (n = 570), the latter defined by isolated vertigo, isolated ataxia, isolated diplopia, isolated speech disturbance (slurred speech) without aphasia, isolated bilateral decreased vision, or isolated unilateral sensory loss involving only one body part (face, arm, hand, or leg) [37]. All patients were treated according to secondary prevention guidelines; the median follow-up was 5.2 years. At baseline, the prevalence of stroke risk factors including atrial fibrillation, arterial stenoses, and patent foramen ovale was similar for nonconsensus and classic TIA. Furthermore, the 90-day stroke risk after the index event was similar for nonconsensus TIA (10.6 percent [95% CI 7.8-12.9]) and classic TIA (11.6 percent [95% CI 9.6-13.6]), as was the 10-year risk of major vascular events (27.1 versus 30.9 percent). Differential diagnosis The differential diagnosis of TIA ( table 1) is discussed in detail separately. (See "Differential diagnosis of transient ischemic attack and acute stroke".) RISK OF RECURRENT STROKE TIA is a neurologic emergency because patients with time-based TIA and minor, nondisabling stroke are at increased risk of recurrent stroke, especially in the days following the event. Factors that affect stroke risk The risk of stroke after TIA appears to vary according to several factors, including time after the index event, presence of vascular pathologies, and the presence of acute infarction on MRI scan. The first days after the event The risk of stroke is highest in the first days after a TIA, ranging from 1.5 to 3.5 percent in the first 48 hours after TIA, making up approximately 40 percent of the 90-day stroke risk [39-42]. The urgency associated with TIA derives also from the observation that TIAs are most likely to occur in the hours and days immediately preceding ischemic stroke. As an example, a study that analyzed four cohorts of patients who had recent ischemic stroke found that TIAs occurred most often in the 48 hours prior to the stroke [43]. Another study found that the risk of ischemic stroke occurring within 24 hours of a probable or definite TIA was approximately 5 percent [42]. Of all ischemic strokes during the 30 days after a first TIA, 42 percent occurred within the first 24 hours. This may be an overestimate related to the difficulty distinguishing a single ischemic event (stroke) with fluctuating symptoms from separate events (TIA followed by stroke) within a https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 10/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate short period of time. Nevertheless, these observations underscore the high early risk of developing a permanent deficit after transient ischemic symptoms and the importance of urgent assessment, risk stratification, and treatment. Given this short time window and high risk of stroke (1.5 to 3.5 percent in the first 48 hours after TIA [39,40]) neurologic evaluation of and intervention for TIA should occur urgently. Recognition and urgent evaluation of TIAs can identify patients who may benefit from preventive therapy or from revascularization of large vessels such as the carotid artery. Premonitory carotid territory TIAs occur in approximately 50 to 75 percent of patients with ischemic stroke from extracranial carotid disease [44-46], and vertebrobasilar TIAs are associated with a risk of subsequent stroke or death that is similar to or possibly higher than that seen with carotid TIAs [47]. Higher risk with vascular pathologies TIA caused by vascular pathologies (ie, large artery atherosclerosis and small vessel disease) appears to confer a higher risk of subsequent stroke than cardiac and other nonvascular subtypes of TIA. A study from the prospective TIAregistry.org project, with over 4700 patients, found that large artery atherosclerosis was an independent risk factor for recurrent stroke [39]. Another prospective population-based study of 1000 patients from the United Kingdom reported that TIA due to small vessel vasculopathy was associated with a higher risk of early stroke than TIA due to other causes [48]. The stroke risk was particularly elevated after multiple stereotyped small vessel TIAs occurring in a brief period of time and characterized by motor symptoms but no cortical signs, the so-called "capsular warning syndrome" [27] or "stuttering lacunar syndrome." Although data are limited, the risk of early (within seven days) stroke after such events may be as high as 40 percent or more [27,48]. Higher risk with infarction There is accumulating evidence suggesting that the findings of acute infarction on diffusion-weighted MRI (DWI) [32,49-52] or acute or chronic ischemic lesions on computed tomography (CT) [53] after a transient ischemic event are important predictors of stroke. As an example, in a pooled analysis of 3206 patients with TIA who were evaluated with DWI, the risk of stroke at seven days was much lower in patients with no infarction compared with those with infarction (0.4 versus 7.1 percent) [20]. In patients with an imaging-positive transient event, the 90-day risk of stroke appears to be as high as 14 percent [32,49,50,54]. In contrast, after an imaging-negative transient event, the corresponding risk is <1 percent. https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 11/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Is the stroke risk after TIA declining over time? In a 2016 report from the TIAregistry.org project, a prospective multinational registry of over 4700 patients with TIA or minor stroke (defined by a modified Rankin scale score of 0 or 1 when first evaluated), the estimated risks of stroke at 2, 30, 90, and 365 days after the index event were 1.5, 2.8, 3.7, and 5.1 percent, respectively [39]. In a 2018 follow-up study, the estimated cumulative risk of stroke at five years after the index event was 9.5 percent [55]. These rates are lower than those previously reported [40,56,57], possibly due to the more rapid implementation of newer and more effective strategies for the secondary prevention of ischemic stroke; the registry included only sites with dedicated systems for the urgent evaluation of TIA, and most patients were seen by a stroke specialist within 24 hours of symptom onset. Independent risk factors for recurrent stroke were multiple infarctions on brain imaging, 2 large artery atherosclerosis, and an ABCD score of 6 or 7. (See 'Stroke risk stratification' below.) A systematic review and meta-analysis of 68 studies published from 1971 to March 2019 that included over 200,000 patients found that the risk of stroke after TIA was 2.4 percent within two days, 3.8 percent within seven days, 4.1 percent within 30 days, and 4.7 percent within 90 days [41]. The incidence of stroke was lower among study populations enrolled after 1999. Similarly, in a longitudinal population-based cohort study from the Framingham Heart Study that included over 14,000 participants from 1948 to 2017 with no history of TIA or stroke at baseline, the risk of stroke after TIA was lower in the epoch of 2000 to 2017 compared with 1948 to 1985 [14]. High-risk lesions There are four pathologic processes that give rise to embolic TIAs or low- flow TIAs and that can produce sudden devastating stroke if not recognized and treated. Internal carotid artery atherosclerosis An atherothrombotic stenotic lesion at the origin of the internal carotid artery that is narrowed to more than 70 percent of its normal lumen diameter poses a threat of embolic or low-flow TIA or stroke [58-61]. Even a 50 percent stenosis may be important when considering carotid endarterectomy for prevention of a secondary stroke or of a primary stroke when a TIA has occurred. In this setting, embolism is more common than low flow as a cause of TIA or stroke. (See "Management of symptomatic carotid atherosclerotic disease".) Prospective natural history studies of asymptomatic atherothrombotic disease at the origin of the internal carotid artery (mostly asymptomatic carotid artery bruits) suggest that the rate of ipsilateral stroke increases dramatically when the residual lumen diameter narrows to greater than 70 percent stenosis ( figure 8 and figure 9) [62-64]. In one series of 500 patients with asymptomatic cervical bruits, the incidence of stroke was 1.7 percent per https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 12/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate year overall but 5.5 percent per year in those with more than a 75 percent carotid artery stenosis [63]. This degree of stenosis corresponds to a residual lumen diameter of 1.5 mm, the precise point at which pressure drops across the stenotic lesion [65,66]. When the pressure drops, flow to the ipsilateral middle cerebral artery stem is in part supplied by collateral circulation from the circle of Willis and from the external carotid to ophthalmic to distal internal carotid artery system ( figure 6 and figure 7). Less flow is provided by the internal carotid artery as the lesion further narrows. We believe that this provides a milieu for thrombus formation at the site of the stenosis and subsequent embolism. When the circle of Willis is compromised, low-flow TIA ensues. Intracranial atherothrombotic disease Intracranial atherothrombotic disease that produces low-flow or embolic TIA most commonly occurs at the distal vertebral artery/vertebrobasilar junction/proximal basilar artery site. The potential of this lesion to precipitate a disastrous stroke by thrombosis, thrombus propagation, and embolism is extremely important. The other two most important, but less common, sites include the siphon portion of the internal carotid artery and the middle cerebral artery stem. The common carotid artery origin and the vertebral artery origin are much less problematic since they only rarely give rise to artery-to-artery emboli. The ability to noninvasively diagnose and follow these intracranial arterial lesions with precision through MRI angiography, CT angiography, duplex Doppler, and transcranial Doppler flow assessment allows for important preventive therapeutic considerations. (See "Intracranial large artery atherosclerosis: Treatment and prognosis" and "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack".) Arterial, aortic, or cardiac sources of emboli Emboli at the top of the basilar artery or the middle cerebral artery stem that come from a source below arterial, aortic, or cardiac are extremely important to recognize since they may produce fluctuating symptoms or TIAs prior to a devastating stroke. Transient focal symptoms due to an embolus at these sites occur because blood flow reestablishes itself around the embolus. The symptoms may return in abundance and produce a stroke when the embolus itself causes a thrombus that further occludes the artery. This can occur hours or even days after the embolus has lodged at the site because it did not migrate or lyse. Dissection lesions Dissection lesions at the origin of the petrous portion of the internal carotid artery or at the C1-2 level of the vertebral artery as it enters the foramen transversarium cause symptoms of cerebral ischemia due to low flow or embolism, which https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 13/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate occur within minutes, hours, or even days prior to a devastating stroke. Modern neurovascular imaging technology can establish the diagnosis noninvasively. (See "Cerebral and cervical artery dissection: Clinical features and diagnosis" and "Cerebral and cervical artery dissection: Treatment and prognosis".) Stroke risk stratification Methods that can reliably assess the risk of stroke after TIA in individual patients would be useful for triaging patients. The discussion that follows applies to the traditional time-based definition of TIA, which is characterized clinically by the temporary nature (<24 hours) of the associated neurologic symptoms. 2 ABCD2 score 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 2) [67]. 2 Despite the score's simplicity, it is often miscalculated [68]. The ABCD score is tallied as follows (calculator 1): 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) 2 Estimated two-day stroke risks determined by the ABCD score in the combined derivation and validation cohorts were as follows [67]: Score 6 to 7: High two-day stroke risk (8 percent) Score 4 to 5: Moderate two-day stroke risk (4 percent) Score 0 to 3: Low two-day stroke risk (1 percent) 2 The ABCD score was designed to be used in primary care settings to stratify patients according to stroke risk and thus identify those who required emergency assessment by specialists. However, its predictive performance is not satisfactory. A systematic review and meta-analysis of 2 29 studies that included over 13,700 patients with TIA found that the ABCD score did not reliably distinguish those with a low and high risk of recurrent stroke, or those with TIAs and TIA mimics [69]. https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 14/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate

most patients were seen by a stroke specialist within 24 hours of symptom onset. Independent risk factors for recurrent stroke were multiple infarctions on brain imaging, 2 large artery atherosclerosis, and an ABCD score of 6 or 7. (See 'Stroke risk stratification' below.) A systematic review and meta-analysis of 68 studies published from 1971 to March 2019 that included over 200,000 patients found that the risk of stroke after TIA was 2.4 percent within two days, 3.8 percent within seven days, 4.1 percent within 30 days, and 4.7 percent within 90 days [41]. The incidence of stroke was lower among study populations enrolled after 1999. Similarly, in a longitudinal population-based cohort study from the Framingham Heart Study that included over 14,000 participants from 1948 to 2017 with no history of TIA or stroke at baseline, the risk of stroke after TIA was lower in the epoch of 2000 to 2017 compared with 1948 to 1985 [14]. High-risk lesions There are four pathologic processes that give rise to embolic TIAs or low- flow TIAs and that can produce sudden devastating stroke if not recognized and treated. Internal carotid artery atherosclerosis An atherothrombotic stenotic lesion at the origin of the internal carotid artery that is narrowed to more than 70 percent of its normal lumen diameter poses a threat of embolic or low-flow TIA or stroke [58-61]. Even a 50 percent stenosis may be important when considering carotid endarterectomy for prevention of a secondary stroke or of a primary stroke when a TIA has occurred. In this setting, embolism is more common than low flow as a cause of TIA or stroke. (See "Management of symptomatic carotid atherosclerotic disease".) Prospective natural history studies of asymptomatic atherothrombotic disease at the origin of the internal carotid artery (mostly asymptomatic carotid artery bruits) suggest that the rate of ipsilateral stroke increases dramatically when the residual lumen diameter narrows to greater than 70 percent stenosis ( figure 8 and figure 9) [62-64]. In one series of 500 patients with asymptomatic cervical bruits, the incidence of stroke was 1.7 percent per https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 12/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate year overall but 5.5 percent per year in those with more than a 75 percent carotid artery stenosis [63]. This degree of stenosis corresponds to a residual lumen diameter of 1.5 mm, the precise point at which pressure drops across the stenotic lesion [65,66]. When the pressure drops, flow to the ipsilateral middle cerebral artery stem is in part supplied by collateral circulation from the circle of Willis and from the external carotid to ophthalmic to distal internal carotid artery system ( figure 6 and figure 7). Less flow is provided by the internal carotid artery as the lesion further narrows. We believe that this provides a milieu for thrombus formation at the site of the stenosis and subsequent embolism. When the circle of Willis is compromised, low-flow TIA ensues. Intracranial atherothrombotic disease Intracranial atherothrombotic disease that produces low-flow or embolic TIA most commonly occurs at the distal vertebral artery/vertebrobasilar junction/proximal basilar artery site. The potential of this lesion to precipitate a disastrous stroke by thrombosis, thrombus propagation, and embolism is extremely important. The other two most important, but less common, sites include the siphon portion of the internal carotid artery and the middle cerebral artery stem. The common carotid artery origin and the vertebral artery origin are much less problematic since they only rarely give rise to artery-to-artery emboli. The ability to noninvasively diagnose and follow these intracranial arterial lesions with precision through MRI angiography, CT angiography, duplex Doppler, and transcranial Doppler flow assessment allows for important preventive therapeutic considerations. (See "Intracranial large artery atherosclerosis: Treatment and prognosis" and "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack".) Arterial, aortic, or cardiac sources of emboli Emboli at the top of the basilar artery or the middle cerebral artery stem that come from a source below arterial, aortic, or cardiac are extremely important to recognize since they may produce fluctuating symptoms or TIAs prior to a devastating stroke. Transient focal symptoms due to an embolus at these sites occur because blood flow reestablishes itself around the embolus. The symptoms may return in abundance and produce a stroke when the embolus itself causes a thrombus that further occludes the artery. This can occur hours or even days after the embolus has lodged at the site because it did not migrate or lyse. Dissection lesions Dissection lesions at the origin of the petrous portion of the internal carotid artery or at the C1-2 level of the vertebral artery as it enters the foramen transversarium cause symptoms of cerebral ischemia due to low flow or embolism, which https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 13/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate occur within minutes, hours, or even days prior to a devastating stroke. Modern neurovascular imaging technology can establish the diagnosis noninvasively. (See "Cerebral and cervical artery dissection: Clinical features and diagnosis" and "Cerebral and cervical artery dissection: Treatment and prognosis".) Stroke risk stratification Methods that can reliably assess the risk of stroke after TIA in individual patients would be useful for triaging patients. The discussion that follows applies to the traditional time-based definition of TIA, which is characterized clinically by the temporary nature (<24 hours) of the associated neurologic symptoms. 2 ABCD2 score 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 2) [67]. 2 Despite the score's simplicity, it is often miscalculated [68]. The ABCD score is tallied as follows (calculator 1): 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) 2 Estimated two-day stroke risks determined by the ABCD score in the combined derivation and validation cohorts were as follows [67]: Score 6 to 7: High two-day stroke risk (8 percent) Score 4 to 5: Moderate two-day stroke risk (4 percent) Score 0 to 3: Low two-day stroke risk (1 percent) 2 The ABCD score was designed to be used in primary care settings to stratify patients according to stroke risk and thus identify those who required emergency assessment by specialists. However, its predictive performance is not satisfactory. A systematic review and meta-analysis of 2 29 studies that included over 13,700 patients with TIA found that the ABCD score did not reliably distinguish those with a low and high risk of recurrent stroke, or those with TIAs and TIA mimics [69]. https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 14/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate An earlier meta-analysis found that the score performance was poor in settings of low baseline risk and in TIA diagnosed by nonspecialists [70]. 2 The predictive power of the ABCD score is generally lower in hospital settings compared with population-based settings, thus limiting its utility for high-risk populations [67,71,72]. Other risk models Risk models that combine information from acute DWI, noninvasive angiography, and presumed TIA etiology improve the accuracy of stroke risk prediction after TIA [20,32,49,73-77]. There are a number of examples: 2 Several scores are based upon the conventional ABCD score: The Clinical- and Imaging-based Prediction (CIP) model incorporates diffusion-weighted 2 MRI findings with a dichotomized ABCD score [32]. 2 The ABCD -I score adds information about brain infarction on diffusion-weighted MRI or CT [20]. 3 The ABCD -I score assigns points for an earlier TIA within seven days of the index event and further incorporates data from initial diagnostic brain and carotid imaging [73]. The Canadian TIA Score ( table 3) estimates the probability of stroke within seven days of a TIA and is based upon nine items from the history and examination and four items from investigations that were correlated with having an impending stroke [78]. The total score ranges from -3 to 23. In the derivation study, scores 5 were associated with a low risk ( 0.5 percent) of subsequent stroke, while scores from 6 to 9 were associated with an intermediate risk (approximately 1 to 3 percent), and scores 10 were associated with a high risk ( 5 percent). In a prospective cohort study of over 7000 patients with TIA, the 2 2 Canadian TIA Score was more accurate compared with the ABCD or the ABCD -I for predicting subsequent stroke or carotid artery revascularization [79]. The Recurrence Risk Estimator (RRE) score combines clinical (recent history of stroke or TIA plus admission stroke subtype) and imaging information (location, multiplicity, distribution, and age of brain infarcts) [74] for predicting recurrent stroke following TIA with infarction [80,81]. As mentioned above, time-based TIA associated with acute brain infarction is a high-risk condition, and the RRE is the only predictive score that can be used to further stratify the risk in this particular population. The score identifies subsets of patients with a seven-day stroke risk that is as low as 1 percent and as high as 40 percent. The RRE score was externally validated in a multicenter cohort of over 1400 patients with acute ischemic stroke [82]. https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 15/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Additional research and validation of these models is needed to determine whether these stroke risk stratification models have any utility for clinical practice. The requirement for MRI limits the widespread applicability of advanced risk prediction models. 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: Transient ischemic attack (The Basics)") Beyond the Basics topic (see "Patient education: Transient ischemic attack (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Time-based definition The classic, time-based definition of transient ischemic attack (TIA) is a sudden onset of a focal neurologic symptom and/or sign lasting less than 24 hours, caused by a transient decrease in blood supply to the brain, spinal cord, or retina. Although still widely used, this classic definition is inadequate because even relatively brief ischemia can cause permanent neurologic or retinal injury. A substantial proportion of patients with a classically defined TIA (<24 hours in duration) have corresponding ischemic lesions on diffusion-weighted or perfusion-weighted magnetic resonance imaging (MRI) https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 16/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate that could explain the transient clinical manifestations. The associated infarctions are often very small. (See 'Traditional time-based definition of TIA' above.) Tissue-based definition The tissue-based definition of TIA is defined as a transient episode of neurologic dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction. Defining TIA by the absence of infarction means that the end point is biological (tissue injury) rather than arbitrary (24 hours). In addition, this tissue- based definition encourages the use of neurodiagnostic tests to identify brain injury and its cause. (See 'Tissue-based definition of TIA' above.) Mechanisms The symptoms of a TIA depend in part upon the pathophysiologic subtype, which are divided into three main mechanisms (see 'Mechanisms and clinical manifestations' above): Embolic TIA, which may be artery-to-artery, or due to a cardioaortic or unknown source. (See 'Embolic TIA' above.) Lacunar or small penetrating vessel TIA. (See 'Lacunar or small vessel TIA' above.) Large artery, low-flow TIA. (See 'Low-flow TIA' above.) Neurologic emergency TIA is a neurologic emergency. Therefore, the initial evaluation of suspected TIA and minor ischemic stroke requires urgent evaluation ( algorithm 1). (See 'Urgency of evaluation' above and "Initial evaluation and management of transient ischemic attack and minor ischemic stroke", section on 'Urgent investigations'.) Clinical features and diagnosis The diagnosis of TIA is based upon the clinical features of the transient attack and the neuroimaging findings. (See 'Diagnosis' above.) Typical TIAs 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 (see 'Typical TIA' above): - - - Transient monocular blindness (amaurosis fugax) Aphasia or dysarthria Hemianopia Hemiparesis and/or hemisensory loss Atypical TIAs Atypical spells suggestive of TIA ( table 1) may be less likely to have an ischemic cause, but atypical TIAs characterized by negative focal symptoms (where "negative" indicates a loss of some neurologic function) have similar short- and long- term risks of subsequent ischemic stroke, as do patients with typical TIAs, and should therefore be investigated and treated as true TIAs. (See 'Atypical TIA' above.) https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 17/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Differential diagnosis The differential diagnosis of TIA is summarized in the table ( table 1) and discussed in detail separately. (See "Differential diagnosis of transient ischemic attack and acute stroke".) Risk of stroke Both traditionally defined TIA (ie, time-based, lasting <24 hours) and minor ischemic stroke are associated with a high early risk of recurrent stroke. The stroke risk in 2 the first two days after TIA is approximately 1.5 to 3.5 percent. The ABCD score ( table 2) was designed to identify patients at high risk of ischemic stroke in this time period, but its predictive performance is not optimal. Risk stratification models that combine information from brain imaging, vascular imaging, and presumed TIA etiology in addition to the clinical 2 ABCD score may improve the accuracy of stroke risk prediction after TIA. (See 'Risk of recurrent stroke' above.) 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. Sacco RL, Kasner SE, Broderick JP, et al. An updated definition of stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013; 44:2064. 3. Albers GW, Caplan LR, Easton JD, et al. Transient ischemic attack proposal for a new definition. N Engl J Med 2002; 347:1713. 4. Ay H, Koroshetz WJ, Benner T, et al. Transient ischemic attack with infarction: a unique syndrome? Ann Neurol 2005; 57:679. https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 18/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate 5. F rster A, Gass A, Kern R, et al. Brain imaging in patients with transient ischemic attack: a comparison of computed tomography and magnetic resonance imaging. Eur Neurol 2012; 67:136. 6. Sorensen AG, Ay H. Transient ischemic attack: definition, diagnosis, and risk stratification. Neuroimaging Clin N Am 2011; 21:303. 7. Toole JF. The Willis lecture: transient ischemic attacks, scientific method, and new realities. Stroke 1991; 22:99. 8. Kidwell CS, Alger JR, Di Salle F, et al. Diffusion MRI in patients with transient ischemic attacks. Stroke 1999; 30:1174. 9. Engelter ST, Provenzale JM, Petrella JR, Alberts MJ. Diffusion MR imaging and transient ischemic attacks. Stroke 1999; 30:2762. 10. Crisostomo RA, Garcia MM, Tong DC. Detection of diffusion-weighted MRI abnormalities in patients with transient ischemic attack: correlation with clinical characteristics. Stroke 2003; 34:932. 11. Rovira A, Rovira-Gols A, Pedraza S, et al. Diffusion-weighted MR imaging in the acute phase of transient ischemic attacks. AJNR Am J Neuroradiol 2002; 23:77. 12. Ay H, Oliveira-Filho J, Buonanno FS, et al. 'Footprints' of transient ischemic attacks: a diffusion-weighted MRI study. Cerebrovasc Dis 2002; 14:177. 13. Virani SS, Alonso A, Aparicio HJ, et al. Heart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association. Circulation 2021; 143:e254. 14. Lioutas VA, Ivan CS, Himali JJ, et al. Incidence of Transient Ischemic Attack and Association With Long-term Risk of Stroke. JAMA 2021; 325:373. 15. Cancelli I, Janes F, Gigli GL, et al. Incidence of transient ischemic attack and early stroke risk: validation of the ABCD2 score in an Italian population-based study. Stroke 2011; 42:2751. 16. Kleindorfer D, Panagos P, Pancioli A, et al. Incidence and short-term prognosis of transient ischemic attack in a population-based study. Stroke 2005; 36:720. 17. Johnston SC, Fayad PB, Gorelick PB, et al. Prevalence and knowledge of transient ischemic attack among US adults. Neurology 2003; 60:1429. 18. Wang Y, Zhao X, Jiang Y, et al. Prevalence, knowledge, and treatment of transient ischemic attacks in China. Neurology 2015; 84:2354. 19. Ovbiagele B, Kidwell CS, Saver JL. Epidemiological impact in the United States of a tissue- based definition of transient ischemic attack. Stroke 2003; 34:919. 20. Giles MF, Albers GW, Amarenco P, et al. Addition of brain infarction to the ABCD2 Score (ABCD2I): a collaborative analysis of unpublished data on 4574 patients. Stroke 2010; https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 19/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate 41:1907. 21. Mullen MT, Cucchiara BL. Redefinition of transient ischemic attack improves prognosis of transient ischemic attack and ischemic stroke: an example of the will rogers phenomenon. Stroke 2011; 42:3612. 22. Kimura K, Minematsu K, Yasaka M, et al. The duration of symptoms in transient ischemic attack. Neurology 1999; 52:976. 23. Topcuoglu MA, Rocha EA, Siddiqui AK, et al. Isolated Upper Limb Weakness From Ischemic Stroke: Mechanisms and Outcome. J Stroke Cerebrovasc Dis 2018; 27:2712. 24. Helenius J, Arsava EM, Goldstein JN, et al. Concurrent acute brain infarcts in patients with monocular visual loss. Ann Neurol 2012; 72:286. 25. Fisher CM. Lacunar strokes and infarcts: a review. Neurology 1982; 32:871. 26. Kappelle LJ, van Latum JC, Koudstaal PJ, van Gijn J. Transient ischaemic attacks and small- vessel disease. Dutch TIA Study Group. Lancet 1991; 337:339. 27. Donnan GA, O'Malley HM, Quang L, et al. The capsular warning syndrome: pathogenesis and clinical features. Neurology 1993; 43:957. 28. Herv D, Gautier-Bertrand M, Labreuche J, et al. Predictive values of lacunar transient ischemic attacks. Stroke 2004; 35:1430. 29. 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. 30. Ali S, Khan MA, Khealani B. Limb-shaking Transient Ischemic Attacks: case report and review of literature. BMC Neurol 2006; 6:5. 31. Richardson TE, Beech P, Cloud GC. Limb-shaking TIA: a case of cerebral hypoperfusion in severe cerebrovascular disease in a young adult. BMC Neurol 2021; 21:260. 32. Ay H, Arsava EM, Johnston SC, et al. Clinical- and imaging-based prediction of stroke risk after transient ischemic attack: the CIP model. Stroke 2009; 40:181. 33. Fisher CM. Late-life migraine accompaniments further experience. Stroke 1986; 17:1033. 34. Special report from the National Institute of Neurological Disorders and Stroke. Classification of cerebrovascular diseases III. Stroke 1990; 21:637. 35. Amarenco P. Transient Ischemic Attack. N Engl J Med 2020; 382:1933. 36. Lavall e PC, Sissani L, Labreuche J, et al. Clinical Significance of Isolated Atypical Transient Symptoms in a Cohort With Transient Ischemic Attack. Stroke 2017; 48:1495. 37. Tuna MA, Rothwell PM, Oxford Vascular Study. Diagnosis of non-consensus transient ischaemic attacks with focal, negative, and non-progressive symptoms: population-based https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 20/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate validation by investigation and prognosis. Lancet 2021; 397:902. 38. Paul NL, Simoni M, Rothwell PM, Oxford Vascular Study. Transient isolated brainstem symptoms preceding posterior circulation stroke: a population-based study. Lancet Neurol 2013; 12:65. 39. Amarenco P, Lavall e PC, Labreuche J, et al. One-Year Risk of Stroke after Transient Ischemic Attack or Minor Stroke. N Engl J Med 2016; 374:1533. 40. Wu CM, McLaughlin K, Lorenzetti DL, et al. Early risk of stroke after transient ischemic attack: a systematic review and meta-analysis. Arch Intern Med 2007; 167:2417. 41. Shahjouei S, Sadighi A, Chaudhary D, et al. A 5-Decade Analysis of Incidence Trends of Ischemic Stroke After Transient Ischemic Attack: A Systematic Review and Meta-analysis. JAMA Neurol 2021; 78:77. 42. Chandratheva A, Mehta Z, Geraghty OC, et al. Population-based study of risk and predictors of stroke in the first few hours after a TIA. Neurology 2009; 72:1941. 43. Rothwell PM, Warlow CP. Timing of TIAs preceding stroke: time window for prevention is very short. Neurology 2005; 64:817. 44. Mohr JP, Caplan LR, Melski JW, et al. The Harvard Cooperative Stroke Registry: a prospective registry. Neurology 1978; 28:754. 45. Pessin MS, Hinton RC, Davis KR, et al. Mechanisms of acute carotid stroke. Ann Neurol 1979; 6:245. 46. Russo LS Jr. Carotid system transient ischemic attacks: clinical, racial, and angiographic correlations. Stroke 1981; 12:470. 47. Flossmann E, Rothwell PM. Prognosis of vertebrobasilar transient ischaemic attack and minor stroke. Brain 2003; 126:1940. 48. Paul NL, Simoni M, Chandratheva A, Rothwell PM. Population-based study of capsular warning syndrome and prognosis after early recurrent TIA. Neurology 2012; 79:1356. 49. Calvet D, Touz E, Oppenheim C, et al. DWI lesions and TIA etiology improve the prediction of stroke after TIA. Stroke 2009; 40:187. 50. Asimos AW, Rosamond WD, Johnson AM, et al. Early diffusion weighted MRI as a negative predictor for disabling stroke after ABCD2 score risk categorization in transient ischemic attack patients. Stroke 2009; 40:3252. 51. Purroy F, Montaner J, Rovira A, et al. Higher risk of further vascular events among transient ischemic attack patients with diffusion-weighted imaging acute ischemic lesions. Stroke 2004; 35:2313. https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 21/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate 52. Al-Khaled M, Eggers J. MRI findings and stroke risk in TIA patients with different symptom durations. Neurology 2013; 80:1920. 53. Sciolla R, Melis F, SINPAC Group. Rapid identification of high-risk transient ischemic attacks: prospective validation of the ABCD score. Stroke 2008; 39:297. 54. Giles MF, Albers GW, Amarenco P, et al. Early stroke risk and ABCD2 score performance in tissue- vs time-defined TIA: a multicenter study. Neurology 2011; 77:1222. 55. Amarenco P, Lavall e PC, Monteiro Tavares L, et al. Five-Year Risk of Stroke after TIA or Minor Ischemic Stroke. N Engl J Med 2018; 378:2182. 56. Giles MF, Rothwell PM. Risk of stroke early after transient ischaemic attack: a systematic review and meta-analysis. Lancet Neurol 2007; 6:1063. 57. van Wijk I, Kappelle LJ, van Gijn J, et al. Long-term survival and vascular event risk after transient ischaemic attack or minor ischaemic stroke: a cohort study. Lancet 2005; 365:2098. 58. North American Symptomatic Carotid Endarterectomy Trial Collaborators, Barnett HJM, Taylor DW, et al. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991; 325:445. 59. Kistler JP, Buonanno FS, Gress DR. Carotid endarterectomy specific therapy based on pathophysiology. N Engl J Med 1991; 325:505. 60. MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70-99%) or with mild (0-29%) carotid stenosis. European Carotid Surgery Trialists' Collaborative Group. Lancet 1991; 337:1235. 61. Mayberg MR, Wilson SE, Yatsu F, et al. Carotid endarterectomy and prevention of cerebral ischemia in symptomatic carotid stenosis. Veterans Affairs Cooperative Studies Program 309 Trialist Group. JAMA 1991; 266:3289. 62. Roederer GO, Langlois YE, Jager KA, et al. The natural history of carotid arterial disease in asymptomatic patients with cervical bruits. Stroke 1984; 15:605. 63. Chambers BR, Norris JW. Outcome in patients with asymptomatic neck bruits. N Engl J Med 1986; 315:860. 64. Meissner I, Wiebers DO, Whisnant JP, O'Fallon WM. The natural history of asymptomatic carotid artery occlusive lesions. JAMA 1987; 258:2704. 65. Suwanwela N, Can U, Furie KL, et al. Carotid Doppler ultrasound criteria for internal carotid artery stenosis based on residual lumen diameter calculated from en bloc carotid endarterectomy specimens. Stroke 1996; 27:1965. 66. Can U, Furie KL, Suwanwela N, et al. Transcranial Doppler ultrasound criteria for hemodynamically significant internal carotid artery stenosis based on residual lumen https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 22/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate diameter calculated from en bloc endarterectomy specimens. Stroke 1997; 28:1966. 67. Johnston SC, Rothwell PM, Nguyen-Huynh MN, et al. Validation and refinement of scores to predict very early stroke risk after transient ischaemic attack. Lancet 2007; 369:283. 68. Perry JJ, Sharma M, Sivilotti ML, et al. Prospective validation of the ABCD2 score for patients in the emergency department with transient ischemic attack. CMAJ 2011; 183:1137. 69. Wardlaw JM, Brazzelli M, Chappell FM, et al. ABCD2 score and secondary stroke prevention: meta-analysis and effect per 1,000 patients triaged. Neurology 2015; 85:373. 70. Sanders LM, Srikanth VK, Blacker DJ, et al. Performance of the ABCD2 score for stroke risk post TIA: meta-analysis and probability modeling. Neurology 2012; 79:971. 71. Stead LG, Suravaram S, Bellolio MF, et al. An assessment of the incremental value of the ABCD2 score in the emergency department evaluation of transient ischemic attack. Ann Emerg Med 2011; 57:46. 72. Amarenco P, Labreuche J, Lavall e PC. Patients with transient ischemic attack with ABCD2 <4 can have similar 90-day stroke risk as patients with transient ischemic attack with ABCD2 4. Stroke 2012; 43:863. 73. Merwick A, Albers GW, Amarenco P, et al. Addition of brain and carotid imaging to the ABCD score to identify patients at early risk of stroke after transient ischaemic attack: a multicentre observational study. Lancet Neurol 2010; 9:1060. 74. Ay H, Gungor L, Arsava EM, et al. A score to predict early risk of recurrence after ischemic stroke. Neurology 2010; 74:128. 75. Yaghi S, Rostanski SK, Boehme AK, et al. Imaging Parameters and Recurrent Cerebrovascular Events in Patients With Minor Stroke or Transient Ischemic Attack. JAMA Neurol 2016; 73:572. 76. Kelly PJ, Albers GW, Chatzikonstantinou A, et al. Validation and comparison of imaging- based scores for prediction of early stroke risk after transient ischaemic attack: a pooled analysis of individual-patient data from cohort studies. Lancet Neurol 2016; 15:1238. 77. Lemmens R, Smet S, Thijs VN. Clinical scores for predicting recurrence after transient ischemic attack or stroke: how good are they? Stroke 2013; 44:1198. 78. Perry JJ, Sharma M, Sivilotti ML, et al. A prospective cohort study of patients with transient ischemic attack to identify high-risk clinical characteristics. Stroke 2014; 45:92. 79. Perry JJ, Sivilotti MLA, mond M, et al. Prospective validation of Canadian TIA Score and comparison with ABCD2 and ABCD2i for subsequent stroke risk after transient ischaemic attack: multicentre prospective cohort study. BMJ 2021; 372:n49. https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 23/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate 80. Arsava EM, Furie KL, Schwamm LH, et al. Prediction of early stroke risk in transient symptoms with infarction: relevance to the new tissue-based definition. Stroke 2011; 42:2186. 81. Maier IL, Bauerle M, Kermer P, et al. Risk prediction of very early recurrence, death and progression after acute ischaemic stroke. Eur J Neurol 2013; 20:599. 82. Arsava EM, Kim GM, Oliveira-Filho J, et al. Prediction of Early Recurrence After Acute Ischemic Stroke. JAMA Neurol 2016; 73:396. Topic 1088 Version 24.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 24/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate GRAPHICS Temporal behavior of symptoms in patients with transient ischemic attack (TIA) The probability density function curve of symptom duration for transient symptoms associated with infarction (TSI) indicates the absence of continuity within the first 24 hours. The probability density function is the probability that the variable takes a value in a given interval and is equal to 1 over its entire range of values. The area under curve is almost equal to 1 at around 200 minutes. Also note that the curves for TIA with or without infarction overlap (p = 0.82). The distribution of duration of symptoms as seen here suggests that symptom duration is not a reliable feature to be used for predicting whether a transient neurological spell is associated with infarction. DWI: diffusion-weighted magnetic resonance imaging. Reproduced with permission from: Ay, H, Koroshetz, WJ, Benner, T, et al. Transient ischemic attack with infarction: a unique syndrome. Ann Neurol 2005; 57:679. Copyright 2005 John Wiley & Sons. Graphic 82729 Version 1.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 25/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Anterior cerebral artery distribution and signs and symptoms of occlusion 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 60945 Version 3.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 26/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Middle cerebral artery distribution and signs and symptoms of occlusion 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 81813 Version 2.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 27/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Posterior cerebral artery distribution and signs and symptoms of occlusion 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 60416 Version 2.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 28/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Superior pontine syndrome 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 53412 Version 1.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 29/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - 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/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 30/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - 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/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 31/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate 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: 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 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 32/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate 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 2 ABCD score <4 and no relevant large artery stenosis or DWI lesion on MRI [if imaging available at this stage]) Once the ischemic mechanism is determined, antithrombotic therapy can be modified as necessary Urgent evaluation

https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 23/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate 80. Arsava EM, Furie KL, Schwamm LH, et al. Prediction of early stroke risk in transient symptoms with infarction: relevance to the new tissue-based definition. Stroke 2011; 42:2186. 81. Maier IL, Bauerle M, Kermer P, et al. Risk prediction of very early recurrence, death and progression after acute ischaemic stroke. Eur J Neurol 2013; 20:599. 82. Arsava EM, Kim GM, Oliveira-Filho J, et al. Prediction of Early Recurrence After Acute Ischemic Stroke. JAMA Neurol 2016; 73:396. Topic 1088 Version 24.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 24/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate GRAPHICS Temporal behavior of symptoms in patients with transient ischemic attack (TIA) The probability density function curve of symptom duration for transient symptoms associated with infarction (TSI) indicates the absence of continuity within the first 24 hours. The probability density function is the probability that the variable takes a value in a given interval and is equal to 1 over its entire range of values. The area under curve is almost equal to 1 at around 200 minutes. Also note that the curves for TIA with or without infarction overlap (p = 0.82). The distribution of duration of symptoms as seen here suggests that symptom duration is not a reliable feature to be used for predicting whether a transient neurological spell is associated with infarction. DWI: diffusion-weighted magnetic resonance imaging. Reproduced with permission from: Ay, H, Koroshetz, WJ, Benner, T, et al. Transient ischemic attack with infarction: a unique syndrome. Ann Neurol 2005; 57:679. Copyright 2005 John Wiley & Sons. Graphic 82729 Version 1.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 25/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Anterior cerebral artery distribution and signs and symptoms of occlusion 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 60945 Version 3.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 26/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Middle cerebral artery distribution and signs and symptoms of occlusion 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 81813 Version 2.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 27/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Posterior cerebral artery distribution and signs and symptoms of occlusion 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 60416 Version 2.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 28/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Superior pontine syndrome 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 53412 Version 1.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 29/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - 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/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 30/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - 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/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 31/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate 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: 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 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 32/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate 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 2 ABCD score <4 and no relevant large artery stenosis or DWI lesion on MRI [if imaging 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: Moderate to vigorous exercise most days of the week for those capable Smoking cessation for recent or current tobacco users Mediterranean diet https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 33/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate 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/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 34/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - 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/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 35/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - 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/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 36/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Severity of carotid stenosis predicts stroke risk Relation between the degree of carotid artery stenosis and the annual risk of stroke. Data from Barnett, HJ, Eliasziw, M, Meldrum, HE, Taylor, DW, Neurology 1996; 46:603. Graphic 60048 Version 1.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 37/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Cerebral ischemia events with asymptomatic carotid artery bruits Incidence of ischemic events in 500 patients with asymptomatic carotid artery bruits according to the severity of carotid artery stenosis on initial Doppler ultrasonography. Patients with 75 percent stenosis were at significantly increased risk (P <0.0001). Data from Chambers BR, Norris JW. Outcome in patients with asymptomatic neck bruits. N Engl J Med 1986; 315:860. Graphic 66153 Version 3.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 38/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of 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/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 39/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Canadian TIA score Items Points Clinical findings First TIA (in lifetime) 2 Symptoms 10 min 2 History of carotid stenosis 2 Already on antiplatelet therapy 3 History of gait disturbance 1 History of unilateral weakness 1 History of vertigo 3 Initial triage diastolic blood pressure 110 mm Hg 3 Dysarthria or aphasia (history or examination) 1 Investigations in emergency department Atrial fibrillation on ECG 2 Infarction (new or old) on CT 1 9 Platelet count 400 10 /L 2 Glucose 15 mmol/L 3 Total score (-3 to 23) TIA: transient ischemic attack; ECG: electrocardiography; CT: computed tomography. From: Perry JJ, Sharma M, Sivilotti ML, et al. A prospective cohort study of patients with transient ischemic attack to identify high-risk clinical characteristics. Stroke 2014; 45:92. DOI: 10.1161/STROKEAHA.113.003085. Copyright American Heart Association. Reproduced with permission from Wolters Kluwer Health. Unauthorized reproduction of this material is prohibited. Graphic 134718 Version 1.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 40/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Contributor Disclosures Natalia S Rost, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Erica Camargo Faye, 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/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 41/41

7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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)")

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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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. Validation and refinement of scores to predict very early stroke risk after transient ischaemic attack. Lancet 2007; 369:283. 4. Perry JJ, Sivilotti MLA, mond M, et al. Prospective validation of Canadian TIA Score and comparison with ABCD2 and ABCD2i for subsequent stroke risk after transient ischaemic https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 16/47 7/6/23, 1:08 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate attack: multicentre prospective cohort study. BMJ 2021; 372:n49. 5. Amarenco P, Labreuche J, Lavall e PC, et al. Does ABCD2 score below 4 allow more time to evaluate patients with a transient ischemic attack? Stroke 2009; 40:3091. 6. Coull AJ, Lovett JK, Rothwell PM, Oxford Vascular Study. Population based study of early risk of stroke after transient ischaemic attack or minor stroke: implications for public education and organisation of services. BMJ 2004; 328:326. 7. Ois A, Gomis M, Rodr guez-Campello A, et al. Factors associated with a high risk of recurrence in patients with transient ischemic attack or minor stroke. Stroke 2008; 39:1717. 8. Coutts SB, Hill MD, Simon JE, et al. Silent ischemia in minor stroke and TIA patients identified on MR imaging. Neurology 2005; 65:513. 9. Fischer U, Baumgartner A, Arnold M, et al. What is a minor stroke? Stroke 2010; 41:661. 10. Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force:, Levine SR, Khatri P, et al. Review, historical context, and clarifications of the NINDS rt-PA stroke trials exclusion criteria: Part 1: rapidly improving stroke symptoms. Stroke 2013; 44:2500. 11. Rothwell PM, Giles MF, Chandratheva A, et al. Effect of urgent treatment of transient ischaemic attack and minor stroke on early recurrent stroke (EXPRESS study): a prospective population-based sequential comparison. Lancet 2007; 370:1432. 12. Luengo-Fernandez R, Li L, Silver L, et al. Long-Term Impact of Urgent Secondary Prevention After Transient Ischemic Attack and Minor Stroke: Ten-Year Follow-Up of the EXPRESS Study. Stroke 2022; 53:488. 13. Lavall e PC, Meseguer E, Abboud H, et al. A transient ischaemic attack clinic with round-the- clock access (SOS-TIA): feasibility and effects. Lancet Neurol 2007; 6:953. 14. Kernan WN, Schindler JL. Rapid intervention for TIA: a new standard emerges. Lancet Neurol 2007; 6:940. 15. Johnston SC, Nguyen-Huynh MN, Schwarz ME, et al. National Stroke Association guidelines for the management of transient ischemic attacks. Ann Neurol 2006; 60:301. 16. Cucchiara BL, Kasner SE. All patients should be admitted to the hospital after a transient ischemic attack. Stroke 2012; 43:1446. 17. Amarenco P. Not all patients should be admitted to the hospital for observation after a transient ischemic attack. Stroke 2012; 43:1448. 18. Molina CA, Selim MM. Hospital admission after transient ischemic attack: unmasking wolves in sheep's clothing. Stroke 2012; 43:1450. 19. Ranta A, Barber PA. Transient ischemic attack service provision: A review of available service models. Neurology 2016; 86:947. https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 17/47 7/6/23, 1:08 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate 20. Amarenco P, Lavall e PC, Labreuche J, et al. One-Year Risk of Stroke after Transient Ischemic Attack or Minor Stroke. N Engl J Med 2016; 374:1533. 21. Wu CM, McLaughlin K, Lorenzetti DL, et al. Early risk of stroke after transient ischemic attack: a systematic review and meta-analysis. Arch Intern Med 2007; 167:2417. 22. Rothwell PM, Warlow CP. Timing of TIAs preceding stroke: time window for prevention is very short. Neurology 2005; 64:817. 23. Edlow JA. Risk stratification in TIA patients: "It's the vascular lesion, stupid!". Neurology 2012; 79:958. 24. Shahjouei S, Li J, Koza E, et al. Risk of Subsequent Stroke Among Patients Receiving Outpatient vs Inpatient Care for Transient Ischemic Attack: A Systematic Review and Meta- analysis. JAMA Netw Open 2022; 5:e2136644. 25. Hastrup S, Johnsen SP, Jensen M, et al. Specialized Outpatient Clinic vs Stroke Unit for TIA and Minor Stroke: A Cohort Study. Neurology 2021. 26. Stead LG, Bellolio MF, Suravaram S, et al. Evaluation of transient ischemic attack in an emergency department observation unit. Neurocrit Care 2009; 10:204. 27. Jarhult SJ, Howell ML, Barnaure-Nachbar I, et al. Implementation of a Rapid, Protocol-based TIA Management Pathway. West J Emerg Med 2018; 19:216. 28. Tuna MA, Rothwell PM, Oxford Vascular Study. Diagnosis of non-consensus transient ischaemic attacks with focal, negative, and non-progressive symptoms: population-based validation by investigation and prognosis. Lancet 2021; 397:902. 29. Redgrave JN, Coutts SB, Schulz UG, et al. Systematic review of associations between the presence of acute ischemic lesions on diffusion-weighted imaging and clinical predictors of early stroke risk after transient ischemic attack. Stroke 2007; 38:1482. 30. Ay H, Oliveira-Filho J, Buonanno FS, et al. 'Footprints' of transient ischemic attacks: a diffusion-weighted MRI study. Cerebrovasc Dis 2002; 14:177. 31. Ay H, Koroshetz WJ, Benner T, et al. Transient ischemic attack with infarction: a unique syndrome? Ann Neurol 2005; 57:679. 32. Kidwell CS, Alger JR, Di Salle F, et al. Diffusion MRI in patients with transient ischemic attacks. Stroke 1999; 30:1174. 33. Ay H, Buonanno FS, Rordorf G, et al. Normal diffusion-weighted MRI during stroke-like deficits. Neurology 1999; 52:1784. 34. Saber Tehrani AS, Kattah JC, Mantokoudis G, et al. Small strokes causing severe vertigo: frequency of false-negative MRIs and nonlacunar mechanisms. Neurology 2014; 83:169. https://www.uptodate.com/contents/initial-evaluation-and-management-of-transient-ischemic-attack-and-minor-ischemic-stroke/print 18/47 7/6/23, 1:08 PM Initial evaluation and management of transient ischemic attack and minor ischemic stroke - UpToDate 35. Edlow BL, Hurwitz S, Edlow JA. Diagnosis of DWI-negative acute ischemic stroke: A meta- analysis. Neurology 2017; 89:256. 36. Felfeli P, Wenz H, Al-Zghloul M, et al. Combination of standard axial and thin-section coronal diffusion-weighted imaging facilitates the diagnosis of brainstem infarction. Brain Behav 2017; 7:e00666. 37. Sch nfeld MH, Ritzel RM, Kemmling A, et al. Improved detectability of acute and subacute brainstem infarctions by combining standard axial and thin-sliced sagittal DWI. PLoS One 2018; 13:e0200092. 38. Giles MF, Rothwell PM. 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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.

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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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 7/6/23, 1:08 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

7/6/23, 1:08 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack : Natalia S Rost, MD, MPH, Shadi Yaghi, MD, 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 18, 2023. INTRODUCTION This topic will review the treatment of specific causes of transient ischemic attack (TIA) and ischemic stroke where the potential cause has been identified, emphasizing secondary prevention of recurrent cerebral ischemia and other vascular events. Risk factor management, which is appropriate for all patients with ischemic stroke or TIA, is reviewed in detail elsewhere. (See "Overview of secondary prevention of ischemic stroke".) The initial assessment of patients with cerebral ischemia and acute therapy for ischemic stroke 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".) MEDICAL THERAPY Most patients with an ischemic stroke or TIA should be treated with all available risk reduction strategies, including antithrombotic therapy ( algorithm 1 and algorithm 2), blood pressure reduction, low-density lipoprotein lowering therapy, and lifestyle modification. These strategies are reviewed in detail separately: Overview of secondary prevention of ischemic stroke Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 1/25 7/6/23, 1:08 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate Long-term antithrombotic therapy for the secondary prevention of ischemic stroke Antihypertensive therapy for secondary stroke prevention LARGE ARTERY DISEASE Options for the secondary prevention of ischemic stroke or TIA caused by large artery disease include revascularization for symptomatic internal carotid artery stenosis due to atherosclerosis, and multifactorial risk reduction including treatment with antiplatelet agents, blood pressure control, and low-density lipoprotein cholesterol (LDL-C) lowering therapy. The role of anticoagulation in this setting is quite limited. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) Some specific situations are discussed below for atheromatous carotid, vertebral, and intracranial disease, and for nonatheromatous causes including carotid web, dissection, fibromuscular dysplasia, and moyamoya. Symptomatic carotid stenosis The treatment of symptomatic extracranial carotid atherosclerotic disease requires intensive medical management and may include carotid revascularization with carotid endarterectomy or carotid artery stenting. The importance of medical management, the identification of patients likely to benefit from revascularization, and the choice of revascularization procedure are discussed in detail separately. (See "Management of symptomatic carotid atherosclerotic disease".) Carotid occlusion Carotid artery occlusion may occur without clear symptoms, but it can be associated with TIA and stroke. Older data suggest that the subsequent yearly risk of a stroke ipsilateral to the occluded carotid artery is 2 to 5 percent [1,2]; later retrospective data suggest that the rate of early neurologic deterioration or recurrent stroke after symptomatic carotid occlusion ranges from 8 to 30 percent [3]. In most cases, medical management is the only practical option in the setting of chronic carotid occlusion. Data from small observational studies suggest that recanalization can be achieved by stenting of extracranial carotid artery occlusion [4], but clinical benefit is uncertain. Surgical revascularization is a viable option only when residual flow can be demonstrated in the internal carotid artery (ie, near occlusion), but efficacy is likewise unproven. (See "Management of symptomatic carotid atherosclerotic disease", section on 'Patients unlikely to benefit'.) With acute ischemic stroke related to extracranial internal carotid artery occlusion and a tandem intracranial large artery occlusion, treatment options include acute stenting and/or angioplasty of the extracranial carotid artery combined with mechanical thrombectomy of the intracranial https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 2/25 7/6/23, 1:08 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate occlusion. (See "Mechanical thrombectomy for acute ischemic stroke", section on 'Approach to tandem lesions'.) For isolated acute symptomatic internal carotid artery occlusion, the optimal treatment is uncertain. Limited retrospective data from small observational studies suggest that urgent stenting results in a high revascularization rate, but benefit is unproven [5]. More data are needed to determine whether early secondary prevention with endovascular treatment improves outcomes compared with maximal medical therapy [3]. Historically, some experts used short-term (three to six months) anticoagulation for acute symptomatic occlusion; the rationale for this approach is based on limited evidence that emboli may form and propagate from the stump of the occluded artery after acute occlusion [6,7], but the risk and benefit of such an approach, particularly when compared with dual antiplatelet therapy, remains uncertain. An earlier randomized, controlled trial in patients with symptomatic carotid narrowing or occlusion found that surgical treatment using extracranial to intracranial bypass failed to reduce the risk of ischemic stroke [8], and the later Carotid Occlusion Surgery Study (COSS) trial in patients with symptomatic carotid occlusion and hemodynamic cerebral ischemia also found no benefit for extracranial to intracranial bypass surgery compared with medical therapy alone [9]. Carotid web Carotid web, considered a variant of fibromuscular dysplasia (see 'Fibromuscular dysplasia' below), is a shelf-like projection of intimal fibrous tissue of the internal carotid artery bulb that can be focal or multifocal [10]. It may appear as a filling defect on computed tomographic angiography, magnetic resonance angiography, or conventional contrast angiography (eg, digital subtraction angiography) [11,12]. Carotid web is rarely associated with severe stenosis. However, carotid web may alter hemodynamic flow and increase the risk of platelet aggregation leading to thromboembolism [13]. The optimal management of symptomatic carotid web is uncertain. The 2021 American Heart Association/American Stroke Association guidelines recommend antiplatelet therapy for secondary stroke prevention [14]. The guidelines also note that the risk of recurrent stroke in medically treated patients with symptomatic carotid web is high, and carotid stenting or endarterectomy may be considered to prevent recurrent events, particularly in patients who have a recurrent ischemic stroke despite medical treatment. Extracranial vertebral artery stenosis In most cases, prevention of ischemic stroke and TIA due to extracranial vertebral artery stenosis is managed by intensive medical treatment and multifactorial risk reduction, including the use of antiplatelet agents ( algorithm 1 and https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 3/25 7/6/23, 1:08 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate algorithm 2), antihypertensive drugs, and LDL-C lowering therapy [14]. In addition, angioplasty and stenting is a treatment option [15-18], and surgical transposition of the vertebral artery to the common carotid artery is another alternative for vertebral origin stenosis. However, efficacy for these procedures is uncertain [14,18,19]. In an analysis that pooled individual patient data from three trials comparing stenting with medical treatment for the subgroup with symptomatic extracranial vertebral artery stenosis, there was no significant difference in the risk of any stroke in the stenting group compared with the medical treatment group (hazard ratio [HR] 0.63, 95% CI 0.27-1.46) [18]. Thus, extracranial vertebral artery revascularization is generally considered only when maximal medical therapy has failed to prevent embolism or low-flow recurrent ischemic events. Intracranial large artery atherosclerosis Atherosclerotic stenosis of the major intracranial arteries (carotid siphon, middle cerebral artery, vertebral artery, and basilar artery) is an important cause of ischemic stroke, particularly in Black, Asian, and Hispanic populations. Patients with TIA or ischemic stroke attributed to intracranial atherosclerosis should receive intensive medical management with antiplatelet therapy ( algorithm 1 and algorithm 2) and strict control of vascular risk factors, including the blood pressure control, LDL-C lowering therapy, and physical activity and other lifestyle modification (eg, smoking cessation, weight control, salt restriction, and a healthy diet). (See "Intracranial large artery atherosclerosis: Treatment and prognosis", section on 'Secondary prevention'.) Evidence from randomized controlled trials indicates that intensive medical management is superior to stenting for patients with recently symptomatic high-grade intracranial large artery stenosis [20]. (See "Intracranial large artery atherosclerosis: Treatment and prognosis", section on 'Stenting'.) Dissection Beyond the hyperacute period, antithrombotic therapy with either anticoagulation or antiplatelet drugs is an accepted treatment for ischemic stroke and TIA caused by dissection, although there is controversy regarding the choice between the two. The management of cerebral and cervical artery dissection is reviewed in detail separately. (See "Cerebral and cervical artery dissection: Treatment and prognosis".) Fibromuscular dysplasia Fibromuscular dysplasia (FMD) is a noninflammatory, nonatherosclerotic disorder that leads to arterial stenosis, occlusion, intraluminal thrombus, aneurysm, dissection, and arterial tortuosity [21]. The most frequently involved arteries are the renal and internal carotid arteries, followed by the vertebral, visceral, and external iliac arteries. Disease presentation may vary widely, depending upon the arterial segment involved and the severity of disease. TIA and ischemic stroke are potential manifestations of carotid or vertebral https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 4/25 7/6/23, 1:08 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate artery FMD; hypertension is the most common presenting sign of renal artery FMD. (See "Clinical manifestations and diagnosis of fibromuscular dysplasia".) In patients with an ischemic stroke or TIA attributed to FMD, secondary prevention measures include antiplatelet therapy, blood pressure control, and lifestyle modification [14]. For patients with recurrent ischemic stroke or TIA attributed to carotid artery FMD, treatment using angioplasty with or without stenting is an option [14]. Moyamoya Moyamoya disease (MMD) is a unique cerebrovascular disorder characterized by progressive large intracranial artery narrowing and the development of prominent small vessel collaterals in patients who may have genetic susceptibilities but no underlying risk factors. Moyamoya syndrome (MMS) refers to patients with moyamoya angiographic findings who also have an associated medical condition. (See "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis", section on 'Classification and terminology'.) Ischemic stroke and TIA affecting the anterior circulation are the most common clinical presentations. Hemorrhagic complications of moyamoya, mainly intracerebral hemorrhage, represent a significant clinical burden, particularly in adults. (See "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis", section on 'Clinical presentations'.) Secondary stroke prevention for patients with symptomatic moyamoya is largely centered on surgical revascularization techniques. Antiplatelet therapy is reasonable [14], but evidence regarding clinical benefit is limited. In adults, hemorrhage may be the predominant manifestation of moyamoya, and anticoagulation is generally not recommended. (See "Moyamoya disease and moyamoya syndrome: Treatment and prognosis".) For children and adults with asymptomatic or symptomatic ischemic MMD or MMS, some experts use long-term therapy with aspirin or cilostazol. This also applies to patients who undergo surgical revascularization. Rotational vertebral artery syndrome (bow hunter) Rotational vertebral artery syndrome is a rare cause of posterior circulation stroke due to vertebral artery compression by bony elements of the cervical spine (usually at C1 to C2) during physiologic head rotation. Antithrombotic therapy is reasonable in patients with ischemic stroke or TIA, and surgical interventions may be considered in patients who have recurrent ischemic symptoms while on antithrombotic treatment. (See "Posterior circulation cerebrovascular syndromes", section on 'Extracranial vertebral arteries' and "Causes of vertigo", section on 'Rotational vertebral artery syndrome'.) https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 5/25 7/6/23, 1:08 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate SMALL ARTERY DISEASE Cerebral small artery disease, often referred to as small vessel disease, may cause a TIA or lacunar infarction due to the occlusion of a small penetrating branch of a large cerebral artery. (See "Lacunar infarcts".) Early antiplatelet therapy is indicated for most patients with TIA or acute ischemic stroke due to small artery disease who are not receiving oral anticoagulants, as shown in the algorithms ( algorithm 1 and algorithm 2). In the acute setting, most patients with a low-risk TIA or moderate to major ischemic stroke are treated with aspirin alone; patients with a high-risk TIA or minor ischemic stroke may benefit from dual antiplatelet therapy using aspirin and clopidogrel for 21 days rather than aspirin alone. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Efficacy of DAPT'.) Beyond the acute phase of stroke, long-term antiplatelet therapy for secondary stroke prevention should be continued with either aspirin, clopidogrel, or the combination of aspirin- extended-release dipyridamole, although use of the latter has become increasingly rare in practice. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) In addition to antiplatelet therapy, attention to hypertension, serum lipids, blood glucose, and other modifiable risk factors is important for preventing lacunar strokes in patients with small artery disease. (See "Overview of secondary prevention of ischemic stroke".) CARDIOGENIC EMBOLISM Cardiogenic embolism is responsible for 14 to 30 percent of ischemic strokes [22]. In addition to atrial fibrillation, cardiac sources of embolism for which anticoagulation therapy may be indicated include left ventricular thrombus, cardiomyopathy, valvular disease, and congenital heart disease [14]. Minor potential sources of cardiogenic embolism include patent foramen ovale (PFO), left ventricular regional wall motion abnormalities, severe mitral annular calcification, mitral valve prolapse, mitral valve strands, and aortic valve disease ( table 1) [23]. The risk of stroke associated with these sources is low or uncertain, and except for PFO, the efficacy of and need for specific treatment is undefined [24]. Atrial fibrillation Atrial fibrillation is a major risk factor for ischemic stroke. Anticoagulation with one of the direct oral anticoagulants (DOACs; dabigatran, rivaroxaban, apixaban, or https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 6/25 7/6/23, 1:08 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate edoxaban) or warfarin is the most effective treatment to reduce stroke risk [14]. In most patients with atrial fibrillation, DOACs are preferred over warfarin due to convenience and lower risk of intracranial hemorrhage [25]. This subject is reviewed in greater detail elsewhere. (See "Stroke in patients with atrial fibrillation" and "Atrial fibrillation in adults: Use of oral anticoagulants".) For secondary stroke prevention, virtually all patients with atrial fibrillation who have a history of stroke or TIA of cardioembolic origin should be treated with lifelong anticoagulation in the absence of contraindications. (See "Stroke in patients with atrial fibrillation", section on 'Long- term anticoagulation'.) Placement of a left atrial appendage occlusion device may be an option for patients with nonvalvular atrial fibrillation who have a contraindication to long-term anticoagulation or strong preference to avoid long-term anticoagulation. (See "Atrial fibrillation: Left atrial appendage occlusion".) In rare cases when the patient is unwilling or unable to take anticoagulation despite careful consideration of the advantages of oral anticoagulation, or is not a candidate for left atrial appendage occlusion device placement, dual antiplatelet therapy is an alternative to therapy with aspirin alone. This issue is discussed in detail separately. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Alternatives to anticoagulation'.) Cardiac tumors Cardiac tumors, mainly left-sided myxoma and fibroelastoma, are rare causes of cardioembolic TIA or ischemic stroke. Surgical tumor resection via open heart surgery is the main treatment option to prevent recurrent stroke [14]. (See "Cardiac tumors".) Congenital heart disease Patients with cyanotic congenital heart disease are at increased risk for thromboembolism. The 2021 American Heart Association (AHA)/American Stroke Association (ASA) guidelines state that it is reasonable to treat patients with cardioembolic ischemic stroke or TIA attributed to congenital heart disease with warfarin anticoagulation [14]. (See "Medical management of cyanotic congenital heart disease in adults", section on 'Thromboembolism'.) The Fontan procedure is a palliative operation that diverts systemic venous return to the lungs in patients with an anatomic or functional single ventricle. For patients with Fontan circulation who have a history of thromboembolism, warfarin anticoagulation is advised [14]. (See "Overview of the management and prognosis of patients with Fontan circulation" and "Management of complications in patients with Fontan circulation", section on 'Thrombosis'.) Cardiomyopathy For patients in sinus rhythm with prior ischemic stroke or TIA who have either dilated cardiomyopathy (left ventricular ejection fraction 35 percent) or restrictive https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 7/25 7/6/23, 1:08 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate cardiomyopathy, and without evidence of left atrial or left ventricular thrombus, the 2021 AHA/ASA guidelines note that the effectiveness of anticoagulation compared with antiplatelet therapy is uncertain, and the choice should be individualized [14]. The role of antithrombotic treatment for individuals with heart failure and prior thromboembolic events is reviewed in greater detail elsewhere. (See "Antithrombotic therapy in patients with heart failure".) Left ventricular thrombus Patients with left ventricular thrombus in the specific setting of an acute myocardial infarction have a significantly increased risk of embolic events. The 2021 American Heart Association/American Stroke Association guidelines state that patients with ischemic stroke or TIA in the setting of a left ventricular mural thrombus should be treated with warfarin (target international normalized ratio 2.5; range 2 to 3) for at least three months [14]. Despite very limited supporting evidence, some experts consider using a DOAC rather than warfarin due to convenience, as long as there is no specific indication for warfarin (eg, prosthetic heart valve). The issue of left ventricular thrombus and acute myocardial infarction is discussed in greater detail separately. (See "Left ventricular thrombus after acute myocardial infarction".) Patent foramen ovale Patent foramen ovale (PFO) device closure is more effective than medical therapy alone for select patients 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). Evaluation and treatment are discussed in detail separately. (See "Stroke associated with patent foramen ovale (PFO): Evaluation".) Valvular disease With atrial fibrillation Patients with atrial fibrillation and valvular heart disease should be treated with oral anticoagulation. The choice between warfarin and DOAC therapy depends upon the type of underlying valvular disease; warfarin is generally preferred for patients with atrial fibrillation and moderate to severe mitral stenosis or a mechanical heart valve, while a DOAC may be preferred for patients with atrial fibrillation and other types of valvular disease (eg, mild mitral stenosis, bioprosthetic valves, or native aortic, pulmonary, or tricuspid valve disease) [14]. (See "Atrial fibrillation in adults: Use of oral anticoagulants", section on 'Patients with valvular heart disease' and "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism'.) Without atrial fibrillation For patients in sinus rhythm with ischemic stroke or TIA and native valvular disease or bioprosthetic heart valves, the 2021 AHA/ASA guidelines recommend antiplatelet therapy [14]. This includes patients with mitral annular calcification or mitral valve prolapse. https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 8/25 7/6/23, 1:08 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate The 2021 AHA/ASA guidelines state that the role of oral anticoagulation has not been adequately studied for patients who have rheumatic mitral valve disease without atrial fibrillation and no other likely cause for ischemic stroke or TIA [14]. However, some experts consider a prior embolic event in patients with moderate to severe mitral stenosis as one of the indications for long-term oral anticoagulation with a vitamin K antagonist. (See "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism'.) Note that paroxysmal occult atrial fibrillation and infective endocarditis should be considered as potential causes when embolization occurs in patients with mitral stenosis who are in sinus rhythm. Mitral and aortic valvular disease is reviewed in greater detail elsewhere. (See "Clinical manifestations and diagnosis of mitral annular calcification" and "Clinical manifestations and diagnosis of aortic stenosis in adults", section on 'Embolic events' and "Arrhythmic complications of mitral valve prolapse".) Mechanical heart valves All prosthetic heart valves require antithrombotic prophylaxis [14,26]. Antithrombotic therapy for mechanical and bioprosthetic heart valves is discussed in detail separately. (See "Antithrombotic therapy for mechanical heart valves" and "Overview of the management of patients with prosthetic heart valves", section on 'Antithrombotic therapy'.) Infective endocarditis Infective endocarditis is an important cause of embolic stroke and TIA for which anticoagulation is hazardous. Endocarditis must be excluded in any patient with a TIA or stroke and other suggestive findings such as fever and a heart murmur. Treatment consists of antibiotic therapy for the infection. Early valve surgery is indicated for patients with left-sided native valve infective endocarditis and one or more additional features, including symptoms or signs of heart failure, complicated infection, persistent infection, and/or recurrent embolic events. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis" and "Antimicrobial therapy of left-sided native valve endocarditis" and "Antithrombotic therapy in patients with infective endocarditis".). AORTIC ATHEROSCLEROSIS There are conflicting data regarding the stroke risk associated with aortic atherosclerosis. However, most reports evaluating secondary stroke risk have found that complex aortic https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 9/25 7/6/23, 1:08 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate atherosclerosis is a risk factor for recurrent stroke, especially for aortic plaques 4 mm and mobile plaques. This issue is discussed separately. (See "Stroke: Etiology, classification, and epidemiology", section on 'Aortic atherosclerosis'.) The optimal treatment for patients with stroke or TIA attributed to aortic disease is not clear; the 2021 American Heart Association/American Stroke Association (AHA/ASA) guidelines recommend antiplatelet therapy (including short-term dual antiplatelet therapy for minor stroke) and intensive lipid management to a low-density lipoprotein cholesterol target <70 mg/dL to prevent recurrent stroke [14]. Medical therapy for secondary prevention of aortic atheromatous disease is discussed in greater detail separately. (See "Thromboembolism from aortic plaque", section on 'Treatment'.) The open-label ARCH trial was terminated prematurely due to slow recruitment and is therefore inconclusive [27]. The ARCH trial enrolled 349 adults with ischemic stroke, TIA, or peripheral embolism who had thoracic aortic plaque 4 mm and no other identified embolic source; patients were randomly assigned to treatment with dual antiplatelet therapy (aspirin 75 to 150 mg daily in combination with clopidogrel 75 mg daily) or warfarin (target international normalized ratio 2.5). At a median follow-up of 3.4 years, the primary endpoint, a composite of cerebral infarction, myocardial infarction, peripheral embolism, vascular death, or intracranial hemorrhage, was lower in the antiplatelet group compared with the warfarin group (7.6 versus 11.3 percent, respectively), but the difference was not statistically significant (adjusted hazard ratio 0.76, 95% CI 0.36-1.61). SICKLE CELL DISEASE Stroke is a frequent complication of sickle cell disease (SCD), and the risk of recurrent stroke is high. Stroke risk can be reduced with chronic transfusion therapy. (See "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease" and "Prevention of stroke (initial or recurrent) in sickle cell disease".) For patients with SCD and ischemic stroke or TIA, the 2014 American Heart Association/American Stroke Association (AHA/ASA) guidelines recommend regular blood transfusions to reduce hemoglobin S to <30 percent of total hemoglobin [14]. In addition, the guidelines note that treatment with hydroxyurea is reasonable if transfusion therapy is not available or practical. General measures including traditional stroke risk factor identification and management as well as the use of antiplatelet agents (for prior ischemic stroke) are also reasonable. https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 10/25 7/6/23, 1:08 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate The prevention of stroke in patients with SCD is discussed in greater detail separately. (See "Prevention of stroke (initial or recurrent) in sickle cell disease".) HYPERCOAGULABLE STATES Antiphospholipid syndrome The antiphospholipid syndrome (APS) is a hypercoagulable state characterized by recurrent arterial or venous thromboembolism, or pregnancy loss, in association with antibodies directed against plasma proteins that may be bound to anionic phospholipids. The presence of such antibodies may be detected as lupus anticoagulants, anticardiolipin antibodies, or anti-beta2 glycoprotein-I antibodies. (See "Diagnosis of antiphospholipid syndrome".) This disorder has been referred to as primary antiphospholipid syndrome when it occurs alone; however, it can also be seen in association with systemic lupus erythematosus, other rheumatic disorders, and autoimmune diseases. (See "Clinical manifestations of antiphospholipid syndrome".) Due to the high rate of recurrent thrombosis, long-term anticoagulation is the mainstay of therapy for patients with thrombotic APS. However, for patients with arterial thromboembolism, including ischemic stroke, data on the optimal therapeutic approach to prevent recurrent thromboembolism are limited. While experts agree that anticoagulation with warfarin (international normalized ratio range, 2 to 3) is the first-line therapy for patients with APS and arterial thromboembolism, some suggest adding low-dose aspirin for most patients with arterial events, particularly those with additional risk factors for atherosclerotic vascular disease. Direct oral anticoagulants (DOACs) may be less effective than warfarin for thrombosis prevention, particularly among patients with known or possible APL who are considered high risk and/or have a history of arterial thrombosis. (See "Management of antiphospholipid syndrome", section on 'Secondary thrombosis prevention'.) Inherited thrombophilias Inherited thrombophilias are hypercoagulable states that include a number of disorders: Protein C deficiency Protein S deficiency Antithrombin III deficiency Activated protein C resistance Factor V Leiden as a cause of activated protein C resistance Prothrombin G20210A mutation https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 11/25 7/6/23, 1:08 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate These conditions are thought to be rare causes of ischemic stroke in adults, but may be more important causes of ischemic stroke in children. (See "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors", section on 'Hematologic'.) The 2021 American Heart Association/American Stroke Association (AHA/ASA) guidelines note that it is uncertain whether testing for these hematologic traits is beneficial in the context of secondary stroke prevention [14]. Suspicion for hypercoagulable states as the cause of stroke may be heightened in younger patients with cryptogenic stroke, a history or family history of unprovoked thrombosis, prior spontaneous abortion, or concomitant systemic signs and symptoms suggestive of hypercoagulability. The same guidelines note that for patients with ischemic stroke or TIA of unknown source (despite a thorough diagnostic evaluation) who are found to have an inherited thrombophilia, antiplatelet treatment is reasonable to reduce the risk of recurrent stroke or TIA [14]. The evaluation and management of these conditions is discussed in greater detail separately. (See "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" and "Cerebral venous thrombosis: Treatment and prognosis".) Cancer-related hypercoagulable state Patients with cancer may be at increased risk for stroke due to hypercoagulability and other potential mechanisms, including compression or invasion of blood vessels, marantic endocarditis, infections, paraneoplastic disorders, and complications of cancer therapies [28,29]. (See "Cancer-associated hypercoagulable state: Causes and mechanisms".) For patients with TIA or ischemic stroke attributed to cancer hypercoagulability, optimal treatment for secondary stroke prevention is unknown, and data are limited [29]. Empiric treatment with low molecular weight heparin is often used, but the clinical risk and benefit compared with antiplatelets remains uncertain [30]. In patients with venous thromboembolism (VTE) and cancer, anticoagulant therapy is the mainstay of treatment. Low molecular weight heparin or DOACs are preferred in patients without renal insufficiency, whereas warfarin is the preferred treatment in patients with renal insufficiency (eg, creatinine clearance <30 mL/minute). (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy".) The 2021 AHA/ASA guidelines note only that in the setting of atrial fibrillation and cancer, it is reasonable to consider anticoagulation with DOACs in preference to warfarin for stroke prevention [14]. https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 12/25 7/6/23, 1:08 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate CRYPTOGENIC STROKE Cryptogenic stroke is variably defined and generally designates the category of brain infarction that is not attributed to an established source of cardioembolism, large artery atherosclerosis, small artery disease, or other determined cause of stroke. However, the term cryptogenic stroke has been applied to patients with an incomplete diagnostic evaluation, a complete but unrevealing evaluation, or an evaluation that identifies multiple potential causes of stroke. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Classification'.) Embolic stroke of undetermined source (ESUS) is a subcategory of cryptogenic stroke defined as a nonlacunar brain infarct without proximal arterial stenosis or cardioembolic sources; ESUS requires a full standardized stroke evaluation to exclude other causes. While the less well- defined term of cryptogenic stroke has been reported to account for approximately 25 to 40 percent of ischemic strokes, the more specific term of ESUS consistently accounts for approximately 20 percent of ischemic strokes. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Embolic stroke of undetermined source'.) For secondary prevention, most patients with a cryptogenic ischemic stroke or TIA should be treated with blood pressure control, low-density lipoprotein cholesterol lowering therapy, and lifestyle modification. Initial antiplatelet therapy is advised while awaiting the results of long- term cardiac monitoring. For patients initially diagnosed with cryptogenic stroke who have atrial fibrillation of any duration detected on long-term monitoring, even if detected remotely from the incident stroke, anticoagulant therapy with warfarin or a direct oral anticoagulant is advised rather than antiplatelet therapy. (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" and "Society guideline links: Fibromuscular dysplasia".) 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 https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 13/25 7/6/23, 1:08 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate 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: Transient ischemic attack (Beyond the Basics)" and "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)" and "Patient education: Ischemic stroke treatment (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Large artery disease Secondary prevention for ischemic stroke or transient ischemic attack (TIA) attributed to large artery disease may include the following measures: Symptomatic internal carotid stenosis In addition to medical management, revascularization is generally beneficial for patients with recently symptomatic internal carotid artery atherosclerotic stenosis with 50 to 99 percent luminal narrowing. In the setting of complete carotid occlusion, medical management is the only practical option. (See 'Symptomatic carotid stenosis' above.) Extracranial vertebral artery In most cases, ischemic stroke and TIA due to extracranial vertebral artery stenosis is managed by intensive medical treatment with multifactorial risk reduction. (See 'Extracranial vertebral artery stenosis' above.) Intracranial atherosclerosis Aggressive medical management is superior to stenting for patients with recently symptomatic high-grade intracranial large artery stenosis.

These conditions are thought to be rare causes of ischemic stroke in adults, but may be more important causes of ischemic stroke in children. (See "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors", section on 'Hematologic'.) The 2021 American Heart Association/American Stroke Association (AHA/ASA) guidelines note that it is uncertain whether testing for these hematologic traits is beneficial in the context of secondary stroke prevention [14]. Suspicion for hypercoagulable states as the cause of stroke may be heightened in younger patients with cryptogenic stroke, a history or family history of unprovoked thrombosis, prior spontaneous abortion, or concomitant systemic signs and symptoms suggestive of hypercoagulability. The same guidelines note that for patients with ischemic stroke or TIA of unknown source (despite a thorough diagnostic evaluation) who are found to have an inherited thrombophilia, antiplatelet treatment is reasonable to reduce the risk of recurrent stroke or TIA [14]. The evaluation and management of these conditions is discussed in greater detail separately. (See "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" and "Cerebral venous thrombosis: Treatment and prognosis".) Cancer-related hypercoagulable state Patients with cancer may be at increased risk for stroke due to hypercoagulability and other potential mechanisms, including compression or invasion of blood vessels, marantic endocarditis, infections, paraneoplastic disorders, and complications of cancer therapies [28,29]. (See "Cancer-associated hypercoagulable state: Causes and mechanisms".) For patients with TIA or ischemic stroke attributed to cancer hypercoagulability, optimal treatment for secondary stroke prevention is unknown, and data are limited [29]. Empiric treatment with low molecular weight heparin is often used, but the clinical risk and benefit compared with antiplatelets remains uncertain [30]. In patients with venous thromboembolism (VTE) and cancer, anticoagulant therapy is the mainstay of treatment. Low molecular weight heparin or DOACs are preferred in patients without renal insufficiency, whereas warfarin is the preferred treatment in patients with renal insufficiency (eg, creatinine clearance <30 mL/minute). (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy".) The 2021 AHA/ASA guidelines note only that in the setting of atrial fibrillation and cancer, it is reasonable to consider anticoagulation with DOACs in preference to warfarin for stroke prevention [14]. https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 12/25 7/6/23, 1:08 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate CRYPTOGENIC STROKE Cryptogenic stroke is variably defined and generally designates the category of brain infarction that is not attributed to an established source of cardioembolism, large artery atherosclerosis, small artery disease, or other determined cause of stroke. However, the term cryptogenic stroke has been applied to patients with an incomplete diagnostic evaluation, a complete but unrevealing evaluation, or an evaluation that identifies multiple potential causes of stroke. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Classification'.) Embolic stroke of undetermined source (ESUS) is a subcategory of cryptogenic stroke defined as a nonlacunar brain infarct without proximal arterial stenosis or cardioembolic sources; ESUS requires a full standardized stroke evaluation to exclude other causes. While the less well- defined term of cryptogenic stroke has been reported to account for approximately 25 to 40 percent of ischemic strokes, the more specific term of ESUS consistently accounts for approximately 20 percent of ischemic strokes. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)", section on 'Embolic stroke of undetermined source'.) For secondary prevention, most patients with a cryptogenic ischemic stroke or TIA should be treated with blood pressure control, low-density lipoprotein cholesterol lowering therapy, and lifestyle modification. Initial antiplatelet therapy is advised while awaiting the results of long- term cardiac monitoring. For patients initially diagnosed with cryptogenic stroke who have atrial fibrillation of any duration detected on long-term monitoring, even if detected remotely from the incident stroke, anticoagulant therapy with warfarin or a direct oral anticoagulant is advised rather than antiplatelet therapy. (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" and "Society guideline links: Fibromuscular dysplasia".) 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 https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 13/25 7/6/23, 1:08 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate 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: Transient ischemic attack (Beyond the Basics)" and "Patient education: Stroke symptoms and diagnosis (Beyond the Basics)" and "Patient education: Ischemic stroke treatment (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Large artery disease Secondary prevention for ischemic stroke or transient ischemic attack (TIA) attributed to large artery disease may include the following measures: Symptomatic internal carotid stenosis In addition to medical management, revascularization is generally beneficial for patients with recently symptomatic internal carotid artery atherosclerotic stenosis with 50 to 99 percent luminal narrowing. In the setting of complete carotid occlusion, medical management is the only practical option. (See 'Symptomatic carotid stenosis' above.) Extracranial vertebral artery In most cases, ischemic stroke and TIA due to extracranial vertebral artery stenosis is managed by intensive medical treatment with multifactorial risk reduction. (See 'Extracranial vertebral artery stenosis' above.) Intracranial atherosclerosis Aggressive medical management is superior to stenting for patients with recently symptomatic high-grade intracranial large artery stenosis. (See 'Intracranial large artery atherosclerosis' above.) Arterial dissection Antithrombotic therapy with either antiplatelet or anticoagulant agents is used for the secondary prevention of ischemic stroke and TIA caused by cervical arterial dissection. (See 'Dissection' above.) https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 14/25 7/6/23, 1:08 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate Small artery disease Antiplatelet therapy and treatment of modifiable risk factors is the mainstay for secondary stroke prevention in patients with lacunar stroke or TIA due to small artery disease. (See 'Small artery disease' above.) Cardiogenic embolism Virtually all patients with atrial fibrillation who have a history of stroke or TIA should be treated with oral anticoagulation in the absence of contraindications. (See 'Atrial fibrillation' above.) Other cardiac sources of embolism for which anticoagulation is often indicated include: Left ventricular thrombus (see 'Left ventricular thrombus' above) Cardiomyopathy (see 'Cardiomyopathy' above) Prosthetic heart valves (see 'Valvular disease' above) Moderate to severe mitral stenosis, even in the absence of atrial fibrillation (see 'Valvular disease' above) Congenital heart disease (see 'Congenital heart disease' above) Patent foramen ovale (PFO) device closure is more effective than medical therapy alone for select patients with a PFO-associated stroke. Evaluation and treatment are discussed in detail separately. (See "Stroke associated with patent foramen ovale (PFO): Evaluation".) Aortic atherosclerosis The optimal treatment for the prevention of ischemic stroke and TIA attributed to aortic arch atherosclerosis is not clear. Medical management with antiplatelet and low-density lipoprotein cholesterol lowering therapy is reasonable. (See 'Aortic atherosclerosis' above.) Sickle cell disease Stroke is a frequent complication of sickle cell disease, and the risk of recurrent stroke is high. Stroke risk can be reduced with chronic transfusion therapy. (See 'Sickle cell disease' above and "Prevention of stroke (initial or recurrent) in sickle cell disease".) Hypercoagulable states Anticoagulation with warfarin is the gold standard for patients with antiphospholipid syndrome and arterial thromboembolism; some experts add low- dose aspirin for selected patients with arterial events who also have additional risk factors for atherosclerotic vascular disease. With TIA or ischemic stroke attributed to cancer hypercoagulability, the optimal treatment for secondary stroke prevention is unknown. Inherited thrombophilias are thought to be rare causes of ischemic stroke in adults. For patients with ischemic stroke or TIA of unknown source (despite a thorough diagnostic https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 15/25 7/6/23, 1:08 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate evaluation) who are found to have an inherited thrombophilia, antiplatelet treatment is reasonable. (See 'Hypercoagulable states' above.) 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. Klijn CJ, Kappelle LJ, Tulleken CA, van Gijn J. Symptomatic carotid artery occlusion. A reappraisal of hemodynamic factors. Stroke 1997; 28:2084. 2. Klijn CJ, Kappelle LJ, Algra A, van Gijn J. Outcome in patients with symptomatic occlusion of the internal carotid artery or intracranial arterial lesions: a meta-analysis of the role of baseline characteristics and type of antithrombotic treatment. Cerebrovasc Dis 2001; 12:228. 3. Khazaal O, Neale N, Acton EK, et al. Early neurologic deterioration with symptomatic isolated internal carotid artery occlusion: a cohort study, systematic review, and meta- analysis. Stroke Vasc Interv Neurol 2022; 2. 4. Myrcha P, Gloviczki P. A systematic review of endovascular treatment for chronic total occlusion of the internal carotid artery. Ann Transl Med 2021; 9:1203. 5. Jovin TG, Gupta R, Uchino K, et al. Emergent stenting of extracranial internal carotid artery occlusion in acute stroke has a high revascularization rate. Stroke 2005; 36:2426. 6. Barnett HJ. Delayed cerebral ischemic episodes distal to occlusion of major cerebral arteries. Neurology 1978; 28:769. 7. Barnett HJ, Peerless SJ, Kaufmann JC. "Stump" on internal carotid artery a source for further cerebral embolic ischemia. Stroke 1978; 9:448. 8. EC/IC Bypass Study Group. Failure of extracranial-intracranial arterial bypass to reduce the risk of ischemic stroke. Results of an international randomized trial. N Engl J Med 1985; 313:1191. 9. Powers WJ, Clarke WR, Grubb RL Jr, et al. Extracranial-intracranial bypass surgery for stroke prevention in hemodynamic cerebral ischemia: the Carotid Occlusion Surgery Study randomized trial. JAMA 2011; 306:1983. https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 16/25 7/6/23, 1:08 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate 10. Rainer WG, Cramer GG, Newby JP, Clarke JP. Fibromuscular hyperplasia of the carotid artery causing positional cerebral ischemia. Ann Surg 1968; 167:444. 11. Choi PM, Singh D, Trivedi A, et al. Carotid Webs and Recurrent Ischemic Strokes in the Era of CT Angiography. AJNR Am J Neuroradiol 2015; 36:2134. 12. Boesen ME, Eswaradass PV, Singh D, et al. MR imaging of carotid webs. Neuroradiology 2017; 59:361. 13. Mac Grory B, Emmer BJ, Roosendaal SD, et al. Carotid web: an occult mechanism of embolic stroke. J Neurol Neurosurg Psychiatry 2020; 91:1283. 14. 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. 15. Coward LJ, McCabe DJ, Ederle J, et al. Long-term outcome after angioplasty and stenting for symptomatic vertebral artery stenosis compared with medical treatment in the Carotid And Vertebral Artery Transluminal Angioplasty Study (CAVATAS): a randomized trial. Stroke 2007; 38:1526. 16. Jenkins JS, Patel SN, White CJ, et al. Endovascular stenting for vertebral artery stenosis. J Am Coll Cardiol 2010; 55:538. 17. Stayman AN, Nogueira RG, Gupta R. A systematic review of stenting and angioplasty of symptomatic extracranial vertebral artery stenosis. Stroke 2011; 42:2212. 18. Markus HS, Harshfield EL, Compter A, et al. Stenting for symptomatic vertebral artery stenosis: a preplanned pooled individual patient data analysis. Lancet Neurol 2019; 18:666. 19. Xu R, Zhang X, Liu S, et al. Percutaneous transluminal angioplasty and stenting for vertebral artery stenosis. Cochrane Database Syst Rev 2022; 5:CD013692. 20. Chimowitz MI, Lynn MJ, Derdeyn CP, et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med 2011; 365:993. 21. Gornik HL, Persu A, Adlam D, et al. First International Consensus on the diagnosis and management of fibromuscular dysplasia. Vasc Med 2019; 24:164. 22. Arboix A, Alio J. Acute cardioembolic cerebral infarction: answers to clinical questions. Curr Cardiol Rev 2012; 8:54. 23. Ay H, Furie KL, Singhal A, et al. An evidence-based causative classification system for acute ischemic stroke. Ann Neurol 2005; 58:688. 24. Homma S, Di Tullio MR, Sciacca RR, et al. Effect of aspirin and warfarin therapy in stroke patients with valvular strands. Stroke 2004; 35:1436. https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 17/25 7/6/23, 1:08 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate 25. 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. 26. 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. 27. 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. 28. Salazar-Camelo RA, Moreno-Vargas EA, Cardona AF, Bayona-Ortiz HF. Ischemic stroke: A paradoxical manifestation of cancer. Crit Rev Oncol Hematol 2021; 157:103181. 29. Dearborn JL, Urrutia VC, Zeiler SR. Stroke and Cancer- A Complicated Relationship. J Neurol Transl Neurosci 2014; 2:1039. 30. Navi BB, Iadecola C. Ischemic stroke in cancer patients: A review of an underappreciated pathology. Ann Neurol 2018; 83:873. Topic 1119 Version 29.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 18/25 7/6/23, 1:08 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate GRAPHICS 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 https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 19/25 7/6/23, 1:08 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate Graphic 131695 Version 3.0 https://www.uptodate.com/contents/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 20/25 7/6/23, 1:08 PM Overview of secondary prevention for specific causes of 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/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 21/25 7/6/23, 1:08 PM Overview of secondary prevention for specific causes of 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/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 22/25 7/6/23, 1:08 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - 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/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 23/25 7/6/23, 1:08 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - 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/overview-of-secondary-prevention-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 24/25 7/6/23, 1:08 PM Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack - UpToDate Contributor Disclosures Natalia S Rost, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Shadi Yaghi, MD, 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-for-specific-causes-of-ischemic-stroke-and-transient-ischemic-attack/print 25/25

7/7/23, 11:13 AM Clinical features and diagnosis of Takayasu arteritis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Clinical features and diagnosis of Takayasu arteritis : Peter A Merkel, MD, MPH : Kenneth J Warrington, MD : Philip Seo, MD, MHS 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 10, 2023. INTRODUCTION Takayasu arteritis (TAK) is classified as a large-vessel vasculitis because it primarily affects the aorta and its primary branches. It also shares some histologic and clinical features with giant cell (temporal) arteritis (GCA), the other major large-vessel vasculitis. Patients may present initially with constitutional symptoms but later develop symptoms associated with vascular damage. The pathogenesis, pathology, clinical manifestations, and diagnosis of TAK will be reviewed here. The treatment of this disorder is discussed separately (see "Treatment of Takayasu arteritis"). Overviews of the vasculitides in children and in adults are also discussed elsewhere. (See "Vasculitis in children: Incidence and classification" and "Overview of and approach to the vasculitides in adults".) EPIDEMIOLOGY Women are affected in 80 to 90 percent of cases, with an age of onset that is usually between 10 and 40 years [1,2]. It has a worldwide distribution, with the greatest prevalence in Asia [3-5]. In Japan, it has been estimated that 150 new cases occur each year [6]. PATHOGENESIS The pathogenesis of Takayasu arteritis (TAK) is poorly understood. Cell-mediated mechanisms are thought to be of primary importance and may be similar to those in giant cell arteritis (GCA) https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-takayasu-arteritis/print 1/28 7/7/23, 11:13 AM Clinical features and diagnosis of Takayasu arteritis - UpToDate [7] (see "Pathogenesis of giant cell arteritis"). Some studies have identified genetic links to disease susceptibility that may help explain differences in prevalence geographically and could lead to a deeper understanding of key underlying pathways of disease pathogenesis [8,9]. Immunohistopathologic examination has shown that the infiltrating cells in aortic tissue mainly consist of cytotoxic lymphocytes, especially gamma delta T lymphocytes [10]. These cells may cause vascular injury by releasing large amounts of the cytolytic protein perforin. Recognition of heat shock protein-65 might facilitate recognition and adhesion of the infiltrating cells. In another report, the T cell receptors on the infiltrating T cells had a restricted repertoire, suggesting that a specific but as yet unidentified antigen in aortic tissue might be targeted [11]. This change was not seen in atherosclerotic aortic aneurysms. Additional data suggest that mast cells may play a role in regulating vascular lesions in TAK. A small study including 30 patients with TAK found an increase in mast cell numbers in TAK arterial lesions compared with noninflammatory aortic biopsy lesions [12]. The inflammation may be localized to a portion of the thoracic or abdominal aorta and branches, or may involve the entire vessel. Although there is considerable variability in disease expression (possibly due to geographic differences [13]), the initial vascular lesions frequently occur in the left middle or proximal subclavian artery. As the disease progresses, the left common carotid, vertebral, brachiocephalic, right middle or proximal subclavian artery, right carotid, vertebral arteries, and aorta may also be affected. The abdominal aorta and pulmonary arteries are involved in approximately 50 percent of patients [14]. Patterns of arterial disease in TAK may be important clues for underlying disease pathogenesis [15]. The inflammatory process within the vessel can lead to narrowing, occlusion, or dilation of involved portions of the arteries, which causes a wide variety of symptoms. CLINICAL FEATURES Symptoms and signs The onset of symptoms in Takayasu arteritis (TAK) tends to be subacute, which often leads to a delay in diagnosis that can range from months to years [16], during which time vascular disease may start and progress to become symptomatic. It is not uncommon for the consequences of the arterial disease to be the first sign of TAK noticed at presentation. As progression of narrowing, occlusion, or dilation of arteries occurs, there is resulting pain in arms or legs (limb claudication) and/or cyanosis, lightheadedness or other symptoms of reduced blood flow, arterial pain and tenderness, or nonspecific constitutional symptoms. The following features can be seen [17-21]: https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-takayasu-arteritis/print 2/28 7/7/23, 11:13 AM Clinical features and diagnosis of Takayasu arteritis - UpToDate Constitutional symptoms Constitutional symptoms are common in the early phase of TAK, including weight loss and low-grade fever. Fatigue is very common. Arthralgias Arthralgias or myalgias occur in about one-half of cases. Clinically evident synovitis is less common. Articular symptoms can be transient or continuous over several months or longer. Carotidynia Tenderness of a carotid artery (carotidynia) is observed in 10 to 30 percent of patients at presentation [17]. Absent or weak peripheral pulse(s) Absent or diminished peripheral pulses is most common at the level of the radial arteries and is often asymmetric [18]. In unusually severe cases, occlusion of the vessels to the extremities may result in ischemic ulcerations or gangrene; however, such complications are usually precluded by the development of collateral arterial circulation in the areas involved by vasculitis, protecting extremities from critical ischemia. Collateral vessels are evidence of the slow progression of the disease. Limb claudication Limb claudication may be observed. Subclavian artery involvement is common, and a stenotic lesion proximal to the origin of the vertebral artery can lead to neurologic symptoms or syncope related to the so-called subclavian steal syndrome [22]. In this phenomenon, retrograde flow through the vertebral artery supplies the subclavian distal to the stenosis and vasodilation of the arterial bed in the upper limb with exercise compromises posterior cerebral blood flow (see "Overview of upper extremity peripheral artery disease", section on 'Presentation' and "Subclavian steal syndrome", section on 'Clinical features'). Other claudicatory symptoms are common, including mild to severe upper- or lower-extremity pain with modest activity, often limiting patients' functional capacity for activities of daily living, ambulation, or employment. Arterial bruit In patients with stenoses, bruits are usually audible over the subclavian arteries, brachial arteries, carotid arteries, and abdominal vessels. Clinical signs of aortic regurgitation due to dilatation of the ascending aorta may be present in patients who have this abnormality, and moderate to severe stenosis can be present even in the absence of a bruit. (See "Examination of the arterial pulse" and "Clinical manifestations and diagnosis of chronic aortic regurgitation in adults".) Discrepant blood pressure between arms Reduced blood pressure in one or both arms is common; a differential of more than 10 mmHg between the arms is typically present and pressures may be unmeasurable, especially by automated devices. It is imperative for patients and clinicians to be aware of such unreliable blood pressure readings to ensure https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-takayasu-arteritis/print 3/28 7/7/23, 11:13 AM Clinical features and diagnosis of Takayasu arteritis - UpToDate proper pressures are recorded in limbs not affected by arterial narrowing; this frequently requires measuring the blood pressure in legs. Hypertension Hypertension develops in more than one-half of cases due to narrowing of one or both renal arteries, or narrowing and decreased elasticity of the aorta and branches. Severe (malignant) hypertension may occur. However, narrowing or occlusion of the arteries in the arms may make it difficult to assess the blood pressure. In these cases, the blood pressure may be measured using a wide cuff on an uninvolved thigh, or by direct measurements of the proximal aorta via arterial catheterization. Because TAK often affects young people, modest elevations in blood pressure are often overlooked. (See "Blood pressure measurement in the diagnosis and management of hypertension in adults".) Angina Angina pectoris occurs due to coronary artery ostial narrowing from aortitis or coronary arteritis. Myocardial infarction and death may occur. Gastrointestinal symptoms Abdominal pain, particularly post-prandial pain, diarrhea, and gastrointestinal hemorrhage may result from mesenteric artery ischemia [21]. Skin lesions Skin lesions resembling erythema nodosum or pyoderma gangrenosum are found over the legs in a minority of cases. Respiratory symptoms The pulmonary arteries are involved pathologically in up to 50 percent of cases; however, symptoms related to pulmonary arteritis are less common [20]. Pulmonary manifestations include chest pain, dyspnea, hemoptysis, and pulmonary hypertension [21]. Dyspnea may also be due to angina or heart failure resulting from aortic dilation, aortic regurgitation, or malignant hypertension. Neurologic symptoms Involvement of the carotid and vertebral arteries causes decreased cerebral blood flow, leading to lightheadedness, vertigo, syncope, orthostasis, headaches, convulsions, and strokes. Visual impairment is a late manifestation of severe disease and is due to arterial insufficiency [19]. Physical examination Several aspects of the physical examination merit particular attention whenever a patient with TAK is seen in clinical practice. Measurement of blood pressure should be done in all four extremities to evaluate for arterial stenoses and accurately measure the true central arterial pressure. Many patients with TAK will have partial or complete occlusion of one or both subclavian, axillary, or brachial arteries, or the brachiocephalic artery, leading to falsely low pressure readings in the ipsilateral arm. Similarly, femoral or more distal arterial stenoses will falsely lower leg blood pressures and stenosis of the aorta may lead to bilateral low blood pressure readings. It is important that clinicians, nurses, and other clinical staff enter all four https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-takayasu-arteritis/print 4/28 7/7/23, 11:13 AM Clinical features and diagnosis of Takayasu arteritis - UpToDate extremity blood pressure readings into a patient's medical records to best allow for determination of which readings are reliable and to gain insight into the patient's vascular anatomy. Bruits should be listened for over the bilateral carotid, subclavian, axillary, renal, and femoral arteries, as well as the abdominal aorta. Cardiac auscultation may reveal signs of aortic valvular disease, pulmonary hypertension, or heart failure. Pulses should be felt for and evaluated (full, reduced, absent) at bilateral temporal, carotid, brachial, femoral, and dorsal pedal arteries, and any arterial tenderness should also be noted. Signs of limb ischemia should be sought. Availability of a device using Doppler technology can enhance the vascular examination in patients with TAK. Physical examination may reveal findings suggestive of vascular disease. Many of the abnormal exam findings above have been shown to be fairly specific, although not highly sensitive, for identification of arterial lesions subsequently confirmed by imaging tests [23]. Laboratory findings Laboratory abnormalities in patients with TAK are nonspecific and generally reflect an inflammatory process [17]. Acute phase reactants such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) may be elevated; however, these tests do not reliably reflect disease activity and can be normal in the setting of active disease [21]. Other abnormalities that may be observed in the complete blood count include a normochromic normocytic anemia suggestive of the anemia of chronic disease as well as a leukocytosis and/or thrombocytosis. DIAGNOSIS Our approach In most cases, a clinical diagnosis of Takayasu arteritis (TAK) can be made in a patient with both suggestive clinical findings (eg, constitutional symptoms, hypertension, diminished or absent pulses, and/or arterial bruits) and imaging showing narrowing of the aorta and/or its primary branches (see 'Symptoms and signs' above and 'Imaging' below). It is appropriate to consider the conditions listed below (see 'Differential diagnosis' below) and selectively conduct additional testing as clinically indicated. Occasionally, the diagnosis of TAK is made incidentally either in patients with imaging consistent with vasculitis obtained for other clinical indications (eg, "aortitis" suspected on an abdominal computed tomography [CT] obtained to evaluate for possible malignancy or incidentally discovered aortic aneurysm) or when vasculitis is found on histologic examination of surgically removed segments of arteries. In such circumstances, we recommend examining other regions of the aorta and its primary branches with either magnetic resonance angiography (MRA) or CT https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-takayasu-arteritis/print 5/28 7/7/23, 11:13 AM Clinical features and diagnosis of Takayasu arteritis - UpToDate angiography (CTA) and considering the possibility of a diagnosis of another form of large-vessel vasculitis. (See 'Differential diagnosis' below.) There are no diagnostic laboratory tests for TAK. Testing for acute phase reactants such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) may provide additional support for the presence of a systemic inflammatory process; however, normal values of ESR or CRP should not markedly deter making the diagnosis of TAK. Imaging Imaging studies are essential for establishing the diagnosis of TAK and for determining the extent of vascular involvement. Patients with suspected TAK should undergo imaging of the arterial tree by MRA or CTA to evaluate the arterial lumen. The diagnostic and physiologic importance of arterial wall enhancement on MR or CT imaging remain uncertain. In general, we favor using MRA to evaluate for TAK since it avoids the radiation exposure and risks of iodinated contrast of CTA; similarly, if periodic repeat studies are anticipated, MRA is again the preferred choice. Imaging of the arterial tree of the chest, abdomen, head and neck, or other areas by MRA or CTA demonstrates smoothly tapered luminal narrowing or occlusion ( image 1) that is sometimes accompanied by thickening of the wall of the vessel ( image 2A-B) [24-29]. Color Doppler ultrasound examination of the common carotid and proximal subclavian arteries may show vessel wall thickening and luminal narrowing, especially if bruits or diminished pulses are found on examination, and may provide complementary information to MRA/CTA about hemodynamics. With the increased availability of ultrasound within rheumatology practices, there is increased interest in using this imaging modality to follow the disease course in TAK. However, ultrasound examination cannot reach vessels in deeper areas, and multiple procedures and more time are necessary to cover the same regions seen by a single MR or CT study. While conventional arteriography generally provides clear outlines of the lumen of involved arteries ( image 3), it does not allow arterial wall thickening to be assessed (the importance of which is not fully clear) and is an invasive test associated with some risks. Therefore, if a therapeutic intervention (eg, stenting for revascularization) is not anticipated, a less invasive imaging technique is preferred. (See "Treatment of Takayasu arteritis", section on 'Revascularization'.) Catheter-based angiography allows for the measurement of core blood pressure, and this may be needed when four-limb arterial stenosis prevents accurate blood pressure assessments; documenting aortic pressures should always be part of this procedure. Furthermore, cardiac catheterization may be a critically important form of angiography to perform when cardiac https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-takayasu-arteritis/print 6/28 7/7/23, 11:13 AM Clinical features and diagnosis of Takayasu arteritis - UpToDate ischemia is suspected, although in some situations CT-based coronary imaging may be performed. When selected site angiography is planned, it may be quite appropriate to extend the scope of the study to include more/all of the aorta and primary branches since the initial risk of arterial puncture was already planned; time, costs, and the risks of using additional contrast dye must be considered. Positron emission tomography (PET), often in combination with CT (PET-CT) or MR (PET-MR) is an increasingly utilized test to evaluate for possible large-vessel vasculitis. The finding of "hot" segments (ie, those with increased standardized uptake values [SUVs]) in the right clinical setting may be quite suggestive of large-vessel vasculitis. There is increasing use of PET to aid in the diagnosis of TAK. There is less consensus on this test's usefulness as a measure of disease activity, and the role of PET to measure disease activity in large-vessel vasculitis remains under study [30]. Histopathology The diagnosis of TAK is seldom made histologically since biopsy of the large arteries is obviously impractical. However, occasionally arterial tissue may become available after a revascularization procedure or aneurysm repair. Such tissue samples should be sought whenever reasonably feasible if it will help either establish a diagnosis or evaluate the state of the disease (eg, active inflammation versus inactive scar) and lead to change in therapy. Active inflammation is indicated by the presence of mononuclear cells, predominantly lymphocytes, histiocytes, macrophages, and plasma cells [31]. Giant cells and granulomatous inflammation are typically found in the media [32]. Destruction of the elastic lamina and the muscular media can lead to aneurysmal dilation of the affected vessel. Alternatively, progressive inflammation and dense scarring may proceed from the adventitia leading to a compromise of the vascular lumen. Intimal proliferation may also contribute to the development of stenotic arterial lesions. If active inflammation abates, dense scar tissue remains as an indication of prior vasculitis. Nomenclature and classification criteria The disease names and definitions of the vasculitides continue to evolve as our understanding of the pathogenesis advances. The international Chapel Hill Consensus Conference (CHCC) has developed one of the most widely used nomenclature systems, which specifies the names and definitions for most forms of vasculitis [33,34]. The CHCC nomenclature system has changed over the past few decades, and definitions that were put forth by the CHCC in 1994 have since been revised in the 2012 CHCC ( table 1 and table 2). Classification criteria have been developed for TAK as a means of categorizing patients for research studies. The 1990 American College of Rheumatology (ACR) classification criteria were https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-takayasu-arteritis/print 7/28 7/7/23, 11:13 AM Clinical features and diagnosis of Takayasu arteritis - UpToDate developed to help distinguish one form of vasculitis from another, but they are limited in terms of their use in clinical practice [2,35,36]. Age at disease onset 40 years Claudication of the extremities Decreased pulsation of one or both brachial arteries Difference of at least 10 mmHg in systolic blood pressure between the arms Bruit over one or both subclavian arteries or the abdominal aorta Arteriographic narrowing or occlusion of the entire aorta, its primary branches, or large arteries in the proximal upper or lower extremities, not due to arteriosclerosis, fibromuscular dysplasia, or other causes Patients are said to have TAK if at least three of the six criteria are present. The 2022 ACR/European Alliance of Associations for Rheumatology (EULAR) classification criteria for TAK uses a weighted algorithm that includes clinical and imaging criteria ( table 3). These criteria were constructed in part to reflect the growing role of noninvasive imaging for the evaluation of patients with TAK [37]. It is anticipated that these new 2022 ACR/EULAR classification criteria will gradually gain acceptance for use in research studies. (See "Overview of and approach to the vasculitides in adults", section on 'Nomenclature'.) The main role for these criteria and nomenclatures systems is for clinical research purposes. None has been validated for establishing clinical diagnoses, and while these criteria may inform clinicians' approach to evaluating patients, these criteria should not be used as diagnostic criteria. DIFFERENTIAL DIAGNOSIS The differential diagnosis of Takayasu arteritis (TAK) includes atherosclerotic, inflammatory, infectious, and hereditary diseases that affect the large arteries. Giant cell arteritis Perhaps the most difficult distinction is between TAK and giant cell arteritis (GCA). Both conditions involve the aorta and its major branches and are indistinguishable histopathologically. Distinction between the two disorders can usually be made based upon the age of the patient and the distribution of lesions ( table 4) [38,39], although such a dichotomy is strongly driven the by the somewhat arbitrary age-based criteria. https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-takayasu-arteritis/print 8/28 7/7/23, 11:13 AM Clinical features and diagnosis of Takayasu arteritis - UpToDate However, with the increasing recognition of overlapping clinical features of these two conditions, and especially that GCA may involve the aorta and its major branches in at least 30 percent of patients, the differentiation between TAK and GCA has become more difficult [40,41]. (See "Diagnosis of giant cell arteritis" and "Clinical manifestations of giant cell arteritis".) Other forms of large-vessel vasculitis/aortitis There are several other diseases associated with aortitis that can present with clinical and radiographic features identical to TAK, including Cogan syndrome, relapsing polychondritis, and spondyloarthritis. However, in most of these situations, the finding of other clinical features pathognomonic for the specific diagnosis can differentiate among these types of aortitis. (See "Cogan syndrome" and "Clinical manifestations of relapsing polychondritis" and "Overview of the clinical manifestations and classification of spondyloarthritis".) Beh et syndrome Arterial involvement in Beh et syndrome can lead to dilatations and aneurysms of the medium- and large-sized arteries. However, patients with Beh et are likely to have other clinical features such as oral and/or genital ulcerations, ocular disease, and arthritis. (See "Clinical manifestations and diagnosis of Beh et syndrome".) IgG4-related disease IgG4-related disease has been recognized as a rare cause of noninfectious aortitis. Histologic evidence of lymphoplasmocytes and storiform fibrosis as well as non-arterial manifestations of disease can differentiate IgG4-related disease from TAK. (See "Pathogenesis and clinical manifestations of IgG4-related disease", section on 'Aortitis and periaortitis'.) Infectious aortitis Similar to TAK, patients with infectious aortitis may present with nonspecific symptoms such as fever and elevated acute phase reactants. However, patients with TAK will have negative blood cultures. Infections of the aorta usually lead to aneurysm formation. Mycobacterial infection of the aorta can present with a more chronic process that bacterial infections. On CT angiography (CTA), patients with infectious aneurysms may have a perivascular fluid collection or intramural air, whereas inflammatory aneurysms often have findings suggestive of periaortic fibrosis and adhesions of adjacent structures (see "Overview of infected (mycotic) arterial aneurysm", section on 'Differential diagnosis'). All patients with aortitis should be tested for syphilis. (See "Syphilis: Screening and diagnostic testing", section on 'Approach to testing'.) Genetic causes of aortic aneurysms Genetic defects that lead to abnormalities in connective tissue metabolism can predispose patients to thoracic aortic aneurysm and dissection. Examples include Marfan syndrome, vascular Ehlers-Danlos syndrome, Loeys- https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-takayasu-arteritis/print 9/28 7/7/23, 11:13 AM Clinical features and diagnosis of Takayasu arteritis - UpToDate Dietz syndrome, and Turner syndrome. Patients with these conditions generally do not have systemic symptoms as do patients with TAK. These conditions are associated with a specific genetic abnormality and other typical clinical features. (See "Epidemiology, risk factors, pathogenesis, and natural history of thoracic aortic aneurysm and dissection", section on 'Syndromic connective tissue disorders' and "Epidemiology, risk factors, pathogenesis, and natural history of thoracic aortic aneurysm and dissection", section on 'Turner syndrome'.) Fibromuscular dysplasia Fibromuscular dysplasia must be considered when large arterial stenosis are seen. However, this syndrome often has characteristic radiographic findings, is usually more focal in its involvement, and is not associated with the systemic symptoms of TAK. (See "Clinical manifestations and diagnosis of fibromuscular dysplasia".) Atherosclerosis It is likely that atherosclerosis is the cause of more lesions of the aorta and its major branches than all forms of inflammatory disease combined. Differentiating atherosclerosis from vasculitis may be easier in younger people but can be a challenge in many patients. Longer, smoother, non-calcified lesions are more characteristic of non- atherosclerotic disease. However, atherosclerosis can be associated with some degree of inflammation and increased signal on positron emission tomography (PET), and luminal characteristics are not fully reliable when evaluating lesions. Furthermore, patients with large-vessel vasculitis can also develop atherosclerosis. Evaluation of all patients with TAK for risk factors and evidence of atherosclerosis is appropriate. (See "Overview of established risk factors for cardiovascular 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: Takayasu arteritis".) 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/clinical-features-and-diagnosis-of-takayasu-arteritis/print 10/28 7/7/23, 11:13 AM Clinical features and diagnosis of Takayasu arteritis - 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.) Beyond the Basics topics (see "Patient education: Vasculitis (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Epidemiology Takayasu arteritis (TAK) is an uncommon chronic vasculitis of unknown etiology, which primarily affects the aorta and its primary branches. Women are affected in 80 to 90 percent of cases, with an age of onset that is usually between 10 and 40 years. It has a worldwide distribution, with the greatest prevalence in Asia. (See 'Introduction' above and 'Epidemiology' above.) Pathogenesis The pathogenesis of TAK is poorly understood. The inflammation may be localized to a portion of the thoracic or abdominal aorta and branches, or may involve the entire vessel. Although there is considerable variability in disease expression, the initial vascular lesions frequently occur in the left middle or proximal subclavian artery. As the disease progresses, the left common carotid, vertebral, brachiocephalic, right middle or proximal subclavian artery, right carotid, vertebral arteries, and aorta may also be affected. The abdominal aorta and pulmonary arteries are involved in approximately 50 percent of patients. The inflammatory process within the vessel can lead to narrowing, occlusion, or dilation of involved portions of the arteries in which causes a wide variety of symptoms. (See 'Pathogenesis' above.) Clinical manifestations The onset of symptoms in TAK tends to be subacute, which often leads to a delay in diagnosis that can range from months to years, during which time vascular disease may start and progress. It is not uncommon for the consequences of the arterial disease to be the first sign of TAK noticed at presentation. As progression of narrowing, occlusion, or dilation of arteries occurs, there is resulting pain in arms or legs (limb claudication) and/or cyanosis, lightheadedness or other symptoms of reduced blood flow, arterial pain and tenderness, or nonspecific constitutional symptoms. (See 'Symptoms and signs' above.) Physical examination The physical examination of a patients with TAK should particularly focus on accurate measurements of blood pressure, palpation of pulses, https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-takayasu-arteritis/print 11/28 7/7/23, 11:13 AM Clinical features and diagnosis of Takayasu arteritis - UpToDate identification of bruits, and careful cardiac auscultation. (See 'Physical examination' above.) Diagnosis The diagnosis of TAK should be suspected in a patient who has constitutional symptoms, hypertension, diminished or absent pulses, and/or arterial bruits. In most cases, the diagnosis is based upon suggestive clinical features and specific imaging findings of the aorta and/or its branches. Additionally, TAK or other forms of large-vessel vasculitis must be considered either in patients incidentally found to have findings suspicious for vasculitis on imaging obtained for other clinical indications or when vasculitis is found on histologic examination of surgically removed segments of arteries. (See 'Our approach' above.) Laboratory findings There are no diagnostic laboratory tests for TAK. Testing for acute phase reactants such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) may provide additional support for the presence of a systemic inflammatory process; however, normal values of ESR or CRP should not markedly deter making the diagnosis of TAK. (See 'Our approach' above and 'Laboratory findings' above.) Imaging Imaging studies are essential for establishing the diagnosis of TAK and for determining the extent of vascular involvement. Patients with suspected TAK should undergo imaging of the arterial tree by magnetic resonance angiography (MRA) or CT angiography (CTA) to evaluate the arterial lumen. In general, we favor using MRA to evaluate for TAK, since it avoids the radiation exposure and risks of iodinated contrast of CTA; similarly, if periodic repeat studies are anticipated, MRA is again the preferred choice. Imaging of the arterial tree of the chest, abdomen, head and neck, or other areas by MRA or CTA demonstrates smoothly tapered luminal narrowing or occlusion ( image 1) that is sometimes accompanied by thickening of the wall of the vessel ( image 2A-B). There is an increasing use of positron emission tomography (PET), often in combination with CT (PET- CT) or MR (PET-MR) to aid in the diagnosis of TAK, but there is less consensus on this test's usefulness as a measure of disease activity, and its role remains under study. (See 'Imaging' above.) Differential diagnosis Conditions that should be considered in the differential diagnosis of TAK include giant cell (temporal) arteritis (GCA), IgG4-related disease, Beh et syndrome, infectious aortitis, fibromuscular dysplasia, atherosclerosis, genetic causes of aneurysms such as Ehlers-Danlos syndrome, and other diseases which can feature large-vessel vasculitis/aortitis such as Cogan syndrome, relapsing polychondritis, and spondyloarthropathies. (See 'Differential diagnosis' above.) https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-takayasu-arteritis/print 12/28 7/7/23, 11:13 AM Clinical features and diagnosis of Takayasu arteritis - UpToDate ACKNOWLEDGMENT The editorial staff at UpToDate acknowledge Gene Hunder, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Lupi-Herrera E, S nchez-Torres G, Marcushamer J, et al. Takayasu's arteritis. Clinical study of 107 cases. Am Heart J 1977; 93:94. 2. Arend WP, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum 1990; 33:1129. 3. Dabague J, Reyes PA. Takayasu arteritis in Mexico: a 38-year clinical perspective through literature review. Int J Cardiol 1996; 54 Suppl:S103. 4. Hall S, Barr W, Lie JT, et al. Takayasu arteritis. A study of 32 North American patients. Medicine (Baltimore) 1985; 64:89. 5. Ishikawa K. Natural history and classification of occlusive thromboaortopathy (Takayasu's disease). Circulation 1978; 57:27. 6. Koide K. Takayasu arteritis in Japan. Heart Vessels Suppl 1992; 7:48. 7. Weyand CM, Goronzy JJ. Medium- and large-vessel vasculitis. N Engl J Med 2003; 349:160. 8. Ortiz-Fern ndez L, Saruhan-Direskeneli G, Alibaz-Oner F, et al. Identification of susceptibility loci for Takayasu arteritis through a large multi-ancestral genome-wide association study. Am J Hum Genet 2021; 108:84. 9. Terao C, Yoshifuji H, Matsumura T, et al. Genetic determinants and an epistasis of LILRA3 and HLA-B*52 in Takayasu arteritis. Proc Natl Acad Sci U S A 2018; 115:13045. 10. Seko Y, Minota S, Kawasaki A, et al. Perforin-secreting killer cell infiltration and expression of a 65-kD heat-shock protein in aortic tissue of patients with Takayasu's arteritis. J Clin Invest 1994; 93:750. 11. Seko Y, Sato O, Takagi A, et al. Restricted usage of T-cell receptor Valpha-Vbeta genes in infiltrating cells in aortic tissue of patients with Takayasu's arteritis. Circulation 1996; 93:1788. 12. Le Joncour A, Desbois AC, Leroyer AS, et al. Mast cells drive pathologic vascular lesions in Takayasu arteritis. J Allergy Clin Immunol 2022; 149:292. https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-takayasu-arteritis/print 13/28 7/7/23, 11:13 AM Clinical features and diagnosis of Takayasu arteritis - UpToDate 13. Cid MC, Font C, Coll-Vinent B, Grau JM. Large vessel vasculitides. Curr Opin Rheumatol 1998; 10:18. 14. Yamada I, Shibuya H, Matsubara O, et al. Pulmonary artery disease in Takayasu's arteritis: angiographic findings. AJR Am J Roentgenol 1992; 159:263. 15. Goel R, Gribbons KB, Carette S, et al. Derivation of an angiographically based classification system in Takayasu's arteritis: an observational study from India and North America. Rheumatology (Oxford) 2020; 59:1118. 16. Sreih AG, Cronin K, Shaw DG, et al. Diagnostic delays in vasculitis and factors associated with time to diagnosis. Orphanet J Rare Dis 2021; 16:184. 17. Mason JC. Takayasu arteritis advances in diagnosis and management. Nat Rev Rheumatol 2010; 6:406. 18. Serra R, Butrico L, Fugetto F, et al. Updates in Pathophysiology, Diagnosis and Management of Takayasu Arteritis. Ann Vasc Surg 2016; 35:210. 19. Rodr guez-Pla A, de Miguel G, L pez-Contreras J, et al. Bilateral blindness in Takayasu's disease. Scand J Rheumatol 1996; 25:394. 20. Nakabayashi K, Kurata N, Nangi N, et al. Pulmonary artery involvement as first manifestation in three cases of Takayasu arteritis. Int J Cardiol 1996; 54 Suppl:S177. 21. Kerr GS, Hallahan CW, Giordano J, et al. Takayasu arteritis. Ann Intern Med 1994; 120:919. 22. Yoneda S, Nukada T, Tada K, et al. Subclavian steal in Takayasu's arteritis. A hemodynamic study by means of ultrasonic Doppler flowmetry. Stroke 1977; 8:264. 23. Grayson PC, Tomasson G, Cuthbertson D, et al. Association of vascular physical examination findings and arteriographic lesions in large vessel vasculitis. J Rheumatol 2012; 39:303. 24. Hata A, Numano F. Magnetic resonance imaging of vascular changes in Takayasu arteritis. Int J Cardiol 1995; 52:45. 25. Yamada I, Numano F, Suzuki S. Takayasu arteritis: evaluation with MR imaging. Radiology 1993; 188:89. 26. Yamada I, Nakagawa T, Himeno Y, et al. Takayasu arteritis: evaluation of the thoracic aorta with CT angiography. Radiology 1998; 209:103. 27. Paul JF, Hernigou A, Lefebvre C, et al. Electron beam CT features of the pulmonary artery in Takayasu's arteritis. AJR Am J Roentgenol 1999; 173:89. 28. Kissin EY, Merkel PA. Diagnostic imaging in Takayasu arteritis. Curr Opin Rheumatol 2004; 16:31. 29. Keenan NG, Mason JC, Maceira A, et al. Integrated cardiac and vascular assessment in https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-takayasu-arteritis/print 14/28 7/7/23, 11:13 AM Clinical features and diagnosis of Takayasu arteritis - UpToDate Takayasu arteritis by cardiovascular magnetic resonance. Arthritis Rheum 2009; 60:3501. 30. Grayson PC, Alehashemi S, Bagheri AA, et al. 18 F-Fluorodeoxyglucose-Positron Emission Tomography As an Imaging Biomarker in a Prospective, Longitudinal Cohort of Patients With Large Vessel Vasculitis. Arthritis Rheumatol 2018; 70:439. 31. Fassbender HG. Pathology and pathobiology of rheumatic diseases, Second Edition, Springe r-Verlag, Berlin 2002. p.304. 32. Nasu T. Takayasu's truncoarteritis. Pulseless disease or aortitis syndrome. Acta Pathol Jpn 1982; 32 Suppl 1:117. 33. Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 2013; 65:1. 34. Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum 1994; 37:187. 35. Ishikawa K. Diagnostic approach and proposed criteria for the clinical diagnosis of Takayasu's arteriopathy. J Am Coll Cardiol 1988; 12:964. 36. Sharma BK, Jain S, Suri S, Numano F. Diagnostic criteria for Takayasu arteritis. Int J Cardiol 1996; 54 Suppl:S141.

(CRP) may provide additional support for the presence of a systemic inflammatory process; however, normal values of ESR or CRP should not markedly deter making the diagnosis of TAK. (See 'Our approach' above and 'Laboratory findings' above.) Imaging Imaging studies are essential for establishing the diagnosis of TAK and for determining the extent of vascular involvement. Patients with suspected TAK should undergo imaging of the arterial tree by magnetic resonance angiography (MRA) or CT angiography (CTA) to evaluate the arterial lumen. In general, we favor using MRA to evaluate for TAK, since it avoids the radiation exposure and risks of iodinated contrast of CTA; similarly, if periodic repeat studies are anticipated, MRA is again the preferred choice. Imaging of the arterial tree of the chest, abdomen, head and neck, or other areas by MRA or CTA demonstrates smoothly tapered luminal narrowing or occlusion ( image 1) that is sometimes accompanied by thickening of the wall of the vessel ( image 2A-B). There is an increasing use of positron emission tomography (PET), often in combination with CT (PET- CT) or MR (PET-MR) to aid in the diagnosis of TAK, but there is less consensus on this test's usefulness as a measure of disease activity, and its role remains under study. (See 'Imaging' above.) Differential diagnosis Conditions that should be considered in the differential diagnosis of TAK include giant cell (temporal) arteritis (GCA), IgG4-related disease, Beh et syndrome, infectious aortitis, fibromuscular dysplasia, atherosclerosis, genetic causes of aneurysms such as Ehlers-Danlos syndrome, and other diseases which can feature large-vessel vasculitis/aortitis such as Cogan syndrome, relapsing polychondritis, and spondyloarthropathies. (See 'Differential diagnosis' above.) https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-takayasu-arteritis/print 12/28 7/7/23, 11:13 AM Clinical features and diagnosis of Takayasu arteritis - UpToDate ACKNOWLEDGMENT The editorial staff at UpToDate acknowledge Gene Hunder, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Lupi-Herrera E, S nchez-Torres G, Marcushamer J, et al. Takayasu's arteritis. Clinical study of 107 cases. Am Heart J 1977; 93:94. 2. Arend WP, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum 1990; 33:1129. 3. Dabague J, Reyes PA. Takayasu arteritis in Mexico: a 38-year clinical perspective through literature review. Int J Cardiol 1996; 54 Suppl:S103. 4. Hall S, Barr W, Lie JT, et al. Takayasu arteritis. A study of 32 North American patients. Medicine (Baltimore) 1985; 64:89. 5. Ishikawa K. Natural history and classification of occlusive thromboaortopathy (Takayasu's disease). Circulation 1978; 57:27. 6. Koide K. Takayasu arteritis in Japan. Heart Vessels Suppl 1992; 7:48. 7. Weyand CM, Goronzy JJ. Medium- and large-vessel vasculitis. N Engl J Med 2003; 349:160. 8. Ortiz-Fern ndez L, Saruhan-Direskeneli G, Alibaz-Oner F, et al. Identification of susceptibility loci for Takayasu arteritis through a large multi-ancestral genome-wide association study. Am J Hum Genet 2021; 108:84. 9. Terao C, Yoshifuji H, Matsumura T, et al. Genetic determinants and an epistasis of LILRA3 and HLA-B*52 in Takayasu arteritis. Proc Natl Acad Sci U S A 2018; 115:13045. 10. Seko Y, Minota S, Kawasaki A, et al. Perforin-secreting killer cell infiltration and expression of a 65-kD heat-shock protein in aortic tissue of patients with Takayasu's arteritis. J Clin Invest 1994; 93:750. 11. Seko Y, Sato O, Takagi A, et al. Restricted usage of T-cell receptor Valpha-Vbeta genes in infiltrating cells in aortic tissue of patients with Takayasu's arteritis. Circulation 1996; 93:1788. 12. Le Joncour A, Desbois AC, Leroyer AS, et al. Mast cells drive pathologic vascular lesions in Takayasu arteritis. J Allergy Clin Immunol 2022; 149:292. https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-takayasu-arteritis/print 13/28 7/7/23, 11:13 AM Clinical features and diagnosis of Takayasu arteritis - UpToDate 13. Cid MC, Font C, Coll-Vinent B, Grau JM. Large vessel vasculitides. Curr Opin Rheumatol 1998; 10:18. 14. Yamada I, Shibuya H, Matsubara O, et al. Pulmonary artery disease in Takayasu's arteritis: angiographic findings. AJR Am J Roentgenol 1992; 159:263. 15. Goel R, Gribbons KB, Carette S, et al. Derivation of an angiographically based classification system in Takayasu's arteritis: an observational study from India and North America. Rheumatology (Oxford) 2020; 59:1118. 16. Sreih AG, Cronin K, Shaw DG, et al. Diagnostic delays in vasculitis and factors associated with time to diagnosis. Orphanet J Rare Dis 2021; 16:184. 17. Mason JC. Takayasu arteritis advances in diagnosis and management. Nat Rev Rheumatol 2010; 6:406. 18. Serra R, Butrico L, Fugetto F, et al. Updates in Pathophysiology, Diagnosis and Management of Takayasu Arteritis. Ann Vasc Surg 2016; 35:210. 19. Rodr guez-Pla A, de Miguel G, L pez-Contreras J, et al. Bilateral blindness in Takayasu's disease. Scand J Rheumatol 1996; 25:394. 20. Nakabayashi K, Kurata N, Nangi N, et al. Pulmonary artery involvement as first manifestation in three cases of Takayasu arteritis. Int J Cardiol 1996; 54 Suppl:S177. 21. Kerr GS, Hallahan CW, Giordano J, et al. Takayasu arteritis. Ann Intern Med 1994; 120:919. 22. Yoneda S, Nukada T, Tada K, et al. Subclavian steal in Takayasu's arteritis. A hemodynamic study by means of ultrasonic Doppler flowmetry. Stroke 1977; 8:264. 23. Grayson PC, Tomasson G, Cuthbertson D, et al. Association of vascular physical examination findings and arteriographic lesions in large vessel vasculitis. J Rheumatol 2012; 39:303. 24. Hata A, Numano F. Magnetic resonance imaging of vascular changes in Takayasu arteritis. Int J Cardiol 1995; 52:45. 25. Yamada I, Numano F, Suzuki S. Takayasu arteritis: evaluation with MR imaging. Radiology 1993; 188:89. 26. Yamada I, Nakagawa T, Himeno Y, et al. Takayasu arteritis: evaluation of the thoracic aorta with CT angiography. Radiology 1998; 209:103. 27. Paul JF, Hernigou A, Lefebvre C, et al. Electron beam CT features of the pulmonary artery in Takayasu's arteritis. AJR Am J Roentgenol 1999; 173:89. 28. Kissin EY, Merkel PA. Diagnostic imaging in Takayasu arteritis. Curr Opin Rheumatol 2004; 16:31. 29. Keenan NG, Mason JC, Maceira A, et al. Integrated cardiac and vascular assessment in https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-takayasu-arteritis/print 14/28 7/7/23, 11:13 AM Clinical features and diagnosis of Takayasu arteritis - UpToDate Takayasu arteritis by cardiovascular magnetic resonance. Arthritis Rheum 2009; 60:3501. 30. Grayson PC, Alehashemi S, Bagheri AA, et al. 18 F-Fluorodeoxyglucose-Positron Emission Tomography As an Imaging Biomarker in a Prospective, Longitudinal Cohort of Patients With Large Vessel Vasculitis. Arthritis Rheumatol 2018; 70:439. 31. Fassbender HG. Pathology and pathobiology of rheumatic diseases, Second Edition, Springe r-Verlag, Berlin 2002. p.304. 32. Nasu T. Takayasu's truncoarteritis. Pulseless disease or aortitis syndrome. Acta Pathol Jpn 1982; 32 Suppl 1:117. 33. Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 2013; 65:1. 34. Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum 1994; 37:187. 35. Ishikawa K. Diagnostic approach and proposed criteria for the clinical diagnosis of Takayasu's arteriopathy. J Am Coll Cardiol 1988; 12:964. 36. Sharma BK, Jain S, Suri S, Numano F. Diagnostic criteria for Takayasu arteritis. Int J Cardiol 1996; 54 Suppl:S141. 37. Grayson PC, Ponte C, Suppiah R, et al. 2022 American College of Rheumatology/EULAR Classification Criteria for Takayasu Arteritis. Arthritis Rheumatol 2022; 74:1872. 38. Hunder GG. Giant cell arteritis and polymyalgia rheumatica. Med Clin North Am 1997; 81:195. 39. Michel BA, Arend WP, Hunder GG. Clinical differentiation between giant cell (temporal) arteritis and Takayasu's arteritis. J Rheumatol 1996; 23:106. 40. Grayson PC, Maksimowicz-McKinnon K, Clark TM, et al. Distribution of arterial lesions in Takayasu's arteritis and giant cell arteritis. Ann Rheum Dis 2012; 71:1329. 41. Maksimowicz-McKinnon K, Clark TM, Hoffman GS. Takayasu arteritis and giant cell arteritis: a spectrum within the same disease? Medicine (Baltimore) 2009; 88:221. Topic 8238 Version 27.0 https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-takayasu-arteritis/print 15/28 7/7/23, 11:13 AM Clinical features and diagnosis of Takayasu arteritis - UpToDate GRAPHICS Takayasu aortitis on MRI A 33-year-old man with Takayasu aortitis. The MRI shows narrowing of the region of the isthmus (arrowhead) as well as diffuse irregular narrowing of the abdominal aorta (arrow). MRI: magnetic resonance imaging. Graphic 95682 Version 1.0 https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-takayasu-arteritis/print 16/28 7/7/23, 11:13 AM Clinical features and diagnosis of Takayasu arteritis - UpToDate Fusiform aneurysm and wall thickening in a patient with Takayasu arteritis Enlargement of the descending thoracic aorta and thickening of the vessel wall (arrows) is apparent in this contrast-enhanced CT scan. These findings suggest an active inflammatory process. CT: computed tomography. Reproduced with permission from: Sueyoshi E, Sakamoto I, Hayashi K. Aortic aneurysms in patients with Takayasu's arteritis: CT evaluation. Am J Roentgenology 2000; 175:1727. Copyright 2000 American Roentgen Ray Society. Graphic 62264 Version 6.0 https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-takayasu-arteritis/print 17/28 7/7/23, 11:13 AM Clinical features and diagnosis of Takayasu arteritis - UpToDate Fusiform aneurysm Enlargement of the contrast-filled descending thoracic aneurysm has occurred despite treatment with glucocorticoids. Reproduced with permission from: Sueyoshi E, Sakamoto I, Hayashi K. Aortic aneurysms in patients with Takayasu's arteritis: CT evaluation. Am J Roentgenology 2000; 175:1727. Copyright 2000 American Roentgen Ray Society. Graphic 70960 Version 5.0 https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-takayasu-arteritis/print 18/28 7/7/23, 11:13 AM Clinical features and diagnosis of Takayasu arteritis - UpToDate Takayasu aortitis on aortography A 13-year-old female with Takayasu aortitis. The aortogram shows tubular narrowing of the isthmus of the aorta (arrow). Graphic 93976 Version 2.0 https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-takayasu-arteritis/print 19/28 7/7/23, 11:13 AM Clinical features and diagnosis of Takayasu arteritis - UpToDate Names for vasculitides adopted by the 2012 International Chapel Hill Consensus Conference on the Nomenclature of Vasculitides Large-vessel vasculitis Takayasu arteritis Giant cell arteritis Medium-vessel vasculitis Polyarteritis nodosa Kawasaki disease Small-vessel vasculitis ANCA-associated vasculitis Microscopic polyangiitis Granulomatosis with polyangiitis (Wegener's) Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) Immune complex small-vessel vasculitis Anti-glomerular basement membrane disease Cryoglobulinemic vasculitis IgA vasculitis (Henoch-Sch nlein) Hypocomplementemic urticarial vasculitis (anti-C1q vasculitis) Variable-vessel vasculitis Beh et's syndrome Cogan's syndrome Single-organ vasculitis Cutaneous leukocytoclastic angiitis Cutaneous arteritis Primary central nervous system vasculitis Isolated aortitis Others Vasculitis associated with systemic disease Lupus vasculitis Rheumatoid vasculitis https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-takayasu-arteritis/print 20/28 7/7/23, 11:13 AM Clinical features and diagnosis of Takayasu arteritis - UpToDate Sarcoid vasculitis Others Vasculitis associated with probable etiology Hepatitis C virus-associated cryoglobulinemic vasculitis Hepatitis B virus-associated vasculitis Syphilis-associated aortitis Drug-associated immune complex vasculitis Drug-associated ANCA-associated vasculitis Cancer-associated vasculitis Others ANCA: antineutrophil cytoplasmic antibody; IgA: immunoglobulin A. Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 2013; 65:1. Reproduced with permission from John Wiley & Sons, Inc. Copyright 2013 by the American College of Rheumatology. All rights reserved. Graphic 90188 Version 4.0 https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-takayasu-arteritis/print 21/28 7/7/23, 11:13 AM Clinical features and diagnosis of Takayasu arteritis - UpToDate Definitions for vasculitides adopted by the 2012 International Chapel Hill Consensus Conference on the Nomenclature of Vasculitides (CHCC2012) CHCC2012 name CHCC2012 definition Large-vessel vasculitis Vasculitis affecting large arteries more often than other vasculitides. Large arteries are the aorta and its major branches. Any size artery may be affected. Takayasu arteritis (TAK) Arteritis, often granulomatous, predominantly affecting the aorta and/or its major branches. Onset usually in patients younger than 50 years. Giant cell arteritis (GCA) Arteritis, often granulomatous, usually affecting the aorta and/or its major branches, with a predilection for the branches of the carotid and vertebral arteries. Often involves the temporal artery. Onset usually in patients older than 50 years and often associated with polymyalgia rheumatica. Medium-vessel vasculitis Vasculitis predominantly affecting medium arteries defined as the main visceral arteries and their branches. Any size artery may be affected. Inflammatory aneurysms and stenoses are common. Polyarteritis nodosa (PAN) Necrotizing arteritis of medium or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules, and not associated with antineutrophil cytoplasmic antibodies (ANCAs). Kawasaki disease (KD) Arteritis associated with the mucocutaneous lymph node syndrome and predominantly affecting medium and small arteries. Coronary arteries are often involved. Aorta and large arteries may be involved. Usually occurs in infants and young children. Small-vessel vasculitis Vasculitis predominantly affecting small vessels, defined as small intraparenchymal arteries, arterioles, capillaries, and venules. Medium arteries and veins may be affected. ANCA-associated vasculitis (AAV) Necrotizing vasculitis, with few or no immune deposits, predominantly affecting small vessels (ie, capillaries, venules, arterioles, and small arteries), associated with myeloperoxidase (MPO) ANCA or proteinase 3 (PR3) ANCA. Not all patients have ANCA. Add a prefix indicating ANCA reactivity, eg, MPO-ANCA, PR3-ANCA, ANCA-negative. Microscopic polyangiitis (MPA) Necrotizing vasculitis, with few or no immune deposits, predominantly affecting small vessels (ie, capillaries, venules, or arterioles). Necrotizing arteritis involving small and medium arteries may be present. Necrotizing glomerulonephritis is very common. Pulmonary capillaritis often occurs. Granulomatous inflammation is absent. Granulomatosis with polyangiitis (Wegener's) (GPA) Necrotizing granulomatous inflammation usually involving the upper and lower respiratory tract, and necrotizing vasculitis affecting predominantly small to medium vessels (eg, capillaries, venules, https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-takayasu-arteritis/print 22/28 7/7/23, 11:13 AM Clinical features and diagnosis of Takayasu arteritis - UpToDate arterioles, arteries and veins). Necrotizing glomerulonephritis is common. Eosinophilic Eosinophil-rich and necrotizing granulomatous inflammation often granulomatosis with polyangiitis (Churg- Strauss) (EGPA) involving the respiratory tract, and necrotizing vasculitis predominantly affecting small to medium vessels, and associated with asthma and eosinophilia. ANCA is more frequent when glomerulonephritis is present. Immune complex vasculitis Vasculitis with moderate to marked vessel-wall deposits of immunoglobulin and/or complement components predominantly affecting small vessels (ie, capillaries, venules, arterioles, and small arteries). Glomerulonephritis is frequent. Anti-glomerular basement membrane Vasculitis affecting glomerular capillaries, pulmonary capillaries, or both, with GBM deposition of anti-GBM autoantibodies. Lung (anti-GBM) disease involvement causes pulmonary hemorrhage, and renal involvement causes glomerulonephritis with necrosis and crescents. Cryoglobulinemic Vasculitis with cryoglobulin immune deposits affecting small vessels vasculitis (CV) (predominantly capillaries, venules, or arterioles) and associated with serum cryoglobulins. Skin, glomeruli, and peripheral nerves are often involved. IgA vasculitis (Henoch- Vasculitis, with IgA1-dominant immune deposits, affecting small Sch nlein) (IgAV) vessels (predominantly capillaries, venules, or arterioles). Often involves skin and gastrointestinal tract, and frequently causes arthritis. Glomerulonephritis indistinguishable from IgA nephropathy may occur. Hypocomplementemic Vasculitis accompanied by urticaria and hypocomplementemia urticarial vasculitis (HUV) (anti-C1q vasculitis) affecting small vessels (ie, capillaries, venules, or arterioles), and associated with anti-C1q antibodies. Glomerulonephritis, arthritis, obstructive pulmonary disease, and ocular inflammation are common. Variable-vessel vasculitis Vasculitis with no predominant type of vessel involved that can affect vessels of any size (small, medium, and large) and type (arteries, veins, and capillaries). Beh et's syndrome Vasculitis occurring in patients with Beh et's syndrome that can affect arteries or veins. Beh et's syndrome is characterized by recurrent oral and/or genital aphthous ulcers accompanied by cutaneous, ocular, articular, gastrointestinal, and/or central nervous system inflammatory lesions. Small-vessel vasculitis, thromboangiitis, thrombosis, arteritis, and arterial aneurysms may occur. Cogan's syndrome Vasculitis occurring in patients with Cogan's syndrome. Cogan's syndrome is characterized by ocular inflammatory lesions, including interstitial keratitis, uveitis, and episcleritis, and inner ear disease, including sensorineural hearing loss and vestibular dysfunction. Vasculitic manifestations may include arteritis (affecting small, https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-takayasu-arteritis/print 23/28 7/7/23, 11:13 AM Clinical features and diagnosis of Takayasu arteritis - UpToDate medium, or large arteries), aortitis, aortic aneurysms, and aortic and mitral valvulitis. Single-organ vasculitis Vasculitis in arteries or veins of any size in a single organ that has no features that indicate that it is a limited expression of a systemic vasculitis. The involved organ and vessel type should be included in the name (eg, cutaneous small-vessel vasculitis, testicular arteritis, central nervous system vasculitis). Vasculitis distribution may be unifocal or multifocal (diffuse) within an organ. Some patients originally diagnosed as having single-organ vasculitis will develop additional disease manifestations that warrant redefining the case as one of the systemic vasculitides (eg, cutaneous arteritis later becoming systemic polyarteritis nodosa, etc). Vasculitis associated with Vasculitis that is associated with and may be secondary to (caused by) systemic disease a systemic disease. The name (diagnosis) should have a prefix term specifying the systemic disease (eg, rheumatoid vasculitis, lupus vasculitis, etc). Vasculitis associated with probable etiology Vasculitis that is associated with a probable specific etiology. The name (diagnosis) should have a prefix term specifying the association (eg, hydralazine-associated microscopic polyangiitis, hepatitis B virus- associated vasculitis, hepatitis C virus-associated cryoglobulinemic vasculitis, etc). Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 2013; 65:1. Reproduced with permission from John Wiley & Sons, Inc. Copyright 2013 by the American College of Rheumatology. All rights reserved. Graphic 90189 Version 5.0 https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-takayasu-arteritis/print 24/28 7/7/23, 11:13 AM Clinical features and diagnosis of Takayasu arteritis - UpToDate 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for Takayasu arteritis Considerations when applying these criteria These classification criteria should be applied to classify the patient as having Takayasu arteritis when a diagnosis of medium-vessel or large-vessel vasculitis has been made Alternate diagnoses mimicking vasculitis should be excluded prior to applying the criteria Absolute requirements Age 60 years at time of diagnosis Evidence of vasculitis on imaging* Additional clinical criteria Female sex +1 Angina or ischemic cardiac pain +2 Arm or leg claudication +2 Vascular bruit +2 Reduced pulse in upper extremity +2 Carotid artery abnormality +2 Systolic blood pressure difference in arms 20 mmHg +1 Additional imaging criteria Number of affected arterial territories (select one) +1 One arterial territory +2 Two arterial territories +3 Three or more arterial territories Symmetric involvement of paired arteries +1 Abdominal aorta involvement with renal or mesenteric involvement +3 Sum the scores for 10 items, if present. A score of 5 points is needed for the classification of Takayasu arteritis. Evidence of vasculitis in the aorta or branch arteries must be confirmed by vascular imaging (eg, computed tomographic/catheter-based/magnetic resonance angiography, ultrasound, positron emission tomography). Bruit detected by auscultation of a large artery, including the aorta, carotid, subclavian, axillary, brachial, renal, or iliofemoral arteries. https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-takayasu-arteritis/print 25/28 7/7/23, 11:13 AM Clinical features and diagnosis of Takayasu arteritis - UpToDate Reduction or absence of pulse by physical examination of the axillary, brachial, or radial arteries. Reduction or absence of pulse of the carotid artery or tenderness of the carotid artery. Number of arterial territories with luminal damage (eg, stenosis, occlusion, or aneurysm) detected by angiography or ultrasonography from the following 9 territories: thoracic aorta, abdominal aorta, mesenteric, left or right carotid, left or right subclavian, left or right renal arteries. Bilateral luminal damage (stenosis, occlusion, or aneurysm) detected by angiography or ultrasonography in any of the following paired vascular territories: carotid, subclavian, or renal arteries. Luminal damage (stenosis, occlusion, aneurysm) detected by angiography or ultrasonography involving the abdominal aorta and either the renal or mesenteric arteries. From: Grayson PC, Ponte C, Suppiah R, et al. 2022 American College of Rheumatology/EULAR classi cation criteria for Takayasu arteritis. Ann Rheum Dis 2022; 81:1654. Copyright 2022 The Authors (or their employers). Reproduced with permission from BMJ Publishing Group Ltd. Graphic 140336 Version 1.0 https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-takayasu-arteritis/print 26/28 7/7/23, 11:13 AM Clinical features and diagnosis of Takayasu arteritis - UpToDate Distinguishing features of giant cell versus Takayasu arteritis Finding Giant cell arteritis Takayasu arteritis Female-to-male ratio 3:2 7:1 Age at onset >50 years <40 years Ethnic ancestry European Asian Histopathology Granulomatous inflammation Granulomatous inflammation Primary vessels involved External carotid artery branches Aorta and branches Renovascular hypertension Rare Common HLA association HLA-DR4 HLA-Bw52 Course Self-limited Chronic Response to corticosteroids Excellent Excellent Surgical intervention needed Rare Common HLA: human leukocyte antigen. Adapted from Michel, BA, Arend, WP, Hunder, GG. Clinical di erentiation between giant cell (temporal) arteritis and Takayasu's arteritis. J Rheumatol 1996; 23:106. Graphic 68594 Version 2.0 https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-takayasu-arteritis/print 27/28 7/7/23, 11:13 AM Clinical features and diagnosis of Takayasu arteritis - UpToDate Contributor Disclosures Peter A Merkel, MD, MPH Equity Ownership/Stock Options: Kyverna [Systemic lupus erythematosus]. Grant/Research/Clinical Trial Support: AbbVie [Vasculitis]; AstraZeneca [Vasculitis]; Boehringer Ingelheim [Scleroderma]; Bristol-Myers Squibb [Vasculitis]; ChemoCentryx [Vasculitis]; Electra [Vasculitis]; Genentech/Roche [Vasculitis]; GlaxoSmithKline [Vasculitis]; InflaRx [Vasculitis]; Sanofi [Vasculitis]; Takeda [Vasculitis]. Consultant/Advisory Boards: AbbVie [Vasculitis]; AstraZeneca [Vasculitis]; Boehringer Ingelheim [Scleroderma]; Bristol-Myers Squibb [Vasculitis]; ChemoCentryx [Vasculitis]; CSL Behring [Scleroderma, vasculitis]; Dynacure [Vasculitis]; EMDSerono [Vasculitis]; GlaxoSmithKline [Vasculitis]; InflaRx [Vasculitis]; Janssen [Vasculitis]; Kyverna [Scleroderma, vasculitis]; MiroBio [Vasculitis]; Neutrolis [Vasculitis]; Novartis [Vasculitis]; NS Pharma [Vasculitis]; Otsuka [Vasculitis]; Q32 [Vasculitis]; Regeneron [Vasculitis]; Sparrow [Vasculitis]; Takeda [Vasculitis]. All of the relevant financial relationships listed have been mitigated. Kenneth J Warrington, MD Grant/Research/Clinical Trial Support: Eli Lilly [Giant cell arteritis]; GSK [Giant cell arteritis]; Kiniksa [Giant cell arteritis]. Other Financial Interest: Chemocentryx [Honoraria ANCA-associated vasculitis]. All of the relevant financial relationships listed have been mitigated. Philip Seo, MD, MHS 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-features-and-diagnosis-of-takayasu-arteritis/print 28/28

7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Clinical manifestations and diagnosis of polyarteritis nodosa in adults : Peter A Merkel, MD, MPH : Gene G Hunder, MD : Philip Seo, MD, MHS 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 16, 2022. INTRODUCTION Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis that typically affects medium-sized muscular arteries, with additional involvement of small arteries [1,2]. Unlike some other vasculitides (eg, microscopic polyarteritis, granulomatosis with polyangiitis), polyarteritis nodosa is not associated with antineutrophil cytoplasmic antibodies (ANCA) [3]. (See "Overview of and approach to the vasculitides in adults".) Patients typically present with systemic symptoms. The kidneys, skin, joints, muscles, nerves, and gastrointestinal tract are commonly involved, usually in some combination and sometimes all at once by the time of diagnosis. PAN can affect virtually any organ but has a striking tendency to spare the lungs. Clinical variants or subsets of PAN include single-organ disease and cutaneous-only PAN. (See "Cutaneous polyarteritis nodosa".) The spectrum of disease known as PAN has evolved and narrowed substantially due to the identification and classification of other forms of vasculitis that had previously been considered PAN. Most importantly, the establishment and acceptance of microscopic polyangiitis as a distinct disease, and the routine availability and recognition of ANCA testing as critical to diagnosing vasculitides other than PAN, have led to more patients with vasculitis being classified as not having PAN. Patient cohorts of PAN included in case series and other research studies published prior to the 1990s almost certainly included a mixture of the newer definition of PAN with microscopic polyangiitis and possibly other forms of vasculitis. Thus, case series of PAN https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 1/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate published after this time period that specifically exclude patients with MPA provide important updated information about this disease [4]. (See "Overview of and approach to the vasculitides in adults" and "Clinical spectrum of antineutrophil cytoplasmic autoantibodies".) The clinical manifestations and diagnosis of PAN will be reviewed here. Treatment is presented separately. (See "Treatment and prognosis of polyarteritis nodosa".) Microscopic polyangiitis and other ANCA-associated systemic vasculitides (eg, granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis [Churg-Strauss]) that characteristically affect small vessels such as arterioles, capillaries, and venules, as well as muscular arteries, are discussed separately. (See "Overview of and approach to the vasculitides in adults" and "Pathogenesis of antineutrophil cytoplasmic autoantibody-associated vasculitis" and "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis" and "Clinical spectrum of antineutrophil cytoplasmic autoantibodies".) EPIDEMIOLOGY Population prevalence estimates for polyarteritis nodosa (PAN) range from 2 to 33 per million [5- 7]. The annual incidence in three regions of Europe was estimated to be 4.4 to 9.7 per million [8]. The variation in estimates may be partly explained by differences in diagnostic criteria, but regional variations also appear to exist [8-10]. The marked reduction in hepatitis B virus infection in many parts of the world has been associated with a parallel reduction in prevalence of PAN. The diagnosis is most commonly made in middle-aged or older adults, and the incidence rises with age, with a peak in the sixth decade of life [5,8,9]. There appears to be a 1.5:1 male predominance. Children can also be affected by PAN. (See "Vasculitis in children: Incidence and classification".) ETIOLOGY Most cases of polyarteritis nodosa (PAN) are idiopathic, although hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, and hairy cell leukemia are important in the pathogenesis of some cases [11-14]. PAN in these settings is called secondary PAN and is also discussed elsewhere in topics related to the underlying disease. (See "Kidney disease associated with hepatitis B virus infection", section on 'Polyarteritis nodosa (PAN)' and "Overview of kidney disease associated with hepatitis C virus infection", section on 'Polyarteritis nodosa' and "Clinical features and diagnosis of hairy cell leukemia".) https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 2/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate In one report from France, HBV accounted for one-third of the cases of PAN, but even higher prevalence rates are possible in areas with endemic HBV infection [4,11]. HBV-related PAN has the same clinical features as non-HBV-related PAN and typically occurs within four months after the onset of HBV infection. In some children with a form of vasculitis that has features similar to PAN, recessive loss of function mutations of the gene encoding adenosine deaminase 2 (ADA2), a growth factor that is the major extracellular adenosine deaminase, have been shown to be associated with the vasculitis [15]. Exome sequencing of genomic deoxyribonucleic acid (DNA) was performed in 24 patients from multiply affected families of Georgian Jewish or German ancestry, or unrelated affected patients of Turkish ancestry, who had been diagnosed clinically with a PAN-like vasculitis. In almost all cases, the onset of disease was during childhood. ADA2 activity was significantly reduced in the serum specimens from the patients when compared with controls. This study, along with a related study also involving ADA2 and vasculopathy, provide data about genetic susceptibility and pathophysiology for at least a subset of patients with PAN-like disease [16]. (See "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors", section on 'Metabolic disorders' and "Vasculitis in children: Incidence and classification", section on 'Polyarteritis nodosa' and "Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis".) The understanding of the clinical spectrum of deficiency of ADA2 (DADA2) continues to be described. In a study of 118 patients with PAN, 9 (7.6 percent) were identified as having rare nonsynonymous variants in ADA2. Four patients (3.4 percent) were biallelic for pathogenic or likely pathogenic variants, and 5 patients (4.2 percent) were monoallelic carriers for 3 variants of uncertain significance and 2 likely pathogenic variants [17]. Thus, it is important to consider testing for DADA2 in all patients with PAN. (See "Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis", section on 'Diagnosis'.) Some patients with PAN have also been diagnosed with the adult-onset inflammatory disorder referred to as VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome [18]. Such patients appear to truly have PAN but also have VEXAS, which is currently associated with a quite poor prognosis. VEXAS should be considered in male patients with PAN with unexplained cytopenias and/or highly difficult-to-control symptoms of vasculitis. (See "Autoinflammatory diseases mediated by NFkB and/or aberrant TNF activity", section on 'Vacuoles, E1 enzyme, X- linked, autoinflammatory, somatic (VEXAS) syndrome'.) PATHOGENESIS https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 3/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate The pathogenetic mechanisms in polyarteritis nodosa (PAN) are poorly understood. It seems likely that in terms of pathogenesis and pathophysiology, PAN represents a spectrum of disease rather than a single entity [19]. In some subsets of cases (eg, those associated with hepatitis B), immune complexes are thought to play a role. However, the mechanism(s) through which immune complex-mediated disease leads to medium-sized arterial inflammation and yet mostly spares arterioles, capillaries, and venules in PAN is unknown. In other subsets of this disease, immune complexes may play a less central role. Thickening of the inflamed vessel wall and intimal proliferation can cause luminal narrowing, reducing blood flow and predisposing to thrombosis of affected vessels. The resulting ischemia or infarction of tissue causes varied clinical manifestations that are discussed in more detail below. As an example, involvement of branches of the renal arteries or intrarenal vessels such as the intralobular or arcuate arteries causes renal ischemia, activation of the renin-angiotensin system, and hypertension [20]. In addition to arterial narrowing and thrombosis, inflammation can cause weakening of the vessel wall that leads to aneurysm formation. Aneurysmal rupture may result in life-threatening bleeding. PATHOLOGY Regardless of the initiating event or underlying cause, established polyarteritis nodosa (PAN) is characterized by segmental transmural inflammation of muscular arteries [2]. In contrast to some other forms of systemic vasculitis, PAN does not involve veins. The cellular infiltrate contains polymorphonuclear leukocytes and mononuclear cells. Fragments of white blood cells (leukocytoclasis) may be noted. Necrosis of the arterial wall results in a homogeneous, eosinophilic appearance referred to as fibrinoid necrosis. Disruption of the internal and external elastic lamina is noted and may contribute to the development of aneurysmal dilation [21]. Lesions that appear to be of different ages are typically found within a single sample. Granulomatous inflammation does not occur in PAN, and its presence suggests other diagnoses. CLINICAL FEATURES Patients with polyarteritis nodosa (PAN) typically present with systemic symptoms (fatigue, weight loss, weakness, fever, arthralgias) and signs (skin lesions, hypertension, renal insufficiency, neurologic dysfunction, abdominal pain) of multisystem involvement ( table 1). https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 4/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate Skin disease Skin manifestations of PAN may commonly include purpura, livedo reticularis, and ulcers, and less commonly tender erythematous nodules and bullous or vesicular eruption [4,22,23]. The nodules in PAN are reminiscent of erythema nodosum or nodular vasculitis, but adequate biopsy specimens demonstrate necrotizing vasculitis within the walls of medium-sized arteries, usually in the deep dermis or embedded between fat lobules in the subcutaneous fat, as well as small-sized arteries. (See "Panniculitis: Recognition and diagnosis", section on 'Inflammatory disorders'.). It is important to realize that dermatopathologists view arterial size as relative to those vessels seen in the skin; thus, "medium-sized" arteries in the skin may be smaller than other "medium- sized" arteries elsewhere, such as branches of the celiac axis or coronary arteries. (See "Evaluation of adults with cutaneous lesions of vasculitis".) The palpable purpuric lesions seen in PAN are identical to those seen in other forms of vasculitis usually associated with small vessel disease (eg, immunoglobulin A vasculitis [Henoch-Sch nlein purpura], antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, and mixed cryoglobulinemia). Biopsy of these skin lesions reveals leukocytoclastic vasculitis ( picture 1). Such findings illustrate that PAN does not exclusively involve medium-sized, muscular arteries but also includes small arteries [24]. However, presentations consistent with only small-vessel involvement essentially exclude PAN. Skin lesions may be focal or diffuse and are more frequently and often more marked over the lower extremities. Limb edema is common. Progressive skin involvement may be severe, including infarction and gangrene of the fingers, toes, or other areas and ulceration extending into the subcutaneous tissue. However, digital and limb ischemia often reflects involvement of arteries larger than "medium-sized" skin vessels. Many of the skin manifestations of PAN result from involvement of vessels within the subcutaneous tissues. For nodules and ulcers, small 2 to 4 mm "punch" biopsies of the skin that sample only the epidermis and superficial dermis are unlikely to include muscular arteries and thus are of limited value. Elliptical surgical skin biopsies that include deeper dermis and subcutaneous fat may be more helpful in diagnosis. As mentioned above, "medium-sized" arteries in the skin may actually be quite small compared with other medium-sized arteries (such as coronary or mesenteric arteries), but they are still muscular and are larger than the small, superficial precapillary arteries associated with purpura. Renal disease In autopsy studies, the kidneys are the most commonly involved organ. Renal involvement frequently leads to variable degrees of renal insufficiency and hypertension. In https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 5/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate addition, rupture of renal arterial aneurysms can cause perirenal hematomas. Multiple renal infarctions may also develop in those with severe vasculitis. Incomplete luminal narrowing of the inflamed arteries leads to glomerular ischemia but not inflammation or necrosis. Thus, the urinalysis, when abnormal, shows only sub-nephrotic and often minimal proteinuria and perhaps modest hematuria, but red blood cell casts (indicative of a glomerular focus of inflammation) are usually absent [1,2]. In patients with red blood cell casts, alternative diagnoses should be considered, including ANCA-associated vasculitis or systemic lupus erythematosus. Hypertension is a common finding in patients with PAN and renal involvement. As noted above, renal ischemia, leading to activation of the renin-angiotensin system, is thought to be the primary mechanism [20]. Neurologic disease A mononeuropathy multiplex (or asymmetric polyneuropathy) affecting named nerves (eg, radial, ulnar, peroneal), typically with both motor and sensory deficits, is one of the most common findings in patients with PAN, occurring in up to 70 percent of patients [4,25-27]. The neuropathy is generally asymmetric at onset, but additional nerve branches become affected over time, leading to a more confluent distal symmetric polyneuropathy. Involvement of the central nervous system occurs in 5 to 10 percent of patients with PAN and may include stroke [4,28-30]. Central nervous involvement in PAN should raise concern that deficiency of adenosine deaminase 2 (DADA2) is actually the correct diagnosis. (See 'Etiology' above.) Gastrointestinal disease Abdominal pain is an early symptom in patients with mesenteric arteritis [31]. The discomfort may be intermittent or continuous and may be most prominent after meals ("intestinal angina"). Weight loss may ensue due to decreased food intake and/or malabsorption. Progressive disease can result in bowel infarction with perforation [32]. Other gastrointestinal symptoms that may be seen include nausea, vomiting, melena, bloody or nonbloody diarrhea, and life-threatening gastrointestinal bleeding [33]. Perforation during colonoscopy may be more frequent in patients with PAN. If colonoscopy is otherwise indicated in a patient with suspected or known PAN, minimal insufflation during the procedure is recommended; and if ischemic areas of bowel are noted, early termination of the study is recommended [33]. Ischemia due to vasculitis affects the small intestine more commonly than other areas of the gastrointestinal tract. In addition, a subset of patients has predominantly mesenteric arterial involvement with little or no clinical evidence of extraintestinal vasculitis. Rare presentations https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 6/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate resembling acute cholecystitis or appendicitis result from acute vasculitis limited to the cystic or appendiceal artery, respectively [31]. Segmental pancreatic infarction and necrotizing pancreatitis, albeit rare, may occur [34]. Coronary artery disease Although overt myocardial infarction is uncommon, myocardial ischemia may result from narrowing or occlusion of the coronary arteries [35]. Heart failure may result from either vasculitis of the coronary arteries, resulting in ischemic cardiomyopathy, or from uncontrolled hypertension caused by renal disease. Muscle disease Muscle involvement is common; symptoms include myalgia and muscle weakness. Serum creatinine kinase levels may be elevated but are seldom high enough to trigger suspicion of an inflammatory myopathy [36]. When muscle pain or claudication are present, muscle biopsy has an approximately 50 percent sensitivity for PAN [37]. Other Virtually any organ of the body may be affected in patients with PAN: Orchitis with testicular tenderness and pain occurs in more than 10 percent of patients, and testicular biopsy in patients with these symptoms can often be diagnostic of PAN [38]. Several abnormalities of the eye may occur, including ischemic retinopathy with hemorrhages and retinal detachment, as well as ischemic optic neuropathy [39,40]. Breast and uterine involvement may be seen in selected patients [21] Involvement of bronchial arteries has been described in PAN [41]. However, the presence of capillaritis or other lung parenchymal involvement by vasculitis strongly suggests another disease process, such as microscopic polyangiitis, granulomatosis with polyangiitis, or eosinophilic granulomatosis with polyangiitis (Churg-Strauss) [41]. Splenic infarction can occur due to arteritis. DIAGNOSIS A clinical diagnosis of polyarteritis nodosa (PAN) is suspected based upon the presence of characteristic symptoms, physical findings, and compatible laboratory test results. However, because of the relative rarity of this disease and the potentially severe adverse effects related to treatment, the diagnosis should be confirmed by biopsy whenever possible. In the absence of an obvious site for biopsy, angiography sometimes reveals microaneurysms of blood vessels in the renal, hepatic, or mesenteric circulations. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 7/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate A general approach to diagnosis in a patient suspected of having vasculitis is discussed in more detail elsewhere (see "Overview of and approach to the vasculitides in adults", section on 'Diagnostic approach'). The following is a brief summary with a focus on those features considered to be of particular importance in PAN. Arteritis consistent with PAN can occur in individual organs without evident systemic involvement. Such cases may be discovered either through biopsy or angiography during an evaluation for vasculitis or "incidentally" upon pathologic review of a surgical specimen, sometimes obtained for other reasons. Whether to label such cases of medium-vessel vasculitis in a single organ as PAN is controversial. However, in all such cases, a comprehensive evaluation for other manifestations of PAN, as described in this section, is warranted to help establish the diagnosis and determine extent of disease to guide treatment plans. History The medical history serves to identify clinical manifestations that might be due to PAN. It may also identify other possible causes of the patient's symptoms (see 'Differential diagnosis' below) such as: Drug exposure Including prescription and illicit drugs associated with drug-induced vasculitis (eg, amphetamines), or injection drug use and the associated risk of hepatitis B and C virus (HBV and HCV) infection. Almost every class of drugs has been implicated as possibly causal of vasculitis, but not all such drug-induced vasculitides fit the pattern of PAN. Alternative diagnosis Other systemic inflammatory diseases (eg, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis), infectious diseases (eg, chronic viral hepatitis, bacterial endocarditis), embolic disorders (eg, atherosclerosis and recent arterial catheterization), or thrombotic disorders. (See 'Differential diagnosis' below.) Physical examination A careful physical examination helps to determine the extent of vascular lesions, the distribution of affected organs, and the presence of additional disease processes. Skin manifestations and the presence of objective evidence of motor weakness (eg, a foot- or wrist-drop) or sensory loss should be sought. A full vascular examination is warranted. If there is no evidence of overt gastrointestinal bleeding, a positive test for occult blood may be indicative of mesenteric vasculitis. Laboratory testing There is no diagnostic laboratory test for PAN. Basic laboratory tests help ascertain the extent of organs affected and their degree of involvement. Basic laboratory analysis includes complete blood count, serum creatinine, muscle enzyme concentrations, liver function studies, hepatitis (HBV and HCV) serologies, and urinalysis. Acute- https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 8/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate phase proteins are typically elevated, as evidenced by increased erythrocyte sedimentation rate and C reactive protein concentrations, but are neither sensitive nor specific enough for the diagnosis of PAN (or most other vasculitides) to substantially impact diagnostic decision making. Chest radiography is used to exclude diseases, particularly other forms of vasculitis with a greater propensity for involving the lungs. Blood cultures should be obtained in all patients suspected of having a systemic vasculitis in order to exclude endovascular infection. Additional laboratory testing is valuable in narrowing the differential diagnosis. This includes the following assays, depending upon the alternative diagnoses being considered based upon the patients signs and symptoms: Antineutrophil cytoplasmic antibodies (ANCA) Antinuclear antibodies (ANA) Complement components (C3 and C4) Cryoglobulins Serum and urine immunofixation electrophoresis to test for monoclonal gammopathy Testing for human immunodeficiency virus Testing for deficiency of adenosine deaminase 2 (DADA2) (see "Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis", section on 'Diagnosis') Testing for VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome (see "Autoinflammatory diseases mediated by NFkB and/or aberrant TNF activity", section on 'Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome') A positive immunofluorescence test for ANCA, if confirmed by enzyme-linked immunosorbent assay (ELISA) testing to be due to antibodies with specificity for proteinase-3 (PR3) or myeloperoxidase (MPO), strongly argues against PAN and in favor of one of the ANCA-associated vasculitides. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies".) High titers of ANA suggest an underlying autoimmune disease such as systemic lupus erythematosus (SLE), systemic sclerosis (scleroderma), or an overlap syndrome, all of which may sometimes be associated with vasculitis. In patients with a positive ANA for whom there is clinical suspicion of a systemic rheumatic disease, additional serologic testing is indicated. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults" and "Diagnosis and classification of Sj gren s disease" and "Measurement and clinical significance of antinuclear antibodies".) https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 9/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate In a patient with a history of inflammatory arthritis, testing for rheumatoid factor (RF) and anti- cyclic citrullinated peptide (CCP) antibodies is helpful when rheumatoid vasculitis is under consideration. RF is also positive in mixed cryoglobulinemia, which is usually associated with HCV. Mixed cryoglobulinemia is suggested by the presence of cryoglobulins and complement consumption. Although cryoglobulinemia is typically associated with small vessel disease (eg, glomerulonephritis, leukocytoclastic vasculitis, capillaritis), it has been linked to some cases of PAN, particularly in the setting of HCV or HBV infection. (See "Clinical manifestations and diagnosis of rheumatoid vasculitis" and "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis".) Lyme disease is a consideration in patients with mononeuropathy multiplex or polyradiculopathy. Serologic testing for Lyme disease is probably unnecessary in the absence of neurologic involvement. (See "Clinical manifestations of Lyme disease in adults" and "Diagnosis of Lyme disease".) Human immunodeficiency virus (HIV) infection can cause mononeuritis multiplex, and co- infection with HIV is common among patients with HBV or HCV infections. (See "Epidemiology, clinical manifestations, diagnosis, and treatment of HIV-associated distal symmetric polyneuropathy (HIV-DSPN)".) Biopsy The presence of PAN may be suspected from the clinical and radiologic findings, but the diagnosis should ideally be confirmed by biopsy of a clinically affected organ. Biopsy of clinically normal tissue has a much lower yield. This was illustrated in a retrospective study of patients with PAN, eosinophilic granulomatosis with polyangiitis (Churg-Strauss), and other systemic vasculitides with gastrointestinal involvement [31]. Upper and lower gastrointestinal lesions, though frequently apparent at endoscopy, rarely provide histopathologic confirmation of vasculitis; none of the biopsies from the upper gastrointestinal tract obtained in 17 patients showed histologic signs of vasculitis. Colorectal biopsies, performed in six patients, were diagnostic in three (one with PAN and two with granulomatosis with polyangiitis). Skin biopsies in PAN establishing that vasculitis is present are quite helpful diagnostically, even if they are not specific for PAN versus other forms of vasculitis. As is always the case, interpretation of the biopsy results must take into consideration the full clinical situation. Renal biopsy in classic polyarteritis nodosa may reveal pathognomonic inflammation of the medium-sized arteries ( picture 2) [42]. Affected arteries may not be seen due to sampling error. However, the presence of small microaneurysms in the kidneys may increase the risk of bleeding from a renal biopsy; thus, some advocate performing a renal biopsy only in those patients in whom the arteriography is negative. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 10/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate Biopsies of medium-sized vessels are not safe or practical, and it is not uncommon for PAN to be diagnosed by combining the findings on angiography with other clinical features. This approach should lead clinicians to regularly reassess the patient's case and be open to other diagnoses. Arteriography and cross-sectional imaging An alternative to biopsy for diagnosis is conventional mesenteric or renal arteriography [1,2]. These studies will often be diagnostic, demonstrating multiple aneurysms and irregular constrictions in the larger vessels with occlusion of smaller penetrating arteries ( image 1). Less invasive angiography techniques (eg, computed tomography [CT] and magnetic resonance imaging [MRI]), can also be used [43,44]. In the proper clinical setting, the finding of wedge- shaped areas of ischemia in the kidney may be of value in demonstrating renal vascular involvement. The demonstration of renal infarctions, however, is less specific for PAN than are the microaneurysms demonstrated most readily by conventional arteriography. CT and MR angiography continue to improve with respect to resolution for vascular disease and utility to both establish the extent of disease in PAN and to allow for serial images to track disease course and treatment response. These techniques have the advantage of helping to avoid repeat catheter-based angiography. DIFFERENTIAL DIAGNOSIS The differential diagnosis of polyarteritis nodosa (PAN) is broad, including infectious diseases that affect the vasculature or are complicated by systemic vasculitis. Immunosuppressive therapies that might be appropriate for systemic vasculitis may mask the symptoms and delay the diagnosis of an infectious disease. Noninfectious disorders, particularly those that can cause widespread arterial embolism, thrombosis, or vasospasm, must be considered as these diseases are also not appropriately treated with immunosuppression. Other systemic vasculitides, although treated in a similar fashion to PAN, may have distinctive manifestations. The differential diagnosis of vasculitis is discussed in more detail elsewhere. (See "Overview of and approach to the vasculitides in adults", section on 'Differential diagnosis'.) Among infectious diseases, the following may cause clinical manifestations that either mimic vasculitis or cause vascular inflammation: Infective endocarditis or other bacteremic disease Mycotic aneurysm with distal embolization Hepatitis B or C virus infection HIV infection https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 11/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate Other disorders that may mimic vasculitis of medium sized arteries include: Atherosclerosis Embolic diseases (eg, left atrial myxoma, cholesterol crystals) Thrombotic disorders (eg, catastrophic antiphospholipid syndrome) Fibromuscular dysplasia Ergotism Radiation fibrosis Necrotic arachnidism (Loxosceles species spider bites) Malignant atrophic papulosis (Degos disease or syndrome) Segmental arterial mediolysis (SAM) Other causes of malignant hypertension Other systemic vasculitides to consider are: Granulomatosis with polyangiitis and microscopic polyangiitis Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) Immunoglobulin A vasculitis (Henoch-Sch nlein purpura) Cryoglobulinemic vasculitis Drug-induced vasculitis Vasculitis secondary to connective tissue disease (eg, systemic lupus erythematosus, rheumatoid arthritis) Glomerulonephritis is much more typical of microscopic polyangiitis than PAN. Among patients with glomerulonephritis, the urinalysis typically has mild to moderate proteinuria, with an active sediment containing red cells and cellular and granular casts. (See "Glomerular disease: Evaluation and differential diagnosis in adults".) A mononeuropathy multiplex (or asymmetric polyneuropathy) with motor and sensory deficits is one of the most common findings in patients with PAN [25-27]. If present, this finding is highly suggestive of vasculitis; diabetic neuropathy is the only other common cause of this problem in developed countries [45]. Other forms of systemic vasculitis commonly associated with mononeuropathy multiplex are the antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides and mixed cryoglobulinemia. Also consider the presence of genetic disorders that have been associated with PAN: Adenosine deaminase deficiency (see "Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis", section on 'Diagnosis') https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 12/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome (see "Autoinflammatory diseases mediated by NFkB and/or aberrant TNF activity", section on 'Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome') Finally, with the increasing use and availability of cross-sectional abdominal imaging by CT or magnetic resonance (MR), more patients are being identified with incidentally discovered abnormalities of medium-sized arteries. Such patients may be labeled as having PAN, but clinicians need to be careful to avoid misdiagnosis of this rare disease based on radiographic data alone, especially without concomitant and physiologically concordant clinical manifestations of disease and/or evidence of change in arterial disease. Incidentally found medium-vessel disease is a quite difficult clinical scenario for which careful "watchful waiting" without treatment but with repeat imaging in three to six months may be appropriate. Classification criteria The American College of Rheumatology (ACR) has established ten criteria for the classification of polyarteritis nodosa in a patient with a vasculitis [46]. A sensitivity and specificity for the diagnosis of polyarteritis of 82 and 87 percent, respectively, has been found in the patient with a documented vasculitis in whom at least three of the following criteria are present: Otherwise unexplained weight loss greater than 4 kg Livedo reticularis Testicular pain or tenderness Myalgias (excluding that of the shoulder and hip girdle), weakness of muscles, tenderness of leg muscles, or polyneuropathy Mononeuropathy or polyneuropathy New-onset diastolic blood pressure greater than 90 mmHg Elevated levels of serum blood urea nitrogen (>40 mg/dL or 14.3 mmol/L) or creatinine (>1.5 mg/dL or 132 micromol/L) Evidence of hepatitis B virus infection via serum antibody or antigen serology Characteristic arteriographic abnormalities not resulting from noninflammatory disease processes ( image 1) A biopsy of small- or medium-sized artery containing polymorphonuclear cells PAN was defined by the Chapel Hill Consensus Conference (CHCC) as: "Necrotizing inflammation of medium-sized or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules" [47]. It is important to remember that neither the ACR Classification Criteria nor the CHCC nomenclature was meant to be used for the diagnosis of vasculitis [48]. Until validated https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 13/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate diagnostic criteria for PAN are established, the diagnosis of PAN is informed by the ACR and CHCC approaches but remains a clinical diagnosis that importantly includes exclusion of entities that mimic this rare 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: Vasculitis" and "Society guideline links: Polyarteritis nodosa".) 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: Polyarteritis nodosa (The Basics)") Beyond the Basics topics (see "Patient education: Vasculitis (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Definition and epidemiology Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis that typically affects medium-sized muscular arteries, with occasional involvement of small muscular arteries. The spectrum of disease known as PAN has evolved and narrowed substantially due to the identification and classification of other forms of vasculitis that had previously been considered PAN, particularly microscopic polyangiitis (MPA). Unlike MPA, PAN is not associated with the presence of antineutrophil cytoplasmic antibodies (ANCA). The diagnosis is most commonly made in middle-aged or https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 14/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate older adults, and the incidence rises with age, with a peak in the sixth decade of life. (See 'Introduction' above and 'Epidemiology' above.) Etiology, pathogenesis, and pathology Most cases of PAN are idiopathic, although hepatitis B virus infection, hepatitis C virus infection, and hairy cell leukemia are important in the pathogenesis of some cases, which are termed secondary PAN. The pathogenetic mechanisms in PAN are poorly understood. It seems likely that, in terms of pathogenesis and pathophysiology, PAN represents a spectrum of disease rather than a single entity. Regardless of the underlying cause, established PAN is characterized by segmental transmural inflammation of muscular arteries; it does not involve veins, unlike other forms of systemic vasculitis. (See 'Etiology' above and 'Pathogenesis' above and 'Pathology' above.) Clinical features Patients with PAN typically present with systemic symptoms (fatigue, weight loss, weakness, fever, arthralgias) and signs (skin lesions, hypertension, renal insufficiency, neurologic dysfunction, abdominal pain) of multisystem involvement ( table 1). (See 'Clinical features' above.) Diagnosis A clinical diagnosis of PAN is suspected based upon the presence of characteristic symptoms, physical findings, and compatible laboratory test results. However, because of the relative rarity of this disease and because of the potentially severe

rheumatoid arthritis) Glomerulonephritis is much more typical of microscopic polyangiitis than PAN. Among patients with glomerulonephritis, the urinalysis typically has mild to moderate proteinuria, with an active sediment containing red cells and cellular and granular casts. (See "Glomerular disease: Evaluation and differential diagnosis in adults".) A mononeuropathy multiplex (or asymmetric polyneuropathy) with motor and sensory deficits is one of the most common findings in patients with PAN [25-27]. If present, this finding is highly suggestive of vasculitis; diabetic neuropathy is the only other common cause of this problem in developed countries [45]. Other forms of systemic vasculitis commonly associated with mononeuropathy multiplex are the antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides and mixed cryoglobulinemia. Also consider the presence of genetic disorders that have been associated with PAN: Adenosine deaminase deficiency (see "Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis", section on 'Diagnosis') https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 12/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome (see "Autoinflammatory diseases mediated by NFkB and/or aberrant TNF activity", section on 'Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome') Finally, with the increasing use and availability of cross-sectional abdominal imaging by CT or magnetic resonance (MR), more patients are being identified with incidentally discovered abnormalities of medium-sized arteries. Such patients may be labeled as having PAN, but clinicians need to be careful to avoid misdiagnosis of this rare disease based on radiographic data alone, especially without concomitant and physiologically concordant clinical manifestations of disease and/or evidence of change in arterial disease. Incidentally found medium-vessel disease is a quite difficult clinical scenario for which careful "watchful waiting" without treatment but with repeat imaging in three to six months may be appropriate. Classification criteria The American College of Rheumatology (ACR) has established ten criteria for the classification of polyarteritis nodosa in a patient with a vasculitis [46]. A sensitivity and specificity for the diagnosis of polyarteritis of 82 and 87 percent, respectively, has been found in the patient with a documented vasculitis in whom at least three of the following criteria are present: Otherwise unexplained weight loss greater than 4 kg Livedo reticularis Testicular pain or tenderness Myalgias (excluding that of the shoulder and hip girdle), weakness of muscles, tenderness of leg muscles, or polyneuropathy Mononeuropathy or polyneuropathy New-onset diastolic blood pressure greater than 90 mmHg Elevated levels of serum blood urea nitrogen (>40 mg/dL or 14.3 mmol/L) or creatinine (>1.5 mg/dL or 132 micromol/L) Evidence of hepatitis B virus infection via serum antibody or antigen serology Characteristic arteriographic abnormalities not resulting from noninflammatory disease processes ( image 1) A biopsy of small- or medium-sized artery containing polymorphonuclear cells PAN was defined by the Chapel Hill Consensus Conference (CHCC) as: "Necrotizing inflammation of medium-sized or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules" [47]. It is important to remember that neither the ACR Classification Criteria nor the CHCC nomenclature was meant to be used for the diagnosis of vasculitis [48]. Until validated https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 13/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate diagnostic criteria for PAN are established, the diagnosis of PAN is informed by the ACR and CHCC approaches but remains a clinical diagnosis that importantly includes exclusion of entities that mimic this rare 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: Vasculitis" and "Society guideline links: Polyarteritis nodosa".) 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: Polyarteritis nodosa (The Basics)") Beyond the Basics topics (see "Patient education: Vasculitis (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Definition and epidemiology Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis that typically affects medium-sized muscular arteries, with occasional involvement of small muscular arteries. The spectrum of disease known as PAN has evolved and narrowed substantially due to the identification and classification of other forms of vasculitis that had previously been considered PAN, particularly microscopic polyangiitis (MPA). Unlike MPA, PAN is not associated with the presence of antineutrophil cytoplasmic antibodies (ANCA). The diagnosis is most commonly made in middle-aged or https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 14/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate older adults, and the incidence rises with age, with a peak in the sixth decade of life. (See 'Introduction' above and 'Epidemiology' above.) Etiology, pathogenesis, and pathology Most cases of PAN are idiopathic, although hepatitis B virus infection, hepatitis C virus infection, and hairy cell leukemia are important in the pathogenesis of some cases, which are termed secondary PAN. The pathogenetic mechanisms in PAN are poorly understood. It seems likely that, in terms of pathogenesis and pathophysiology, PAN represents a spectrum of disease rather than a single entity. Regardless of the underlying cause, established PAN is characterized by segmental transmural inflammation of muscular arteries; it does not involve veins, unlike other forms of systemic vasculitis. (See 'Etiology' above and 'Pathogenesis' above and 'Pathology' above.) Clinical features Patients with PAN typically present with systemic symptoms (fatigue, weight loss, weakness, fever, arthralgias) and signs (skin lesions, hypertension, renal insufficiency, neurologic dysfunction, abdominal pain) of multisystem involvement ( table 1). (See 'Clinical features' above.) Diagnosis A clinical diagnosis of PAN is suspected based upon the presence of characteristic symptoms, physical findings, and compatible laboratory test results. However, because of the relative rarity of this disease and because of the potentially severe adverse effects related to treatment, the diagnosis should be confirmed by biopsy whenever possible. In the absence of an obvious site for biopsy, angiography sometimes reveals microaneurysms of blood vessels in the renal, hepatic, or mesenteric circulations. (See 'Diagnosis' above.) Classification criteria The diagnosis of PAN is informed by the classification criteria developed by the American College of Rheumatology and by the definitions and nomenclature of the Chapel Hill Consensus Conference, but there are no validated diagnostic criteria for PAN. Thus, the diagnosis remains a clinical diagnosis that importantly includes exclusion of entities that mimic this rare disease. (See 'Classification criteria' above.) Differential diagnosis The differential diagnosis of PAN is broad, including infectious diseases that affect the vasculature or that are complicated by systemic vasculitis; noninfectious disorders, particularly those that can cause widespread arterial embolism, thrombosis, or vasospasm; and other systemic vasculitides. (See 'Differential diagnosis' above.) https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 15/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Balow JE. Renal vasculitis. Kidney Int 1985; 27:954. 2. Sato O, Cohn DL. Polyarteritis and microscopic polyangiitis. In: Rheumatology, Klippel JH, Di eppe PA (Eds), Mosby, St Louis 2003. 3. Kallenberg CG, Brouwer E, Weening JJ, Tervaert JW. Anti-neutrophil cytoplasmic antibodies: current diagnostic and pathophysiological potential. Kidney Int 1994; 46:1. 4. Pagnoux C, Seror R, Henegar C, et al. Clinical features and outcomes in 348 patients with polyarteritis nodosa: a systematic retrospective study of patients diagnosed between 1963 and 2005 and entered into the French Vasculitis Study Group Database. Arthritis Rheum 2010; 62:616. 5. Mahr A, Guillevin L, Poissonnet M, Aym S. Prevalences of polyarteritis nodosa, microscopic polyangiitis, Wegener's granulomatosis, and Churg-Strauss syndrome in a French urban multiethnic population in 2000: a capture-recapture estimate. Arthritis Rheum 2004; 51:92. 6. Reinhold-Keller E, Zeidler A, Gutfleisch J, et al. Giant cell arteritis is more prevalent in urban than in rural populations: results of an epidemiological study of primary systemic vasculitides in Germany. Rheumatology (Oxford) 2000; 39:1396. 7. Haugeberg G, Bie R, Bendvold A, et al. Primary vasculitis in a Norwegian community hospital: a retrospective study. Clin Rheumatol 1998; 17:364. 8. Watts RA, Lane SE, Scott DG, et al. Epidemiology of vasculitis in Europe. Ann Rheum Dis 2001; 60:1156. 9. Watts RA, Lane SE, Bentham G, Scott DG. Epidemiology of systemic vasculitis: a ten-year study in the United Kingdom. Arthritis Rheum 2000; 43:414. 10. Watts RA, Gonzalez-Gay MA, Lane SE, et al. Geoepidemiology of systemic vasculitis: comparison of the incidence in two regions of Europe. Ann Rheum Dis 2001; 60:170. 11. Guillevin L, Mahr A, Callard P, et al. Hepatitis B virus-associated polyarteritis nodosa: clinical characteristics, outcome, and impact of treatment in 115 patients. Medicine (Baltimore) 2005; 84:313. 12. Ramos-Casals M, Mu oz S, Medina F, et al. Systemic autoimmune diseases in patients with hepatitis C virus infection: characterization of 1020 cases (The HISPAMEC Registry). J Rheumatol 2009; 36:1442. 13. Hasler P, Kistler H, Gerber H. Vasculitides in hairy cell leukemia. Semin Arthritis Rheum 1995; 25:134. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 16/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate 14. Carpenter MT, West SG. Polyarteritis nodosa in hairy cell leukemia: treatment with interferon-alpha. J Rheumatol 1994; 21:1150. 15. Navon Elkan P, Pierce SB, Segel R, et al. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N Engl J Med 2014; 370:921. 16. Zhou Q, Yang D, Ombrello AK, et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med 2014; 370:911. 17. Schnappauf O, Sampaio Moura N, Aksentijevich I, et al. Sequence-Based Screening of Patients With Idiopathic Polyarteritis Nodosa, Granulomatosis With Polyangiitis, and Microscopic Polyangiitis for Deleterious Genetic Variants in ADA2. Arthritis Rheumatol 2021; 73:512. 18. Beck DB, Ferrada MA, Sikora KA, et al. Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease. N Engl J Med 2020; 383:2628. 19. Ozen S. The changing face of polyarteritis nodosa and necrotizing vasculitis. Nat Rev Rheumatol 2017; 13:381. 20. Stockigt JR, Topliss DJ, Hewett MJ. High-renin hypertension in necrotizing vasculitis. N Engl J Med 1979; 300:1218. 21. Ng WF, Chow LT, Lam PW. Localized polyarteritis nodosa of breast report of two cases and a review of the literature. Histopathology 1993; 23:535. 22. Gibson LE, Su WP. Cutaneous vasculitis. Rheum Dis Clin North Am 1995; 21:1097. 23. Karlsberg PL, Lee WM, Casey DL, et al. Cutaneous vasculitis and rheumatoid factor positivity as presenting signs of hepatitis C virus-induced mixed cryoglobulinemia. Arch Dermatol 1995; 131:1119. 24. Leavitt RY, Fauci AS. Polyangiitis overlap syndrome. Classification and prospective clinical experience. Am J Med 1986; 81:79. 25. Ohkoshi N, Mizusawa H, Oguni E, Shoji S. Sural nerve biopsy in vasculitic neuropathies: morphometric analysis of the caliber of involved vessels. J Med 1996; 27:153. 26. Tervaert JW, Kallenberg C. Neurologic manifestations of systemic vasculitides. Rheum Dis Clin North Am 1993; 19:913. 27. Moore PM. Neurological manifestation of vasculitis: update on immunopathogenic mechanisms and clinical features. Ann Neurol 1995; 37 Suppl 1:S131. 28. Provenzale JM, Allen NB. Neuroradiologic findings in polyarteritis nodosa. AJNR Am J Neuroradiol 1996; 17:1119. 29. Cohen RD, Conn DL, Ilstrup DM. Clinical features, prognosis, and response to treatment in polyarteritis. Mayo Clin Proc 1980; 55:146. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 17/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate 30. Reichart MD, Bogousslavsky J, Janzer RC. Early lacunar strokes complicating polyarteritis nodosa: thrombotic microangiopathy. Neurology 2000; 54:883. 31. Pagnoux C, Mahr A, Cohen P, Guillevin L. Presentation and outcome of gastrointestinal involvement in systemic necrotizing vasculitides: analysis of 62 patients with polyarteritis nodosa, microscopic polyangiitis, Wegener granulomatosis, Churg-Strauss syndrome, or rheumatoid arthritis-associated vasculitis. Medicine (Baltimore) 2005; 84:115. 32. Zizic TM, Classen JN, Stevens MB. Acute abdominal complications of systemic lupus erythematosus and polyarteritis nodosa. Am J Med 1982; 73:525. 33. Levine SM, Hellmann DB, Stone JH. Gastrointestinal involvement in polyarteritis nodosa (1986-2000): presentation and outcomes in 24 patients. Am J Med 2002; 112:386. 34. Flaherty J, Bradley EL 3rd. Acute pancreatitis as a complication of polyarteritis nodosa. Int J Pancreatol 1999; 25:53. 35. Kastner D, Gaffney M, Tak T. Polyarteritis nodosa and myocardial infarction. Can J Cardiol 2000; 16:515. 36. Plumley SG, Rubio R, Alasfar S, Jasin HE. Polyarteritis nodosa presenting as polymyositis. Semin Arthritis Rheum 2002; 31:377. 37. Fort JG, Griffin R, Tahmoush A, Abruzzo JL. Muscle involvement in polyarteritis nodosa: report of a patient presenting clinically as polymyositis and review of the literature. J Rheumatol 1994; 21:945. 38. Teichman JM, Mattrey RF, Demby AM, Schmidt JD. Polyarteritis nodosa presenting as acute orchitis: a case report and review of the literature. J Urol 1993; 149:1139. 39. Akova YA, Jabbur NS, Foster CS. Ocular presentation of polyarteritis nodosa. Clinical course and management with steroid and cytotoxic therapy. Ophthalmology 1993; 100:1775. 40. Hsu CT, Kerrison JB, Miller NR, Goldberg MF. Choroidal infarction, anterior ischemic optic neuropathy, and central retinal artery occlusion from polyarteritis nodosa. Retina 2001; 21:348. 41. Boki KA, Dafni U, Karpouzas GA, et al. Necrotizing vasculitis in Greece: clinical, immunological and immunogenetic aspects. A study of 66 patients. Br J Rheumatol 1997; 36:1059. 42. Jennette JC, Falk RJ. The pathology of vasculitis involving the kidney. Am J Kidney Dis 1994; 24:130. 43. Kato T, Fujii K, Ishii E, et al. A case of polyarteritis nodosa with lesions of the superior mesenteric artery illustrating the diagnostic usefulness of three-dimensional computed tomographic angiography. Clin Rheumatol 2005; 24:628. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 18/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate 44. Schmidt WA. Use of imaging studies in the diagnosis of vasculitis. Curr Rheumatol Rep 2004; 6:203. 45. Hellmann DB, Laing TJ, Petri M, et al. Mononeuritis multiplex: the yield of evaluations for occult rheumatic diseases. Medicine (Baltimore) 1988; 67:145. 46. Lightfoot RW Jr, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa. Arthritis Rheum 1990; 33:1088. 47. Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 2013; 65:1. 48. Watts RA, Suppiah R, Merkel PA, Luqmani R. Systemic vasculitis is it time to reclassify? Rheumatology (Oxford) 2011; 50:643. Topic 8245 Version 33.0 https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 19/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate GRAPHICS Clinical manifestations of systemic polyarteritis nodosa Manifestation Frequency, percent Systemic symptoms 80 Fever, malaise, weight loss Neuropathy 75 Mononeuritis multiplex, polyneuropathy Arthralgias and/or myalgias 60 Articular and/or diffuse extremity pain Cutaneous 50 Livedo reticularis, purpura, ulcers Renal disease 50 Elevated creatinine, hematuria, glomerulonephritis Gastrointestinal symptoms 40 Abdominal pain, rectal bleeding Hypertension 35 New onset Respiratory manifestations 25 Infiltrates, nodules, cavities Central nervous system disease 20 Stroke, confusion Orchitis 20 Testicular pain, swelling Cardiac involvement 10 Cardiomyopathy, pericarditis Peripheral vascular disease 10 Claudication, ischemia, necrosis Adapted from: Pagnoux C, Seror R, Henegar C, et al. Clinical features and outcomes in 348 patients with polyarteritis nodosa. Arthritis Rheum 2010; 62:616. Graphic 53997 Version 6.0 https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 20/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate Leukocytoclastic vasculitis Leukocytoclastic vasculitis appearing as raised purpura. This lesion can occur with any vasculitic syndrome and in the collagen vascular diseases. Courtesy of Marvin I Schwarz, MD. Graphic 78697 Version 2.0 https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 21/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate Polyarteritis nodosa Light micrograph of a small muscular renal artery in polyarteritis nodosa. There is diffuse inflammation of the adventitia and marked thickening of the inner layers by loose connective tissue (arrows). The lumen (L) is significantly narrowed. Involvement of a vessel this large would be unusual in microscopic polyarteritis or granulomatosis with polyangiitis. Courtesy of Helmut Rennke, MD. Graphic 74893 Version 5.0 Normal glomerulus Light micrograph of a normal glomerulus. There are only one or two cells per capillary tuft, the capillary lumens are open, the thickness of the glomerular capillary wall (long arrow) is similar to that of the tubular basement membranes (short arrow), and the https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 22/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate mesangial cells and mesangial matrix are located in the central or stalk regions of the tuft (arrows). Courtesy of Helmut G Rennke, MD. Graphic 75094 Version 6.0 https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 23/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate Kidney arteriogram in polyarteritis nodosa Kidney arteriogram in large-vessel polyarteritis nodosa showing characteristic microaneurysms (small arrows) and abrupt cutoffs of small arteries (large arrows). From: Rose BD. Pathophysiology of Renal Disease, 2d ed, McGraw-Hill, New York, 1987. Graphic 65987 Version 7.0 https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 24/25 7/7/23, 11:14 AM Clinical manifestations and diagnosis of polyarteritis nodosa in adults - UpToDate Contributor Disclosures Peter A Merkel, MD, MPH Equity Ownership/Stock Options: Kyverna [Systemic lupus erythematosus]. Grant/Research/Clinical Trial Support: AbbVie [Vasculitis]; AstraZeneca [Vasculitis]; Boehringer Ingelheim [Scleroderma]; Bristol-Myers Squibb [Vasculitis]; ChemoCentryx [Vasculitis]; Electra [Vasculitis]; Genentech/Roche [Vasculitis]; GlaxoSmithKline [Vasculitis]; InflaRx [Vasculitis]; Sanofi [Vasculitis]; Takeda [Vasculitis]. Consultant/Advisory Boards: AbbVie [Vasculitis]; AstraZeneca [Vasculitis]; Boehringer Ingelheim [Scleroderma]; Bristol-Myers Squibb [Vasculitis]; ChemoCentryx [Vasculitis]; CSL Behring [Scleroderma, vasculitis]; Dynacure [Vasculitis]; EMDSerono [Vasculitis]; GlaxoSmithKline [Vasculitis]; InflaRx [Vasculitis]; Janssen [Vasculitis]; Kyverna [Scleroderma, vasculitis]; MiroBio [Vasculitis]; Neutrolis [Vasculitis]; Novartis [Vasculitis]; NS Pharma [Vasculitis]; Otsuka [Vasculitis]; Q32 [Vasculitis]; Regeneron [Vasculitis]; Sparrow [Vasculitis]; Takeda [Vasculitis]. All of the relevant financial relationships listed have been mitigated. Gene G Hunder, MD No relevant financial relationship(s) with ineligible companies to disclose. Philip Seo, MD, MHS 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-manifestations-and-diagnosis-of-polyarteritis-nodosa-in-adults/print 25/25

7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Clinical manifestations of giant cell arteritis : Carlo Salvarani, MD, Francesco Muratore, MD : Kenneth J Warrington, MD, Jonathan Trobe, MD : Philip Seo, MD, MHS 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, 2022. INTRODUCTION Giant cell arteritis (GCA, also known as Horton disease, cranial arteritis, and temporal arteritis) is categorized as a vasculitis of large- and medium-sized vessels because it can involve the aorta and great vessels. It also shares some histopathologic features with Takayasu arteritis, the other major "large vessel" (LV) vasculitis. Systemic symptoms are common in GCA and vascular involvement can be widespread, causing stenosis and aneurysm of affected vessels. It is the targeting of the tiny muscular arteries from cranial branches of the aortic arch, however, that gives rise to many of the most characteristic symptoms of GCA. The most feared complication, visual loss, is one potential consequence of the cranial phenotype of GCA. The clinical manifestations of GCA will be reviewed here. The pathogenesis, diagnosis, and treatment of this disorder are discussed separately. (See "Pathogenesis of giant cell arteritis" and "Diagnosis of giant cell arteritis" and "Treatment of giant cell arteritis".) EPIDEMIOLOGY Giant cell arteritis (GCA) is the most common idiopathic systemic vasculitis [1]. In the United States, the lifetime risk of developing GCA has been estimated at approximately 1 percent in women and 0.5 percent in men [2]. The greatest risk factor for developing GCA is aging. The disease almost never occurs before age 50 years, and its incidence rises steadily thereafter, peaking between the ages of 70 to 79 [3], https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 1/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate with over 80 percent of patients older than 70 years of age [4,5]. One study found the mean age at incidence of GCA to be 76.7 years [6]. In addition to age, ethnicity is a major risk factor for GCA. The highest incidence figures are found in Scandinavian countries and among Americans of Scandinavian descent. In Olmsted County, Minnesota, the annual incidence of GCA was 15 per 100,000 persons over the age of 50, similar to that in Scandinavian countries [3,7]. This similarity probably reflects shared genetic risk factors, as many of the inhabitants of Olmsted County during the period of study were descended from Scandinavians and northern Europeans. In Southern Europe and Mediterranean countries, incidence rates are lower, with less than 10 per 100,000 persons over the age of 50 [5,8,9]. GCA is less common in Latin American, Asian, Arab, and African American populations, though formal data on these populations are scant [10]. Autopsy studies suggest that GCA is more frequent than reported in studies of clinically diagnosed cases. A study from Sweden found arteritis in 1.6 percent of 889 postmortem cases in which sections of the temporal artery and two transverse sections of the aorta were made [11]. As with many systemic rheumatic diseases, females are affected more frequently than males, in a ratio of almost 3:1 in populations of Scandinavian descent [3]. The ratio of women to men is lower in Mediterranean countries. Familial aggregation of GCA is not unusual [12]. (See "Pathogenesis of giant cell arteritis", section on 'Predisposing factors'.) Most studies have found that life expectancy is not, or is only marginally, reduced in GCA [13-15], with the exception of the subset of patients who develop aortic aneurysm or aortic dissection or rupture [16]. (See 'Large vessel involvement' below.) ASSOCIATION WITH POLYMYALGIA RHEUMATICA Polymyalgia rheumatica (PMR) is characterized by aching and morning stiffness about the shoulder and hip girdles, in the neck, and in the torso. PMR is closely linked to giant cell arteritis (GCA), occurring in approximately 40 to 50 percent of patients with GCA [17]. Conversely, GCA is found in approximately 10 percent of patients with PMR. (See "Clinical manifestations and diagnosis of polymyalgia rheumatica".) The precise nature of the relationship between GCA and PMR is not completely understood. In some patients, symptoms and signs of the two conditions occur simultaneously, while in others they appear separately over time. https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 2/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate CLINICAL FEATURES The onset of symptoms in giant cell arteritis (GCA) tends to be subacute, but abrupt presentations over a few days can occur. Although many of the clinical manifestations of GCA are nonspecific, some characteristic findings strongly suggest the diagnosis ( table 1). Constitutional symptoms Systemic symptoms associated with GCA are frequent and include fever, fatigue, and weight loss. Fevers occur in up to one-half of patients with GCA and are usually low-grade. However, in approximately 15 percent of patients, fevers exceed 39 C (102.2 F), often leading to misdiagnoses of infections [18]. One study found that one in six fevers of unknown origin in older adults was due to GCA [19]. Anorexia and weight loss are usually minor, but, like fever, may be significant [20]. We estimate that in approximately 10 percent of patients with GCA, constitutional symptoms and/or laboratory evidence of inflammation dominate the clinical presentation and may be the only clues to the diagnosis (see 'Laboratory findings' below). Thus, in an older adult with fever or constitutional symptoms not explained by an initial evaluation for infection or malignancy, a diagnosis of GCA warrants consideration. Headache Headache is a common presentation of GCA, occurring in more than two-thirds of patients [17,21]. The quality of headache in GCA, apart from the occasional specific complaint of tenderness of the scalp to touch, has no defining characteristics. Its salient feature is that it is new. Although headache is the chief complaint in many patients presenting with GCA, in some this symptom must be elicited by direct questioning. Classically, headaches due to GCA are located over the temples, but they can also be frontal, occipital, unilateral, or generalized. The headaches can progressively worsen, wax and wane, or sometimes recede before treatment is started. Jaw claudication Nearly one-half of GCA patients experience jaw claudication, a symptom that involves mandibular pain or fatigue brought on by mastication and relieved by stopping. In some cases, patients note a trismus-like symptom, with either perceived or actual limitation of temporomandibular joint excursion. Claudication symptoms occasionally affect the tongue during eating or with repeated swallowing. In an analysis of the diagnostic value of temporal artery biopsies, which correlated positive biopsies with clinical symptoms, jaw claudication was the symptom most highly associated with a positive biopsy [22]. Among 134 patients who underwent temporal artery biopsy, jaw https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 3/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate claudication was present in 54 percent of those with positive biopsies, compared with only 3 percent of those whose biopsies were negative. Ocular involvement Transient visual loss (amaurosis fugax) Transient monocular (and, rarely, binocular) impairment of vision can be an early manifestation of GCA. With transient monocular visual loss (TMVL), affected patients typically note an abrupt partial field defect or temporary curtain effect in the field of vision of one eye. Patients with polymyalgia rheumatica (PMR) or GCA are often sensitized to the potential for vision loss. It can be useful in the course of evaluating the possible significance of a reported visual disturbance to inquire if the patient tried to cover each eye; explicit monocular visual loss would heighten concern for GCA. Transient visual loss can be a harbinger of permanent visual loss, and thus mandates urgent attention in a patient with suspected PMR or GCA. (See "Amaurosis fugax (transient monocular or binocular visual loss)", section on 'Other causes of ischemia'.) Permanent vision loss Unquestionably the most feared complication of GCA remains that of permanent loss of vision, which commonly is painless and sudden, may be partial or complete, and may be unilateral or bilateral. Even in the era of effective therapy, the incidence of permanent partial or complete loss of vision in one or both eyes due to GCA as described from multiple centers has ranged from 15 to 20 percent of patients [23-28]; a more recent report found a lower incidence of 8.2 percent [29]. Though permanent visual loss may be preceded by single or multiple episodes of transient visual loss, it can also occur with devastating swiftness. Once established, visual loss is rarely reversible [30]. Moreover, it has been estimated that within one week, further loss of vision in the unaffected eye ensues in 25 to 50 percent of untreated patients [31]. If vision is intact, however, the prompt initiation of adequate glucocorticoid treatment virtually abolishes the subsequent risk of sight loss. If there is preexisting visual loss, such treatment will markedly reduce the risk of further deterioration, but will not improve established visual loss [32]. Fast-track clinics for the diagnosis of GCA might help to identify patients sooner and therefore initiate adequate treatment before complications such as blindness occur. (See "Treatment of giant cell arteritis".) Risk factors To date, no definite ways of stratifying risk factors for permanent visual loss in GCA have been established. Age, hypertension, thrombocytosis, jaw claudication, and other features have been proposed as risk factors, but in most studies, only prior transient visual loss has been identified as the strongest predictor for subsequent permanent visual loss [25- 28,32,33]. https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 4/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate Several studies have found a reduced risk of visual complications in patients with GCA who have heightened inflammatory status, as indicated by fever, elevations of the acute phase reactants, and anemia [34-36]. Pretreatment levels of the erythrocyte sedimentation rate (ESR) and C- reactive protein (CRP) in GCA, for example, correlate inversely with the risk of visual symptoms. A strong inflammatory response could protect against ischemic lesions by two means: first, patients with pronounced inflammatory features might be seen sooner in the clinic and thus receive more prompt treatment, and, second, interleukin (IL) 6, a key inflammatory cytokine, is endowed with angiogenic properties, and might therefore counteract arteritis-induced ischemia [32]. Causes of vision loss Permanent loss of vision in GCA results from arteritic anterior ischemic optic neuropathy (AION), central or branch retinal artery occlusion (CRAO/BRAO), posterior ischemic optic neuropathy (PION), or, rarely, cerebral ischemia [37-39]. Anterior ischemic optic neuropathy At least 85 percent of cases of vision loss in patients with GCA are caused by AION. The ischemic insult in arteritic AION is typically the consequence of occlusion of the posterior ciliary artery, a branch of the ophthalmic artery from the internal carotid artery, and the main arterial supply to the optic nerve. Only a small percentage of the total occurrences of AION are due to GCA. Most AION is nonarteritic and commonly secondary to atherosclerotic disease [40]. Approximately 40 percent of patients who suffer nonarteritic AION regain some amount of visual acuity, in contrast to visual loss due to GCA, which is more often massive and irreversible [28]. The concurrence of AION with occlusion of the cilioretinal artery, an anatomic variant present in approximately one-fifth of the population, is almost always due to arteritic disease [41]. Central retinal artery occlusion CRAO is a less common cause of visual loss in GCA. Atherosclerosis, especially involving the carotid arteries, accounts for the bulk of cases of CRAO. BRAOs, though reported, are unusual in GCA. (See "Central and branch retinal artery occlusion", section on 'Other inflammatory disease' and "Central and branch retinal artery occlusion", section on 'Central retinal artery occlusion'.) Posterior ischemic optic neuropathy PION, which results from interruption of blood flow to the retrobulbar portion of the optic nerve, is an unusual occurrence in GCA, but should be considered in the differential diagnosis of PION presenting in an older adult. (See "Posterior ischemic optic neuropathy".) Cerebral ischemia Homonymous hemianopia is a visual field defect involving either the two right or the two left halves of the visual fields of both eyes. The most common cause in GCA is an occipital lobe infarction resulting from a lesion in the vertebrobasilar circulation. https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 5/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate In rare cases, bilateral occipital lobe involvement leads to bilateral homonymous field defects and to the development of cortical blindness (see "Homonymous hemianopia"). GCA rarely affects the intracerebral vessels, which is discussed further below. (See 'Central nervous system involvement' below.) Ophthalmic syndromes Diplopia Extraocular motility disorders occur in approximately 5 percent of patients with GCA [42]. In the context of other symptoms suggestive of GCA, diplopia has a high specificity for the disease [43]. Diplopia, which is usually transient, can result from ischemia to almost any portion of the oculomotor system, including the brainstem, oculomotor nerves, and the extraocular muscles themselves [39,44]. The Charles Bonnet syndrome The Charles Bonnet syndrome refers to the phenomenon of visual hallucinations in psychologically normal individuals who have visual loss due to lesions in either peripheral or central visual pathways. Its occurrence in GCA is rare [45]. Musculoskeletal involvement Symptoms of PMR occurring in a patient with GCA include characteristic proximal polyarthralgias and myalgias, sometimes accompanied by peripheral synovitis, and on occasion, distal extremity swelling with pitting edema (also known as remitting seronegative symmetrical synovitis with pitting edema [RS3PE]) [46]. (See "Clinical manifestations and diagnosis of polymyalgia rheumatica", section on 'Differential diagnosis'.) Large vessel involvement Large vessel (LV) GCA refers to involvement of the aorta and its major proximal branches, especially in the upper extremities. The clinical consequences of LV GCA comprise aneurysms and dissections of the aorta, particularly the thoracic aorta, as well as stenosis, occlusion, and ectasia of large arteries. Subclinical LV GCA can also underlie systemic presentations of GCA, where fever and other constitutional symptoms predominate, without cranial symptomatology. (See 'Constitutional symptoms' above.) A variety of imaging modalities have demonstrated the frequency and extent of LV involvement ( image 1 and image 2 and image 3). In a study of 35 consecutive patients with biopsy- proven GCA, fluorodeoxyglucose positron emission tomography (FDG-PET) showed vascular uptake of FDG at the subclavian arteries in 74 percent and at the thoracic aorta in 51 percent [47]. Computed tomographic (CT) angiography of 40 patients with newly diagnosed, biopsy- proven GCA found evidence of arteritis in two-thirds of patients, mainly affecting the aorta (65 percent), but also affecting the brachiocephalic trunk (47 percent), subclavian arteries (42 percent), and femoral arteries (30 percent) [48]. Studies using color-coded duplex ultrasonography have regularly identified involvement of the subclavian, axillary, or brachial https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 6/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate arteries in at least 30 percent of patients with GCA [49-51]. (See "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'Duplex ultrasound'.) Symptomatically evident LV involvement is less commonly observed; a fair estimate of its incidence will require prospective studies incorporating standardized imaging protocols. But the clinical take-home point is important: Subclinical LV involvement is present in a significant percentage of patients with GCA. The clinical phenotype of LV-GCA differs somewhat from that of cranial arteritis. One study compared the clinical features of 74 patients with angiographically diagnosed subclavian or axillary involvement of GCA (or LV GCA) with those of 74 patients with biopsy-proven temporal artery GCA (or cranial artery GCA) [52]. In contrast to those with cranial artery GCA, patients with LV GCA were younger at disease onset (66 versus 72 years), less likely to have headaches (14 versus 57 percent), and more likely to have arm claudication at presentation (51 versus 0 percent). Among the 57 patients with LV GCA in whom a temporal artery biopsy was eventually performed, positive biopsy findings were detected in only 33 patients (58 percent). Another larger retrospective study from the same tertiary care institution comparing 120 patients with radiographic evidence of subclavian artery vasculitis with 240 patents with positive temporal artery biopsies found similar results [53]. The patients with LV vasculitis were younger (68 years versus 76 years), had a longer duration of symptoms prior to the diagnosis of GCA (median 3.5 months versus 2.2 months), fewer cranial symptoms (41 versus 83 percent), and less sight loss (4 versus 11 percent). Temporal artery biopsies, performed in 79 of the 120 patients with LV vasculitis, were positive in only one-half (52 percent). Clinical features of the cranial and LV phenotypes overlap. Systematic screening of patients with the cranial phenotype can demonstrate large artery involvement. On the other hand, temporal artery biopsies are positive in only approximately one-half of patients with LV GCA, underlining the essential role of imaging for the diagnosis of this phenotype. (See "Diagnosis of giant cell arteritis", section on 'Evaluation for large vessel giant cell arteritis'.) Systemic presentation of GCA Systemic symptoms and signs can accompany the clinical presentation of both the cranial and LV phenotypes. Temporal artery biopsy or ultrasound is required to diagnose the former, imaging for the latter. In a study utilizing FDG-PET/CT for the evaluation of 240 patients with fever or inflammation of unknown origin, LV vasculitis accounted for 21 percent of 190 patients with a finalized diagnosis [54]. Aortic aneurysm The incidence of aortic aneurysms in GCA is heavily influenced by the methodologies used for detection and definition of aneurysms [55]. Clinical recognition of aortic aneurysms/dilatation has been described in 10 to 20 percent of cases [56-59], most https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 7/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate studies favoring the lower figure. The thoracic aorta, especially the ascending aorta, is affected more often than the abdominal aorta. In these cases, there is often little or no clinical or laboratory evidence of systemic activity of GCA. Estimates of the magnitude of increased risk for aortic aneurysms in GCA compared with the general population vary. An early population-based cohort study of 96 patients with biopsy-proven GCA suggested that patients with GCA were 17 times more likely to develop thoracic aortic aneurysms and 2.4 times more likely to develop isolated abdominal aortic aneurysms than were persons of the same age and sex [60]. Another study of a large database in the United Kingdom examined the cumulative incidence of aortic aneurysms based on diagnostic codes; while corroborating the increased risk of aortic aneurysms in patients with GCA, the relative risk of aortic aneurysms compared with controls was found to be 2.0 [61]. Aortic dilatation has been reported both in the early and late course of GCA (15 to 23 percent of newly diagnosed GCA patients and 22.2 and 33.3 percent of patients after a median disease duration of 5.4 and 10.3 years, respectively) [48,58,62-64]. The time course between the diagnosis of the GCA and the discovery of aortic aneurysm varies, often depending on whether systematic imaging is obtained, but clinical recognition of an aortic aneurysm is delayed in the majority of patients. In a descriptive study of 41 patients with GCA who developed thoracic aortic aneurysms, three patients developed aneurysms before GCA was diagnosed, GCA and aneurysms were diagnosed simultaneously in five patients, and in the remaining 33 patients, aneurysms were detected a median of seven years after the diagnosis of GCA [65]. Additional studies confirm that aortic aneurysm are a late complication of GCA, appearing 5 to 10 years after initial diagnosis [16,56,59]. Histopathologic examination of specimens obtained from surgery or autopsy shows a range of findings, from fibrosis to varying degrees of active aortitis, including giant cells. These findings suggest two mechanisms of disease: chronic or late recrudescent aortitis causing elastin and collagen disruption, or mechanical stress on an aortic wall that had been weakened in the early active phase of the disease. Whether the behavior of aneurysms in GCA resembles or differs from aneurysms of other etiologies is uncertain. One study has suggested that the rate of growth of aneurysms due to GCA is more rapid than those of degenerative etiology [59]. Unfortunately for the clinician, predictive factors for the development of aortic aneurysms in GCA have not been clearly delineated. Inconsistencies in classification and data collection make it difficult to assign with confidence prognostic roles for age, sex, duration, and such traditional risk https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 8/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate factors as smoking, hypertension, and hyperlipidemia. Aneurysms in GCA have not correlated with intensity and duration of glucocorticoid therapy [16,56]. Aortic dissection While subclinical or clinical aortitis is common in GCA, the related major complications, namely aortic dissection and/or rupture, occur less frequently. In two retrospective studies from large referral centers, aortic dissection or rupture was identified in 1 and 6 percent of all patients with GCA [56,57]. Aortic dissection, which mainly affects the ascending thoracic aorta, can occur early or late in the course of disease. Aneurysm size does not appear to be a predictor of aortic dissection or rupture, while active aortitis may play a role [59,66]. Although longevity in GCA is overall unaffected, epidemiologic data indicate that survival of the subset of patients with aortic aneurysm and dissection is decreased (standardized mortality ratio 2.63; 95% CI 1.78-3.73) [16]. Risk factors for aortic dissection due to GCA have not been clarified. Other large artery involvement GCA can affect the subclavian arteries distal to the take- off of the vertebral arteries and extend through the axillary arteries to the proximal brachial arteries. Arterial bruits, diminished or absent blood pressures, and arm claudication can develop. Cold intolerance of the involved extremity is common, but explicit digital ulcerations and gangrene are rare because of adequate collateral arterial supply. On imaging, upper-extremity arterial involvement in GCA is characteristically bilateral. Gradual tapering of vessels, with occasional occlusion, is typical ( image 4) [67]. The vessel wall is circumferentially affected, in contrast to the eccentric appearance of atherosclerosis. Clinically evident lower-extremity arterial involvement can occur but is uncommon [68]. Less common manifestations Central nervous system involvement Stroke is uncommon in GCA. In descriptive cohorts, the frequency of stroke within the first four weeks of the diagnosis of GCA, and thus construed as potentially disease-related, has ranged from 1.5 to 7.5 percent [27,69,70]. Clinical experience is most consistent with the lower end of these ranges. GCA is an unusual cause of ischemic stroke. In a population-based stroke registry, only 0.15 percent of 4086 cases of ischemic stroke satisfied criteria for the diagnosis of GCA [71]. https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 9/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate Stroke due to GCA has two notable clinical features: Vertebrobasilar involvement is frequent, and intracranial involvement is rare [32]. Though strokes due to GCA can occur in the distribution of both the internal carotid and vertebrobasilar arteries, they are conspicuously more common in the latter location [69,72,73]. More than one-half of strokes attributable to GCA occur in the vertebrobasilar system [69,72]. This figure contrasts with population-based studies of transient ischemic attacks and stroke overall, which occur five times more often in the territory of the internal carotid arteries compared with the vertebrobasilar arteries [74]. Arteritic involvement of the vertebral arteries can result in vertigo, ataxia, dysarthria, homonymous hemianopsia, or bilateral cortical blindness [44]. Bilateral vertebral artery involvement, which causes rapidly progressive brainstem and/or cerebellar neurologic deficits with high mortality, is highly suggestive of GCA [75]. Documented involvement of intracranial vessels in GCA is limited [44,76,77]. In 1 review of 463 patients with a clinical diagnosis of central nervous system vasculitis at the Mayo Clinic, only 2 patients had compelling evidence of intracranial GCA [76]. In a subsequent case series of 185 patients with GCA evaluated at Mayo Clinic, 9 cases of GCA with intracranial involvement were identified [77]. The major findings were a high incidence of neurologic deficits and poor prognosis despite treatment. Other clinical cases of intracranial involvement in the setting of GCA are described [78], and 3 Tesla (3T) magnetic resonance imaging (MRI) has shown vessel wall enhancement of intradural arteries in a small number of GCA patients [79]. Though reported, other neurologic problems including peripheral neuropathy, myelopathy, higher cortical dysfunction or dementia, and pachymeningitis are uncommon complications of GCA [80-82]. Upper respiratory tract symptoms Patients with GCA can present upper respiratory tract symptoms, in particular a nonproductive cough [83]. The cause of cough is unknown, but may result from vasculitis in the area of cough receptors, which are located throughout the respiratory tree, or vasculitis of the ascending pharyngeal artery, a branch of the external carotid artery. Vasculitis of the bronchial arteries has been observed in the postmortem examination of a patient with disseminated GCA [84]. Other head and neck involvement Branches of the external carotid artery are often affected in GCA ( figure 1), including the superficial temporal artery ( figure 2). Jaw claudication results from arteritic involvement of the muscles of mastication (masseter, temporalis, and medial and lateral pterygoid muscles), all of which are supplied by the branches of the external carotid artery. Involvement of other branches of the external carotid artery https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 10/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate accounts for many of the other extracranial symptoms that can accompany the presentation of GCA, including: Maxillary and dental pain Facial swelling Throat pain Tongue pain and macroglossia [85] Lingual infarction (causing ulceration of the tongue) and scalp necrosis are uncommon, owing to the rich collateral circulation of these tissues, but occasionally are seen, usually in neglected cases of longstanding duration [86,87]. Atypical features A variety of unusual presentations of GCA have been reported, including: Dysarthria [88] Sensorineural hearing loss [89] Breast mass [90] Female genital tract involvement (ovary, fallopian tubes, or uterus; usually found by chance on histopathologic inspection of surgical specimens) [91] Mesenteric ischemia [92] Pericarditis [93] PHYSICAL EXAMINATION FINDINGS Cardiovascular findings Abnormal pulses In the setting of large vessel (LV) disease, diminished pulses and discrepant blood pressure in the arms can occur. On each visit, the carotid, brachial, radial, femoral, and pedal pulses should be palpated, and blood pressures in both arms measured. Temporal artery abnormalities The frontal or parietal branches of the superficial temporal arteries may be thickened, nodular, tender, or occasionally erythematous ( picture 1). Pulses may be decreased or absent. The occipital arteries and, less often, the postauricular or facial arteries may be enlarged or tender. A meta-analysis performed to identify the utility of various clinical features in the diagnosis of GCA included 21 studies reported between 1996 and 2000 [43]. The studies represented a total of 2680 patients who had undergone temporal artery biopsy, of whom 1050 (39 percent) had biopsy-proven GCA. Likelihood ratios (LR) for positive temporal artery biopsies https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 11/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate were calculated for various features of the physical examination. The following observations were made: A prominent or enlarged temporal artery LR 4.3 (ie, a patient with such a finding was more than four times as likely to have a positive temporal artery biopsy than one without such a finding) An absent temporal artery pulse LR 2.7 Temporal artery tenderness LR 2.6 Though these findings illustrate the potential value of the physical examination in evaluating patients with possible giant cell arteritis (GCA), in a sizeable number of patients with biopsy-proven GCA, clinical examination of the temporal arteries is unremarkable; conversely, prominence of the frontal branches of the temporal arteries in older adults is not infrequent or of pathologic consequence. Bruits Auscultation for bruits should be regularly performed. Bruits can be heard on auscultation of the carotid or supraclavicular areas, over the axillary, brachial, or femoral arteries, and over the abdominal aorta. Heart murmur Murmurs of aortic regurgitation may signal the development of an ascending aortic aneurysm with secondary dilatation of the aortic valve. Ocular findings Fundoscopy is indicated in patients with subjective change in visual acuity. In a patient with transient monocular visual loss (TMVL), the ophthalmologic examination can be entirely normal. Some patients have cotton wool spots in the retina, indicative of local, retinal ischemia, depending upon the site of critical vascular lesions. In patients with acute visual loss from arteritic anterior ischemic optic neuropathy (AION), ophthalmoscopic examination shows changes of ischemic optic neuropathy with a swollen pale disc and blurred margins ( picture 2). In patients with permanent visual loss, later findings include optic disc pallor. Fundoscopy can be valuable in differentiating nonarteritic AION from arteritic AION, as occurs in GCA. The affected swollen optic nerve is often pale immediately in GCA, whereas pallor is delayed in nonarteritic AION. The finding of associated retinal or choroidal ischemia in addition to AION is highly suggestive of GCA. Finally, the absence of a crowded optic disc in the unaffected eye of a patient with AION should make the diagnosis of nonarteritic AION unlikely and should increase the probability of arteritic AION [40]. https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 12/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate In posterior ischemic optic neuropathy (PION), acuity is reduced but the appearance of the optic nerve on ophthalmoscopic examination is normal in the acute phase because the ischemic insult has occurred well behind the optic disc. A relative afferent pupillary defect (APD), an objective means of identifying ipsilateral optic nerve dysfunction, will be present unless both eyes have symmetrical optic nerve dysfunction. In PION, the finding of an APD can be a useful sign to implicate optic neuropathy as a probable cause of visual loss even when the optic nerve appears normal. Diplopia is typically transient but if present, can be associated with reduced extraocular movements; diplopia due to a brainstem stroke results in skew deviation. Musculoskeletal findings In patients who also have polymyalgia rheumatica (PMR), active range of motion of the shoulders, neck, and hips can be limited, which in some patients can also be accompanied by distal synovitis, especially affecting the wrists and metacarpophalangeal joints. (See "Clinical manifestations and diagnosis of polymyalgia rheumatica".) LABORATORY FINDINGS Laboratory findings useful in the assessment of giant cell arteritis (GCA) include routine hematologic testing, selected serum chemistry tests, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Hematologic abnormalities A normochromic anemia is often present prior to therapy and improves promptly after the institution of glucocorticoids. The anemia is occasionally profound [94]. Many patients also have a reactive thrombocytosis [95,96]. The leukocyte count is usually normal or minimally elevated, even in the setting of widespread systemic inflammation. Erythrocyte sedimentation rate and C-reactive protein A characteristic laboratory abnormality in many patients with GCA is a high ESR, which can reach 100 mm/hour [43,96]. The CRP is nearly always commensurately elevated, though prospective head-to-head studies on the use of the ESR and CRP for the diagnosis and management of GCA are lacking. Among patients with a paraproteinemia or some other cause of a spuriously elevated or depressed ESR, the CRP level is more reliable. (See "Acute phase reactants", section on 'Clinical use'.) Less striking elevations of the ESR [43], however, may also occur. In a population-based study of 167 patients from Olmsted County, 18 (11 percent) had an ESR less than 50 mm/hour and 9 (5 percent) less than 40 mm/hour before treatment was initiated. The patients with an ESR less than 40 mm/hour were less likely to experience systemic symptoms such as malaise, fever, or weight loss; nevertheless, their clinical manifestations, including risk of visual loss, were https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 13/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate indistinguishable from those in patients with a higher ESR [97]. In another series of 173 biopsy- proven cases, 12 patients (5.8 percent) had ESR values less than 46 mm/hour [98]. An additional retrospective study from Olmsted County found normal values for both the ESR and CRP in 4 percent of 177 patients with biopsy-proven GCA at the time of diagnosis [99]. Neither the ESR nor the CRP is a specific biomarker for GCA. Abnormalities in the ESR and CRP can help calibrate the diagnostic probability of GCA, but normal values do not absolve the clinician of the responsibility to pursue the diagnosis in an appropriate clinical setting, nor do marked elevations certify that a diagnosis of GCA is correct. (See "Diagnosis of giant cell arteritis".) Other laboratory abnormalities Elevated serum concentrations of hepatic enzymes, especially the alkaline phosphatase, occur in 25 to 35 percent of patients. The elevations are typically modest and revert to normal with glucocorticoid therapy. The serum albumin level is often moderately decreased at diagnosis but responds quickly to the institution of glucocorticoids. Elevated serum interleukin (IL) 6 concentrations appear to be related closely to clinical disease activity in GCA [100] and may better correlate with clinical relapse than the ESR [101]. However, IL-6 assays are not routinely available, and their clinical utility remains unproven. IMAGING FINDINGS The posterior-anterior (PA) and lateral chest radiograph can show aneurysmal dilation of the ascending aorta, but has limited sensitivity. A detailed discussion of the other imaging modalities used to evaluate the extent of involvement of the aorta and large arteries is presented separately. (See "Clinical manifestations and diagnosis of thoracic aortic aneurysm", section on 'Imaging 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: Giant cell arteritis and polymyalgia rheumatica".) INFORMATION FOR PATIENTS https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 14/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - 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 topics (see "Patient education: Polymyalgia rheumatica and giant cell arteritis (The Basics)") Beyond the Basics topics (see "Patient education: Vasculitis (Beyond the Basics)" and "Patient education: Polymyalgia rheumatica and giant cell arteritis (Beyond the Basics)") SUMMARY Epidemiology The major risk factor for developing giant cell arteritis (GCA, also known as

ascending aortic aneurysm with secondary dilatation of the aortic valve. Ocular findings Fundoscopy is indicated in patients with subjective change in visual acuity. In a patient with transient monocular visual loss (TMVL), the ophthalmologic examination can be entirely normal. Some patients have cotton wool spots in the retina, indicative of local, retinal ischemia, depending upon the site of critical vascular lesions. In patients with acute visual loss from arteritic anterior ischemic optic neuropathy (AION), ophthalmoscopic examination shows changes of ischemic optic neuropathy with a swollen pale disc and blurred margins ( picture 2). In patients with permanent visual loss, later findings include optic disc pallor. Fundoscopy can be valuable in differentiating nonarteritic AION from arteritic AION, as occurs in GCA. The affected swollen optic nerve is often pale immediately in GCA, whereas pallor is delayed in nonarteritic AION. The finding of associated retinal or choroidal ischemia in addition to AION is highly suggestive of GCA. Finally, the absence of a crowded optic disc in the unaffected eye of a patient with AION should make the diagnosis of nonarteritic AION unlikely and should increase the probability of arteritic AION [40]. https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 12/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate In posterior ischemic optic neuropathy (PION), acuity is reduced but the appearance of the optic nerve on ophthalmoscopic examination is normal in the acute phase because the ischemic insult has occurred well behind the optic disc. A relative afferent pupillary defect (APD), an objective means of identifying ipsilateral optic nerve dysfunction, will be present unless both eyes have symmetrical optic nerve dysfunction. In PION, the finding of an APD can be a useful sign to implicate optic neuropathy as a probable cause of visual loss even when the optic nerve appears normal. Diplopia is typically transient but if present, can be associated with reduced extraocular movements; diplopia due to a brainstem stroke results in skew deviation. Musculoskeletal findings In patients who also have polymyalgia rheumatica (PMR), active range of motion of the shoulders, neck, and hips can be limited, which in some patients can also be accompanied by distal synovitis, especially affecting the wrists and metacarpophalangeal joints. (See "Clinical manifestations and diagnosis of polymyalgia rheumatica".) LABORATORY FINDINGS Laboratory findings useful in the assessment of giant cell arteritis (GCA) include routine hematologic testing, selected serum chemistry tests, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Hematologic abnormalities A normochromic anemia is often present prior to therapy and improves promptly after the institution of glucocorticoids. The anemia is occasionally profound [94]. Many patients also have a reactive thrombocytosis [95,96]. The leukocyte count is usually normal or minimally elevated, even in the setting of widespread systemic inflammation. Erythrocyte sedimentation rate and C-reactive protein A characteristic laboratory abnormality in many patients with GCA is a high ESR, which can reach 100 mm/hour [43,96]. The CRP is nearly always commensurately elevated, though prospective head-to-head studies on the use of the ESR and CRP for the diagnosis and management of GCA are lacking. Among patients with a paraproteinemia or some other cause of a spuriously elevated or depressed ESR, the CRP level is more reliable. (See "Acute phase reactants", section on 'Clinical use'.) Less striking elevations of the ESR [43], however, may also occur. In a population-based study of 167 patients from Olmsted County, 18 (11 percent) had an ESR less than 50 mm/hour and 9 (5 percent) less than 40 mm/hour before treatment was initiated. The patients with an ESR less than 40 mm/hour were less likely to experience systemic symptoms such as malaise, fever, or weight loss; nevertheless, their clinical manifestations, including risk of visual loss, were https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 13/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate indistinguishable from those in patients with a higher ESR [97]. In another series of 173 biopsy- proven cases, 12 patients (5.8 percent) had ESR values less than 46 mm/hour [98]. An additional retrospective study from Olmsted County found normal values for both the ESR and CRP in 4 percent of 177 patients with biopsy-proven GCA at the time of diagnosis [99]. Neither the ESR nor the CRP is a specific biomarker for GCA. Abnormalities in the ESR and CRP can help calibrate the diagnostic probability of GCA, but normal values do not absolve the clinician of the responsibility to pursue the diagnosis in an appropriate clinical setting, nor do marked elevations certify that a diagnosis of GCA is correct. (See "Diagnosis of giant cell arteritis".) Other laboratory abnormalities Elevated serum concentrations of hepatic enzymes, especially the alkaline phosphatase, occur in 25 to 35 percent of patients. The elevations are typically modest and revert to normal with glucocorticoid therapy. The serum albumin level is often moderately decreased at diagnosis but responds quickly to the institution of glucocorticoids. Elevated serum interleukin (IL) 6 concentrations appear to be related closely to clinical disease activity in GCA [100] and may better correlate with clinical relapse than the ESR [101]. However, IL-6 assays are not routinely available, and their clinical utility remains unproven. IMAGING FINDINGS The posterior-anterior (PA) and lateral chest radiograph can show aneurysmal dilation of the ascending aorta, but has limited sensitivity. A detailed discussion of the other imaging modalities used to evaluate the extent of involvement of the aorta and large arteries is presented separately. (See "Clinical manifestations and diagnosis of thoracic aortic aneurysm", section on 'Imaging 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: Giant cell arteritis and polymyalgia rheumatica".) INFORMATION FOR PATIENTS https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 14/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - 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 topics (see "Patient education: Polymyalgia rheumatica and giant cell arteritis (The Basics)") Beyond the Basics topics (see "Patient education: Vasculitis (Beyond the Basics)" and "Patient education: Polymyalgia rheumatica and giant cell arteritis (Beyond the Basics)") SUMMARY Epidemiology The major risk factor for developing giant cell arteritis (GCA, also known as Horton disease, cranial arteritis, and temporal arteritis) is aging. The disease almost never occurs before age 50 years, and its incidence rises steadily thereafter. Although systemic manifestations are characteristic of GCA and although vascular involvement can be widespread, clinical manifestations of the disease most frequently result from involvement of the cranial branches of arteries originating from the aortic arch. The most sinister complication of GCA, visual loss, is one potential result of the major phenotype of the disease, that of cranial arteritis. (See 'Introduction' above and 'Epidemiology' above.) Clinical features and association with polymyalgia rheumatica The onset of symptoms in GCA tends to be subacute, but abrupt presentations occur in some patients. When taking the patient's history, the clinician must ask about the following types of symptoms: systemic symptoms, such as fever, fatigue, and weight loss; headache; jaw claudication, which is the symptom most highly predictive of a positive temporal artery for the diagnosis of GCA; visual symptoms, particularly transient monocular visual loss (TMVL or amaurosis fugax) and diplopia; and symptoms of polymyalgia rheumatica (PMR). Other symptoms can also be present. (See 'Clinical features' above and 'Association with polymyalgia rheumatica' above.) https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 15/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate Ocular involvement A variety of ocular syndromes are associated with GCA. The most common are TMVL and anterior ischemic optic neuropathy (AION). It is estimated that bilateral blindness will develop in 25 to 50 percent of untreated patients who present with loss of vision in one eye. (See 'Permanent vision loss' above.) Large vessel involvement Subclinical involvement of the aorta and large arteries is frequent, a delayed clinical consequence of which can be aortic aneurysm. (See 'Large vessel involvement' above.) Physical examination findings Careful temporal arteries palpation, measurement of the blood pressures in both arms, and assessment of the arterial tree by palpation and auscultation should be performed in all patients with suspected GCA. (See 'Physical examination findings' above.) Laboratory findings Laboratory findings useful in the assessment of GCA include routine hematologic testing, selected serum chemistry tests, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). (See 'Laboratory findings' above.) ACKNOWLEDGMENTS The UpToDate editorial staff acknowledges William P Docken, MD and James T Rosenbaum, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Gonz lez-Gay MA, Garc a-Porr a C. Systemic vasculitis in adults in northwestern Spain, 1988-1997. Clinical and epidemiologic aspects. Medicine (Baltimore) 1999; 78:292. 2. Crowson CS, Matteson EL, Myasoedova E, et al. The lifetime risk of adult-onset rheumatoid arthritis and other inflammatory autoimmune rheumatic diseases. Arthritis Rheum 2011; 63:633. 3. Gonzalez-Gay MA, Vazquez-Rodriguez TR, Lopez-Diaz MJ, et al. Epidemiology of giant cell arteritis and polymyalgia rheumatica. Arthritis Rheum 2009; 61:1454. 4. Salvarani C, Crowson CS, O'Fallon WM, et al. Reappraisal of the epidemiology of giant cell arteritis in Olmsted County, Minnesota, over a fifty-year period. Arthritis Rheum 2004; 51:264. https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 16/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate 5. Gonzalez-Gay MA, Miranda-Filloy JA, Lopez-Diaz MJ, et al. Giant cell arteritis in northwestern Spain: a 25-year epidemiologic study. Medicine (Baltimore) 2007; 86:61. 6. Kermani TA, Sch fer VS, Crowson CS, et al. Increase in age at onset of giant cell arteritis: a population-based study. Ann Rheum Dis 2010; 69:780. 7. Garvey TD, Koster MJ, Crowson CS, Warrington KJ. Incidence, survival, and diagnostic trends in GCA across seven decades in a North American population-based cohort. Semin Arthritis Rheum 2021; 51:1193. 8. Bas-Lando M, Breuer GS, Berkun Y, et al. The incidence of giant cell arteritis in Jerusalem over a 25-year period: annual and seasonal fluctuations. Clin Exp Rheumatol 2007; 25:S15. 9. Salvarani C, Macchioni P, Zizzi F, et al. Epidemiologic and immunogenetic aspects of polymyalgia rheumatica and giant cell arteritis in northern Italy. Arthritis Rheum 1991; 34:351. 10. De Smit E, Palmer AJ, Hewitt AW. Projected worldwide disease burden from giant cell arteritis by 2050. J Rheumatol 2015; 42:119. 11. Ostberg G. An arteritis with special reference to polymyalgia arteritica. Acta Pathol Microbiol Scand Suppl 1973; 237:Suppl 237:1. 12. Liozon E, Ouattara B, Rhaiem K, et al. Familial aggregation in giant cell arteritis and polymyalgia rheumatica: a comprehensive literature review including 4 new families. Clin Exp Rheumatol 2009; 27:S89. 13. Gran JT, Myklebust G, Wilsgaard T, Jacobsen BK. Survival in polymyalgia rheumatica and temporal arteritis: a study of 398 cases and matched population controls. Rheumatology (Oxford) 2001; 40:1238. 14. Hill CL, Black RJ, Nossent JC, et al. Risk of mortality in patients with giant cell arteritis: A systematic review and meta-analysis. Semin Arthritis Rheum 2017; 46:513. 15. Li L, Neogi T, Jick S. Mortality in Patients With Giant Cell Arteritis: A Cohort Study in UK Primary Care. Arthritis Care Res (Hoboken) 2018; 70:1251. 16. Kermani TA, Warrington KJ, Crowson CS, et al. Large-vessel involvement in giant cell arteritis: a population-based cohort study of the incidence-trends and prognosis. Ann Rheum Dis 2013; 72:1989. 17. Gonzalez-Gay MA, Barros S, Lopez-Diaz MJ, et al. Giant cell arteritis: disease patterns of clinical presentation in a series of 240 patients. Medicine (Baltimore) 2005; 84:269. 18. Calamia KT, Hunder GG. Giant cell arteritis (temporal arteritis) presenting as fever of undetermined origin. Arthritis Rheum 1981; 24:1414. https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 17/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate 19. Knockaert DC, Vanneste LJ, Bobbaers HJ. Fever of unknown origin in elderly patients. J Am Geriatr Soc 1993; 41:1187. 20. Jones JG. Clinical features of giant cell arteritis. Baillieres Clin Rheumatol 1991; 5:413. 21. Myklebust G, Gran JT. A prospective study of 287 patients with polymyalgia rheumatica and temporal arteritis: clinical and laboratory manifestations at onset of disease and at the time of diagnosis. Br J Rheumatol 1996; 35:1161. 22. Gabriel SE, O'Fallon WM, Achkar AA, et al. The use of clinical characteristics to predict the results of temporal artery biopsy among patients with suspected giant cell arteritis. J Rheumatol 1995; 22:93. 23. Aiello PD, Trautmann JC, McPhee TJ, et al. Visual prognosis in giant cell arteritis. Ophthalmology 1993; 100:550. 24. Font C, Cid MC, Coll-Vinent B, et al. Clinical features in patients with permanent visual loss due to biopsy-proven giant cell arteritis. Br J Rheumatol 1997; 36:251. 25. Gonz lez-Gay MA, Garc a-Porr a C, Llorca J, et al. Visual manifestations of giant cell arteritis. Trends and clinical spectrum in 161 patients. Medicine (Baltimore) 2000; 79:283. 26. Liozon E, Herrmann F, Ly K, et al. Risk factors for visual loss in giant cell (temporal) arteritis: a prospective study of 174 patients. Am J Med 2001; 111:211. 27. Nesher G, Berkun Y, Mates M, et al. Risk factors for cranial ischemic complications in giant cell arteritis. Medicine (Baltimore) 2004; 83:114. 28. Salvarani C, Cimino L, Macchioni P, et al. Risk factors for visual loss in an Italian population- based cohort of patients with giant cell arteritis. Arthritis Rheum 2005; 53:293. 29. Chen JJ, Leavitt JA, Fang C, et al. Evaluating the Incidence of Arteritic Ischemic Optic Neuropathy and Other Causes of Vision Loss from Giant Cell Arteritis. Ophthalmology 2016; 123:1999. 30. Danesh-Meyer H, Savino PJ, Gamble GG. Poor prognosis of visual outcome after visual loss from giant cell arteritis. Ophthalmology 2005; 112:1098. 31. Jonasson F, Cullen JF, Elton RA. Temporal arteritis. A 14-year epidemiological, clinical and prognostic study. Scott Med J 1979; 24:111. 32. Soriano A, Muratore F, Pipitone N, et al. Visual loss and other cranial ischaemic complications in giant cell arteritis. Nat Rev Rheumatol 2017; 13:476. 33. Liozon E, Dalmay F, Lalloue F, et al. Risk Factors for Permanent Visual Loss in Biopsy-proven Giant Cell Arteritis: A Study of 339 Patients. J Rheumatol 2016; 43:1393. 34. Cid MC, Font C, Oristrell J, et al. Association between strong inflammatory response and low risk of developing visual loss and other cranial ischemic complications in giant cell https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 18/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate (temporal) arteritis. Arthritis Rheum 1998; 41:26. 35. Cid MC, Hern ndez-Rodr guez J, Esteban MJ, et al. Tissue and serum angiogenic activity is associated with low prevalence of ischemic complications in patients with giant-cell arteritis. Circulation 2002; 106:1664. 36. Nesher G, Nesher R, Mates M, et al. Giant cell arteritis: intensity of the initial systemic inflammatory response and the course of the disease. Clin Exp Rheumatol 2008; 26:S30. 37. Miller NR. Visual manifestations of temporal arteritis. Rheum Dis Clin North Am 2001; 27:781. 38. Hayreh SS, Podhajsky PA, Zimmerman B. Ocular manifestations of giant cell arteritis. Am J Ophthalmol 1998; 125:509. 39. Vodopivec I, Rizzo JF 3rd. Ophthalmic manifestations of giant cell arteritis. Rheumatology (Oxford) 2018; 57:ii63. 40. Biousse V, Newman NJ. Ischemic Optic Neuropathies. N Engl J Med 2015; 372:2428. 41. Hayreh SS. Anterior ischaemic optic neuropathy. Differentiation of arteritic from non- arteritic type and its management. Eye (Lond) 1990; 4 ( Pt 1):25. 42. Caselli RJ, Hunder GG. Neurologic complications of giant cell (temporal) arteritis. Semin Neurol 1994; 14:349. 43. Smetana GW, Shmerling RH. Does this patient have temporal arteritis? JAMA 2002; 287:92. 44. Wilkinson IM, Russell RW. Arteries of the head and neck in giant cell arteritis. A pathological study to show the pattern of arterial involvement. Arch Neurol 1972; 27:378. 45. Razavi M, Jones RD, Manzel K, et al. Steroid-responsive charles bonnet syndrome in temporal arteritis. J Neuropsychiatry Clin Neurosci 2004; 16:505. 46. Salvarani C, Hunder GG. Musculoskeletal manifestations in a population-based cohort of patients with giant cell arteritis. Arthritis Rheum 1999; 42:1259. 47. Blockmans D, de Ceuninck L, Vanderschueren S, et al. Repetitive 18F-fluorodeoxyglucose positron emission tomography in giant cell arteritis: a prospective study of 35 patients. Arthritis Rheum 2006; 55:131. 48. Prieto-Gonz lez S, Arguis P, Garc a-Mart nez A, et al. Large vessel involvement in biopsy- proven giant cell arteritis: prospective study in 40 newly diagnosed patients using CT angiography. Ann Rheum Dis 2012; 71:1170. 49. Schmidt WA, Seifert A, Gromnica-Ihle E, et al. Ultrasound of proximal upper extremity arteries to increase the diagnostic yield in large-vessel giant cell arteritis. Rheumatology (Oxford) 2008; 47:96. https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 19/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate 50. Aschwanden M, Kesten F, Stern M, et al. Vascular involvement in patients with giant cell arteritis determined by duplex sonography of 2x11 arterial regions. Ann Rheum Dis 2010; 69:1356. 51. Ghinoi A, Pipitone N, Nicolini A, et al. Large-vessel involvement in recent-onset giant cell arteritis: a case-control colour-Doppler sonography study. Rheumatology (Oxford) 2012; 51:730. 52. Brack A, Martinez-Taboada V, Stanson A, et al. Disease pattern in cranial and large-vessel giant cell arteritis. Arthritis Rheum 1999; 42:311. 53. Muratore F, Kermani TA, Crowson CS, et al. Large-vessel giant cell arteritis: a cohort study. Rheumatology (Oxford) 2015; 54:463. 54. Sch nau V, Vogel K, Englbrecht M, et al. The value of 18F-FDG-PET/CT in identifying the cause of fever of unknown origin (FUO) and inflammation of unknown origin (IUO): data from a prospective study. Ann Rheum Dis 2018; 77:70. 55. Mackie SL, Hensor EM, Morgan AW, Pease CT. Should I send my patient with previous giant cell arteritis for imaging of the thoracic aorta? A systematic literature review and meta- analysis. Ann Rheum Dis 2014; 73:143. 56. Nuenninghoff DM, Hunder GG, Christianson TJ, et al. Incidence and predictors of large- artery complication (aortic aneurysm, aortic dissection, and/or large-artery stenosis) in patients with giant cell arteritis: a population-based study over 50 years. Arthritis Rheum 2003; 48:3522. 57. Gonzalez-Gay MA, Garcia-Porrua C, Pi eiro A, et al. Aortic aneurysm and dissection in patients with biopsy-proven giant cell arteritis from northwestern Spain: a population-based study. Medicine (Baltimore) 2004; 83:335. 58. Garc a-Mart nez A, Hern ndez-Rodr guez J, Arguis P, et al. Development of aortic aneurysm/dilatation during the followup of patients with giant cell arteritis: a cross- sectional screening of fifty-four prospectively followed patients. Arthritis Rheum 2008; 59:422. 59. Kebed DT, Bois JP, Connolly HM, et al. Spectrum of Aortic Disease in the Giant Cell Arteritis Population. Am J Cardiol 2018; 121:501. 60. Evans JM, O'Fallon WM, Hunder GG. Increased incidence of aortic aneurysm and dissection in giant cell (temporal) arteritis. A population-based study. Ann Intern Med 1995; 122:502. 61. Robson JC, Kiran A, Maskell J, et al. The relative risk of aortic aneurysm in patients with giant cell arteritis compared with the general population of the UK. Ann Rheum Dis 2015; 74:129. https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 20/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate 62. Agard C, Barrier JH, Dupas B, et al. Aortic involvement in recent-onset giant cell (temporal) arteritis: a case-control prospective study using helical aortic computed tomodensitometric scan. Arthritis Rheum 2008; 59:670. 63. Garc a-Mart nez A, Arguis P, Prieto-Gonz lez S, et al. Prospective long term follow-up of a cohort of patients with giant cell arteritis screened for aortic structural damage (aneurysm or dilatation). Ann Rheum Dis 2014; 73:1826. 64. Muratore F, Crescentini F, Spaggiari L, et al. Aortic dilatation in patients with large vessel vasculitis: A longitudinal case control study using PET/CT. Semin Arthritis Rheum 2019; 48:1074. 65. Evans JM, Bowles CA, Bjornsson J, et al. Thoracic aortic aneurysm and rupture in giant cell arteritis. A descriptive study of 41 cases. Arthritis Rheum 1994; 37:1539. 66. Kermani TA, Warrington KJ, Crowson CS, et al. Predictors of Dissection in Aortic Aneurysms From Giant Cell Arteritis. J Clin Rheumatol 2016; 22:184. 67. Klein RG, Hunder GG, Stanson AW, Sheps SG. Large artery involvement in giant cell (temporal) arteritis. Ann Intern Med 1975; 83:806. 68. Kermani TA, Matteson EL, Hunder GG, Warrington KJ. Symptomatic lower extremity vasculitis in giant cell arteritis: a case series. J Rheumatol 2009; 36:2277. 69. Gonzalez-Gay MA, Vazquez-Rodriguez TR, Gomez-Acebo I, et al. Strokes at time of disease diagnosis in a series of 287 patients with biopsy-proven giant cell arteritis. Medicine (Baltimore) 2009; 88:227. 70. Salvarani C, Della Bella C, Cimino L, et al. Risk factors for severe cranial ischaemic events in an Italian population-based cohort of patients with giant cell arteritis. Rheumatology (Oxford) 2009; 48:250. 71. Wiszniewska M, Devuyst G, Bogousslavsky J. Giant cell arteritis as a cause of first-ever stroke. Cerebrovasc Dis 2007; 24:226. 72. Caselli RJ, Hunder GG, Whisnant JP. Neurologic disease in biopsy-proven giant cell (temporal) arteritis. Neurology 1988; 38:352. 73. de Boysson H, Liozon E, Larivi re D, et al. Giant Cell Arteritis-related Stroke: A Retrospective Multicenter Case-control Study. J Rheumatol 2017; 44:297. 74. Turney TM, Garraway WM, Whisnant JP. The natural history of hemispheric and brainstem infarction in Rochester, Minnesota. Stroke 1984; 15:790. 75. R egg S, Engelter S, Jeanneret C, et al. Bilateral vertebral artery occlusion resulting from giant cell arteritis: report of 3 cases and review of the literature. Medicine (Baltimore) 2003; 82:1. https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 21/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate 76. Salvarani C, Giannini C, Miller DV, Hunder G. Giant cell arteritis: Involvement of intracranial arteries. Arthritis Rheum 2006; 55:985. 77. Sanchez-Alvarez C, Hawkins AS, Koster MJ, et al. Clinical and Radiographic Features of Giant Cell Arteritis With Intracranial Involvement. ACR Open Rheumatol 2020; 2:471. 78. Alsolaimani RS, Bhavsar SV, Khalidi NA, et al. Severe intracranial involvement in giant cell arteritis: 5 cases and literature review. J Rheumatol 2016; 43:648. 79. Siemonsen S, Brekenfeld C, Holst B, et al. 3T MRI reveals extra- and intracranial involvement in giant cell arteritis. AJNR Am J Neuroradiol 2015; 36:91. 80. Caselli RJ, Hunder GG. Neurologic aspects of giant cell (temporal) arteritis. Rheum Dis Clin North Am 1993; 19:941. 81. Caselli RJ, Daube JR, Hunder GG, Whisnant JP. Peripheral neuropathic syndromes in giant cell (temporal) arteritis. Neurology 1988; 38:685. 82. Uribe JA, Aggarwal I, Witthayaweerasak J, et al. Refractory Giant Cell Arteritis Complicated by Vision Loss From Optic Atrophy and Maculopathy Associated With Pachymeningitis. J Neuroophthalmol 2018; 38:17. 83. Larson TS, Hall S, Hepper NG, Hunder GG. Respiratory tract symptoms as a clue to giant cell arteritis. Ann Intern Med 1984; 101:594. 84. Sendino A, Barbado FJ, Gonz lez-Anglada I, et al. Temporal arteritis: a form of systemic panarteritis. Ann Rheum Dis 1992; 51:1082. 85. Helfrich DJ, Mulhern LM, Luparello FJ, Smith W Jr. Giant cell arteritis of the tongue presenting as macroglossia. J Rheumatol 1988; 15:1026. 86. Tsianakas A, Ehrchen JM, Presser D, et al. Scalp necrosis in giant cell arteritis: case report and review of the relevance of this cutaneous sign of large-vessel vasculitis. J Am Acad Dermatol 2009; 61:701. 87. Brodmann M, Dorr A, Hafner F, et al. Tongue necrosis as first symptom of giant cell arteritis (GCA). Clin Rheumatol 2009; 28 Suppl 1:S47. 88. Lee CC, Su WW, Hunder GG. Dysarthria associated with giant cell arteritis. J Rheumatol 1999; 26:931. 89. Amor-Dorado JC, Llorca J, Garcia-Porrua C, et al. Audiovestibular manifestations in giant cell arteritis: a prospective study. Medicine (Baltimore) 2003; 82:13. 90. Hern ndez-Rodr guez J, Tan CD, Molloy ES, et al. Vasculitis involving the breast: a clinical and histopathologic analysis of 34 patients. Medicine (Baltimore) 2008; 87:61. 91. Bajocchi G, Zamorani G, Cavazza A, et al. Giant-cell arteritis of the female genital tract associated with occult temporal arteritis and FDG-PET evidence of large-vessel vasculitis. https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 22/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate Clin Exp Rheumatol 2007; 25:S36. 92. Scola CJ, Li C, Upchurch KS. Mesenteric involvement in giant cell arteritis. An underrecognized complication? Analysis of a case series with clinicoanatomic correlation. Medicine (Baltimore) 2008; 87:45. 93. Bablekos GD, Michaelides SA, Karachalios GN, et al. Pericardial involvement as an atypical manifestation of giant cell arteritis: report of a clinical case and literature review. Am J Med Sci 2006; 332:198. 94. Weiss LM, Gonzalez E, Miller SB, Agudelo CA. Severe anemia as the presenting manifestation of giant cell arteritis. Arthritis Rheum 1995; 38:434. 95. Foroozan R, Danesh-Meyer H, Savino PJ, et al. Thrombocytosis in patients with biopsy- proven giant cell arteritis. Ophthalmology 2002; 109:1267. 96. Gonzalez-Gay MA, Lopez-Diaz MJ, Barros S, et al. Giant cell arteritis: laboratory tests at the time of diagnosis in a series of 240 patients. Medicine (Baltimore) 2005; 84:277. 97. Salvarani C, Hunder GG. Giant cell arteritis with low erythrocyte sedimentation rate: frequency of occurence in a population-based study. Arthritis Rheum 2001; 45:140. 98. Liozon E, Jauberteau-Marchan MO, Ly K, et al. Giant cell arteritis with a low erythrocyte sedimentation rate: comments on the article by Salvarani and Hunder. Arthritis Rheum 2002; 47:692. 99. Kermani TA, Schmidt J, Crowson CS, et al. Utility of erythrocyte sedimentation rate and C- reactive protein for the diagnosis of giant cell arteritis. Semin Arthritis Rheum 2012; 41:866. 100. Roche NE, Fulbright JW, Wagner AD, et al. Correlation of interleukin-6 production and disease activity in polymyalgia rheumatica and giant cell arteritis. Arthritis Rheum 1993; 36:1286. 101. Weyand CM, Fulbright JW, Hunder GG, et al. Treatment of giant cell arteritis: interleukin-6 as a biologic marker of disease activity. Arthritis Rheum 2000; 43:1041. Topic 8225 Version 36.0 https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 23/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate GRAPHICS Giant cell arteritis: Clinical findings in 100 patients Finding Number Sex (female/male) 69/31 Duration of manifestations before diagnosis 7* Onset (gradual/sudden) 64/36 Weight loss or anorexia 50 Malaise, fatigue, or weakness 40 Fever 42 Polymyalgia rheumatica 39 Other musculoskeletal pains 30 Synovitis 15 Sore throat 9 Symptoms related to arteries 83 Headache 68 Visual symptoms Transient 16 Fixed 14 Jaw claudication 45 Swallowing claudication or dysphagia 8 Tongue claudication 6 Limb claudication 4 Signs related to arteries 66 Artery tenderness 27 Decreased temporal artery pulsations 46 Erythematous, nodular, or swollen scalp arteries 23 Large artery bruits 21 Decreased large artery pulses 7 Visual loss 14 Ophthalmoscopic abnormalities 18 https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 24/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate Extraocular muscle weakness 2 Raynaud phenomenon 3 Central nervous system abnormalities 15 Range 1 to 48 months before diagnosis. Adapted from: Calamia, KT, Hunder, GG. Clin Rheum Dis 1980; 6:389. Graphic 54634 Version 3.0 https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 25/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate Aortitis in GCA on MR angiography (A) Parasagittal MR angiography image of the aorta demonstrates diffuse thickening and peripheral enhancement of the aortic wall along the aortic arch, the descending aorta, and the proximal abdominal aorta in a patient with biopsy-proven GCA. https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 26/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate (B) High-resolution, axial-delayed MR angiography image of the aorta shows thickening and enhancement of the aortic wall. GCA: giant cell arteritis; MR: magnetic resonance. Courtesy of William Docken, MD. Graphic 101604 Version 5.0 https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 27/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate MRA of the aorta and great vessels in GCA Stenosis of the proximal and distal right subclavian artertery in a patient with large vessel GCA. The right axil artery is completely occluded; the right brachial artery is reconstituted via collateral channels. The distal left subclavian artery is severely stenosed. https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 28/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate MRA: magnetic resonance angiogram; GCA: giant cell arteritis. Courtesy of William Docken, MD. Graphic 101605 Version 4.0 https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 29/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate PET CT scan of GCA patient with aortic involvement PET CT scan of a patient with biopsy-proven GCA, showing increased FDG uptake in the walls of the ascending and descending aorta. PET: positron emission tomography; CT: computed tomography; GCA: giant cell arteritis; FDG: fluorodeoxyglucose. From: Docken WP. Two in ammatory conditions polymyalgia rheumatica and giant cell arteritis-share clinical connection. The Rheumatologist 2013. http://www.the- rheumatologist.org/article/two-in ammatory-conditionspolymyalgia-rheumatica-and- giant-cell-arteritisshare-clinical-connection/. Copyright 2013 American College of Rheumatology. Reproduced with permission of John Wiley & Sons Inc. This image has been provided by or is owned by Wiley. Further permission is needed before it can be downloaded to PowerPoint, printed, shared or emailed. Please contact Wiley's permissions department either via email: [email protected] or use the RightsLink service by clicking on the 'Request Permission' link accompanying this article on Wiley Online Library (http://onlinelibrary.wiley.com). Graphic 100635 Version 3.0 https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 30/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate Narrowing of the left subclavian artery in giant cell arteritis Angiogram of the left subclavian artery in GCA, showing several areas of severe vascular narrowing but a proliferation of small blood vessels forming excellent collateral circulation. The long, smooth arterial tapering in large vessel GCA is often not amenable to revascularization interventions such as angioplasty or stent placement. Those types of interventions are rarely necessary. GCA: giant cell arteritis. Courtesy of John H Stone, MD, MPH. Graphic 73553 Version 8.0 https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 31/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate External carotid artery anatomy External carotid artery and its branches in the lateral view. Reproduced with permission from: U acker R. Atlas Of Vascular Anatomy: An Angiographic Approach, Second Edition. Philadelphia: Lippincott Williams & Wilkins, 2007. Copyright 2007 Lippincott Williams & Wilkins. Graphic 50495 Version 1.0 https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 32/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate Course of the superficial temporal artery Graphic 82875 Version 2.0 https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 33/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate Enlarged temporal artery Visibly enlarged temporal artery in a patient with GCA (arrows). GCA: giant cell arteritis. Courtesy of Gene G Hunder, MD. Graphic 77618 Version 4.0 https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 34/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate Ischemic optic neuropathy Ischemic optic neuropathy in a patient with giant cell artertitis who lost vision abruptly four days prior to this examination. The optic disc is swollen and its margins are blurred. Courtesy of Gene Hunder, MD. Graphic 70141 Version 1.0 https://www.uptodate.com/contents/clinical-manifestations-of-giant-cell-arteritis/print 35/36 7/7/23, 11:15 AM Clinical manifestations of giant cell arteritis - UpToDate Contributor Disclosures Carlo Salvarani, MD No relevant financial relationship(s) with ineligible companies to disclose. Francesco Muratore, MD No relevant financial relationship(s) with ineligible companies to disclose. Kenneth J Warrington, MD Grant/Research/Clinical Trial Support: Eli Lilly [Giant cell arteritis]; GSK [Giant cell arteritis]; Kiniksa [Giant cell arteritis]. Other Financial Interest: Chemocentryx [Honoraria ANCA-associated vasculitis]. All of the relevant financial relationships listed have been mitigated. Jonathan Trobe, MD No relevant financial relationship(s) with ineligible companies to disclose. Philip Seo, MD, MHS 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-manifestations-of-giant-cell-arteritis/print 36/36

7/7/23, 11:16 AM Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss) - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg- Strauss) : Talmadge E King, Jr, MD : Kevin R Flaherty, MD, MS, Richard J Glassock, MD, MACP, Bruce S Bochner, MD : Paul Dieffenbach, 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 31, 2022. INTRODUCTION Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) abbreviated EGPA, which was previously called the Churg-Strauss syndrome (CSS) or allergic granulomatosis and angiitis, is a multisystem disorder characterized by allergic rhinitis, asthma, and prominent peripheral blood eosinophilia [1-9]. EGPA is classified as a vasculitis of the small and medium sized arteries, although the vasculitis is often not apparent in the initial phases of the disease. The most involved organ is the lung, followed by the skin. EGPA, however, can affect any organ system, including the cardiovascular, gastrointestinal, renal, and central nervous systems. Vasculitis of extrapulmonary organs is largely responsible for the morbidity and mortality associated with EGPA. The epidemiology, pathogenesis, and pathology of EGPA will be reviewed here. The clinical features, diagnosis, treatment and prognosis of this disorder, as well as the approach to patients with vasculitis and/or eosinophilia are discussed separately. (See "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)" and "Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): Treatment and prognosis" and "Overview of and approach to the vasculitides in adults" and "Approach to the patient with unexplained eosinophilia".) https://www.uptodate.com/contents/epidemiology-pathogenesis-and-pathology-of-eosinophilic-granulomatosis-with-polyangiitis-churg-strauss/print 1/14 7/7/23, 11:16 AM Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss) - UpToDate EPIDEMIOLOGY The epidemiology of EGPA remains unclear because of the uncertainties related to diagnosis [10]. Approximately 10 percent of patients with a major form of vasculitis are recognized to have EGPA. Among the three anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (EGPA, granulomatosis with polyangiitis (GPA), and microscopic polyangiitis), EGPA is least common [5]. Prevalence in Europe ranges from 10.7 to 14/million. In the United States, the prevalence is approximately 18/million. The highest prevalence reported is from Australia, at 22.3 cases/million [11]. (See "Overview of and approach to the vasculitides in adults".) The mean age at diagnosis of EGPA is 40 years [12]. EGPA is an uncommon cause of vasculitis in people older than 65 years, accounting for 5 percent of histologically proven vasculitis among 38 older adult patients with various systemic forms of angiitis [13,14]. EGPA is also rare in children and adolescents; when it does occur in this age group, it appears to follow a more aggressive course with prominent pulmonary and cardiovascular manifestations [15-17]. EGPA does not exhibit sex predominance [12,18]. A cross-sectional nationwide survey in Japan estimated the prevalence of EGPA at 17.8/1,000,000 [19]. The mean age at onset was 55 14 years ( SD). Among the patients tested for myeloperoxidase (MPO) anti-neutrophil cytoplasmic antibody (p-ANCA), 50 percent were positive; however, only 2.5 percent were positive for proteinase3 (PR3) c-ANCA. There was female predominance (2:1). PATHOGENESIS Abnormal immune function The exact pathogenesis of EGPA is unknown. Antineutrophil cytoplasmic antibodies (ANCA) are detected in about 40 to 60 percent of patients, and EGPA is classified among the ANCA-positive vasculitides [12,19-22]. However, it is not known whether ANCAs have a pathogenic role in EGPA or whether they just reflect one end of the spectrum of EGPA manifestations. (See "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)", section on 'Antineutrophil cytoplasmic antibodies' and "Pathogenesis of antineutrophil cytoplasmic autoantibody-associated vasculitis".) In addition, EGPA is characterized by several other abnormalities in immune function [23-26]: The prominence of allergic features (allergic rhinitis, asthma, and positive skin tests) suggests heightened Th2 immunity [25]. https://www.uptodate.com/contents/epidemiology-pathogenesis-and-pathology-of-eosinophilic-granulomatosis-with-polyangiitis-churg-strauss/print 2/14 7/7/23, 11:16 AM Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss) - UpToDate Pulmonary angiocentric granulomatosis suggests heightened Th1 immunity [26]. The number of peripheral blood CD4+CD25+ T cells (T regulatory cells) that produce IL-10 were decreased in patients with EGPA compared with asthma or chronic eosinophilic pneumonia and were increased in patients with EGPA in remission [27]. These observations suggest that T regulatory cells may influence which patients with asthma and chronic eosinophilic pneumonia will develop active EGPA. Abnormal eosinophil function is likely due to a combination of increased eosinophil recruitment by Th2 cytokines and decreased eosinophil apoptosis [23]. Altered humoral immunity is suggested by hypergammaglobulinemia, especially IgE, and rheumatoid factor positivity in some patients. Genetic factors Genetic factors may also play a role. In a study of 48 patients and 350 healthy controls, both HLA-DRB1*07 and HLA-DRB4 were more prevalent among patients with EGPA and HLA-DRB4 correlated with the number of vasculitic manifestations [28]. A genome wide association study (GWAS) that included 676 patients with EGPA and 6809 healthy controls identified genetic distinctions between ANCA-myeloperoxidase positive (MPO+) and ANCA-negative disease, correlating with different clinical features [21]. Variants in the regions of BCL2L11, LPP, C5orf56-IRF1-IL5, and 10p14 were associated with EGPA, consistent with a polygenic disease and suggesting a role for susceptibility to eosinophilia in EGPA pathogenesis. When comparing MPO+ patients with MPO- patients, the study noted an association with HLA- DQ in MPO+ EGPA that was not present in MPO- EGPA, suggesting two potential subtypes of EGPA: an eosinophilic autoimmune (MPO+) disease and a mucosal barrier dysfunction (MPO-) subtype. Polymorphisms in the interleukin (IL)-10 gene have been associated with EGPA. In a study of 103 patients with EGPA, genotyping identified three single nucleotide polymorphisms (SNPs) relating to the interleukin (IL)-10 gene [29]. The IL-10 -3575/-1082/-592 TAC haplotype (part of IL 10.2) was strongly associated with EGPA (OR=2.16) and negatively associated with granulomatosis with polyangiitis (GPA). Three-fourths of the patients were ANCA negative. (See "Genetics of asthma".) ASSOCIATION WITH MEDICATIONS Several medications have been associated with the appearance of EGPA. In the case of asthma therapies such as leukotriene modifying agents, inhaled glucocorticoids, and omalizumab, it https://www.uptodate.com/contents/epidemiology-pathogenesis-and-pathology-of-eosinophilic-granulomatosis-with-polyangiitis-churg-strauss/print 3/14 7/7/23, 11:16 AM Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss) - UpToDate appears that this is more likely an unmasking of underlying disease rather than a causal relationship, as described below. Leukotriene modifying agents EGPA has been reported as a rare complication in patients with systemic glucocorticoid-dependent asthma who were treated with a leukotriene modifying agent (LTMA; eg, zafirlukast, montelukast, pranlukast, zileuton), usually in the setting of reduction in the dose of oral glucocorticoids [30-43]. It is believed that LTMAs may unmask underlying EGPA in the following ways [44,45]: Glucocorticoid withdrawal is facilitated by LTMA therapy, leading to elaboration of EGPA disease manifestations. Patients who have undiagnosed but escalating EGPA are prescribed a LTMA because of worsening symptoms. The LTMA is insufficient to control EGPA and the disease becomes manifest (ie, confounding by indication). However, it is difficult to completely exclude the possibility that LTMAs play a causal role in the development of EGPA in some patients [30-42,46]. Inhaled glucocorticoids The onset of clinical evidence of EGPA has also occurred when the addition or increase in inhaled glucocorticoids allowed reduction in the dose of systemic glucocorticoids, which in turn led to an "unmasking" of EGPA symptoms as described above [38]. Omalizumab EGPA has also been noted in patients receiving omalizumab (a humanized anti- IgE antibody) for treatment of severe asthma [47-49]. The appearance of EGPA symptoms preceded treatment with omalizumab or coincided with tapering of systemic glucocorticoids, suggesting that omalizumab had been added in the setting of escalating EGPA or that it allowed "unmasking" of underlying EGPA. It remains unclear whether or not omalizumab can be used in the treatment of EGPA [50]. (See "Anti-IgE therapy", section on 'Other issues'.) Cocaine An unusual EGPA-like vasculitis has been associated with the use of free base cocaine [51]. The diagnosis of EGPA in patients who use cocaine is a complicated issue because both acute and chronic eosinophilic pneumonia are manifestations of cocaine toxicity and antineutrophil cytoplasmic antibodies are detected in the majority of patients with cocaine- induced midline destructive lesions of the nose [52]. (See "Pulmonary complications of cocaine use", section on 'Acute pulmonary toxicity and crack lung' and "Pulmonary complications of cocaine use", section on 'Chronic toxicity'.) The anti-neutrophil cytoplasmic antibodies (ANCAs) associated with cocaine-induced midline destructive lesions appear to be different from those associated with EGPA. ANCAs from patients https://www.uptodate.com/contents/epidemiology-pathogenesis-and-pathology-of-eosinophilic-granulomatosis-with-polyangiitis-churg-strauss/print 4/14 7/7/23, 11:16 AM Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss) - UpToDate with cocaine-induced midline destructive lesions typically recognize human neutrophil elastase as the target antigen, although autoantibodies to proteinase 3 and other serine proteases are also seen [53]. In contrast, ANCAs from patients with EGPA commonly react to myeloperoxidase and not human neutrophil elastase [52]. Sera from patients with granulomatosis with polyangiitis (GPA) typically react with proteinase 3, but not human neutrophil elastase. (See "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg- Strauss)", section on 'Antineutrophil cytoplasmic antibodies'.) PATHOLOGY The major histopathologic findings of EGPA from any affected organ includes the following, although they may not all be present (especially in patients who have been partially treated) [54- 56]: Eosinophilic infiltration Prominent and sometimes quite extensive areas of necrosis An eosinophilic, giant cell vasculitis, especially of the small arteries and veins Interstitial and perivascular necrotizing granulomas ( picture 1) Pathologic findings in different organs include: In the lung, asthmatic bronchitis, eosinophilic pneumonia, extravascular granulomas, or vasculitis (affecting arteries, veins, or capillaries) may be seen. In some cases, the inflammatory lesions extend along the pleura and interlobular septa. The granulomas in EGPA typically have a border of palisading histiocytes and multinucleated giant cells surrounding a central necrotic zone consisting of the necrotic eosinophils. The vascular infiltrates are often composed of chronic inflammatory cells, eosinophilic infiltrates, epithelioid histiocytes, multinucleated giant cells and/or neutrophils. Diffuse pulmonary hemorrhage and capillaritis may be seen. In the kidney, necrotizing crescentic glomerulonephritis is the most common finding, but eosinophilic interstitial nephritis, mesangial glomerulonephritis, and focal segmental glomerulosclerosis are also seen [57,58]. Endomyocardial biopsies typically reveal eosinophilic infiltration and endomyocarditis, but not vasculitis [59]. Skin biopsy typically reveals a leukocytoclastic vasculitis with eosinophil infiltration [60]. Palisading granulomas and/or eosinophilic infiltration of dermal nerve fibers may also be https://www.uptodate.com/contents/epidemiology-pathogenesis-and-pathology-of-eosinophilic-granulomatosis-with-polyangiitis-churg-strauss/print 5/14 7/7/23, 11:16 AM Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss) - UpToDate noted. The histopathologic findings may vary with the phase of disease [61,62]. (See "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)", section on 'Phases of disease'.) During the prevasculitic phase, tissue infiltration by eosinophils may be present without overt vasculitis. During the vasculitic phase, a nondestructive infiltration of vessel walls is noted and may be more common than a necrotizing vasculitis. In the postvasculitic phase, healed vascular lesions resembled organized thrombi, but are associated with extensive destruction of the elastica. In this later phase, eosinophilic infiltration may be absent. 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: Vasculitis".) SUMMARY AND RECOMMENDATIONS Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) abbreviated EGPA, which was previously called the Churg-Strauss syndrome (CSS) or allergic granulomatosis and angiitis, is a multisystem disorder characterized by allergic rhinitis, asthma, and prominent peripheral blood eosinophilia. (See 'Introduction' above.) The exact etiology is unknown. Antineutrophil cytoplasmic antibodies (ANCA) are detected in about 40 to 60 percent of patients and EGPA is classified among the ANCA-positive vasculitides. Several other abnormalities in immunologic function occur in EGPA, including heightened Th1 and Th2 lymphocyte function, increased eosinophil recruitment and decreased eosinophil apoptosis. (See 'Pathogenesis' above.) Genetic factors such as human leukocyte antigen (HLA) class and certain interleukin-10 polymorphisms may play a role in EGPA pathogenesis. (See 'Genetic factors' above.) Several asthma medications, such as the leukotriene modifying agents, inhaled glucocorticoids, and omalizumab, have been associated with the appearance of EGPA. https://www.uptodate.com/contents/epidemiology-pathogenesis-and-pathology-of-eosinophilic-granulomatosis-with-polyangiitis-churg-strauss/print 6/14 7/7/23, 11:16 AM Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss) - UpToDate However, it appears that the association is most likely due to unmasking of the underlying disease or intensification of therapy in a patient with escalating EGPA, rather than a causal relationship. (See 'Association with medications' above.) A EGPA-like illness can rarely occur after the use of free base cocaine. However, the ANCAs associated with cocaine use recognize different target proteases than the typical ANCAs associated with EGPA. (See 'Cocaine' above.) The major histopathologic findings of EGPA from any affected organ include the following, although they may not all be present: eosinophilic infiltration; prominent and sometimes extensive areas of necrosis; an eosinophilic, giant cell vasculitis, especially of the small arteries and veins; and also interstitial and perivascular necrotizing granulomas ( picture 1). (See 'Pathology' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. CHURG J, STRAUSS L. Allergic granulomatosis, allergic angiitis, and periarteritis nodosa. Am J Pathol 1951; 27:277. 2. Churg A. Pulmonary angiitis and granulomatosis revisited. Hum Pathol 1983; 14:868. 3. Sinico RA, Bottero P. Churg-Strauss angiitis. Best Pract Res Clin Rheumatol 2009; 23:355. 4. Pagnoux C, Guilpain P, Guillevin L. Churg-Strauss syndrome. Curr Opin Rheumatol 2007; 19:25. 5. Keogh KA, Specks U. Churg-Strauss syndrome. Semin Respir Crit Care Med 2006; 27:148. 6. Guillevin L, Cohen P, Gayraud M, et al. Churg-Strauss syndrome. Clinical study and long- term follow-up of 96 patients. Medicine (Baltimore) 1999; 78:26. 7. Lanham JG, Elkon KB, Pusey CD, Hughes GR. Systemic vasculitis with asthma and eosinophilia: a clinical approach to the Churg-Strauss syndrome. Medicine (Baltimore) 1984; 63:65. 8. Masi AT, Hunder GG, Lie JT, et al. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum 1990; 33:1094. 9. Szczeklik W, Jakie a B, Adamek D, Musia J. Cutting edge issues in the Churg-Strauss syndrome. Clin Rev Allergy Immunol 2013; 44:39. 10. Schwartz RA, Churg J. Churg-Strauss syndrome. Br J Dermatol 1992; 127:199. https://www.uptodate.com/contents/epidemiology-pathogenesis-and-pathology-of-eosinophilic-granulomatosis-with-polyangiitis-churg-strauss/print 7/14 7/7/23, 11:16 AM Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss) - UpToDate 11. Mohammad AJ. An update on the epidemiology of ANCA-associated vasculitis. Rheumatology (Oxford) 2020; 59:iii42. 12. Conron M, Beynon HL. Churg-Strauss syndrome. Thorax 2000; 55:870. 13. Mouthon L, Le Toumelin P, Andre MH, et al. Polyarteritis nodosa and Churg-Strauss angiitis: characteristics and outcome in 38 patients over 65 years. Medicine (Baltimore) 2002; 81:27. 14. Abril A, Calamia KT, Cohen MD. The Churg Strauss syndrome (allergic granulomatous angiitis): review and update. Semin Arthritis Rheum 2003; 33:106. 15. Zwerina J, Eger G, Englbrecht M, et al. Churg-Strauss syndrome in childhood: a systematic literature review and clinical comparison with adult patients. Semin Arthritis Rheum 2009; 39:108. 16. Gendelman S, Zeft A, Spalding SJ. Childhood-onset eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome): a contemporary single-center cohort. J Rheumatol 2013; 40:929. 17. Iudici M, Pu chal X, Pagnoux C, et al. Brief Report: Childhood-Onset Systemic Necrotizing Vasculitides: Long-Term Data From the French Vasculitis Study Group Registry. Arthritis Rheumatol 2015; 67:1959. 18. Harrold LR, Andrade SE, Go AS, et al. Incidence of Churg-Strauss syndrome in asthma drug users: a population-based perspective. J Rheumatol 2005; 32:1076. 19. Sada KE, Amano K, Uehara R, et al. A nationwide survey on the epidemiology and clinical features of eosinophilic granulomatosis with polyangiitis (Churg-Strauss) in Japan. Mod Rheumatol 2014; 24:640. 20. Sinico RA, Di Toma L, Maggiore U, et al. Prevalence and clinical significance of antineutrophil cytoplasmic antibodies in Churg-Strauss syndrome. Arthritis Rheum 2005; 52:2926. 21. Lyons PA, Peters JE, Alberici F, et al. Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status. Nat Commun 2019; 10:5120. 22. Moiseev S, Bossuyt X, Arimura Y, et al. International Consensus on ANCA Testing in Eosinophilic Granulomatosis with Polyangiitis. Am J Respir Crit Care Med 2020. 23. Hellmich B, Ehlers S, Csernok E, Gross WL. Update on the pathogenesis of Churg-Strauss syndrome. Clin Exp Rheumatol 2003; 21:S69. 24. Zwerina J, Axmann R, Jatzwauk M, et al. Pathogenesis of Churg-Strauss syndrome: recent insights. Autoimmunity 2009; 42:376. 25. Schmitt WH, Csernok E, Kobayashi S, et al. Churg-Strauss syndrome: serum markers of lymphocyte activation and endothelial damage. Arthritis Rheum 1998; 41:445. https://www.uptodate.com/contents/epidemiology-pathogenesis-and-pathology-of-eosinophilic-granulomatosis-with-polyangiitis-churg-strauss/print 8/14 7/7/23, 11:16 AM Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss) - UpToDate 26. Hellmich B, Csernok E, Gross WL. Proinflammatory cytokines and autoimmunity in Churg- Strauss syndrome. Ann N Y Acad Sci 2005; 1051:121. 27. Tsurikisawa N, Saito H, Tsuburai T, et al. Differences in regulatory T cells between Churg- Strauss syndrome and chronic eosinophilic pneumonia with asthma. J Allergy Clin Immunol 2008; 122:610. 28. Vaglio A, Martorana D, Maggiore U, et al. HLA-DRB4 as a genetic risk factor for Churg- Strauss syndrome. Arthritis Rheum 2007; 56:3159. 29. Wieczorek S, Hellmich B, Arning L, et al. Functionally relevant variations of the interleukin-10 gene associated with antineutrophil cytoplasmic antibody-negative Churg-Strauss syndrome, but not with Wegener's granulomatosis. Arthritis Rheum 2008; 58:1839. 30. Wechsler ME, Garpestad E, Flier SR, et al. Pulmonary infiltrates, eosinophilia, and cardiomyopathy following corticosteroid withdrawal in patients with asthma receiving zafirlukast. JAMA 1998; 279:455. 31. Franco J, Art s MJ. Pulmonary eosinophilia associated with montelukast. Thorax 1999; 54:558. 32. Green RL, Vayonis AG. Churg-Strauss syndrome after zafirlukast in two patients not receiving systemic steroid treatment. Lancet 1999; 353:725. 33. Kinoshita M, Shiraishi T, Koga T, et al. Churg-Strauss syndrome after corticosteroid withdrawal in an asthmatic patient treated with pranlukast. J Allergy Clin Immunol 1999; 103:534. 34. Martin RM, Wilton LV, Mann RD. Prevalence of Churg-Strauss syndrome, vasculitis, eosinophilia and associated conditions: retrospective analysis of 58 prescription-event monitoring cohort studies. Pharmacoepidemiol Drug Saf 1999; 8:179. 35. Wechsler ME, Finn D, Gunawardena D, et al. Churg-Strauss syndrome in patients receiving montelukast as treatment for asthma. Chest 2000; 117:708. 36. Hauser T, Mahr A, Metzler C, et al. The leucotriene receptor antagonist montelukast and the risk of Churg-Strauss syndrome: a case-crossover study. Thorax 2008; 63:677. 37. D'Cruz DP, Barnes NC, Lockwood CM. Difficult asthma or Churg-Strauss syndrome? BMJ 1999; 318:475. 38. Le Gall C, Pham S, Vignes S, et al. Inhaled corticosteroids and Churg-Strauss syndrome: a report of five cases. Eur Respir J 2000; 15:978. 39. Cooper SM, Libman BS, Lazarovich M. Churg-strauss syndrome in a group of patients receiving fluticasone for asthma. J Rheumatol 2002; 29:2651. https://www.uptodate.com/contents/epidemiology-pathogenesis-and-pathology-of-eosinophilic-granulomatosis-with-polyangiitis-churg-strauss/print 9/14 7/7/23, 11:16 AM Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss) - UpToDate 40. Tuggey JM, Hosker HS. Churg-Strauss syndrome associated with montelukast therapy. Thorax 2000; 55:805. 41. Katsura T, Yoshida F, Takinishi Y. The Churg-Strauss syndrome after pranlukast treatment in a patient not receiving corticosteroids. Ann Intern Med 2003; 139:386. 42. Nathani N, Little MA, Kunst H, et al. Churg-Strauss syndrome and leukotriene antagonist use: a respiratory perspective. Thorax 2008; 63:883. 43. Keogh KA, Specks U. Churg-Strauss syndrome: clinical presentation, antineutrophil cytoplasmic antibodies, and leukotriene receptor antagonists. Am J Med 2003; 115:284. 44. Specks, U. Pulmonary vasculitis. In: Interstitial Lung Disease, 5th, Schwarz, MI, King, TE Jr (E ds), People's Medical Publishing House, Shelton, CT, USA 2011. p.765. 45. Keogh KA. Leukotriene receptor antagonists and Churg-Strauss syndrome: cause, trigger or merely an association? Drug Saf 2007; 30:837. 46. Bibby S, Healy B, Steele R, et al. Association between leukotriene receptor antagonist therapy and Churg-Strauss syndrome: an analysis of the FDA AERS database. Thorax 2010; 65:132. 47. Wechsler ME, Wong DA, Miller MK, Lawrence-Miyasaki L. Churg-strauss syndrome in patients treated with omalizumab. Chest 2009; 136:507. 48. Ruppert AM, Averous G, Stanciu D, et al. Development of Churg-Strauss syndrome with controlled asthma during omalizumab treatment. J Allergy Clin Immunol 2008; 121:253. 49. Nazir S, Tachamo N, Fareedy SB, et al. Omalizumab-associated eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Ann Allergy Asthma Immunol 2017; 118:372. 50. Basta F, Mazzuca C, Nucera E, et al. Omalizumab in eosinophilic granulomatosis with polyangiitis: friend or foe? A systematic literature review. Clin Exp Rheumatol 2020; 38 Suppl 124:214. 51. Orriols R, Mu oz X, Ferrer J, et al. Cocaine-induced Churg-Strauss vasculitis. Eur Respir J 1996; 9:175. 52. Wiesner O, Russell KA, Lee AS, et al. Antineutrophil cytoplasmic antibodies reacting with human neutrophil elastase as a diagnostic marker for cocaine-induced midline destructive lesions but not autoimmune vasculitis. Arthritis Rheum 2004; 50:2954. 53. Peikert T, Finkielman JD, Hummel AM, et al. Functional characterization of antineutrophil cytoplasmic antibodies in patients with cocaine-induced midline destructive lesions. Arthritis Rheum 2008; 58:1546. 54. Churg A. Recent advances in the diagnosis of Churg-Strauss syndrome. Mod Pathol 2001; 14:1284. https://www.uptodate.com/contents/epidemiology-pathogenesis-and-pathology-of-eosinophilic-granulomatosis-with-polyangiitis-churg-strauss/print 10/14 7/7/23, 11:16 AM Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss) - UpToDate 55. Katzenstein AL. Diagnostic features and differential diagnosis of Churg-Strauss syndrome in the lung. A review. Am J Clin Pathol 2000; 114:767. 56. Lie JT. Illustrated histopathologic classification criteria for selected vasculitis syndromes. American College of Rheumatology Subcommittee on Classification of Vasculitis. Arthritis Rheum 1990; 33:1074. 57. Sinico RA, Di Toma L, Maggiore U, et al. Renal involvement in Churg-Strauss syndrome. Am J Kidney Dis 2006; 47:770. 58. Clutterbuck EJ, Evans DJ, Pusey CD. Renal involvement in Churg-Strauss syndrome. Nephrol Dial Transplant 1990; 5:161. 59. Neumann T, Manger B, Schmid M, et al. Cardiac involvement in Churg-Strauss syndrome: impact of endomyocarditis. Medicine (Baltimore) 2009; 88:236. 60. Kawakami T, Soma Y, Kawasaki K, et al. Initial cutaneous manifestations consistent with mononeuropathy multiplex in Churg-Strauss syndrome. Arch Dermatol 2005; 141:873. 61. Churg A, Brallas M, Cronin SR, Churg J. Formes frustes of Churg-Strauss syndrome. Chest 1995; 108:320. 62. Hueto-Perez-de-Heredia JJ, Dominguez-del-Valle FJ, Garcia E, et al. Chronic eosinophilic pneumonia as a presenting feature of Churg-Strauss syndrome. Eur Respir J 1994; 7:1006. Topic 4363 Version 21.0 https://www.uptodate.com/contents/epidemiology-pathogenesis-and-pathology-of-eosinophilic-granulomatosis-with-polyangiitis-churg-strauss/print 11/14 7/7/23, 11:16 AM Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss) - UpToDate GRAPHICS Granuloma in eosinophilic granulomatosis with polyangiitis (Churg-Strauss) Low power photomicrograph shows the palisading granuloma of eosinophilic granulomatosis with polyangiitis (Churg-Strauss) characterized by an area of necrobiosis (arrow) permeated by disintegrating neutrophils and palisaded by a histiocytic infiltrate. There may or may not be an accompanying vasculitis. Courtesy of Cynthia Magro, MD. Graphic 50143 Version 3.0 https://www.uptodate.com/contents/epidemiology-pathogenesis-and-pathology-of-eosinophilic-granulomatosis-with-polyangiitis-churg-strauss/print 12/14 7/7/23, 11:16 AM Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss) - UpToDate Contributor Disclosures Talmadge E King, Jr, MD No relevant financial relationship(s) with ineligible companies to disclose. Kevin R Flaherty, MD, MS Grant/Research/Clinical Trial Support: Boehringer Ingelheim [IPF]. Consultant/Advisory Boards: Arrowhead [Interstitial lung disease]; AstraZeneca [Interstitial lung disease]; Bellerophon [Interstitial lung disease]; CSL Behring [Interstitial lung disease]; Daewong Pharmaceuticals [Interstitial lung disease]; DevPro [Interstitial lung disease]; Dispersol [Interstitial lung disease]; Fibrogen [Interstitial lung disease]; Horizon [Interstitial lung disease]; Immunmet [Interstitial lung disease]; Insilco [Interstitial lung disease]; Lupin [Interstitial lung disease]; NeRRe Therapeutics [Interstitial lung disease]; Pliant [Interstitial lung disease]; Polarean [Interstitial lung disease]; PureHealth [Interstitial lung disease]; PureTech [Interstitial lung disease]; Respivant [Interstitial lung disease]; Roche/Genentech [Interstitial lung disease]; Shionogi [Interstitial lung disease]; Sun Pharmaceuticals [Interstitial lung disease]; Trevi Pharmaceuticals [Interstitial lung disease]; United Therapeutics [Interstitial lung disease]; Vicore [Interstitial lung disease]. All of the relevant financial relationships listed have been mitigated. Richard J Glassock, MD, MACP Employment: Karger Publishers [Associate Editor of Nephrology Viewpoints blog for American Journal of Nephrology]. Equity Ownership/Stock Options: Reata [Alport syndrome, pulmonary hypertension, diabetic nephropathy]. Consultant/Advisory Boards: Alexion [Pharmaceutical development]; Arrowhead [Complement-mediated GN]; Aurinia [Voclosporin, lupus nephritis]; BioCryst [IgA nephropathy and C3GN]; Calliditas [IgA nephropathy]; Chinook [Pharmaceutical development]; Equillium Bio [IgA nephropathy, lupus nephritis]; Horizon Pharma [IgA nephropathy]; Ionis [IgA N and anti-PLA2R antibody- associated MN]; National Institutes of Health [NEPTUNE study chair]; Nephro-Sys [Novel agent for GN]; Novartis [IgA nephropathy]; Omeros [IgA nephropathy]; Otsuka Pharmaceuticals [IgA nephropathy]; Renasight [Genetics in kidney disease]; River Renal [R3RE-01 in primary FSGS]; Therini Bio [Novel agent for GN]; Travere [Focal segmental glomerulosclerosis, IgA nephropathy, membranous nephropathy]; Vera pharamaceuticals [Pharmaceutical development]; Vertex Inc [Novel drug compound for treatment of APOL1-related FSGS]. Speaker's Bureau: Aurinia [Lupus nephritis]. Other Financial Interest: American Association of Kidney Patients [Board member; non-profit voluntary health organization]; Oxford Medical Publishers [Primary glomerular disease]; University Kidney Research Organization [Nephrology]. All of the relevant financial relationships listed have been mitigated. Bruce S Bochner, MD Equity Ownership/Stock Options: Allakos [Eosinophil and mast cell-related diseases]. Patent Holder: anti-Siglec-8 antibodies [Lirentelimab/AK002, eosinophil and mast cell-associated disease]. Grant/Research/Clinical Trial Support: NIAID [Siglec-6, Siglec-8, asthma, anaphylaxis, food allergy, Bruton's tyrosine kinase, mastocytosis, nanoparticle targeting]. Consultant/Advisory Boards: Acelyrin, Inc [Eosinophil and mast cell-related diseases]; Allakos [Eosinophil and mast cell-related diseases]; Blueprint Medicines [Eosinophil and mast cell-related diseases]; Lupagen, Inc [Eosinophil and mast cell-related diseases]; Regeneron [Eosinophil and mast cell-related diseases]; Sanofi [Eosinophil and mast cell-related diseases]; StealthBio Therapeutics [Eosinophil and mast cell-related diseases]; Third Harmonic Bio [Eosinophil and mast cell-related diseases]. Other Financial Interest: Elsevier [Publication royalties]; Johns Hopkins University School of Medicine [Royalties related to licensing of intellectual property to Allakos, Inc]. All of the relevant financial relationships listed have been mitigated. Paul Dieffenbach, 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. https://www.uptodate.com/contents/epidemiology-pathogenesis-and-pathology-of-eosinophilic-granulomatosis-with-polyangiitis-churg-strauss/print 13/14 7/7/23, 11:16 AM Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss) - UpToDate Conflict of interest policy https://www.uptodate.com/contents/epidemiology-pathogenesis-and-pathology-of-eosinophilic-granulomatosis-with-polyangiitis-churg-strauss/print 14/14

7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy : Peter A Merkel, MD, MPH, Andre A Kaplan, MD, Ronald J Falk, MD : Gerald B Appel, MD, Fernando C Fervenza, MD, PhD : Albert Q Lam, MD, Philip Seo, MD, MHS 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 26, 2023. INTRODUCTION Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are related systemic vasculitides that, along with eosinophilic granulomatosis with polyangiitis (Churg-Strauss), make up the antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides. Both GPA and MPA are associated with ANCA, have many identical clinical manifestations, have many similar histologic features, and may have similar outcomes. There is, however, substantial heterogeneity among these disorders. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis".) Therapy for GPA and MPA has two main components: induction of remission with immunosuppressive therapy and maintenance of remission with immunosuppressive therapy for a variable period to prevent relapse. Induction and maintenance therapy of GPA and MPA will be reviewed here. The clinical manifestations and diagnosis of these disorders and the treatment of resistant and relapsing disease are discussed elsewhere: (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis".) (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of disease resistant to initial therapy".) https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 1/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of relapsing disease".) GENERAL PRINCIPLES Goals of therapy The goal of therapy in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) is to achieve long-standing remission. Treatment consists of an initial induction phase aimed to put patients with active disease into remission, followed by a maintenance phase that is intended to extend remission and prevent relapse. Definitions of response Complete remission Complete remission is defined as the absence of active disease (ie, the absence of any clinical manifestations that are deemed secondary to ongoing active vasculitis) [1-5]. Complete remission does not mean that all parameters have returned to baseline, because persistent abnormalities may reflect irreversible injury induced during the period of active inflammation. As an example, a patient in whom the systemic symptoms and signs resolve and the urine sediment becomes inactive is considered to be in remission, even if there is persistent proteinuria or persistent or even slowly worsening kidney function impairment. Partial remission Partial remission is more difficult to define but implies the persistence of some inflammation despite immunosuppressive therapies. Defining and characterizing the impact of "partial remission" is further complicated by recognition that some clinical trials in GPA and MPA defined a state of remission as including patients with a single item of nonsevere disease activity [6]. Distinguishing partial remission from other disease states Partial remission (ie, ongoing low-level inflammation) may be difficult to distinguish from other processes that result in persistent symptoms, such as organ damage from prior inflammation and chronic infection. The distinction may be particularly challenging for disease affecting the sinuses and respiratory tract. As an example, a nodule in the lung may represent active vasculitis, a scar, a malignancy in a patient treated with an alkylating agent, or an infection. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of disease resistant to initial therapy", section on 'Exclusion of alternative diagnoses'.) In the kidneys, as in other inflammatory glomerular diseases such as lupus nephritis, persistent proteinuria (as determined by urine dipstick) could reflect either ongoing https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 2/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate inflammation or irreversible glomerular injury and thus, as an isolated finding, is not necessarily indicative of active disease [7]. Similarly, isomorphic hematuria, which is characteristic of extraglomerular bleeding, could reflect cyclophosphamide-induced bladder toxicity. (See "Etiology and evaluation of hematuria in adults", section on 'Red cell morphology'.) Partial remission inadequate as treatment goal Partial remission may not be an adequate goal for therapy. In a retrospective study of 167 patients with GPA or MPA who were followed for five years, achieving a low disease activity state (defined as a Birmingham Vasculitis Activity Score 3 and use of prednisone 7.5 mg daily) was associated with more organ damage than prolonged complete remission (Vasculitis Damage Index score 3.7 versus 2.2) [8]. However, there is no consensus definition of low disease activity state in GPA or MPA. Thus, while partial remission is clearly better than no remission, it should not be the ultimate goal of successful treatment. Persistent dysmorphic (ie, glomerular) hematuria ( picture 1A-B) may be evidence of incomplete remission in patients who have a stable serum creatinine and no other evidence of disease activity. Patients with this finding may require additional therapy to prevent progressive kidney injury and should be followed more closely with thoughts of a potential biopsy. (See "Etiology and evaluation of hematuria in adults", section on 'Red cell morphology'.) Relapse Relapse is defined as the recurrence of signs or symptoms of active vasculitis in any organ system after remission is achieved. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of relapsing disease".) INITIAL TREATMENT APPROACH Immunosuppressive therapy is warranted in almost all patients with active granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). The choice of therapy is discussed below. Our management strategy is generally consistent with guidelines developed by professional organizations including the American College of Rheumatology (ACR)/Vasculitis Foundation [9] and Kidney Disease: Improving Global Outcomes (KDIGO) [10]. Assessment of disease severity Our approach to initial therapy depends largely upon the severity of disease and the organ systems involved. Other factors that may influence initial choice of therapy include patient-specific factors. https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 3/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Organ-threatening or life-threatening disease Organ- or life-threatening features include, but are not limited to, the following (see 'Organ- or life-threatening disease' below): Active glomerulonephritis Pulmonary hemorrhage Cerebral vasculitis Progressive peripheral or cranial neuropathy Orbital pseudotumor Scleritis Gastrointestinal bleeding due to vasculitis Cardiac disease due to vasculitis (pericarditis, myocarditis) Non-organ-threatening and non-life-threatening disease Patients with non-organ- or non-life-threatening disease have no evidence of "active glomerulonephritis" (ie, normal serum creatinine and no red cell casts or proteinuria) and none of the organ-threatening or life-threatening manifestations listed above. Such patients may have rhinosinusitis, arthritis, and/or pulmonary nodules. Non-organ-threatening and non-life-threatening disease can still result in substantial disease burden and long-term damage. (See 'Non- organ- and non-life-threatening disease' below.) Organ- or life-threatening disease Induction therapy In patients with GPA or MPA who have organ- or life-threatening disease, we recommend an induction regimen consisting of glucocorticoids in combination with either rituximab or cyclophosphamide rather than monotherapy with glucocorticoids. Some authors/editors choose a rituximab-based regimen for the majority of patients, given its comparable efficacy and different side-effect profile compared with cyclophosphamide [11]. Other authors/editors favor a cyclophosphamide-based regimen as initial therapy, particularly in patients presenting with more severe kidney disease and/or pulmonary hemorrhage, or if rituximab is difficult to access [12]. In patients with concerns about fertility, alopecia, and malignancy or those who have been previously treated with a course of cyclophosphamide; in children; and in frail older adults, some prefer rituximab as the initial therapy ( algorithm 1) [12]. Some authorities treat with glucocorticoids in combination with both rituximab and cyclophosphamide. However, no trials have shown that this approach is superior to the use of either cyclophosphamide or rituximab as initial therapy. The role of plasma exchange in induction therapy is discussed below. (See 'Role of plasma exchange' below and 'Double-positive ANCA and anti-GBM disease' below.) https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 4/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Prior to the introduction of cyclophosphamide as a therapy for GPA or MPA, the majority of patients were treated with glucocorticoid monotherapy, but mortality rates with this therapy were high [2,13]. Observational studies found that the combination of cyclophosphamide plus glucocorticoids as induction therapy was associated with more than a fivefold improvement in survival and a lower frequency of relapse [3,14]. The combination of oral cyclophosphamide and glucocorticoids ultimately induces remission in 75 to 90 percent of patients, with approximately 50 to 70 percent experiencing complete remission by six months [2,3,15-17]. Most remissions occur between three and six months of induction therapy [15,18]. There are two seminal randomized trials that have suggested that rituximab is an effective alternative to cyclophosphamide for the initial treatment of patients who have newly diagnosed disease or relapsed following treatment with cyclophosphamide or other immunosuppressive therapy: The Rituximab for ANCA-Associated Vasculitis (RAVE) trial was a randomized, placebo- controlled, multicenter, noninferiority trial that compared induction therapy with rituximab 2 (375 mg/m per week for four weeks) or oral cyclophosphamide (2 mg/kg per day) in 197 patients with GPA (75 percent of enrolled patients) or MPA (25 percent); 49 percent of patients were newly diagnosed, and the remainder had relapsing disease [19]. All patients received one to three pulses of methylprednisolone (1000 mg) followed by prednisone (1 mg/kg per day). At six months, induction of remission rates in rituximab-treated patients were similar to those treated with cyclophosphamide (64 versus 53 percent, respectively). In addition, in the 100 patients with relapsing disease, rituximab was superior to cyclophosphamide in inducing remission (67 versus 42 percent) at six months. The rates of adverse events were similar between the two groups. Of the 197 patients initially enrolled in RAVE, the 146 patients who achieved complete remission were followed through month 18 [20]. In this trial, rituximab-treated patients received no further therapy, while cyclophosphamide-treated patients were converted to azathioprine immunosuppression within the first six months of treatment. At 18 months, the proportion of patients remaining in complete remission was similar comparing rituximab- with cyclophosphamide-based induction (39 versus 33 percent). In addition, the number of deaths or the rate of severe infections was similar between the treatment groups. In a smaller trial (Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis [RITUXVAS]), 44 patients with newly diagnosed antineutrophil cytoplasmic autoantibody (ANCA)-associated renal vasculitis were assigned in a 3:1 ratio to receive intravenous (IV) methylprednisolone (1000 mg) followed by oral methylprednisolone (1 mg/kg per day with https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 5/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 2 reduction to 5 mg per day by the end of six months) plus either rituximab (375 mg/m per week for four weeks) in combination with two IV cyclophosphamide pulses (15 mg/kg) or IV cyclophosphamide (15 mg/kg every two weeks for three doses followed by infusions every three weeks) for three to six months followed by azathioprine [21,22]. At 12 and 24 months in RITUXVAS, the rate of sustained remission (defined as the absence of disease activity for at least six months) was similar between the rituximab/cyclophosphamide and cyclophosphamide-only groups (76 versus 82 percent). The rate of adverse events at 12 months was also similar between the two groups. An important consideration when reviewing both of these trials is that patients with alveolar hemorrhage requiring mechanical ventilation or with serum creatinine levels >4 mg/dL were excluded from enrollment in the RAVE trial. However, some of the patients in RAVE went on to require mechanical ventilation or had serum creatinine levels >4 mg/dL after enrollment. Thus, there is still some uncertainty about the efficacy of rituximab in this population, although there are also no randomized trial data to support the use of cyclophosphamide in such situations. In a post hoc analysis of 102 patients in the RAVE trial who had kidney involvement at enrollment, 2 of which 62 had an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m , rates of remission were similar between the treatment groups [23]. Although RITUXVAS did include a small number of patients with kidney failure requiring dialysis, patients also received cyclophosphamide initially as part of the trial design. Although few patients over the age of 75 were included in the two aforementioned trials, rituximab appears to be effective in this patient population. In an observational study that included 66 adults aged >75 years with GPA or MPA who received induction therapy with rituximab, 57 (86 percent) achieved remission and two (3 percent) experienced relapse [24]. However, rates of serious infection were high (46.6 per 100 patient-years). (See 'Older patients' below.) It remains uncertain whether the ANCA serotype (ie, proteinase 3 [PR3]-ANCA versus myeloperoxidase [MPO]-ANCA positivity) affects the response to the specific induction regimen. A post hoc analysis of the RAVE trial found that patients who were PR3-ANCA positive and received rituximab were more likely to achieve remission at six months compared with those treated with cyclophosphamide and azathioprine (65 versus 48 percent, respectively; odds ratio 2.11, 95% CI 1.04-4.30). Although this difference was not observed at 12 or 18 months, it should be noted that the patients treated with rituximab received no maintenance therapy while those treated with cyclophosphamide subsequently received azathioprine up to month 18 [25], and these results have not been validated in an independent dataset. No association between treatment and remission was observed in the patients who were MPO-ANCA positive. https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 6/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Rituximab-based regimen If a rituximab-based regimen is selected, either the dose regimen used for rheumatoid arthritis (administering 1 g of rituximab followed 14 days later by 2 another 1 g dose) or the dosing regimen that was used in the RAVE trial (375 mg/m per week for four weeks) can be used. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis", section on 'Initial dose'.) Patients receiving rituximab should also receive glucocorticoids. The glucocorticoid regimen is discussed below. (See 'Glucocorticoid dosing and taper' below.) Several anti-CD20 drugs other than rituximab are available, but none have yet to be studied comprehensively in patients with ANCA-associated vasculitis. However, in a small series of three patients with ANCA-associated vasculitis and a history of anaphylaxis to rituximab, obinutuzumab (an anti-CD20 antibody) appeared to be efficacious and a reasonable alternative [26]. Cyclophosphamide-based regimen If a cyclophosphamide-based regimen is selected, the choice of oral versus IV cyclophosphamide is largely dictated by practice style. Both oral and IV regimens are highly effective. Some clinicians prefer IV cyclophosphamide given the lower cumulative dose associated with this administration and theoretical subsequent lower risk of toxicity. After approximately three to six months, cyclophosphamide is replaced by a medication with a lower risk of toxicity. (See 'Choice of maintenance therapy' below.) IV cyclophosphamide dosing If IV cyclophosphamide is selected, some experts use the regimen employed in the CYCLOPS trial (15 mg/kg every two weeks for three doses and then every three weeks for three to six months) [15], with appropriate dose reductions made in older adults and patients with impaired kidney function. As an example, the cyclophosphamide dose can be reduced by 2.5 mg/kg per pulse for patients age 60 to 70 years and by 5 mg/kg per pulse for patients older than 70 years [15]. We usually reduce the dose by one-half (ie, from 15 mg/kg to 7.5 mg/kg per pulse) in patients with an eGFR <30 2 2 mL/min/1.73 m . Other experts treat with 0.5 g/m every two weeks for three to six months. If the white blood cell and absolute neutrophil count at two weeks are above 2 3500/microL and 1500/microL respectively, we increase the next dose to 0.75 g/m and, after repeating these labs two weeks later, reevaluate the need for a dose reduction back 2 to 0.5 g/m . When using intermittent pulses of cyclophosphamide, some clinicians concomitantly administer mercaptoethane sulfonate (MESNA) to prevent cystitis, although the efficacy of this approach is unproven. A more detailed discussion of dosing, dose adjustments, adverse effects, and the use of MESNA is presented elsewhere. (See "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Intermittent (pulse) cyclophosphamide'.) https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 7/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Oral cyclophosphamide dosing If oral cyclophosphamide is used, it is typically given in a dose of 1.5 to 2 mg/kg per day, with appropriate dose reductions made in older adults and patients with impaired kidney function ( table 1). Therapy is continued until a stable remission is induced, which is usually achieved within three to six months. The white blood cell count should be closely monitored (eg, weekly), and the cyclophosphamide dose should be adjusted to avoid severe leukopenia. The white blood cell count should remain above 3500/microL, and the absolute neutrophil count should remain above 1500/microL. Patients receiving oral or IV cyclophosphamide should also receive glucocorticoids. The regimen is discussed below. (See 'Glucocorticoid dosing and taper' below.) Randomized trials comparing daily oral and monthly IV cyclophosphamide regimens have shown that the rate of induction of remission is almost equivalent [15,16,27-29]. In almost all of these studies, IV therapy had the advantages of lower total cyclophosphamide exposure and lower rates of neutropenia and infection but a trend toward a higher rate of relapse. As an example, a randomized trial (CYCLOPS) including 149 patients with ANCA-associated vasculitis treated with prednisolone and either pulse cyclophosphamide (15 mg/kg every two weeks for three doses and then every three weeks) or daily oral cyclophosphamide (2 mg/kg per day) found no difference in the time to remission or the percentage of patients who achieved remission by nine months (88 percent in both groups) [15]. Most remissions occurred between two and six months. Among the patients who achieved remission by nine months, 19 (14.5 percent) relapsed (10 major and 9 minor). There were more relapses in the IV pulse cyclophosphamide group (13 versus 6), a difference that was not statistically significant, but the study was not designed or powered to assess an effect on relapse. Pulse cyclophosphamide compared with daily oral cyclophosphamide was associated with a lower cumulative cyclophosphamide dose and a lower rate of leukopenia. During a median of 4.3 years of follow- up, more patients in the IV pulse cyclophosphamide group relapsed, but the incidence of end- stage kidney disease (ESKD) was similar [30]. Glucocorticoid dosing and taper Oral glucocorticoid therapy is typically started at 1 mg/kg per day (maximum of 60 to 80 mg/day of oral prednisone or its equivalent) for most patients with organ- or life-threatening disease. High-dose IV ("pulse") glucocorticoids (such as methylprednisone 7 to 15 mg/kg to a maximum dose of 1000 mg/day for three days) are usually limited to patients presenting with manifestations such as rapidly progressive glomerulonephritis, pulmonary hemorrhage, mononeuritis multiplex, or optic neuritis. Daily oral glucocorticoids are then started after the IV therapy. For most patients with GPA or MPA receiving glucocorticoids in combination with a glucocorticoid-sparing agent, we recommend a reduced-dose glucocorticoid tapering regimen https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 8/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate rather than the standard-dosing taper. A variety of reduced-dose prednisone tapering schemes have been employed. As an example, if the initial dose of prednisone is 60 mg/day, it can be reduced by 50 percent to 30 mg in one to two weeks ( table 2). Unless higher doses are required for resistant or relapsing disease, prednisone should be tapered to 5 mg daily or discontinued by four to six months. Concomitant treatment with avacopan may facilitate the use of an even shorter, reduced-dose glucocorticoid regimen, as discussed below. (See 'Avacopan' below.) The use of a reduced-dose glucocorticoid tapering regimen is based upon data from randomized trials demonstrating that patients who receive such a regimen have similar rates of remission compared with those who receive standard-dosing regimens, while experiencing fewer adverse effects [31-33]: In the Plasma Exchange and Glucocorticoids for Treatment of Anti-Neutrophil Cytoplasm Antibody (ANCA)-Associated Vasculitis (PEXIVAS) trial that included 704 patients with newly diagnosed or relapsing severe GPA or MPA, a reduced-dose oral glucocorticoid regimen resulted in similar rates of ESKD and death compared with a standard-dose glucocorticoid regimen and was also associated with fewer serious infections at one year [31]. Serious infections occurred in 96 patients (27 percent) in the reduced-dose glucocorticoid regimen compared with 180 patients (33 percent) in the standard-dose regimen (incidence rate ratio, 0.69 [95% CI 0.52-0.93]). In a second trial that randomly assigned 140 patients with newly diagnosed MPA or GPA (without severe glomerulonephritis or alveolar hemorrhage) to rituximab plus either reduced-dose (0.5 mg/kg/day) or standard-dose (1 mg/kg/day) prednisolone, rates of remission at six months were comparable between the groups (71 versus 69 percent, respectively) [33]. Rates of serious adverse events were lower in the reduced-dose group (19 versus 37 percent), as were serious infections (7 versus 20 percent). Role of plasma exchange The authors/editors of this topic do not fully agree on the extent of the role of plasma exchange, in addition to glucocorticoids and either cyclophosphamide or rituximab, among patients with GPA or MPA: Double-positive anti-GBM and ANCA-associated disease All authors agree with the use of plasma exchange for most patients with GPA or MPA who are concomitantly positive for anti-glomerular basement membrane (anti-GBM) autoantibody [9,11,12]. (See "Anti-GBM (Goodpasture) disease: Treatment and prognosis", section on 'Plasmapheresis plus immunosuppressive therapy'.) https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 9/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Severe kidney disease When to use plasma exchange to treat patients with GPA or MPA and severe active kidney disease is controversial. Some experts institute plasma exchange immediately upon identification of severe kidney disease (eg, serum creatinine >4.0 mg/dL [354 micromol/L] or need for dialysis) while others first consider the response to initial immunosuppressive therapy. The extent to which kidney biopsy findings influence this decision is an area of ongoing interest [34], and some authors suggest that the presence of active inflammation without significant glomerulosclerosis identifies patients most likely to benefit from plasma exchange. Pulmonary hemorrhage Some other authors would also offer plasma exchange to patients with GPA or MPA who present with pulmonary hemorrhage, while other authors would reserve the use of plasma exchange for patients with pulmonary hemorrhage not readily responding to other therapies and optimal supportive care. If plasma exchange is used, we suggest seven sessions over two weeks (60 mL/kg at each session). Albumin is the preferred replacement fluid in patients without bleeding or a recent kidney biopsy. For patients with risk of bleeding or a recent biopsy, we suggest that 1 to 2 liters of fresh frozen plasma be substituted for albumin at the end of the procedure to reverse pheresis-induced depletion of coagulation factors. For patients with active hemorrhage, the replacement fluid should exclusively be fresh frozen plasma. Among patients who develop severe infection in the setting of plasma exchange, a single infusion of IV immune globulin (100 to 400 mg/kg) can be given to partially replenish antibody levels. The rationale for limiting the use of plasma exchange is largely based upon data from the PEXIVAS randomized trial of 704 patients with newly diagnosed or relapsing severe GPA or MPA 2 (defined by an eGFR <50 mL/min/1.73 m or diffuse pulmonary hemorrhage), in which the use of plasma exchange did not reduce the incidence of death or ESKD (hazard ratio [HR] 0.86, 95% CI 0.65-1.13) at one year or during the follow-up period of up to seven years [31]. At baseline, the median serum creatinine level was 3.7 mg/dL (327 micromol/L) and approximately 20 percent of patients required dialysis; approximately 18 percent of patients had pulmonary hemorrhage, less than one-half of whom had severe hemorrhage. All patients received either cyclophosphamide or rituximab, the majority of whom received cyclophosphamide (85 percent). Patients were also randomly assigned to either a standard-dose or reduced-dose glucocorticoid regimen, which is discussed above. (See 'Glucocorticoid dosing and taper' above.) Evidence in support of the use of plasma exchange among patients with severe active kidney disease comes from small, randomized trials and meta-analyses that suggest that plasma exchange may improve short-term kidney outcomes but has no effect on mortality in this patient population [35-39]. A meta-analysis of randomized trials (including the PEXIVAS trial) suggested https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 10/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate that plasma exchange, in addition to standard induction therapy, does not improve mortality and may increase the risk of serious infections but appears to reduce the risk of ESKD at 12 months (relative risk [RR] 0.62, 95% CI 0.39-0.98) [39]. This benefit was greatest for patients at high risk of ESKD (defined as serum creatinine >5.7 mg/dL [500 micromol/L] or requiring dialysis; absolute risk reduction 16.0 percent, 95% CI 4.2-23.6 percent). However, in a retrospective review of 251 patients with ANCA-associated vasculitis who had severe kidney disease (eGFR <30 2 mL/min/1.73 m ), the addition of plasma exchange to standard therapy was not associated with a benefit on remission induction, the rate of ESKD and/or death at 18 months, progression to ESKD, or survival at 24 months [40]. There is more uncertainty regarding the efficacy of plasma exchange in patients with GPA or MPA and severe diffuse alveolar hemorrhage. Although the PEXIVAS trial did not demonstrate improved outcomes with plasma exchange, only a small proportion of the patients enrolled in this trial presented with severe hemorrhage [31]. In addition, retrospective data regarding the effects of plasma exchange on diffuse alveolar hemorrhage have shown mixed results [41-45]. In one study of 73 patients with diffuse alveolar hemorrhage, of whom 34 required mechanical ventilation, the use of plasma exchange was not associated with achieving complete remission at six months [44]. Another analysis of 11 studies including 172 patients with diffuse alveolar hemorrhage reported similar rates of resolution of diffuse alveolar hemorrhage and survival at hospital discharge among patients who received plasma exchange and those who did not [44]. The appropriate role of plasma exchange in treatment of GPA and MPA will continue to evolve as more structured combined analyses of the data to date are conducted and analyses of specific subpopulations (eg, pulmonary hemorrhage) become available. Our approach to the use of plasma exchange is generally consistent with the recommendations of the American College of Rheumatology/Vasculitis Foundation [11] and KDIGO [12]. Alternative regimens Combination with ritixumab and cyclophosphamide Some experts treat with glucocorticoids in combination with both rituximab and cyclophosphamide. However, this approach remains controversial, and there is no expert consensus as to which patients should receive the combination of rituximab and cyclophosphamide for induction of remission for GPA or MPA. This approach is based on several observational studies and limited trial data suggesting there may be a benefit in terms of lower exposure to glucocorticoids and lower infectious complications, while maintaining similar remission rates [21,22,46-50]. As examples: Several observational studies and one small trial have reported results with the use of glucocorticoids, cyclophosphamide, and rituximab for initial therapy in patients with organ- https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 11/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate threatening or life-threatening GPA or MPA [21,22,46-50]. In the RITUXVAS trial mentioned above, patients with newly diagnosed ANCA-associated renal vasculitis were assigned to receive glucocorticoids plus either rituximab in combination with two or three IV cyclophosphamide pulses or IV cyclophosphamide alone [21,22]. There were no differences between the groups in the rates of sustained remission, ESKD, or death. A single-center, observational study examined the outcomes of 120 patients with GPA or MPA treated with rituximab, including 20 who did not receive cyclophosphamide, 45 who had prior exposure to cyclophosphamide, and 65 who received both drugs prior to reaching a remission [48]. Compared with those who received rituximab without cyclophosphamide, patients who were given both drugs concurrently had similar remission rates, a nonsignificantly longer duration of sustained remission, and a nonsignificantly higher mortality. Avacopan Some clinicians use the complement C5a receptor inhibitor avacopan as an adjunctive agent with standard induction therapy to limit the use of glucocorticoids. Avacopan is administered as 30 mg orally twice daily, typically in combination with a shorter, reduced-dose glucocorticoid regimen in which glucocorticoids are tapered over four to six weeks depending upon patient response. Use of avacopan should be avoided in patients with active, untreated, and/or uncontrolled chronic liver disease and patients who are taking moderate to strong CYP3A4 inducers; the dose should be reduced to 30 mg daily in patients who are taking strong CYP3A4 enzyme inhibitors ( table 3). The use of avacopan is supported by evidence from trials demonstrating disease remission with limited use of glucocorticoids [51-53]. In a trial including 331 patients with newly diagnosed or relapsing antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, patients were randomly assigned to receive either oral avacopan 30 mg twice daily or prednisone on a tapering schedule; all patients received standard remission-induction therapy with cyclophosphamide (followed by azathioprine) or rituximab [53]. Approximately 80 percent of patients had kidney involvement. At 26 weeks, the rates of disease remission were similar between the two groups (72 percent in the avacopan group versus 70 percent in the prednisone group). At 52 weeks, sustained remission was higher in the avacopan group than in the prednisone group (66 versus 55 percent). The rate of overall serious adverse events (excluding worsening vasculitis) was similar for both regimens (37 versus 39 percent for avacopan and prednisone, respectively). Similar safety data have been found in a smaller trial of avacopan added to standard-of-care treatment for ANCA vasculitis [52]. It should be noted that glucocorticoids were also used by some patients in the avacopan group in the first few weeks following initiation of treatment, but the mean total dose was approximately one-third of that in the prednisone group (1349 mg versus 3655 mg). In addition, patients in the avacopan group https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 12/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate experienced less glucocorticoid-related toxicity than those in the prednisone group. The safety and efficacy of avacopan beyond 52 weeks have not yet been addressed. Maintenance therapy After attainment of remission with induction immunosuppressive therapy, almost all patients are switched to a maintenance regimen. The authors and reviewers of this topic think that certain low-risk, newly diagnosed patients who were originally MPO-ANCA positive and have attained a complete remission may be safely followed without maintenance therapy. Since PR3-ANCA-positive patients as a group have a higher risk of relapse compared with MPO-ANCA-positive patients, the former are not included in this group. The selection of such MPO-ANCA-positive patients is individualized and is based upon whether the patient has risk factors for relapse (eg, the presence of lung or upper respiratory tract involvement prior to remission) or a tenuous clinical status (eg, an older individual with reduced glomerular filtration rate [GFR] is less likely to tolerate a relapse than a younger individual with normal GFR). If patients are managed without maintenance immunosuppression, they should be followed with frequent clinic visits, regular testing of serum creatinine, and weekly home urine dipsticks. (See 'Monitoring the response to therapy' below.) When to start maintenance therapy The combination of glucocorticoids plus either rituximab or oral or IV cyclophosphamide induces remission in the majority of patients, usually within three to six months after the initiation of therapy. Patients in whom remission or evidence of progressive improvement is not attained within six months should be considered to have disease resistant to the chosen induction regimen and have their treatment regimen altered. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of disease resistant to initial therapy".) The timing of initiation of maintenance therapy depends upon the induction regimen used: For patients treated with rituximab for induction of remission, maintenance therapy typically begins between months four and six after the last induction dose, regardless of the maintenance agent that is used. For patients treated with IV cyclophosphamide for induction of remission, maintenance therapy is started two to four weeks after the last dose of cyclophosphamide if the following white blood cell criteria are met: The white blood cell count is >3500 cells/microL, and the absolute neutrophil count is >1500 cells/microL. When daily oral cyclophosphamide is used for induction of remission, maintenance therapy can be started as soon as the above white blood cell criteria are met. In some patients, maintenance therapy can be started the day after oral cyclophosphamide is stopped. https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 13/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate After approximately three to six months, cyclophosphamide is replaced by a medication with a lower risk of toxicity. This includes any of the alternatives discussed below. (See 'Choice of maintenance therapy' below.) Choice of maintenance therapy In patients who achieve remission after a new diagnosis of GPA or MPA, the choice of maintenance therapy is influenced by disease severity

Alternative regimens Combination with ritixumab and cyclophosphamide Some experts treat with glucocorticoids in combination with both rituximab and cyclophosphamide. However, this approach remains controversial, and there is no expert consensus as to which patients should receive the combination of rituximab and cyclophosphamide for induction of remission for GPA or MPA. This approach is based on several observational studies and limited trial data suggesting there may be a benefit in terms of lower exposure to glucocorticoids and lower infectious complications, while maintaining similar remission rates [21,22,46-50]. As examples: Several observational studies and one small trial have reported results with the use of glucocorticoids, cyclophosphamide, and rituximab for initial therapy in patients with organ- https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 11/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate threatening or life-threatening GPA or MPA [21,22,46-50]. In the RITUXVAS trial mentioned above, patients with newly diagnosed ANCA-associated renal vasculitis were assigned to receive glucocorticoids plus either rituximab in combination with two or three IV cyclophosphamide pulses or IV cyclophosphamide alone [21,22]. There were no differences between the groups in the rates of sustained remission, ESKD, or death. A single-center, observational study examined the outcomes of 120 patients with GPA or MPA treated with rituximab, including 20 who did not receive cyclophosphamide, 45 who had prior exposure to cyclophosphamide, and 65 who received both drugs prior to reaching a remission [48]. Compared with those who received rituximab without cyclophosphamide, patients who were given both drugs concurrently had similar remission rates, a nonsignificantly longer duration of sustained remission, and a nonsignificantly higher mortality. Avacopan Some clinicians use the complement C5a receptor inhibitor avacopan as an adjunctive agent with standard induction therapy to limit the use of glucocorticoids. Avacopan is administered as 30 mg orally twice daily, typically in combination with a shorter, reduced-dose glucocorticoid regimen in which glucocorticoids are tapered over four to six weeks depending upon patient response. Use of avacopan should be avoided in patients with active, untreated, and/or uncontrolled chronic liver disease and patients who are taking moderate to strong CYP3A4 inducers; the dose should be reduced to 30 mg daily in patients who are taking strong CYP3A4 enzyme inhibitors ( table 3). The use of avacopan is supported by evidence from trials demonstrating disease remission with limited use of glucocorticoids [51-53]. In a trial including 331 patients with newly diagnosed or relapsing antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, patients were randomly assigned to receive either oral avacopan 30 mg twice daily or prednisone on a tapering schedule; all patients received standard remission-induction therapy with cyclophosphamide (followed by azathioprine) or rituximab [53]. Approximately 80 percent of patients had kidney involvement. At 26 weeks, the rates of disease remission were similar between the two groups (72 percent in the avacopan group versus 70 percent in the prednisone group). At 52 weeks, sustained remission was higher in the avacopan group than in the prednisone group (66 versus 55 percent). The rate of overall serious adverse events (excluding worsening vasculitis) was similar for both regimens (37 versus 39 percent for avacopan and prednisone, respectively). Similar safety data have been found in a smaller trial of avacopan added to standard-of-care treatment for ANCA vasculitis [52]. It should be noted that glucocorticoids were also used by some patients in the avacopan group in the first few weeks following initiation of treatment, but the mean total dose was approximately one-third of that in the prednisone group (1349 mg versus 3655 mg). In addition, patients in the avacopan group https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 12/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate experienced less glucocorticoid-related toxicity than those in the prednisone group. The safety and efficacy of avacopan beyond 52 weeks have not yet been addressed. Maintenance therapy After attainment of remission with induction immunosuppressive therapy, almost all patients are switched to a maintenance regimen. The authors and reviewers of this topic think that certain low-risk, newly diagnosed patients who were originally MPO-ANCA positive and have attained a complete remission may be safely followed without maintenance therapy. Since PR3-ANCA-positive patients as a group have a higher risk of relapse compared with MPO-ANCA-positive patients, the former are not included in this group. The selection of such MPO-ANCA-positive patients is individualized and is based upon whether the patient has risk factors for relapse (eg, the presence of lung or upper respiratory tract involvement prior to remission) or a tenuous clinical status (eg, an older individual with reduced glomerular filtration rate [GFR] is less likely to tolerate a relapse than a younger individual with normal GFR). If patients are managed without maintenance immunosuppression, they should be followed with frequent clinic visits, regular testing of serum creatinine, and weekly home urine dipsticks. (See 'Monitoring the response to therapy' below.) When to start maintenance therapy The combination of glucocorticoids plus either rituximab or oral or IV cyclophosphamide induces remission in the majority of patients, usually within three to six months after the initiation of therapy. Patients in whom remission or evidence of progressive improvement is not attained within six months should be considered to have disease resistant to the chosen induction regimen and have their treatment regimen altered. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of disease resistant to initial therapy".) The timing of initiation of maintenance therapy depends upon the induction regimen used: For patients treated with rituximab for induction of remission, maintenance therapy typically begins between months four and six after the last induction dose, regardless of the maintenance agent that is used. For patients treated with IV cyclophosphamide for induction of remission, maintenance therapy is started two to four weeks after the last dose of cyclophosphamide if the following white blood cell criteria are met: The white blood cell count is >3500 cells/microL, and the absolute neutrophil count is >1500 cells/microL. When daily oral cyclophosphamide is used for induction of remission, maintenance therapy can be started as soon as the above white blood cell criteria are met. In some patients, maintenance therapy can be started the day after oral cyclophosphamide is stopped. https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 13/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate After approximately three to six months, cyclophosphamide is replaced by a medication with a lower risk of toxicity. This includes any of the alternatives discussed below. (See 'Choice of maintenance therapy' below.) Choice of maintenance therapy In patients who achieve remission after a new diagnosis of GPA or MPA, the choice of maintenance therapy is influenced by disease severity and patient-specific factors. In most patients who achieve remission after induction immunosuppressive therapy, we suggest treatment with rituximab for maintenance of remission. Azathioprine, methotrexate, and mycophenolate are reasonable alternatives and may be preferred based on other patient-specific factors. The choice of agent for patients with relapsing disease is discussed separately. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of relapsing disease".) Examples of patient-specific factors that may influence the choice of the maintenance agent include a prior history of toxicity from a certain drug and/or a comorbid condition that increases the risk of toxicity with a specific agent. As examples: Given the risk of toxicity with use of methotrexate in patients with reduced kidney function, 2 this drug should not be used in patients with an eGFR <60 mL/min/1.73 m or evidence of active renal vasculitis. (See "Chemotherapy nephrotoxicity and dose modification in patients with kidney impairment: Conventional cytotoxic agents", section on 'Methotrexate' and "Major side effects of low-dose methotrexate".) Rituximab should be avoided, or used in conjunction with anti-hepatitis B virus (HBV) therapy, in patients who are positive for hepatitis B surface antigen (HBsAg) or antibodies to the hepatitis B core antigen (anti-HBc) due to the elevated risk of reactivation and potentially fatal hepatitis. Azathioprine is the preferred agent for maintenance therapy in patients who want to become pregnant since methotrexate is contraindicated in pregnancy and the risk of rituximab during gestation is not yet well characterized. Dosing of drugs that are used for maintenance therapy is discussed below. (See 'Dosing of maintenance therapy' below.) The major, well-designed, randomized trials that examined the efficacy of maintenance therapy in patients with GPA or MPA included newly diagnosed patients almost exclusively, rather than relapsed patients. These trials are summarized below: https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 14/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate The Cyclophosphamide versus Azathioprine for Early Remission Phase of Vasculitis (CYCAZAREM) trial, which included 155 patients with newly diagnosed ANCA-positive vasculitis, found that the substitution of azathioprine after induction therapy with oral cyclophosphamide did not increase the rate of relapse [18]. The 144 patients in whom remission was achieved (77 percent at three months and a further 16 percent between three and six months) were randomly assigned to either continued cyclophosphamide (1.5 mg/kg per day) or azathioprine (2 mg/kg per day) while remaining on prednisolone at 10 mg/day. After one year, both groups were treated with azathioprine (1.5 mg/kg per day) plus prednisolone (7.5 mg per day). At 18 months, the rates of relapse were similar between the azathioprine and cyclophosphamide groups (15.5 versus 13.7 percent), and, during the maintenance phase, both groups had a similar number of severe adverse events (eight and seven patients, respectively). However, cyclophosphamide is associated with serious malignancies over the long term and is no longer commonly used for maintenance therapy in patients with GPA or MPA. (See "General toxicity of cyclophosphamide in rheumatic diseases", section on 'Malignancy'.) The Wegener Granulomatosis-Entretien (WEGENT) trial found that azathioprine and methotrexate provide comparable efficacy and are similarly safe when administered for maintenance therapy [54]. In this trial, 126 patients with newly diagnosed GPA or MPA who were in remission after treatment with cyclophosphamide and oral glucocorticoids were randomly assigned to azathioprine (2 mg/kg per day) or methotrexate for 12 months followed by gradual withdrawal over three months [54]. The mean serum creatinine was approximately 2 mg/dL (176 micromol/L) at baseline and 1.5 mg/dL (129 micromol/L) at randomization. At a mean follow-up of 29 months, both drugs were associated with a similar number of adverse effects that required drug discontinuation (11 and 19 percent for azathioprine and methotrexate, respectively) and a similar relapse rate (36 and 33 percent). The majority of relapses (73 percent) occurred after the cessation of maintenance therapy. The best data supporting the use of rituximab as maintenance therapy come from the Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis (MAINRITSAN) trial that compared rituximab with azathioprine in 115 patients who had attained remission after initial therapy using cyclophosphamide plus glucocorticoids; most patients were newly diagnosed rather than relapsed (80 versus 20 percent), had GPA rather than MPA (76 versus 20 percent), and had a positive PR3-ANCA rather than MPO-ANCA (70 versus 23 percent) [55]. Rituximab was given as two 500 mg doses separated by 14 days at baseline and then again at months 6, 12, and 18. Azathioprine was given at a dose of 2 mg/kg per day for 12 months followed by 1.5 mg/kg per day for six months and then 1 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 15/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate mg/kg per day for four additional months. Treatment with rituximab produced a lower rate of major relapse as compared with azathioprine at 28 months (5 versus 29 percent). The number of serious adverse events was similar in both groups. Rituximab also appears to be effective as maintenance therapy in older adults (age >75 years) with GPA or MPA [24]. The International Mycophenolate Mofetil Protocol to Reduce Outbreaks of Vasculitides (IMPROVE) trial was an open-label, randomized, multicenter trial that included 156 patients with newly diagnosed ANCA-associated vasculitis and found that azathioprine was more effective than mycophenolate for maintenance therapy [56]. After induction of remission with cyclophosphamide and glucocorticoids, patients received either azathioprine (starting at 2 mg/kg per day and then reduced to 1.5 and 1 mg/kg per day after 12 and 18 months, respectively) or mycophenolate mofetil (starting at 2000 mg per day and then reduced to 1500 and 1000 mg per day after 12 and 18 months, respectively). Both agents were withdrawn after 42 months of treatment. At a median follow-up of 39 months, relapses were significantly less frequent among those who received azathioprine (38 versus 55 percent, adjusted HR 0.56, 95% CI 0.34-0.91). The rate of adverse events was not significantly higher for those who received azathioprine (16 versus 8 percent, respectively). Data from observational studies and small trials also suggest that mycophenolate mofetil can maintain remission in patients with GPA or MPA [57-62]. As an example, in an open-label trial including 14 patients with GPA who received induction therapy with daily oral cyclophosphamide and prednisone and who were subsequently treated with mycophenolate mofetil (2 g/day), six patients (43 percent) relapsed at a median of 10 months [58]. A similar rate of relapse was noted in a retrospective study of 29 patients who received mycophenolate mofetil for maintenance therapy (48 percent at a mean of 14 months) [59]. Another large trial, the Wegener Granulomatosis Etanercept Trial (WGET), compared etanercept with placebo as add-on therapy in patients who were receiving cyclophosphamide or methotrexate for maintenance [17]. Etanercept provided no additional benefit and may increase the risk for malignancy; therefore, this drug should not be used for maintenance therapy. Dosing of maintenance therapy Dosing of rituximab A variety of rituximab dosing strategies have been used, and it is not clear whether there is any one best option. Maintenance rituximab therapy is typically administered as 500 to 1000 mg every six months [55,63]. Some experts redose rituximab at four-month rather than six-month intervals [47]. Others prefer an "on-demand" dosing strategy, in which peripheral B lymphocyte (CD19-positive cells) counts, which are depleted by rituximab, https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 16/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate and ANCA titers are monitored and the drug is redosed when B lymphocytes reconstitute and the ANCA titer becomes positive. As an example, one study of 53 patients with GPA found that, after remission induction with rituximab, relapse only occurred in patients whose CD19-positive cell count increased above 20 cells/microL and whose PR3-ANCA titers were positive [64]. By contrast, another study found that 29 percent of relapsing patients had depleted CD19-positive cell counts [65]. A randomized trial comparing an individually tailored and fixed-schedule rituximab regimen (500 mg IV every six months) among 162 patients with newly diagnosed or relapsing GPA or MPA who achieved complete remission after induction therapy reported comparable rates of relapse over 28 months [66]. The rates of adverse events and infectious complications were also similar between the two groups. Some experts also routinely monitor serum immunoglobulin levels and reduce the dose of rituximab in patients who develop hypogammaglobulinemia. Others only monitor serum immunoglobulin levels if the patient develops frequent infections. (See "Secondary immunodeficiency induced by biologic therapies", section on 'Hypogammaglobulinemia'.) Rituximab should not be given to patients who are positive for HBsAg or anti-HBc, without concurrent HBV therapy, due to the elevated risk of reactivation and potentially fatal hepatitis. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".) Dosing of azathioprine Azathioprine is typically initiated at a dose of 50 mg/day and gradually increased if thiopurine methyltransferase (TPMT) testing has not been performed prior to initiation of therapy. If this dose is tolerated well at one week, the daily dose can be increased over several weeks to 2 mg/kg per day. If TPMT testing is performed prior to the initiation of therapy and is normal, azathioprine can be initiated at 2 mg/kg per day. The maximum dose should typically not exceed 200 mg/day. In some trials, the dose of azathioprine was reduced at one year to 1.5 mg/kg per day, but this corresponded to an increase in relapse rate [18,67]. Thus, we do not reduce the dose of azathioprine. Azathioprine metabolism and toxicity is predominantly related to TPMT activity, which varies among individuals. However, there is uncertainty regarding the benefits of routine testing for TPMT deficiency before beginning azathioprine. Although some clinicians routinely perform TPMT testing prior to initiating azathioprine, others do not perform such testing but rather initiate therapy at a low dose with close monitoring as the dose is gradually increased. The use of TPMT testing along with other potential adverse effects are discussed in detail separately. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Pharmacogenetics and azathioprine toxicity' and "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Adverse effects'.) https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 17/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Dosing of methotrexate Methotrexate is typically initiated at a dose of 15 mg/week, with increases in dose every two to eight weeks of 5 mg/week up to 25 mg/week. We use the same regimen and approach to titration as that used in rheumatoid arthritis (see "Use of methotrexate in the treatment of rheumatoid arthritis"). This dosing strategy is similar to that used in the WEGENT trial and other studies [54,68]. Although methotrexate can be given both orally and subcutaneously, the bioavailability at such doses is superior through the subcutaneous route. Because methotrexate is a structural analogue of folic acid that can competitively inhibit the binding of dihydrofolic acid (FH2) to the enzyme, dihydrofolate reductase (DHFR), folic acid (1 to 2 mg per day), or folinic acid (5 to 10 mg per week, 24 hours after methotrexate) should be given concurrently to reduce potential toxicity. Given the risk of methotrexate toxicity in patients with reduced kidney function, this drug should 2 not be used in patients with an eGFR <60 mL/min/1.73 m or evidence of active renal vasculitis. Dosing of mycophenolate The target dose of mycophenolate mofetil is typically between 1.5 and 3 g daily, in divided doses. One option is the regimen from the IMPROVE study (starting at 2000 mg per day followed by a reduction to 1500 and 1000 mg per day after 12 and 18 months, respectively), although this dose reduction was associated with an increased rate of relapses when compared with azathioprine in one trial [56]. Additional formulations (eg, enteric- coated mycophenolate sodium), dosing, and monitoring considerations for mycophenolate can be found elsewhere. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases".) Duration of maintenance therapy Our approach to the duration of maintenance therapy is based upon available data and clinical experience; other authorities have a different opinion about when to stop maintenance therapy. In addition, the duration of maintenance therapy should be modified if toxicity occurs: In most patients, we continue maintenance therapy for 12 to 24 months after stable remission has been induced [17,18,54,69]. In patients with multiple risk factors for relapse (eg, PR3-ANCA seropositivity, pulmonary involvement, and upper respiratory tract involvement), we continue maintenance therapy for 24 to 36 months. Some experts would treat such patients indefinitely if the degree of organ damage was severe and a relapse would be poorly tolerated. We continue maintenance therapy indefinitely in patients who have had one or more prior relapses, particularly in those who sustained significant organ damage (eg, those with https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 18/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate limited residual kidney function) and therefore would not tolerate further injury due to relapse. In some patients who have a low risk of relapse (eg, MPO-ANCA seropositivity and no respiratory tract involvement prior to remission), we continue maintenance therapy for 6 to 12 months. However, in such patients who become MPO-ANCA negative at the end of induction therapy, some experts would provide careful monitoring without any maintenance therapy. Only two randomized trials have compared different durations of maintenance therapy: One trial compared standard duration (two years) and extended duration (four years) azathioprine maintenance therapy in 131 patients with newly diagnosed PR3-ANCA- associated vasculitis who received oral cyclophosphamide and glucocorticoids for induction therapy [70]. At four years after diagnosis, rates of relapse-free survival were comparable between the two groups. The Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis (MAINRITSAN)3 trial evaluated the efficacy of an extended rituximab maintenance regimen (500 mg given every 6 months over an additional 18 months) among 97 patients who had achieved complete remission after induction therapy and completing an initial 18-month rituximab maintenance regimen [69]. After 28 months of follow-up, the extended rituximab maintenance group had a lower incidence of relapse compared with the placebo group (4 versus 26 percent, respectively). In the placebo group, relapses were more common among patients who were PR3-ANCA positive than among those who were MPO-ANCA positive (40 versus 12 percent, respectively). Only one patient out of 29 with persistently negative ANCA levels relapsed, and none of five patients with both negative ANCA levels and undetectable CD19+ B cells relapsed. No deaths occurred in either group, and the frequency of adverse events was similar in both groups. In addition, patients at lower risk for relapse (eg, MPO-ANCA-positive disease) may remain in remission without maintenance therapy after induction of remission. Some observational studies have found that discontinuation of maintenance therapy has not been associated with a substantial increase in relapses [71,72]. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of relapsing disease", section on 'Risk factors for relapse'.) Patients who progress to ESKD and are treated with chronic dialysis have a substantially lower rate of relapse than the same patients before they reached ESKD or patients with preserved kidney function. The management of patients with GPA or MPA who have ESKD is presented elsewhere. (See 'Maintenance dialysis' below.) https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 19/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate The use of ANCA titers to predict relapse is presented elsewhere. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of relapsing disease", section on 'Monitoring for relapse'.) Non-organ- and non-life-threatening disease Patients with non-organ- and non-life- threatening GPA include those with rhinosinusitis, arthritis, and/or pulmonary nodules with no other major organ involvement [73-78]. (See 'Assessment of disease severity' above.) For patients with non-organ- and non-life-threatening GPA not involving the kidney, we suggest induction therapy with glucocorticoids combined with weekly oral methotrexate (20 to 25 mg per week orally), rather than glucocorticoids combined with cyclophosphamide, rituximab, or azathioprine. However, given the risk of toxicity in patients with kidney dysfunction, 2 methotrexate should not be used when the eGFR is below 60 mL/min per 1.73 m or if there is evidence of active glomerulonephritis. Rituximab is a reasonable alternative as induction therapy, even in non-organ- and non-life-threatening disease. Azathioprine may be used as an alternative to methotrexate for pregnant patients or patients for whom methotrexate should be avoided due to moderate to severe kidney function impairment. However, there are no high- quality data regarding use of azathioprine for induction of remission in this patient population, and, in our experience, azathioprine may take longer than methotrexate to become maximally effective as an immunosuppressive agent. If rituximab is used, we use the same dose as that used for induction therapy in patients with organ- or life-threatening disease. If azathioprine is used, we use the same dose as that used for maintenance therapy in patients with organ- or life- threatening disease. (See 'Rituximab-based regimen' above and 'Dosing of azathioprine' above.) Methotrexate may be continued as maintenance therapy at the same dose used for induction, provided that patients have responded to induction therapy. Similarly, if rituximab or azathioprine is used as induction therapy, it may also be continued as maintenance therapy. Maintenance dosing for rituximab and azathioprine is similar to that for patients with organ- or life-threatening disease and is discussed above. (See 'Dosing of rituximab' above and 'Dosing of azathioprine' above.) Patients with non-organ- and non-life-threatening disease may be able to be treated with lower doses of glucocorticoids than used for patients with organ- or life-threatening disease. We typically initiate prednisone at 0.5 mg/kg/day (or its equivalent) followed by a reduced-dose glucocorticoid taper. Details about glucocorticoid dosing and taper are presented elsewhere in this topic. (See 'Glucocorticoid dosing and taper' above.) Available data suggest that methotrexate is as effective for induction of remission in patients with non-organ- and non-life-threatening disease but may be associated with a higher relapse https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 20/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate rate. The Nonrenal Wegener's Granulomatosis Treated Alternatively with Methotrexate (NORAM) trial compared methotrexate and cyclophosphamide for both induction and remission in 89 patients with newly diagnosed GPA and six patients with MPA, none of whom had significant kidney involvement (mean serum creatinine of 1 mg/dL [85 micromol/L] and microscopic hematuria in only 28 percent); the majority of patients had upper respiratory tract involvement [76]. At six months, 90 and 94 percent of patients in the methotrexate and cyclophosphamide arms, respectively, achieved remission, although time to remission was two months longer in the methotrexate group. Among the patients who achieved remission, the relapse rate at 18 months was significantly higher with methotrexate (70 versus 47 percent with cyclophosphamide). There was a higher incidence of leukopenia among those treated with cyclophosphamide and a higher incidence of liver function test abnormalities among those treated with methotrexate. Two patients in each group died. Methotrexate was also used for induction of remission among patients with nonsevere disease enrolled in the WGET trial; remission rates with methotrexate were similarly high in this subset of patients with GPA [17]. Monitoring the response to therapy All patients receiving immunosuppressive therapy for GPA or MPA should be closely monitored. Patients with organ- or life-threatening disease are typically admitted to the hospital for treatment with close monitoring of their clinical status and laboratory testing on a daily basis. If the patient has pulmonary hemorrhage, serial chest radiographs and/or a computed tomography (CT) of the chest are reasonable to monitor for worsening alveolar hemorrhage. When the patient's condition is stable enough for discharge from the hospital, we typically schedule follow-up visits every two to four weeks for the first three months. Subsequently, the duration between follow-up visits can then be extended to every two to three months. The goal of these visits is to evaluate the patient's response to therapy (ie, whether a clinical response is achieved) and the toxicity of the regimen (ie, adverse effects, infections due to immunosuppression). We perform the following assessments during these visits: History and physical examination Assessment of blood pressure Measurement of serum creatinine and electrolytes Urinalysis with microscopic examination of the urinary sediment Complete blood count Erythrocyte sedimentation rate and/or C-reactive protein level https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 21/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Clinical practice varies in the monitoring of ANCA titers among patients being treated for GPA or MPA. Some authors and editors routinely monitor ANCA titers, particularly among patients with kidney involvement, to assess the response to therapy and risk of relapse [65,79-82]. Other contributors do not routinely monitor ANCA titers, since ANCA titers do not consistently reflect disease activity. Additional information about ANCA titers in patients with GPA or MPA is presented elsewhere. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of relapsing disease", section on 'Monitoring by the clinician'.) Additional organ-specific testing may be required for some patients. As an example, repeat CT of the chest is advised for patients with tracheal and/or pulmonary involvement to document remission or prior active disease and/or to establish a new baseline. In addition, serial audiograms should be performed in patients with any form of hearing loss related to GPA or MPA. Other treatment considerations Treatment-associated toxicity Cyclophosphamide, rituximab, azathioprine, methotrexate, mycophenolate, and glucocorticoids are all associated with important toxicity. In addition to the toxicities discussed below, cytotoxic agents are toxic to the fetus. (See "Pregnancy in patients with nondialysis chronic kidney disease" and "Safety of rheumatic disease medication use during pregnancy and lactation" and "General principles of the use of cyclophosphamide in rheumatic diseases".) Adverse effects of these drugs are discussed in separate topics: Cyclophosphamide (see "General toxicity of cyclophosphamide in rheumatic diseases") Rituximab (see "Rituximab: Principles of use and adverse effects in rheumatoid arthritis" and "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Rituximab') Azathioprine (see "Pharmacology and side effects of azathioprine when used in rheumatic diseases") Methotrexate (see "Major side effects of low-dose methotrexate") Mycophenolate (see "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases") Glucocorticoids (see "Major side effects of systemic glucocorticoids") https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 22/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Prevention of opportunistic infections and vaccinations We typically administer prophylaxis to prevent Pneumocystis jirovecii pneumonia in all patients initiating immunosuppressive therapy with cyclophosphamide or rituximab in combination with prednisone at a dose 20 mg/day (or equivalent dose of a different glucocorticoid). We discontinue prophylaxis when the dose of prednisone is tapered to less than 5 to 10 mg/day. Most commonly, we use trimethoprim-sulfamethoxazole (one single-strength [80 mg/400 mg] tablet daily or one double-strength [160 mg/800 mg] tablet three times per week). Other prophylactic regimens are discussed in detail separately (see "Treatment and prevention of Pneumocystis pneumonia in patients without HIV"). In one patient cohort, Pneumocystis pneumonia developed in 11 of 180 patients (6 percent) with GPA, all of whom were treated with daily glucocorticoids and a second immunosuppressive drug [83]. In addition to P. jirovecii pneumonia, patients treated with immunosuppressive therapy for GPA or MPA are at high risk for infections [84,85]. Given this increased risk of infection, patients should receive age-appropriate vaccinations, including those against pneumococcus, influenza, and herpes zoster (see "Immunizations in autoimmune inflammatory rheumatic disease in adults"). In one large study, for example, the cumulative incidence of infection was 51 percent during the first year of treatment [84]. Most infections involved the respiratory tract, and most positive cultures revealed Staphylococcus aureus. Management of respiratory tract and upper airway involvement The management of central airway obstruction and diffuse alveolar hemorrhage are discussed separately. (See "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults" and "The diffuse alveolar hemorrhage syndromes", section on 'Treatment'.) The consequences of upper airway involvement are often not improved by initial immunosuppressive therapy and are not considered resistant disease. Nasal ulcers and crusting are common manifestations of upper airway disease in ANCA- associated vasculitis, particularly in GPA. It is often difficult to determine whether these lesions are attributable to vasculitis, infection, or both. Although oral antibiotics are frequently required to treat more severe infections in the upper respiratory tract, some experts prefer a trial of topical therapy for nasal ulcers and crusting. This approach may involve direct application of antibiotic ointment just inside of the nares and/or nasal irrigation with a saline solution to which topical antibiotics have been added. Nasal saline sprays are available over the counter or may be made up as 1 quart of water with 1 teaspoon of brine or pickling salt and 1 teaspoon of baking soda. https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 23/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Lesions of the tracheobronchial tree can cause a variety of problems. The most serious complications include tracheal or bronchial stenosis that can lead to respiratory failure or postobstructive pneumonia. Clinicians should have a low threshold for referring patients with any signs or symptoms of suspected subglottic stenosis (eg, stridor, hoarseness, or unexplained dyspnea) to an otolaryngologist familiar with this problem. Treatment options for these problems include airway dilation with or without stenting. For subglottic stenosis, intralesional injection of glucocorticoids in combination with endoscopic dilation may avoid the need for more invasive surgical procedures [86,87]. Tracheostomy should be avoided whenever possible. When tracheostomy is necessary, most patients are able to have the tracheostomy tube removed. This was illustrated in a retrospective report of 27 patients with ANCA-associated vasculitis: 11 required tracheostomy, and three could not be decannulated [88]. (See "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults".) Stenosing lesions of the nasal passages and destructive lesions of the nasal cartilage and bones may cause discomfort and/or be disfiguring. Reconstructive surgery may provide a functional airway and can restore a more normal-appearing nose [89]. Grafts prepared from a patient's costal or auricular cartilage, iliac or other bone, or dura have been used with varying success. SPECIAL POPULATIONS Pregnant patients There is only limited information on pregnancy complicated by granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) [90,91]. The major challenges in treating active disease during pregnancy are the moderate to high risk of fetal harm associated with various therapies used for induction or maintenance of remission, including cyclophosphamide, methotrexate, and mycophenolate. In addition, there are limited data regarding the safety of rituximab in pregnancy:

https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 21/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Clinical practice varies in the monitoring of ANCA titers among patients being treated for GPA or MPA. Some authors and editors routinely monitor ANCA titers, particularly among patients with kidney involvement, to assess the response to therapy and risk of relapse [65,79-82]. Other contributors do not routinely monitor ANCA titers, since ANCA titers do not consistently reflect disease activity. Additional information about ANCA titers in patients with GPA or MPA is presented elsewhere. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of relapsing disease", section on 'Monitoring by the clinician'.) Additional organ-specific testing may be required for some patients. As an example, repeat CT of the chest is advised for patients with tracheal and/or pulmonary involvement to document remission or prior active disease and/or to establish a new baseline. In addition, serial audiograms should be performed in patients with any form of hearing loss related to GPA or MPA. Other treatment considerations Treatment-associated toxicity Cyclophosphamide, rituximab, azathioprine, methotrexate, mycophenolate, and glucocorticoids are all associated with important toxicity. In addition to the toxicities discussed below, cytotoxic agents are toxic to the fetus. (See "Pregnancy in patients with nondialysis chronic kidney disease" and "Safety of rheumatic disease medication use during pregnancy and lactation" and "General principles of the use of cyclophosphamide in rheumatic diseases".) Adverse effects of these drugs are discussed in separate topics: Cyclophosphamide (see "General toxicity of cyclophosphamide in rheumatic diseases") Rituximab (see "Rituximab: Principles of use and adverse effects in rheumatoid arthritis" and "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Rituximab') Azathioprine (see "Pharmacology and side effects of azathioprine when used in rheumatic diseases") Methotrexate (see "Major side effects of low-dose methotrexate") Mycophenolate (see "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases") Glucocorticoids (see "Major side effects of systemic glucocorticoids") https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 22/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Prevention of opportunistic infections and vaccinations We typically administer prophylaxis to prevent Pneumocystis jirovecii pneumonia in all patients initiating immunosuppressive therapy with cyclophosphamide or rituximab in combination with prednisone at a dose 20 mg/day (or equivalent dose of a different glucocorticoid). We discontinue prophylaxis when the dose of prednisone is tapered to less than 5 to 10 mg/day. Most commonly, we use trimethoprim-sulfamethoxazole (one single-strength [80 mg/400 mg] tablet daily or one double-strength [160 mg/800 mg] tablet three times per week). Other prophylactic regimens are discussed in detail separately (see "Treatment and prevention of Pneumocystis pneumonia in patients without HIV"). In one patient cohort, Pneumocystis pneumonia developed in 11 of 180 patients (6 percent) with GPA, all of whom were treated with daily glucocorticoids and a second immunosuppressive drug [83]. In addition to P. jirovecii pneumonia, patients treated with immunosuppressive therapy for GPA or MPA are at high risk for infections [84,85]. Given this increased risk of infection, patients should receive age-appropriate vaccinations, including those against pneumococcus, influenza, and herpes zoster (see "Immunizations in autoimmune inflammatory rheumatic disease in adults"). In one large study, for example, the cumulative incidence of infection was 51 percent during the first year of treatment [84]. Most infections involved the respiratory tract, and most positive cultures revealed Staphylococcus aureus. Management of respiratory tract and upper airway involvement The management of central airway obstruction and diffuse alveolar hemorrhage are discussed separately. (See "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults" and "The diffuse alveolar hemorrhage syndromes", section on 'Treatment'.) The consequences of upper airway involvement are often not improved by initial immunosuppressive therapy and are not considered resistant disease. Nasal ulcers and crusting are common manifestations of upper airway disease in ANCA- associated vasculitis, particularly in GPA. It is often difficult to determine whether these lesions are attributable to vasculitis, infection, or both. Although oral antibiotics are frequently required to treat more severe infections in the upper respiratory tract, some experts prefer a trial of topical therapy for nasal ulcers and crusting. This approach may involve direct application of antibiotic ointment just inside of the nares and/or nasal irrigation with a saline solution to which topical antibiotics have been added. Nasal saline sprays are available over the counter or may be made up as 1 quart of water with 1 teaspoon of brine or pickling salt and 1 teaspoon of baking soda. https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 23/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Lesions of the tracheobronchial tree can cause a variety of problems. The most serious complications include tracheal or bronchial stenosis that can lead to respiratory failure or postobstructive pneumonia. Clinicians should have a low threshold for referring patients with any signs or symptoms of suspected subglottic stenosis (eg, stridor, hoarseness, or unexplained dyspnea) to an otolaryngologist familiar with this problem. Treatment options for these problems include airway dilation with or without stenting. For subglottic stenosis, intralesional injection of glucocorticoids in combination with endoscopic dilation may avoid the need for more invasive surgical procedures [86,87]. Tracheostomy should be avoided whenever possible. When tracheostomy is necessary, most patients are able to have the tracheostomy tube removed. This was illustrated in a retrospective report of 27 patients with ANCA-associated vasculitis: 11 required tracheostomy, and three could not be decannulated [88]. (See "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults".) Stenosing lesions of the nasal passages and destructive lesions of the nasal cartilage and bones may cause discomfort and/or be disfiguring. Reconstructive surgery may provide a functional airway and can restore a more normal-appearing nose [89]. Grafts prepared from a patient's costal or auricular cartilage, iliac or other bone, or dura have been used with varying success. SPECIAL POPULATIONS Pregnant patients There is only limited information on pregnancy complicated by granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) [90,91]. The major challenges in treating active disease during pregnancy are the moderate to high risk of fetal harm associated with various therapies used for induction or maintenance of remission, including cyclophosphamide, methotrexate, and mycophenolate. In addition, there are limited data regarding the safety of rituximab in pregnancy: (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Cyclophosphamide'.) (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Methotrexate'.) (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Mycophenolate mofetil'.) (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Rituximab'.) https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 24/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate The immunosuppressive drugs considered safer during pregnancy that have been effective in GPA and MPA include glucocorticoids, azathioprine, and cyclosporine (or tacrolimus), particularly in mild to moderate disease. These drugs can also be tried for severe disease, but such an approach may necessitate prolonged use of high-dose glucocorticoids and a slower glucocorticoid taper. Alternatives that could be considered include rituximab or cyclophosphamide in the second or third trimester once organogenesis is complete, although data are limited and the risks and benefits must be weighed carefully. The ongoing online Vasculitis Pregnancy Registry (V-PREG) study is collecting data on maternal and fetal outcomes in antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (and other vasculitides) in order to provide informed guidance to patients and clinicians on the management of vasculitis during pregnancy. Older patients Among patients with GPA or MPA, it is not uncommon for patients to present with new-onset disease at age 75 years or older. Studies have demonstrated that older age is an independent risk factor for worse outcomes in ANCA-associated vasculitis, both due to life- threatening infections and to disease-related morbidity, notably end-stage kidney disease (ESKD) [92,93]. The increased risk of serious infections in older patients and the substantive risk of infection associated with glucocorticoids highlight the need to use "glucocorticoid-sparing" approaches in this patient population. Older patients with ANCA-associated vasculitis respond well to the same treatment approaches to induction of remission as do younger patients [24], and use of rituximab or cyclophosphamide (in reduced dosing based on kidney function and age) should not be withheld due to age. Regimens to maintain remission in ANCA-associated vasculitis are especially important for older patients to avoid repeat use of glucocorticoids and to preserve residual kidney function. However, as with all treatment of ANCA-associated vasculitis, the risks of prolonged immunosuppression and infection must be weighed against the benefits of avoiding a relapse of vasculitis. Patients with end-stage kidney disease Maintenance dialysis Little is known concerning the optimal treatment of patients with GPA or MPA who develop ESKD and require maintenance dialysis. Such patients have a higher risk of death as compared with patients who do not develop ESKD. (See 'Prognosis and other outcomes' below.) Further management varies with the clinical setting: https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 25/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate No active disease If the patient has no evidence of active kidney disease (ie, absence of hematuria with dysmorphic red cells in the urine sediment, which must be distinguished from isomorphic [normomorphic] hematuria that may be due to cyclophosphamide- induced bladder injury) and has no active extrarenal disease, we continue immunosuppressive therapy until the patient has completed three to six months of maintenance therapy. If, at that time, the patient continues to have inactive disease, then we typically discontinue immunosuppressive therapy. (See 'Maintenance therapy' above.) It is unclear how much benefit is provided by usual maintenance therapy to prevent relapse in patients with ESKD since the rate of relapse is substantially reduced in dialysis [94,95]. In an analysis of 229 patients on maintenance dialysis followed for a mean of 4.6 years, the relapse rate decreased from 57 to 7 episodes per 100 person-years before and after dialysis initiation [95]. During the follow-up period, 45 percent of patients had a serious infection and 45 percent had a cardiovascular event, while 13 percent experienced disease relapse. Active kidney but not extrarenal disease If the patient has persistent dysmorphic hematuria and no extrarenal disease, we treat with immunosuppressive therapy in a manner similar to patients without ESKD with appropriate dose adjustments in medications for the kidney failure. The purpose of continued therapy in patients with active kidney but without extrarenal manifestations is that control of the renal vasculitis might result in enough recovery of kidney function to permit the discontinuation of dialysis. However, treating such patients beyond four months is of limited benefit [96]. (See 'Induction therapy' above and 'Maintenance therapy' above.) Active extrarenal disease We and other investigators treat patients on chronic dialysis with active extrarenal GPA or MPA in the same manner as those who do not require maintenance dialysis, with the duration of therapy and therapeutic regimen being based upon patient response and whether relapse has occurred and with appropriate dose adjustments in medications for the kidney failure. (See 'Induction therapy' above and 'Maintenance therapy' above.) Even if a decision is made to discontinue immunosuppressive therapy in patients on chronic dialysis, it is imperative that all patients with a history of GPA or MPA be followed indefinitely for the potential to relapse in other organ systems, even many years following the onset of kidney failure. The following immunosuppressive drugs should either not be used or not be used at standard doses in patients with ESKD: https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 26/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Methotrexate should not be given as maintenance therapy to patients who are on dialysis or have moderate to severe chronic kidney disease. Given the increased risk of severe bone marrow suppression in patients with ESKD, cyclophosphamide should be used cautiously with careful monitoring. Dose adjustment for cyclophosphamide in dialysis patients is not well defined. A suggested approach for oral cyclophosphamide is 50 percent of the usual dose after each hemodialysis session and 75 percent of the usual dose in patients on continuous ambulatory peritoneal dialysis ( table 1). Kidney transplantation Patients who develop ESKD due to GPA or MPA are potential candidates for kidney transplantation. At a minimum, transplantation should be delayed for at least six months from the time of initial presentation or most recent relapse [97]. The presence of a positive ANCA titer at the time of transplantation does not appear to predict recurrence of glomerulonephritis in the transplanted organ. Thus, persistence of an isolated positive ANCA titer is not a contraindication to kidney transplantation. It is likely that the immunosuppression administered for the prevention of allograft rejection contributes to the prevention of disease flares among patients with GPA or MPA [98,99]. Several studies have shown that long-term outcomes of patients with GPA or MPA who receive a kidney transplant are comparable to those of patients transplanted for other causes of ESKD [100-103]. Drug-induced ANCA-associated vasculitis Certain medications (eg, hydralazine, propylthiouracil, minocycline) may induce vasculitis associated with antineutrophil cytoplasmic autoantibody (ANCA), mostly myeloperoxidase (MPO)-ANCA. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Drug-induced ANCA-associated vasculitis'.) The optimal management of drug-associated ANCA and the course of the disease are uncertain given the limited reports in the literature. Discontinuation of the offending agent may be the only intervention necessary for mild cases of ANCA-associated vasculitis induced by medications. Examples include cases presenting with constitutional symptoms, arthralgias/arthritis, or cutaneous vasculitis, but without lung or kidney involvement. Patients with more severe disease manifestations such as lung or kidney involvement, which are common with hydralazine, require treatment with high doses of glucocorticoids and even rituximab or cyclophosphamide. As an example, in one series of 80 cases of hydralazine-induced ANCA-associated glomerulonephritis, 42 of 51 patients with long-term follow-up received https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 27/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate immunosuppressive therapy [104]. (See 'Induction therapy' above and "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Hydralazine'.) Patients with drug-induced ANCA-associated vasculitis do not typically require maintenance therapy; relapse should not occur if the responsible drug is discontinued. However, attributing ANCA-associated vasculitis to a drug may be incorrect, and therefore careful and frequent monitoring of the patient is required after discontinuation of the presumed causative agent. The risk of recurrence with re-exposure to the drug is unclear. Given the potential morbidity associated with drug-induced ANCA-associated vasculitis, we do not advocate for rechallenge with the potentially offending agent. Double-positive ANCA and anti-GBM disease Patients who are double positive for antineutrophil cytoplasmic autoantibody (ANCA) and anti-glomerular basement membrane (anti- GBM) antibodies should be managed initially as patients with anti-GBM disease since this is the more severe lesion. The initial treatment of such patients should include plasmapheresis plus immunosuppressive therapy, even among those with dialysis-requiring kidney failure. These issues are discussed in more detail elsewhere. (See "Anti-GBM (Goodpasture) disease: Treatment and prognosis", section on 'Double-positive anti-GBM and ANCA-associated disease'.) However, unlike patients with single-positive anti-GBM disease, double-positive patients will require maintenance therapy for ANCA disease because of the tendency of vasculitis to relapse. (See 'Maintenance therapy' above.) INVESTIGATIONAL APPROACHES Several investigational agents have been tried or are under investigation for patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA), including abatacept [105], belimumab [106], vilobelimab, and B cell-targeted immunotherapy [107]. Additional studies are required before these therapies can be routinely used in clinical practice. PROGNOSIS AND OTHER OUTCOMES Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are associated with considerable morbidity and mortality that are due to either irreversible organ dysfunction from inflammatory injury or the consequences of prolonged and/or intensive therapy with glucocorticoids and other immunosuppressive agents: https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 28/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Mortality Untreated patients have a 90 percent mortality rate within two years. The long- term survival in patients with GPA and MPA has improved dramatically since the additions of cyclophosphamide and rituximab to the therapeutic regimen [108,109]. However, patients with GPA and MPA still have a higher mortality rate compared with the general population [110,111]. A meta-analysis of observational studies of patients with GPA and MPA reported a 2.7-fold increased risk of death in patients compared with the general population (95% CI 2.26-3.24) [110]. The major causes of death in patients with GPA and MPA are complications from immunosuppressive therapy (primarily infection), complications from the underlying disease (eg, kidney failure, pulmonary failure), and cardiovascular disease [94,112-114]. Higher mortality rates are observed among older adults and those who present with florid organ failure, such as patients with diffuse pulmonary hemorrhage requiring ventilatory support or advanced kidney dysfunction [115,116]. End-stage kidney disease (ESKD) and overall mortality are higher in older adult patients (age >80 years). As an example, a retrospective study including 78 patients >80 years old who had biopsy-proven pauci- immune glomerulonephritis, of whom 93 percent had a positive ANCA, found that ESKD was more common in the untreated group at one year (73 versus 36 percent) [117]. Malignancy risk Some studies suggest that patients with GPA or MPA may have a higher incidence of cancer compared with the general population, with estimates ranging from 10 to 26 percent [118]. The increased risk of malignancy has been described with non- melanoma skin carcinomas (NMSCs), hematologic malignancies, and bladder, breast, lung, prostate, and colorectal carcinomas [119,120]. To some degree, some of the increased risk is associated with immunosuppressive treatment [121]. As treatment regimens for GPA and MPA have evolved over the past decade to include shorter courses of cyclophosphamide, more contemporary studies have suggested that the risk of cancer may be decreasing [119,122]. Infection Approximately 25 to 30 percent of patients with GPA and MPA will develop a serious infection that requires hospitalization, with respiratory infections being the most common [123-126]. Patients are at highest risk for infection in the first year after diagnosis, which is most likely related to the higher intensity of immunosuppression during this time period, including the use of high-dose glucocorticoids [123,127,128]. The use of immunosuppressive agents to treat GPA and MPA is a primary factor contributing to the risk of infection in these patients. Several studies have evaluated the risk of infection associated with different immunosuppressive regimens used to treat GPA https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 29/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate or MPA. As an example, two randomized trials found no difference in infection rates between patients receiving a rituximab-based regimen and those receiving a cyclophosphamide-based regimen as induction therapy [19,21]. Trials comparing different maintenance regimens have reported similar rates of infection among patients treated with azathioprine, methotrexate, mycophenolate mofetil, rituximab, or oral cyclophosphamide [18,54-56]. End-stage kidney disease Since the kidney is a frequent target organ in patients with either GPA or MPA, progressive kidney failure may be observed. In different series with a variable duration of follow-up, ESKD occurred in 10 to 26 percent of patients [2,94,112,115,129-132]. The incidence of ESKD among patients with GPA and MPA has fallen over the past several decades. In a study of an inception cohort of 554 patients with kidney disease at time of diagnosis, the five-year risk of ESKD decreased over time [108]. Serum creatinine at baseline was the only significant predictor of risk of ESKD. The principal determinants of a poor kidney outcome include more severe kidney dysfunction at presentation, lack of response to initial treatment, renal relapses, age greater than 65 years, and prominent fibrotic changes, such as interstitial fibrosis and glomerulosclerosis on initial kidney biopsy [2,115,129,133-135]. By comparison, responsiveness to immunosuppressive therapy and improved kidney function over time can be observed among patients with predominantly active kidney lesions at disease presentation. Severe initial kidney involvement does not preclude the induction of remission or clinically significant improvement in kidney function with appropriate therapy. In a report of newly diagnosed patients, remission was induced in 72 percent of 240 patients with an estimated 3 2 glomerular filtration rate (eGFR) 30 mL/min/1.7 m , 68 percent of 188 patients with an 2 2 eGFR 20 mL/min/1.73 m , and 57 percent of 96 patients with an eGFR 10 mL/min/1.73 m [129]. On the other hand, severe kidney disease at presentation was also a risk factor for cyclophosphamide resistance (odds ratio 1.28 per 1.13 mg/dL [100 micromol/L] elevation in serum creatinine). Among patients who require dialysis during the acute phase of the disease, 55 to 90 percent recover enough function to come off dialysis [3,115,129,136-138], with 40 to 70 percent being maintained off dialysis for three years or more [3,139]. Cardiovascular risk Patients with GPA or MPA may have an increased risk of cardiovascular events, including thromboembolism [140-146]. In a cohort study that examined cardiovascular events among 2306 patients with GPA or MPA and 6918 controls, https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 30/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate a diagnosis of GPA or MPA was associated with an increased risk of ischemic heart disease (HR 1.86, 95% CI 1.62-2.15), heart failure (HR 2.12, 95% CI 1.77-2.54), myocardial infarction (HR 1.62, 95% CI 1.26-2.09), atrial fibrillation (HR 2.08, 95% CI 1.82-2.39), ventricular arrhythmia/defibrillator implantation (HR 2.04, 95% CI 1.16-3.57), and ischemic stroke (HR 1.58, 95% CI 1.31-1.90) [142]. Patients with GPA or MPA also had an increased risk of undergoing percutaneous coronary intervention (HR 1.56, 95% CI 1.17-2.07) and in-hospital cardiac arrest (HR 2.27, 95% CI 1.49-3.48). The reasons for an increased risk of cardiovascular disease among patients with GPA and MPA are not clear, but some investigators speculate this may relate to the impact of nontraditional risk factors, including chronic inflammation, use of glucocorticoids, and chronic kidney disease. As an example, in a retrospective multinational study of 2286 patients with ANCA-associated vasculitis, risk factors for myocardial infarction and stroke included pulmonary and kidney involvement (HR 1.5 and 3.0, respectively), older age, and history of smoking [147]. Clinicians and patients are advised to be vigilant about evaluating and treating established risks of cardiovascular disease, including hypertension, diabetes mellitus, hyperlipidemia, and obesity; these comorbidities may be more prevalent among patients with GPA and MPA. 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: Glomerular disease in adults" and "Society guideline links: Vasculitis".) 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. https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 31/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 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: Granulomatosis with polyangiitis (The Basics)") Beyond the Basics topics (see "Patient education: Vasculitis (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Goals of therapy The goal of therapy in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) is to achieve a rapid, long-standing remission. Treatment consists of an initial induction phase aimed to put patients with active disease into remission, followed by a maintenance phase that is intended to extend remission and prevent relapse. (See 'Goals of therapy' above.) Approach to initial therapy Immunosuppressive therapy is warranted in almost all patients with active GPA or MPA. Our approach to initial therapy depends largely upon the severity of disease and the organ systems involved ( algorithm 1): Organ- or life-threatening features include, but are not limited to, active glomerulonephritis, pulmonary hemorrhage, cerebral vasculitis, progressive peripheral or cranial neuropathy, orbital pseudotumor, gastrointestinal bleeding due to vasculitis, or cardiac disease due to vasculitis (pericarditis, myocarditis). Patients with non-organ- or non-life-threatening disease have no evidence of "active glomerulonephritis" (ie, serum creatinine that is stable compared with baseline and no red cell casts or proteinuria) and no organ-threatening or life-threatening manifestations. (See 'Assessment of disease severity' above.) Organ- or life-threatening disease Induction therapy Rituximab- or cyclophosphamide-based regimen For patients with GPA or MPA who have organ- or life-threatening disease, we recommend an induction regimen consisting of glucocorticoids in combination with either rituximab or cyclophosphamide, rather than glucocorticoid monotherapy (Grade 1B). Some authors/editors choose a rituximab-based regimen for the majority of patients, given its comparable efficacy and different side-effect profile compared with https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 32/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate cyclophosphamide. Other authors/editors favor a cyclophosphamide-based regimen as initial therapy, particularly in patients presenting with more severe kidney disease and/or pulmonary hemorrhage. Some authorities treat with glucocorticoids in combination with both rituximab and cyclophosphamide. (See 'Induction therapy' above.) Glucocorticoid dosing For most patients with GPA or MPA receiving glucocorticoids in combination with a glucocorticoid-sparing agent, we recommend a reduced-dose glucocorticoid tapering regimen rather than the standard-dosing taper (Grade 1B). Dosing of glucocorticoids is discussed above. (See 'Glucocorticoid dosing and taper' above.) Role of plasma exchange The authors/editors of this topic do not fully agree on the role of plasma exchange among patients with GPA or MPA. All authors agree with the use of plasma exchange in most patients with GPA or MPA who are concomitantly positive for anti-glomerular basement membrane (anti-GBM) autoantibody. Other authors would also offer plasma exchange in patients who present with pulmonary hemorrhage and/or severe active kidney disease with kidney biopsy findings showing active inflammation without significant glomerulosclerosis. (See 'Role of plasma exchange' above.) Maintenance therapy In most patients who achieve remission after induction immunosuppressive therapy, we suggest treatment with rituximab for maintenance of remission (Grade 2C). Azathioprine, methotrexate, and mycophenolate are reasonable alternatives and may be preferred based on other patient-specific factors. Maintenance therapy in patients with newly diagnosed GPA or MPA is usually given for 12 to 24 months after stable remission has been induced. (See 'When to start maintenance therapy' above and 'Choice of maintenance therapy' above and 'Dosing of maintenance therapy' above and 'Duration of maintenance therapy' above.) Non-organ- and non-life-threatening disease Patients with non-organ- or non-life- threatening disease have no evidence of "active glomerulonephritis" (ie, serum creatinine that is stable compared with baseline and no red cell casts or proteinuria) and no organ- threatening or life-threatening manifestations. For patients with non-organ- and non-life- threatening GPA not involving the kidney, we suggest initial therapy with glucocorticoids combined with weekly oral methotrexate rather than glucocorticoids combined with cyclophosphamide, rituximab, or azathioprine (Grade 2C). Rituximab is a reasonable alternative as initial therapy, even in non-organ- and non-life-threatening disease. Azathioprine may be used as an alternative to methotrexate for pregnant patients or https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 33/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate patients for whom methotrexate should be avoided due to moderate to severe kidney function impairment. (See 'Non-organ- and non-life-threatening disease' above.) Monitoring All patients receiving immunosuppressive therapy for GPA or MPA should be closely monitored. Patients with organ- or life-threatening disease are typically admitted to the hospital for treatment with close monitoring of their clinical status and laboratory testing on a daily basis. When the patient's condition is stable enough for discharge from the hospital, we typically schedule follow-up visits every two to four weeks for the first three months. Subsequently, the duration between follow-up visits can then be extended to every two to three months. The goal of these visits is to evaluate the patient's response to therapy and the toxicity of the regimen. (See 'Monitoring the response to therapy' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Stone JH, Hoffman GS, Merkel PA, et al. A disease-specific activity index for Wegener's granulomatosis: modification of the Birmingham Vasculitis Activity Score. International Network for the Study of the Systemic Vasculitides (INSSYS). Arthritis Rheum 2001; 44:912. 2. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med 1992; 116:488. 3. Nachman PH, Hogan SL, Jennette JC, Falk RJ. Treatment response and relapse in antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis. J Am Soc Nephrol 1996; 7:33. 4. Mahr AD, Neogi T, Lavalley MP, et al. Assessment of the item selection and weighting in the Birmingham vasculitis activity score for Wegener's granulomatosis. Arthritis Rheum 2008; 59:884. 5. WGET Research Group. Design of the Wegener's Granulomatosis Etanercept Trial (WGET). Control Clin Trials 2002; 23:450. 6. Monti S, Quinn KA, Christensen R, et al. Use and reporting of outcome measures in randomized trials for anti-neutrophil cytoplasmic antibody-associated vasculitis: a systematic literature review. Semin Arthritis Rheum 2020; 50:1314. 7. Rhee RL, Davis JC, Ding L, et al. The Utility of Urinalysis in Determining the Risk of Renal Relapse in ANCA-Associated Vasculitis. Clin J Am Soc Nephrol 2018; 13:251. 8. Delvino P, Sardanelli F, Monti S, et al. Remission and Low Disease Activity in Granulomatosis With Polyangiitis and Microscopic Polyangiitis: Prevalence and Impact on Damage Accrual. https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 34/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Arthritis Care Res (Hoboken) 2023; 75:1158. 9. Chung SA, Langford CA, Maz M, et al. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Antineutrophil Cytoplasmic Antibody- Associated Vasculitis. Arthritis Care Res (Hoboken) 2021; 73:1088. 10. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int 2021; 100:S1. 11. Chung SA, Langford CA, Maz M, et al. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Antineutrophil Cytoplasmic Antibody- Associated Vasculitis. Arthritis Rheumatol 2021; 73:1366. 12. Rovin BH, Adler SG, Barratt J, et al. Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular Diseases. Kidney Int 2021; 100:753. 13. WALTON EW. Giant-cell granuloma of the respiratory tract (Wegener's granulomatosis). Br Med J 1958; 2:265. 14. Hogan SL, Nachman PH, Wilkman AS, et al. Prognostic markers in patients with antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis. J Am Soc Nephrol 1996; 7:23. 15. de Groot K, Harper L, Jayne DR, et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med 2009; 150:670. 16. Adu D, Pall A, Luqmani RA, et al. Controlled trial of pulse versus continuous prednisolone and cyclophosphamide in the treatment of systemic vasculitis. QJM 1997; 90:401. 17. Wegener's Granulomatosis Etanercept Trial (WGET) Research Group. Etanercept plus standard therapy for Wegener's granulomatosis. N Engl J Med 2005; 352:351. 18. Jayne D, Rasmussen N, Andrassy K, et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med 2003; 349:36. 19. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA- associated vasculitis. N Engl J Med 2010; 363:221. 20. Specks U, Merkel PA, Seo P, et al. Efficacy of remission-induction regimens for ANCA- associated vasculitis. N Engl J Med 2013; 369:417. 21. Jones RB, Tervaert JW, Hauser T, et al. Rituximab versus cyclophosphamide in ANCA- associated renal vasculitis. N Engl J Med 2010; 363:211. https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 35/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 22. Jones RB, Furuta S, Tervaert JW, et al. Rituximab versus cyclophosphamide in ANCA-

a reduced-dose glucocorticoid tapering regimen rather than the standard-dosing taper (Grade 1B). Dosing of glucocorticoids is discussed above. (See 'Glucocorticoid dosing and taper' above.) Role of plasma exchange The authors/editors of this topic do not fully agree on the role of plasma exchange among patients with GPA or MPA. All authors agree with the use of plasma exchange in most patients with GPA or MPA who are concomitantly positive for anti-glomerular basement membrane (anti-GBM) autoantibody. Other authors would also offer plasma exchange in patients who present with pulmonary hemorrhage and/or severe active kidney disease with kidney biopsy findings showing active inflammation without significant glomerulosclerosis. (See 'Role of plasma exchange' above.) Maintenance therapy In most patients who achieve remission after induction immunosuppressive therapy, we suggest treatment with rituximab for maintenance of remission (Grade 2C). Azathioprine, methotrexate, and mycophenolate are reasonable alternatives and may be preferred based on other patient-specific factors. Maintenance therapy in patients with newly diagnosed GPA or MPA is usually given for 12 to 24 months after stable remission has been induced. (See 'When to start maintenance therapy' above and 'Choice of maintenance therapy' above and 'Dosing of maintenance therapy' above and 'Duration of maintenance therapy' above.) Non-organ- and non-life-threatening disease Patients with non-organ- or non-life- threatening disease have no evidence of "active glomerulonephritis" (ie, serum creatinine that is stable compared with baseline and no red cell casts or proteinuria) and no organ- threatening or life-threatening manifestations. For patients with non-organ- and non-life- threatening GPA not involving the kidney, we suggest initial therapy with glucocorticoids combined with weekly oral methotrexate rather than glucocorticoids combined with cyclophosphamide, rituximab, or azathioprine (Grade 2C). Rituximab is a reasonable alternative as initial therapy, even in non-organ- and non-life-threatening disease. Azathioprine may be used as an alternative to methotrexate for pregnant patients or https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 33/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate patients for whom methotrexate should be avoided due to moderate to severe kidney function impairment. (See 'Non-organ- and non-life-threatening disease' above.) Monitoring All patients receiving immunosuppressive therapy for GPA or MPA should be closely monitored. Patients with organ- or life-threatening disease are typically admitted to the hospital for treatment with close monitoring of their clinical status and laboratory testing on a daily basis. When the patient's condition is stable enough for discharge from the hospital, we typically schedule follow-up visits every two to four weeks for the first three months. Subsequently, the duration between follow-up visits can then be extended to every two to three months. The goal of these visits is to evaluate the patient's response to therapy and the toxicity of the regimen. (See 'Monitoring the response to therapy' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Stone JH, Hoffman GS, Merkel PA, et al. A disease-specific activity index for Wegener's granulomatosis: modification of the Birmingham Vasculitis Activity Score. International Network for the Study of the Systemic Vasculitides (INSSYS). Arthritis Rheum 2001; 44:912. 2. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med 1992; 116:488. 3. Nachman PH, Hogan SL, Jennette JC, Falk RJ. Treatment response and relapse in antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis. J Am Soc Nephrol 1996; 7:33. 4. Mahr AD, Neogi T, Lavalley MP, et al. Assessment of the item selection and weighting in the Birmingham vasculitis activity score for Wegener's granulomatosis. Arthritis Rheum 2008; 59:884. 5. WGET Research Group. Design of the Wegener's Granulomatosis Etanercept Trial (WGET). Control Clin Trials 2002; 23:450. 6. Monti S, Quinn KA, Christensen R, et al. Use and reporting of outcome measures in randomized trials for anti-neutrophil cytoplasmic antibody-associated vasculitis: a systematic literature review. Semin Arthritis Rheum 2020; 50:1314. 7. Rhee RL, Davis JC, Ding L, et al. The Utility of Urinalysis in Determining the Risk of Renal Relapse in ANCA-Associated Vasculitis. Clin J Am Soc Nephrol 2018; 13:251. 8. Delvino P, Sardanelli F, Monti S, et al. Remission and Low Disease Activity in Granulomatosis With Polyangiitis and Microscopic Polyangiitis: Prevalence and Impact on Damage Accrual. https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 34/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Arthritis Care Res (Hoboken) 2023; 75:1158. 9. Chung SA, Langford CA, Maz M, et al. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Antineutrophil Cytoplasmic Antibody- Associated Vasculitis. Arthritis Care Res (Hoboken) 2021; 73:1088. 10. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int 2021; 100:S1. 11. Chung SA, Langford CA, Maz M, et al. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Antineutrophil Cytoplasmic Antibody- Associated Vasculitis. Arthritis Rheumatol 2021; 73:1366. 12. Rovin BH, Adler SG, Barratt J, et al. Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular Diseases. Kidney Int 2021; 100:753. 13. WALTON EW. Giant-cell granuloma of the respiratory tract (Wegener's granulomatosis). Br Med J 1958; 2:265. 14. Hogan SL, Nachman PH, Wilkman AS, et al. Prognostic markers in patients with antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis. J Am Soc Nephrol 1996; 7:23. 15. de Groot K, Harper L, Jayne DR, et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med 2009; 150:670. 16. Adu D, Pall A, Luqmani RA, et al. Controlled trial of pulse versus continuous prednisolone and cyclophosphamide in the treatment of systemic vasculitis. QJM 1997; 90:401. 17. Wegener's Granulomatosis Etanercept Trial (WGET) Research Group. Etanercept plus standard therapy for Wegener's granulomatosis. N Engl J Med 2005; 352:351. 18. Jayne D, Rasmussen N, Andrassy K, et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med 2003; 349:36. 19. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA- associated vasculitis. N Engl J Med 2010; 363:221. 20. Specks U, Merkel PA, Seo P, et al. Efficacy of remission-induction regimens for ANCA- associated vasculitis. N Engl J Med 2013; 369:417. 21. Jones RB, Tervaert JW, Hauser T, et al. Rituximab versus cyclophosphamide in ANCA- associated renal vasculitis. N Engl J Med 2010; 363:211. https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 35/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 22. Jones RB, Furuta S, Tervaert JW, et al. Rituximab versus cyclophosphamide in ANCA- associated renal vasculitis: 2-year results of a randomised trial. Ann Rheum Dis 2015; 74:1178. 23. Geetha D, Specks U, Stone JH, et al. Rituximab versus cyclophosphamide for ANCA- associated vasculitis with renal involvement. J Am Soc Nephrol 2015; 26:976. 24. Thietart S, Karras A, Augusto JF, et al. Evaluation of Rituximab for Induction and Maintenance Therapy in Patients 75 Years and Older With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. JAMA Netw Open 2022; 5:e2220925. 25. Unizony S, Villarreal M, Miloslavsky EM, et al. Clinical outcomes of treatment of anti- neutrophil cytoplasmic antibody (ANCA)-associated vasculitis based on ANCA type. Ann Rheum Dis 2016; 75:1166. 26. Amudala NA, Boukhlal S, Sheridan B, et al. Obinutuzumab as treatment for ANCA-associated vasculitis. Rheumatology (Oxford) 2022; 61:3814. 27. Guillevin L, Cordier JF, Lhote F, et al. A prospective, multicenter, randomized trial comparing steroids and pulse cyclophosphamide versus steroids and oral cyclophosphamide in the treatment of generalized Wegener's granulomatosis. Arthritis Rheum 1997; 40:2187. 28. Haubitz M, Schellong S, G bel U, et al. Intravenous pulse administration of cyclophosphamide versus daily oral treatment in patients with antineutrophil cytoplasmic antibody-associated vasculitis and renal involvement: a prospective, randomized study. Arthritis Rheum 1998; 41:1835. 29. de Groot K, Adu D, Savage CO, EUVAS (European vasculitis study group). The value of pulse cyclophosphamide in ANCA-associated vasculitis: meta-analysis and critical review. Nephrol Dial Transplant 2001; 16:2018. 30. Harper L, Morgan MD, Walsh M, et al. Pulse versus daily oral cyclophosphamide for induction of remission in ANCA-associated vasculitis: long-term follow-up. Ann Rheum Dis 2012; 71:955. 31. Walsh M, Merkel PA, Peh CA, et al. Plasma Exchange and Glucocorticoids in Severe ANCA- Associated Vasculitis. N Engl J Med 2020; 382:622. 32. Miloslavsky EM, Niles JL, Wallace ZS, et al. Reducing glucocorticoid duration in ANCA- associated vasculitis: A pilot trial. Semin Arthritis Rheum 2018; 48:288. 33. Furuta S, Nakagomi D, Kobayashi Y, et al. Effect of Reduced-Dose vs High-Dose Glucocorticoids Added to Rituximab on Remission Induction in ANCA-Associated Vasculitis: A Randomized Clinical Trial. JAMA 2021; 325:2178. https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 36/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 34. Nezam D, Porcher R, Grolleau F, et al. Kidney Histopathology Can Predict Kidney Function in ANCA-Associated Vasculitides with Acute Kidney Injury Treated with Plasma Exchanges. J Am Soc Nephrol 2022; 33:628. 35. Jayne DR, Gaskin G, Rasmussen N, et al. Randomized trial of plasma exchange or high- dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol 2007; 18:2180. 36. Pusey CD, Rees AJ, Evans DJ, et al. Plasma exchange in focal necrotizing glomerulonephritis without anti-GBM antibodies. Kidney Int 1991; 40:757. 37. Walsh M, Casian A, Flossmann O, et al. Long-term follow-up of patients with severe ANCA- associated vasculitis comparing plasma exchange to intravenous methylprednisolone treatment is unclear. Kidney Int 2013; 84:397. 38. Walsh M, Catapano F, Szpirt W, et al. Plasma exchange for renal vasculitis and idiopathic rapidly progressive glomerulonephritis: a meta-analysis. Am J Kidney Dis 2011; 57:566. 39. Walsh M, Collister D, Zeng L, et al. The effects of plasma exchange in patients with ANCA- associated vasculitis: an updated systematic review and meta-analysis. BMJ 2022; 376:e064604. 40. Casal Moura M, Irazabal MV, Eirin A, et al. Efficacy of Rituximab and Plasma Exchange in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis with Severe Kidney Disease. J Am Soc Nephrol 2020; 31:2688. 41. Gallagher H, Kwan JT, Jayne DR. Pulmonary renal syndrome: a 4-year, single-center experience. Am J Kidney Dis 2002; 39:42. 42. Klemmer PJ, Chalermskulrat W, Reif MS, et al. Plasmapheresis therapy for diffuse alveolar hemorrhage in patients with small-vessel vasculitis. Am J Kidney Dis 2003; 42:1149. 43. Hruskova Z, Casian AL, Konopasek P, et al. Long-term outcome of severe alveolar haemorrhage in ANCA-associated vasculitis: a retrospective cohort study. Scand J Rheumatol 2013; 42:211. 44. Cartin-Ceba R, Diaz-Caballero L, Al-Qadi MO, et al. Diffuse Alveolar Hemorrhage Secondary to Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: Predictors of Respiratory Failure and Clinical Outcomes. Arthritis Rheumatol 2016; 68:1467. 45. de Luna G, Chauveau D, Aniort J, et al. Plasma exchanges for the treatment of severe systemic necrotizing vasculitides in clinical daily practice: Data from the French Vasculitis Study Group. J Autoimmun 2015; 65:49. 46. Pepper RJ, McAdoo SP, Moran SM, et al. A novel glucocorticoid-free maintenance regimen for anti-neutrophil cytoplasm antibody-associated vasculitis. Rheumatology (Oxford) 2019; https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 37/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 58:373. 47. Pendergraft WF 3rd, Cortazar FB, Wenger J, et al. Long-term maintenance therapy using rituximab-induced continuous B-cell depletion in patients with ANCA vasculitis. Clin J Am Soc Nephrol 2014; 9:736. 48. McGregor JG, Hogan SL, Kotzen ES, et al. Rituximab as an immunosuppressant in antineutrophil cytoplasmic antibody-associated vasculitis. Nephrol Dial Transplant 2015; 30 Suppl 1:i123. 49. Cortazar FB, Muhsin SA, Pendergraft WF 3rd, et al. Combination Therapy With Rituximab and Cyclophosphamide for Remission Induction in ANCA Vasculitis. Kidney Int Rep 2018; 3:394. 50. Gulati K, Edwards H, Prendecki M, et al. Combination treatment with rituximab, low-dose cyclophosphamide and plasma exchange for severe antineutrophil cytoplasmic antibody- associated vasculitis. Kidney Int 2021; 100:1316. 51. Jayne DRW, Bruchfeld AN, Harper L, et al. Randomized Trial of C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis. J Am Soc Nephrol 2017; 28:2756. 52. Merkel PA, Niles J, Jimenez R, et al. Adjunctive Treatment With Avacopan, an Oral C5a Receptor Inhibitor, in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. ACR Open Rheumatol 2020; 2:662. 53. Jayne DRW, Merkel PA, Schall TJ, et al. Avacopan for the Treatment of ANCA-Associated Vasculitis. N Engl J Med 2021; 384:599. 54. Pagnoux C, Mahr A, Hamidou MA, et al. Azathioprine or methotrexate maintenance for ANCA-associated vasculitis. N Engl J Med 2008; 359:2790. 55. Guillevin L, Pagnoux C, Karras A, et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med 2014; 371:1771. 56. Hiemstra TF, Walsh M, Mahr A, et al. Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial. JAMA 2010; 304:2381. 57. Nowack R, G bel U, Klooker P, et al. Mycophenolate mofetil for maintenance therapy of Wegener's granulomatosis and microscopic polyangiitis: a pilot study in 11 patients with renal involvement. J Am Soc Nephrol 1999; 10:1965. 58. Langford CA, Talar-Williams C, Sneller MC. Mycophenolate mofetil for remission maintenance in the treatment of Wegener's granulomatosis. Arthritis Rheum 2004; 51:278. 59. Koukoulaki M, Jayne DR. Mycophenolate mofetil in anti-neutrophil cytoplasm antibodies- associated systemic vasculitis. Nephron Clin Pract 2006; 102:c100. https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 38/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 60. Ibernon M, Poveda R, Vidaller A, et al. Mycophenolate mofetil in anti-MPO renal vasculitis: an alternative therapy in case of cyclophosphamide or azathioprine toxicity. Clin Nephrol 2008; 69:395. 61. Iatrou C, Zerbala S, Revela I, et al. Mycophenolate mofetil as maintenance therapy in patients with vasculitis and renal involvement. Clin Nephrol 2009; 72:31. 62. Stassen PM, Tervaert JW, Stegeman CA. Induction of remission in active anti-neutrophil cytoplasmic antibody-associated vasculitis with mycophenolate mofetil in patients who cannot be treated with cyclophosphamide. Ann Rheum Dis 2007; 66:798. 63. Smith RM, Jones RB, Guerry MJ, et al. Rituximab for remission maintenance in relapsing antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2012; 64:3760. 64. Cartin-Ceba R, Golbin JM, Keogh KA, et al. Rituximab for remission induction and maintenance in refractory granulomatosis with polyangiitis (Wegener's): ten-year experience at a single center. Arthritis Rheum 2012; 64:3770. 65. Alberici F, Smith RM, Jones RB, et al. Long-term follow-up of patients who received repeat- dose rituximab as maintenance therapy for ANCA-associated vasculitis. Rheumatology (Oxford) 2015; 54:1153. 66. Charles P, Terrier B, Perrodeau , et al. Comparison of individually tailored versus fixed- schedule rituximab regimen to maintain ANCA-associated vasculitis remission: results of a multicentre, randomised controlled, phase III trial (MAINRITSAN2). Ann Rheum Dis 2018; 77:1143. 67. Pagnoux C, Guillevin L, French Vasculitis Study Group, MAINRITSAN investigators. Rituximab or azathioprine maintenance in ANCA-associated vasculitis. N Engl J Med 2015; 372:386. 68. Langford CA, Talar-Williams C, Barron KS, Sneller MC. Use of a cyclophosphamide-induction methotrexate-maintenance regimen for the treatment of Wegener's granulomatosis: extended follow-up and rate of relapse. Am J Med 2003; 114:463. 69. Charles P, Perrodeau , Samson M, et al. Long-Term Rituximab Use to Maintain Remission of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Randomized Trial. Ann Intern Med 2020; 173:179. 70. Sanders JS, de Joode AA, DeSevaux RG, et al. Extended versus standard azathioprine maintenance therapy in newly diagnosed proteinase-3 anti-neutrophil cytoplasmic antibody-associated vasculitis patients who remain cytoplasmic anti-neutrophil cytoplasmic antibody-positive after induction of remission: a randomized clinical trial. Nephrol Dial Transplant 2016; 31:1453. 71. Hogan SL, Nachman PH, Poulton CJ, et al. Understanding Long-term Remission Off Therapy in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Kidney Int Rep 2019; 4:551. https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 39/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 72. Gapud EJ, Manno R, Seo P, et al. Long-term Clinical Course of Antineutrophil Cytoplasmic Antibody-associated Vasculitis Patients off Maintenance Therapy. Cureus 2018; 10:e2372. 73. Langford CA, Talar-Williams C, Sneller MC. Use of methotrexate and glucocorticoids in the treatment of Wegener's granulomatosis. Long-term renal outcome in patients with glomerulonephritis. Arthritis Rheum 2000; 43:1836. 74. Sneller MC, Hoffman GS, Talar-Williams C, et al. An analysis of forty-two Wegener's granulomatosis patients treated with methotrexate and prednisone. Arthritis Rheum 1995; 38:608. 75. Specks U. Methotrexate for Wegener's granulomatosis: what is the evidence? Arthritis Rheum 2005; 52:2237. 76. De Groot K, Rasmussen N, Bacon PA, et al. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2005; 52:2461. 77. Villa-Forte A, Clark TM, Gomes M, et al. Substitution of methotrexate for cyclophosphamide in Wegener granulomatosis: a 12-year single-practice experience. Medicine (Baltimore) 2007; 86:269. 78. Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management of primary small and medium vessel vasculitis. Ann Rheum Dis 2009; 68:310. 79. Kemna MJ, Damoiseaux J, Austen J, et al. ANCA as a predictor of relapse: useful in patients with renal involvement but not in patients with nonrenal disease. J Am Soc Nephrol 2015; 26:537. 80. G ero lu A, Berden AE, Fiocco M, et al. ANCA-Associated Glomerulonephritis: Risk Factors for Renal Relapse. PLoS One 2016; 11:e0165402. 81. Fussner LA, Hummel AM, Schroeder DR, et al. Factors Determining the Clinical Utility of Serial Measurements of Antineutrophil Cytoplasmic Antibodies Targeting Proteinase 3. Arthritis Rheumatol 2016; 68:1700. 82. van Dam LS, Dirikgil E, Bredewold EW, et al. PR3-ANCAs predict relapses in ANCA-associated vasculitis patients after rituximab. Nephrol Dial Transplant 2021; 36:1408. 83. Ognibene FP, Shelhamer JH, Hoffman GS, et al. Pneumocystis carinii pneumonia: a major complication of immunosuppressive therapy in patients with Wegener's granulomatosis. Am J Respir Crit Care Med 1995; 151:795. 84. McGregor JG, Negrete-Lopez R, Poulton CJ, et al. Adverse events and infectious burden, microbes and temporal outline from immunosuppressive therapy in antineutrophil https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 40/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate cytoplasmic antibody-associated vasculitis with native renal function. Nephrol Dial Transplant 2015; 30 Suppl 1:i171. 85. Niles J. Rituximab in induction therapy for anti-neutrophil cytoplasmic antibody (ANCA) vasculitis. Clin Exp Immunol 2011; 164 Suppl 1:27. 86. Langford CA, Sneller MC, Hallahan CW, et al. Clinical features and therapeutic management of subglottic stenosis in patients with Wegener's granulomatosis. Arthritis Rheum 1996; 39:1754. 87. Hoffman GS, Thomas-Golbanov CK, Chan J, et al. Treatment of subglottic stenosis, due to Wegener's granulomatosis, with intralesional corticosteroids and dilation. J Rheumatol 2003; 30:1017. 88. Gluth MB, Shinners PA, Kasperbauer JL. Subglottic stenosis associated with Wegener's granulomatosis. Laryngoscope 2003; 113:1304. 89. Congdon D, Sherris DA, Specks U, McDonald T. Long-term follow-up of repair of external nasal deformities in patients with Wegener's granulomatosis. Laryngoscope 2002; 112:731. 90. Langford CA, Kerr GS. Pregnancy in vasculitis. Curr Opin Rheumatol 2002; 14:36. 91. Habib A, MacKay K, Abrons HL. Wegener's granulomatosis complicating pregnancy: presentation of two patients and review of the literature. Clin Nephrol 1996; 46:332. 92. Hruskova Z, Tesar V. Management of Elderly Patients with Rapidly Progressive Glomerulonephritis. Blood Purif 2018; 45:213. 93. Weiner M, Goh SM, Mohammad AJ, et al. Outcome and treatment of elderly patients with ANCA-associated vasculitis. Clin J Am Soc Nephrol 2015; 10:1128. 94. Lionaki S, Hogan SL, Jennette CE, et al. The clinical course of ANCA small-vessel vasculitis on chronic dialysis. Kidney Int 2009; 76:644. 95. Kauffmann M, Bobot M, Robert T, et al. Disease Activity and Adverse Events in Patients with ANCA-Associated Vasculitides Undergoing Long-Term Dialysis. Clin J Am Soc Nephrol 2021; 16:1665. 96. Lee T, Gasim A, Derebail VK, et al. Predictors of treatment outcomes in ANCA-associated vasculitis with severe kidney failure. Clin J Am Soc Nephrol 2014; 9:905. 97. Nachman PH, Segelmark M, Westman K, et al. Recurrent ANCA-associated small vessel vasculitis after transplantation: A pooled analysis. Kidney Int 1999; 56:1544. 98. Gera M, Griffin MD, Specks U, et al. Recurrence of ANCA-associated vasculitis following renal transplantation in the modern era of immunosupression. Kidney Int 2007; 71:1296. 99. Geetha D, Eirin A, True K, et al. Renal transplantation in antineutrophil cytoplasmic antibody- associated vasculitis: a multicenter experience. Transplantation 2011; 91:1370. https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 41/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 100. Wallace ZS, Wallwork R, Zhang Y, et al. Improved survival with renal transplantation for end- stage renal disease due to granulomatosis with polyangiitis: data from the United States Renal Data System. Ann Rheum Dis 2018; 77:1333. 101. Hruskova Z, Stel VS, Jayne D, et al. Characteristics and Outcomes of Granulomatosis With Polyangiitis (Wegener) and Microscopic Polyangiitis Requiring Renal Replacement Therapy: Results From the European Renal Association-European Dialysis and Transplant Association Registry. Am J Kidney Dis 2015; 66:613. 102. Tang W, Bose B, McDonald SP, et al. The outcomes of patients with ESRD and ANCA- associated vasculitis in Australia and New Zealand. Clin J Am Soc Nephrol 2013; 8:773. 103. Moran S, Little MA. Renal transplantation in antineutrophil cytoplasmic antibody-associated vasculitis. Curr Opin Rheumatol 2014; 26:37. 104. Santoriello D, Bomback AS, Kudose S, et al. Anti-neutrophil cytoplasmic antibody associated glomerulonephritis complicating treatment with hydralazine. Kidney Int 2021; 100:440. 105. Langford CA, Monach PA, Specks U, et al. An open-label trial of abatacept (CTLA4-IG) in non- severe relapsing granulomatosis with polyangiitis (Wegener's). Ann Rheum Dis 2014; 73:1376. 106. Jayne D, Blockmans D, Luqmani R, et al. Efficacy and Safety of Belimumab and Azathioprine for Maintenance of Remission in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Randomized Controlled Study. Arthritis Rheumatol 2019; 71:952. 107. McClure M, Gopaluni S, Jayne D, Jones R. Publisher Correction: B cell therapy in ANCA- associated vasculitis: current and emerging treatment options. Nat Rev Rheumatol 2018; 14:741. 108. Rhee RL, Hogan SL, Poulton CJ, et al. Trends in Long-Term Outcomes Among Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis With Renal Disease. Arthritis Rheumatol 2016; 68:1711. 109. Wallace ZS, Lu N, Miloslavsky E, et al. Nationwide Trends in Hospitalizations and In-Hospital Mortality in Granulomatosis With Polyangiitis (Wegener's). Arthritis Care Res (Hoboken) 2017; 69:915. 110. Tan JA, Dehghan N, Chen W, et al. Mortality in ANCA-associated vasculitis: ameta-analysis of observational studies. Ann Rheum Dis 2017; 76:1566. 111. Tan JA, Choi HK, Xie H, et al. All-Cause and Cause-Specific Mortality in Patients With Granulomatosis With Polyangiitis: A Population-Based Study. Arthritis Care Res (Hoboken) 2019; 71:155. https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 42/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 112. Robson J, Doll H, Suppiah R, et al. Damage in the anca-associated vasculitides: long-term data from the European vasculitis study group (EUVAS) therapeutic trials. Ann Rheum Dis 2015; 74:177. 113. Lai QY, Ma TT, Li ZY, et al. Predictors for mortality in patients with antineutrophil cytoplasmic autoantibody-associated vasculitis: a study of 398 Chinese patients. J Rheumatol 2014; 41:1849. 114. King C, Harper L, Little M. The complications of vasculitis and its treatment. Best Pract Res Clin Rheumatol 2018; 32:125. 115. Slot MC, Tervaert JW, Franssen CF, Stegeman CA. Renal survival and prognostic factors in patients with PR3-ANCA associated vasculitis with renal involvement. Kidney Int 2003; 63:670. 116. de Joode AA, Sanders JS, Stegeman CA. Renal survival in proteinase 3 and myeloperoxidase ANCA-associated systemic vasculitis. Clin J Am Soc Nephrol 2013; 8:1709. 117. Bomback AS, Appel GB, Radhakrishnan J, et al. ANCA-associated glomerulonephritis in the very elderly. Kidney Int 2011; 79:757. 118. Thet Z, Lam AK, Ranganathan D, et al. Cancer risks along the disease trajectory in antineutrophil cytoplasmic antibody associated vasculitis. Clin Rheumatol 2020; 39:2501. 119. Rahmattulla C, Berden AE, Wakker SC, et al. Incidence of Malignancies in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Diagnosed Between 1991 and 2013. Arthritis Rheumatol 2015; 67:3270. 120. Shang W, Ning Y, Xu X, et al. Incidence of Cancer in ANCA-Associated Vasculitis: A Meta- Analysis of Observational Studies. PLoS One 2015; 10:e0126016. 121. Wester Trejo MAC, Bajema IM, van Daalen EE. Antineutrophil cytoplasmic antibody- associated vasculitis and malignancy. Curr Opin Rheumatol 2018; 30:44. 122. Heijl C, Harper L, Flossmann O, et al. Incidence of malignancy in patients treated for antineutrophil cytoplasm antibody-associated vasculitis: follow-up data from European Vasculitis Study Group clinical trials. Ann Rheum Dis 2011; 70:1415. 123. Mohammad AJ, Segelmark M, Smith R, et al. Severe Infection in Antineutrophil Cytoplasmic Antibody-associated Vasculitis. J Rheumatol 2017; 44:1468. 124. Charlier C, Henegar C, Launay O, et al. Risk factors for major infections in Wegener granulomatosis: analysis of 113 patients. Ann Rheum Dis 2009; 68:658. 125. Goupil R, Brachemi S, Nadeau-Fredette AC, et al. Lymphopenia and treatment-related infectious complications in ANCA-associated vasculitis. Clin J Am Soc Nephrol 2013; 8:416. https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 43/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 126. Garcia-Vives E, Segarra-Medrano A, Martinez-Valle F, et al. Prevalence and Risk Factors for Major Infections in Patients with Antineutrophil Cytoplasmic Antibody-associated Vasculitis: Influence on the Disease Outcome. J Rheumatol 2020; 47:407. 127. Little MA, Nightingale P, Verburgh CA, et al. Early mortality in systemic vasculitis: relative contribution of adverse events and active vasculitis. Ann Rheum Dis 2010; 69:1036. 128. van Assen S, Agmon-Levin N, Elkayam O, et al. EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis 2011; 70:414. 129. Hogan SL, Falk RJ, Chin H, et al. Predictors of relapse and treatment resistance in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis. Ann Intern Med 2005; 143:621. 130. Weidner S, Geuss S, Hafezi-Rachti S, et al. ANCA-associated vasculitis with renal involvement: an outcome analysis. Nephrol Dial Transplant 2004; 19:1403. 131. Aasar d K, Iversen BM, Hammerstr m J, et al. Wegener's granulomatosis: clinical course in 108 patients with renal involvement. Nephrol Dial Transplant 2000; 15:611. 132. Aasar d K, Bostad L, Hammerstr m J, et al. Renal histopathology and clinical course in 94 patients with Wegener's granulomatosis. Nephrol Dial Transplant 2001; 16:953. 133. Hauer HA, Bajema IM, Van Houwelingen HC, et al. Determinants of outcome in ANCA- associated glomerulonephritis: a prospective clinico-histopathological analysis of 96 patients. Kidney Int 2002; 62:1732. 134. Neumann I, Kain R, Regele H, et al. Histological and clinical predictors of early and late renal outcome in ANCA-associated vasculitis. Nephrol Dial Transplant 2005; 20:96. 135. Berden AE, Jones RB, Erasmus DD, et al. Tubular lesions predict renal outcome in antineutrophil cytoplasmic antibody-associated glomerulonephritis after rituximab therapy. J Am Soc Nephrol 2012; 23:313. 136. Mekhail TM, Hoffman GS. Longterm outcome of Wegener's granulomatosis in patients with renal disease requiring dialysis. J Rheumatol 2000; 27:1237. 137. Glassock RJ. Intensive plasma exchange in crescentic glomerulonephritis: help or no help? Am J Kidney Dis 1992; 20:270. 138. Cole E, Cattran D, Magil A, et al. A prospective randomized trial of plasma exchange as additive therapy in idiopathic crescentic glomerulonephritis. The Canadian Apheresis Study Group. Am J Kidney Dis 1992; 20:261. 139. Geffriaud-Ricouard C, No l LH, Chauveau D, et al. Clinical spectrum associated with ANCA of defined antigen specificities in 98 selected patients. Clin Nephrol 1993; 39:125. https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 44/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 140. Berti A, Matteson EL, Crowson CS, et al. Risk of Cardiovascular Disease and Venous Thromboembolism Among Patients With Incident ANCA-Associated Vasculitis: A 20-Year Population-Based Cohort Study. Mayo Clin Proc 2018; 93:597. 141. Houben E, Penne EL, Voskuyl AE, et al. Cardiovascular events in anti-neutrophil cytoplasmic antibody-associated vasculitis: a meta-analysis of observational studies. Rheumatology (Oxford) 2018; 57:555. 142. Nygaard L, Polcwiartek C, Nelveg-Kristensen KE, et al. Long-term cardiovascular outcomes and temporal trends in patients diagnosed with ANCA-associated vasculitis: a Danish nationwide registry study. Rheumatology (Oxford) 2023; 62:735. 143. Liapi M, Jayne D, Merkel PA, et al. Venous thromboembolism in ANCA-associated vasculitis: a population-based cohort study. Rheumatology (Oxford) 2021; 60:4616. 144. Kronbichler A, Leierer J, Shin JI, et al. Association of Pulmonary Hemorrhage, Positive Proteinase 3, and Urinary Red Blood Cell Casts With Venous Thromboembolism in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Arthritis Rheumatol 2019; 71:1888. 145. Englund M, Merkel PA, Tomasson G, et al. Comorbidities in Patients with Antineutrophil Cytoplasmic Antibody-associated Vasculitis versus the General Population. J Rheumatol 2016; 43:1553. 146. Merkel PA, Lo GH, Holbrook JT, et al. Brief communication: high incidence of venous thrombotic events among patients with Wegener granulomatosis: the Wegener's Clinical Occurrence of Thrombosis (WeCLOT) Study. Ann Intern Med 2005; 142:620. 147. Moiseev S, Bulanov N, Crnogorac M, et al. Traditional and Disease-Specific Risk Factors for Cardiovascular Events in ANCA-Associated Vasculitis: A Multinational Retrospective Study. J Rheumatol 2023. Topic 3105 Version 59.0 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 45/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate GRAPHICS Phase-contrast micrograph showing dysmorphic RBCs in urine sediment Phase-contrast microscopy showing dysmorphic red blood cells (RBCs) and acanthocytes in the urinary sediment of a patient with glomerular hematuria. Acanthocytes (arrows) can be recognized as ring forms with vesicle-shaped protrusions. Courtesy of Juan Carlos Q Velez, MD. Graphic 130438 Version 1.0 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 46/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Scanning electron micrograph showing dysmorphic red cells in urine sediment Scanning microscopy showing dysmorphic red cells in a patient with glomerular bleeding. Acanthocytes can be recognized as ring forms with vesicle-shaped protrusions (arrows). Courtesy of Hans K hler, MD. Graphic 62064 Version 3.0 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 47/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Initial induction and maintenance therapy in patients with a diagnosis of GPA or MPA This treatment algorithm applies to patients who are not pregnant. Induction therapy in pregnant patients requires modification due to the potential risk of fetal harm associated with some agents. Refer to UpToDate content on initial immunosuppressive therapy in pregnant patients with GPA or MPA. GPA: granulomatosis with polyangiitis; MPA: microscopic polyangiitis; GBM: glomerular basement membrane; ANCA: antineutrophil cytoplasmic autoantibodies; eGFR: estimated glomerular filtration rate. Refer to UpToDate content on the use of rituximab or cyclophosphamide as induction therapy for patients with GPA or MPA who have organ- or life-threatening disease. The role of plasma exchange, in addition to glucocorticoids and either cyclophosphamide or rituximab, among patients with GPA or MPA is controversial. Refer to UpToDate content on plasma exchange in patients with GPA or MPA. https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 48/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Contraindications to methotrexate include, but are not limited to, heavy alcohol use, chronic liver 2 disease, eGFR <60 mL/min/1.73 m , or evidence of renal vasculitis. Refer to UpToDate content on management of non-organ- and non-life-threatening GPA or MPA. Rituximab is preferred for most patients who achieve remission after induction therapy. Azathioprine, methotrexate, and mycophenolate are reasonable alternatives to rituximab and may be preferred based on other patient-specific factors, such as a prior history of toxicity from a certain drug and/or a comorbid condition that increases the risk of toxicity with a specific agent. Refer to UpToDate content on the choice of maintenance therapy in patients with GPA or MPA. Graphic 111371 Version 3.0 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 49/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Adjusting oral cyclophosphamide dose for adult patients with kidney function impairment Cyclophosphamide (CYC) oral dose Creatinine clearance* (mL/minute) (mg/kg/day) >100 2 50 to 99 1.5 25 to 49 1.2 15 to 24 1 <15 or dialysis 0.8 Initial 2 mg/kg per day dose and adjustments for kidney function impairment are for daily oral administration of "low-dose" cyclophosphamide therapy in rheumatic diseases. For approach, other dose adjustments that may be needed, and duration of therapy, refer to UpToDate topics on the use of cyclophosphamide in rheumatic diseases. CYC: cyclophosphamde; Clcr: creatinine clearance. Can be estimated by using the Cockroft-Gault equation. Clcr = [140-age] * weight (kg)/serum Cr in mg/dL * 72. Multiply result by 0.85 for women. Separate calculators for creatinine clearance using conventional and SI units are available in UpToDate. Usual maximum daily dose is 200 mg. For patients who are overweight or obese, an estimate of ideal or lean body weight is used for estimating Clcr and determining daily CYC weight-based dose. Calculators are available in UpToDate. CYC is variably dialyzable (approximately 20 to 50 percent). Dose may require further adjustment depending upon type of dialysis. For intermittent hemodialysis, give dose after session on dialysis days.

J Am Soc Nephrol 2012; 23:313. 136. Mekhail TM, Hoffman GS. Longterm outcome of Wegener's granulomatosis in patients with renal disease requiring dialysis. J Rheumatol 2000; 27:1237. 137. Glassock RJ. Intensive plasma exchange in crescentic glomerulonephritis: help or no help? Am J Kidney Dis 1992; 20:270. 138. Cole E, Cattran D, Magil A, et al. A prospective randomized trial of plasma exchange as additive therapy in idiopathic crescentic glomerulonephritis. The Canadian Apheresis Study Group. Am J Kidney Dis 1992; 20:261. 139. Geffriaud-Ricouard C, No l LH, Chauveau D, et al. Clinical spectrum associated with ANCA of defined antigen specificities in 98 selected patients. Clin Nephrol 1993; 39:125. https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 44/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate 140. Berti A, Matteson EL, Crowson CS, et al. Risk of Cardiovascular Disease and Venous Thromboembolism Among Patients With Incident ANCA-Associated Vasculitis: A 20-Year Population-Based Cohort Study. Mayo Clin Proc 2018; 93:597. 141. Houben E, Penne EL, Voskuyl AE, et al. Cardiovascular events in anti-neutrophil cytoplasmic antibody-associated vasculitis: a meta-analysis of observational studies. Rheumatology (Oxford) 2018; 57:555. 142. Nygaard L, Polcwiartek C, Nelveg-Kristensen KE, et al. Long-term cardiovascular outcomes and temporal trends in patients diagnosed with ANCA-associated vasculitis: a Danish nationwide registry study. Rheumatology (Oxford) 2023; 62:735. 143. Liapi M, Jayne D, Merkel PA, et al. Venous thromboembolism in ANCA-associated vasculitis: a population-based cohort study. Rheumatology (Oxford) 2021; 60:4616. 144. Kronbichler A, Leierer J, Shin JI, et al. Association of Pulmonary Hemorrhage, Positive Proteinase 3, and Urinary Red Blood Cell Casts With Venous Thromboembolism in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Arthritis Rheumatol 2019; 71:1888. 145. Englund M, Merkel PA, Tomasson G, et al. Comorbidities in Patients with Antineutrophil Cytoplasmic Antibody-associated Vasculitis versus the General Population. J Rheumatol 2016; 43:1553. 146. Merkel PA, Lo GH, Holbrook JT, et al. Brief communication: high incidence of venous thrombotic events among patients with Wegener granulomatosis: the Wegener's Clinical Occurrence of Thrombosis (WeCLOT) Study. Ann Intern Med 2005; 142:620. 147. Moiseev S, Bulanov N, Crnogorac M, et al. Traditional and Disease-Specific Risk Factors for Cardiovascular Events in ANCA-Associated Vasculitis: A Multinational Retrospective Study. J Rheumatol 2023. Topic 3105 Version 59.0 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 45/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate GRAPHICS Phase-contrast micrograph showing dysmorphic RBCs in urine sediment Phase-contrast microscopy showing dysmorphic red blood cells (RBCs) and acanthocytes in the urinary sediment of a patient with glomerular hematuria. Acanthocytes (arrows) can be recognized as ring forms with vesicle-shaped protrusions. Courtesy of Juan Carlos Q Velez, MD. Graphic 130438 Version 1.0 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 46/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Scanning electron micrograph showing dysmorphic red cells in urine sediment Scanning microscopy showing dysmorphic red cells in a patient with glomerular bleeding. Acanthocytes can be recognized as ring forms with vesicle-shaped protrusions (arrows). Courtesy of Hans K hler, MD. Graphic 62064 Version 3.0 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 47/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Initial induction and maintenance therapy in patients with a diagnosis of GPA or MPA This treatment algorithm applies to patients who are not pregnant. Induction therapy in pregnant patients requires modification due to the potential risk of fetal harm associated with some agents. Refer to UpToDate content on initial immunosuppressive therapy in pregnant patients with GPA or MPA. GPA: granulomatosis with polyangiitis; MPA: microscopic polyangiitis; GBM: glomerular basement membrane; ANCA: antineutrophil cytoplasmic autoantibodies; eGFR: estimated glomerular filtration rate. Refer to UpToDate content on the use of rituximab or cyclophosphamide as induction therapy for patients with GPA or MPA who have organ- or life-threatening disease. The role of plasma exchange, in addition to glucocorticoids and either cyclophosphamide or rituximab, among patients with GPA or MPA is controversial. Refer to UpToDate content on plasma exchange in patients with GPA or MPA. https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 48/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Contraindications to methotrexate include, but are not limited to, heavy alcohol use, chronic liver 2 disease, eGFR <60 mL/min/1.73 m , or evidence of renal vasculitis. Refer to UpToDate content on management of non-organ- and non-life-threatening GPA or MPA. Rituximab is preferred for most patients who achieve remission after induction therapy. Azathioprine, methotrexate, and mycophenolate are reasonable alternatives to rituximab and may be preferred based on other patient-specific factors, such as a prior history of toxicity from a certain drug and/or a comorbid condition that increases the risk of toxicity with a specific agent. Refer to UpToDate content on the choice of maintenance therapy in patients with GPA or MPA. Graphic 111371 Version 3.0 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 49/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Adjusting oral cyclophosphamide dose for adult patients with kidney function impairment Cyclophosphamide (CYC) oral dose Creatinine clearance* (mL/minute) (mg/kg/day) >100 2 50 to 99 1.5 25 to 49 1.2 15 to 24 1 <15 or dialysis 0.8 Initial 2 mg/kg per day dose and adjustments for kidney function impairment are for daily oral administration of "low-dose" cyclophosphamide therapy in rheumatic diseases. For approach, other dose adjustments that may be needed, and duration of therapy, refer to UpToDate topics on the use of cyclophosphamide in rheumatic diseases. CYC: cyclophosphamde; Clcr: creatinine clearance. Can be estimated by using the Cockroft-Gault equation. Clcr = [140-age] * weight (kg)/serum Cr in mg/dL * 72. Multiply result by 0.85 for women. Separate calculators for creatinine clearance using conventional and SI units are available in UpToDate. Usual maximum daily dose is 200 mg. For patients who are overweight or obese, an estimate of ideal or lean body weight is used for estimating Clcr and determining daily CYC weight-based dose. Calculators are available in UpToDate. CYC is variably dialyzable (approximately 20 to 50 percent). Dose may require further adjustment depending upon type of dialysis. For intermittent hemodialysis, give dose after session on dialysis days. Adapted with permission from: Rheumatic Disease Clinics of North America 2001. 27(4):863. Copyright 2001 Elsevier Science. Additional information from de Groot et al. Ann Intern Med 2009. 150(10):670. Graphic 60883 Version 9.0 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 50/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Reduced-dose glucocorticoid tapering regimen for patients with GPA and MPA Patient weight Week <50 kg 50 to 75 kg >75 kg 1 50 60 75 2 25 30 40 3 to 4 20 25 30 5 to 6 15 20 25 7 to 8 12.5 15 20 9 to 10 10 12.5 15 11 to 12 7.5 10 12.5 13 to 14 6 7.5 10 15 to 16 5 5 7.5 17 to 18 5 5 7.5 19 to 20 5 5 5 21 to 22 5 5 5 This table provides an example of a reduced-dose, oral glucocorticoid-tapering regimen for a patient with new-onset or relapsing GPA or MPA. Depending on the management by the treating clinicians, it can be initiated immediately or after a course of IV glucocorticoids. After week 22, further reduction in glucocorticoid dose is individualized based on treating provider and patient preference. GPA: granulomatosis with polyangiitis; MPA: microscopic polyangiitis; IV: intravenous. From: Walsh M, Merkel PA, Peh CA et al. Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis. N Engl J Med 2020; 382:622. Copyright 2020 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. Graphic 129362 Version 1.0 https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 51/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Cytochrome P450 3A (including 3A4) inhibitors and inducers Strong inhibitors Moderate inhibitors Strong inducers Moderate inducers Adagrasib Amiodarone Apalutamide Bexarotene Atazanavir Aprepitant Carbamazepine Bosentan Ceritinib Berotralstat Enzalutamide Cenobamate Clarithromycin Cimetidine Fosphenytoin Dabrafenib Cobicistat and Conivaptan Lumacaftor Dexamethasone cobicistat- containing Crizotinib Lumacaftor- Dipyrone ivacaftor Cyclosporine Efavirenz coformulations Mitotane Diltiazem Elagolix, estradiol, Darunavir Phenobarbital and norethindrone Duvelisib Idelalisib therapy pack Phenytoin Dronedarone Indinavir Eslicarbazepine Primidone Erythromycin Itraconazole Etravirine Rifampin Fedratinib Ketoconazole (rifampicin) Lorlatinib Fluconazole Levoketoconazole Mitapivat Fosamprenavir Lonafarnib Modafinil Fosaprepitant Lopinavir Nafcillin Fosnetupitant- Mifepristone* Pexidartinib palonosetron Nefazodone Rifabutin Grapefruit juice Nelfinavir Rifapentine Imatinib Nirmatrelvir- Sotorasib Isavuconazole ritonavir (isavuconazonium St. John's wort Ombitasvir- sulfate) paritaprevir- Lefamulin ritonavir Letermovir Ombitasvir- Netupitant paritaprevir- Nilotinib ritonavir plus Ribociclib dasabuvir Schisandra Posaconazole Verapamil Ritonavir and ritonavir-containing coformulations Saquinavir Telithromycin Tucatinib Voriconazole https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 52/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - 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/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 53/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate Contributor Disclosures Peter A Merkel, MD, MPH Equity Ownership/Stock Options: Kyverna [Systemic lupus erythematosus]. Grant/Research/Clinical Trial Support: AbbVie [Vasculitis]; AstraZeneca [Vasculitis]; Boehringer Ingelheim [Scleroderma]; Bristol-Myers Squibb [Vasculitis]; ChemoCentryx [Vasculitis]; Electra [Vasculitis]; Genentech/Roche [Vasculitis]; GlaxoSmithKline [Vasculitis]; InflaRx [Vasculitis]; Sanofi [Vasculitis]; Takeda [Vasculitis]. Consultant/Advisory Boards: AbbVie [Vasculitis]; AstraZeneca [Vasculitis]; Boehringer Ingelheim [Scleroderma]; Bristol-Myers Squibb [Vasculitis]; ChemoCentryx [Vasculitis]; CSL Behring [Scleroderma, vasculitis]; Dynacure [Vasculitis]; EMDSerono [Vasculitis]; GlaxoSmithKline [Vasculitis]; InflaRx [Vasculitis]; Janssen [Vasculitis]; Kyverna [Scleroderma, vasculitis]; MiroBio [Vasculitis]; Neutrolis [Vasculitis]; Novartis [Vasculitis]; NS Pharma [Vasculitis]; Otsuka [Vasculitis]; Q32 [Vasculitis]; Regeneron [Vasculitis]; Sparrow [Vasculitis]; Takeda [Vasculitis]. All of the relevant financial relationships listed have been mitigated. Andre A Kaplan, MD No relevant financial relationship(s) with ineligible companies to disclose. Ronald J Falk, MD Grant/Research/Clinical Trial Support: National Institutes of Health [ANCA vasculitis, IgA, minimal change, focal segmental glomerulosclerosis, membranous glomerulonephritis, T32 training]. Consultant/Advisory Boards: Vertex Pharmaceuticals Inc [Focal segmental glomerulosclerosis]. All of the relevant financial relationships listed have been mitigated. Gerald B Appel, MD Grant/Research/Clinical Trial Support: Alexion [C3 glomerulopathies]; Calliditas [IgA nephropathy]; ChemoCentryx [C3 glomerulopathies]; Equillium [Lupus nephritis]; Goldfinch [FSGS]; Mallinckrodt [Fibrillary glomerulonephritis]; Novartis [C3GN, IgAN]; Reata [Alport syndrome]; Roche [Glomerular diseases, glomerulonephritis, and lupus nephritis]; Sanofi [Alport syndrome]; Travere [FSGS, IgAN]. Consultant/Advisory Boards: Alexion [Glomerular diseases, glomerulonephritis, lupus nephritis]; Arrowhead [Glomerulonephritis]; Aurinia [Glomerular diseases, glomerulonephritis, lupus nephritis]; Callidaitas [IgAN]; ChemoCentryx [Immunosuppressives]; KIRA Pharma [New immunosuppressives in glomerular kidney disease]; Mallinckrodt [Glomerular diseases, glomerulonephritis, lupus nephritis]; Merck [Glomerular diseases, glomerulonephritis, lupus nephritis]; Novartis [Glomerulonephritis]; Pfizer [Glomerular diseases, glomerulonephritis, lupus nephritis]; Reata [Glomerulonephritis]; Roche [Glomerular diseases, glomerulonephritis, lupus nephritis]; Sanofi [Glomerular diseases, glomerulonephritis,]; Steritas [Reduction of corticosteroid use in clinical practice of treating kidney disease]; Travere [IgAN]. Speaker's Bureau: Aurinia [Lupus nephritis]; GlaxoSmithKline [Lupus nephritis]. All of the relevant financial relationships listed have been mitigated. Fernando C Fervenza, MD, PhD Grant/Research/Clinical Trial Support: Genentech [Membranous nephropathy, fibrillary GN]; Janssen Pharmaceutical [Monoclonal protein-mediated kidney diseases, lupus nephritis]; Morphosys AG [IgA nephropathy]. Consultant/Advisory Boards: Alexion [C3 glomerulopathy, IgA nephropathy]; BioCrystal Pharmaceuticals [C3 glomerulopathy]; ChemoCentryx, Inc [ANCA associated vasculitis]; Equilium, Inc [Lupus nephritis]; Galapagos [Focal segmental glomerulosclerosis]; GlaxoSmithKline [Lupus nephritis]; Novartis [IgA Nephropathy]; Otsuka [IgA nephropathy]; Takeda [IgA nephropathy]; Zyversa Therapeutics [FSGS]. All of the relevant financial relationships listed have been mitigated. Albert Q Lam, MD No relevant financial relationship(s) with ineligible companies to disclose. Philip Seo, MD, MHS 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/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 54/55 7/7/23, 11:17 AM Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy - UpToDate https://www.uptodate.com/contents/granulomatosis-with-polyangiitis-and-microscopic-polyangiitis-induction-and-maintenance-therapy/print 55/55

7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Primary angiitis of the central nervous system in adults : Rula A Hajj-Ali, MD, Leonard H Calabrese, DO : Gene G Hunder, MD, Scott E Kasner, MD : Philip Seo, MD, MHS 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 17, 2022. INTRODUCTION Central nervous system (CNS) vasculitis refers to a broad spectrum of diseases that result in inflammation and destruction of the blood vessels of the brain, spinal cord, and meninges. Angiitis, a synonym for vasculitis, refers generally to blood vessels on both the arterial and venous sides of the circulation. Primary angiitis of the CNS (PACNS) is the preferred name for vasculitis that is confined to the CNS. CNS vasculitis is considered secondary when it occurs in the context of a systemic inflammatory disease, such as a systemic vasculitis or systemic lupus erythematosus (SLE), or an infectious process such as varicella zoster virus. PACNS predominantly affects small- and medium-sized arteries of the brain parenchyma, spinal cord, and leptomeninges, resulting in symptoms and signs of CNS dysfunction. It is defined by inflammation of the cerebral vasculature without angiitis in other organs. The protean manifestations of PACNS, along with the nonspecificity of available investigational modalities, pose a challenge for accurate diagnosis. Clinicians caring for patients with suspected PACNS should be familiar with its mimics to avoid misdiagnosis. PACNS can be mimicked closely in both its clinical presentation and radiologic manifestations by a number of other disorders. The most frequent mimic of PACNS is a group of disorders known collectively as the reversible cerebral vasoconstriction syndromes (RCVS). (See "Reversible cerebral vasoconstriction syndrome".) https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 1/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate The clinical characteristics, diagnosis, and treatment of PACNS will be reviewed here. PACNS in children is discussed separately. (See "Vasculitis in children: Incidence and classification", section on 'Primary angiitis of the central nervous system'.) EPIDEMIOLOGY Primary angiitis of the central nervous system (PACNS) is a rare disease. A retrospective analysis of 101 patients with PACNS reported an annual incidence rate of 2.4 cases per 1,000,000 person- years [1]. There is a 2:1 male predominance among reported cases [2]. The median age at diagnosis is 50 years, although it can occur at almost every age [1]. (See "Vasculitis in children: Incidence and classification", section on 'Primary angiitis of the central nervous system'.) ETIOPATHOGENESIS The cause of primary angiitis of the central nervous system (PACNS) is unknown. Several potential etiologic agents or mechanisms have been proposed, but understanding of the cause of PACNS remains highly speculative. Various infectious agents have been proposed as etiologic factors, such as varicella zoster virus, West Nile virus, Mycoplasma gallisepticum, and human immunodeficiency virus (HIV) [3-11]. Cerebral amyloid angiopathy and PACNS have been described together in some patients, and associations between amyloid deposition have also been proposed as a trigger [12-18]. (See "Cerebral amyloid angiopathy", section on 'Clinical and diagnostic features'.) Although the cause of PACNS is unknown, inflammation of the CNS causes the vessels to become narrowed, occluded, and thrombosed, resulting in tissue ischemia and necrosis of the territories of the involved vessels. PACNS is more likely to affect blood vessels in the cerebral cortex and leptomeninges than subcortical regions. Blood vessels supplying cranial nerves may also be involved. CLINICAL MANIFESTATIONS Primary angiitis of the central nervous system (PACNS) is characterized by a long prodromal period, with few patients presenting acutely [19,20]. The vasculitis can affect any part of the CNS, causing the clinical manifestations to be highly variable and nonspecific [2,21-23]. Headache is the most commonly reported symptom, occurring in about 60 percent of patients [1,2]. The headache typically varies in description, but is usually subacute and insidious, in https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 2/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate contrast to the sudden-onset thunderclap headache that is observed with reversible cerebral vasoconstriction syndromes (RCVS). Other symptoms include cognitive impairment, stroke, and transient ischemic attack, which are present in 30 to 50 percent of patients [1,2,19]. Patients with PACNS who develop strokes usually present with more than a single stroke in different anatomic territories. Other less common symptoms, including cranial neuropathies, ataxia, seizure, and coma, have been reported. Signs and symptoms suggestive of systemic vasculitis, such as peripheral neuropathy, fever, weight loss, or rash, are usually lacking. Spinal cord involvement occurs alone or coincides with parenchymal brain involvement [24]. Angiitis affecting the spinal cord usually presents as a myelopathy, with pain, motor weakness, and sensory findings. (See "Disorders affecting the spinal cord", section on 'Spinal cord infarction'.) Symptoms and signs of untreated PACNS progress over the course of months. In one series, the mean time from symptom onset to diagnosis was 170 days [2]. However, if left untreated, PACNS will progress; thus the diagnosis of PACNS will be less likely in patients presenting with stable symptoms and signs for many months without progression of any radiographic findings. This is an important contrast to the RCVS, which typically have a more acute onset and much shorter time to diagnosis. (See 'Alternative diagnoses' below and "Reversible cerebral vasoconstriction syndrome".) DIAGNOSTIC APPROACH The diagnosis of primary angiitis of the central nervous system (PACNS) is challenging as the symptoms are generally nonspecific and there is no specific diagnostic test. The workup for patients who may have PACNS must proceed simultaneously with the systematic evaluation and exclusion of other disorders. (See 'Alternative diagnoses' below.) When to suspect the diagnosis While there is no characteristic presentation of PACNS, there are some scenarios that are highly suspicious. PACNS should be suspected when strokes, more often recurrent, occur in young patients with no identifiable cardiovascular or hypercoagulable risk factors; in the development of cognitive dysfunction with or without headaches; and in recurrent or persistent focal neurologic symptoms, abnormal cerebrovascular imaging obtained in the setting of an unexplained neurological deficit, or unexplained spinal cord dysfunction not associated with systemic disease or any other process. https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 3/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate Alternative diagnoses The clinician must remember that when PACNS is suspected, the correct diagnosis is usually something else. As a result, careful exclusion of other disorders is essential. Because of the importance of eliminating a lengthy list of alternative diagnoses, the differential diagnosis of PACNS is discussed in detail below before making the diagnosis. The major categories of disease in the differential diagnosis of PACNS are presented below: Infection When considering a diagnosis of PACNS, it is most important to rule out infection since unwarranted immunosuppression can have devastating consequences. A number of bacterial, mycobacterial, viral, fungal, and rickettsial infections can mimic PACNS. Prompt culture of all potential sites of infection, including the cerebrospinal fluid (CSF), is therefore essential. The detection of pathogens associated with CNS vasculitis, especially in the setting of a chronic meningitis, may be enhanced via the use of a variety of serologies and targeted molecular studies (ie, polymerase chain reaction [PCR]). The application of next-generation sequencing has demonstrated some utility in detecting novel pathogens not clinically suspected and obviating the need for brain biopsy, but its place in the diagnostic algorithm remains to be established [25]. Organisms that cause subacute or chronic infections are the ones most likely to imitate PACNS. The major organisms of concern are: Treponema pallidum. (See "Neurosyphilis".) Borrelia burgdorferi. (See "Clinical manifestations of Lyme disease in adults".) Bartonella species. (See "Bartonella infections in people with HIV", section on 'Bacillary angiomatosis'.) Mycobacterium tuberculosis. (See "Central nervous system tuberculosis: An overview".) Herpesviruses such as varicella zoster virus and cytomegalovirus. Varicella zoster has been associated with a wide range of vascular disease ranging from granulomatous involvement of the aorta, to a syndrome resembling giant cell arteritis, granulomatous angiitis of the central nervous system, and stroke, and thus should be carefully searched for in virtually all settings [26] (see "Varicella zoster virus vasculopathy"). The clinical implications of identifying positive serology for varicella zoster virus in the absence of detectable virus remains controversial [27]. Hepatitis B and C viruses, which can be associated with polyarteritis nodosa and mixed cryoglobulinemia, respectively. (See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults" and "Overview of cryoglobulins and cryoglobulinemia".) https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 4/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate HIV infection. (See "Approach to the patient with HIV and central nervous system lesions".) Fungi such as Aspergillus, Coccidioides, and Histoplasma species. (See "Pathogenesis, clinical manifestations, and diagnosis of brain abscess".) Cysticercosis can involve middle-size cerebral vessels of the subarachnoid space, often without clinical evidence of cerebral ischemia [28]. Cysticercosis is endemic in many regions of Central and South America, sub-Saharan Africa, India, and Asia. (See "Cysticercosis: Clinical manifestations and diagnosis".) Reversible cerebral vasoconstriction syndromes The RCVS are a group of disorders linked by prolonged but reversible vasoconstriction of the cerebral arteries [29]. The RCVS are typically associated with severe, acute-onset headaches that can recur intermittently for days to weeks, sometimes accompanied by neurologic symptoms and signs. The headaches associated with the RCVS are usually "thunderclap" in nature. Ischemic and/or hemorrhagic stroke may occur in the setting of RCVS. Thus, despite the reversibility of vasoconstriction, these disorders are not always characterized by benign prognoses. (See "Reversible cerebral vasoconstriction syndrome".) While there are some signs and symptoms common to both conditions, including headache, focal deficits, stroke, seizures, and angiographic irregularities, the nature of the headaches and imaging abnormalities are quite different and discussed separately. (See "Reversible cerebral vasoconstriction syndrome", section on 'Angiographic differential'.) Systemic vasculitis involving the brain Some forms of vasculitis can involve the CNS. The ones most likely to do so are the following: Beh et syndrome (see "Clinical manifestations and diagnosis of Beh et syndrome", section on 'Neurologic disease') Polyarteritis nodosa (see "Clinical manifestations and diagnosis of polyarteritis nodosa in adults", section on 'Neurologic disease') Vasculitides associated with antineutrophil cytoplasmic antibodies, including granulomatosis with polyangiitis, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (see "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis" and "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg- Strauss)") https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 5/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate Cryoglobulinemic vasculitis (see "Overview of cryoglobulins and cryoglobulinemia") The diagnosis of CNS vasculitis secondary to a systemic form of vasculitis is usually inferred from biopsy or angiography of a non-CNS site. In most such patients, the systemic vasculitis is an established diagnosis before the CNS is involved. We assign high importance to performing a thorough evaluation to exclude an infectious etiology of the CNS process, given the immunosuppressive treatments that patients are usually receiving for their systemic vasculitis. Other systemic rheumatic diseases CNS manifestations due to other systemic rheumatic diseases may reflect vasculitis or other mechanisms and can occur with or without systemic symptoms. In this setting, diagnosis of the underlying diseases is frequently based upon vasculitic or non-vasculitic clinical features in organs outside the CNS, combined with selected laboratory results. The systemic rheumatic diseases most likely to involve the CNS and create confusion with the diagnosis of PACNS are: Systemic lupus erythematosus and related conditions Systemic lupus erythematosus (SLE), Sj gren's disease, mixed connective tissue disease, and dermatomyositis can all be associated with CNS involvement. (See "Neurologic and neuropsychiatric manifestations of systemic lupus erythematosus" and "Clinical manifestations of Sj gren s disease: Extraglandular disease" and "Clinical manifestations and diagnosis of mixed connective tissue disease" and "Clinical manifestations of dermatomyositis and polymyositis in adults".) Neuropathologic abnormalities in lupus include multifocal microinfarcts, cortical atrophy, gross infarcts, hemorrhage, ischemic demyelination, and patchy, multiple sclerosis-like demyelination. The most common microscopic brain finding in SLE is microvasculopathy, described as "healed vasculitis" consistent with hyalinization, thickening, and thrombus formation [30-32]. Nonvasculitic autoimmune inflammatory meningoencephalitis Nonvasculitic autoimmune inflammatory meningoencephalitis (NAIM) is a syndrome characterized clinically by dementia that occurs in some patients with this disorder at a younger age of onset, rapid progression with significant cognitive and behavioral features, absence of family history, abnormal electroencephalography (EEG) findings, and elevated levels of inflammatory markers [33]. The CNS involvement that may be seen in Hashimoto thyroiditis is considered as a form of NAIM. The pathologic findings of NAIM are those of a panencephalitis without evidence of a vasculitis [33]. Patients with NAIM are usually https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 6/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate successfully treated with glucocorticoids. (See "Hashimoto encephalopathy", section on 'Nonvasculitic autoimmune inflammatory meningoencephalitis'.) Rheumatoid arthritis Rheumatoid vasculitis occasionally involves the CNS. However, the most common neurologic manifestation of rheumatoid vasculitis is vasculitic neuropathy. (See "Clinical manifestations and diagnosis of rheumatoid vasculitis".) Antiphospholipid syndrome The antiphospholipid syndrome can cause CNS dysfunction due to strokes caused by intracerebral clotting events, emboli associated with verrucous endocarditis, and white matter lesions suggestive of a vasculopathy. (See "Clinical manifestations of antiphospholipid syndrome".) Many but not all cases of the Sneddon syndrome, the combination of livedo reticularis and cerebrovascular lesions, are associated with antiphospholipid antibodies. However, the Sneddon syndrome is unlikely to be confused with PACNS if the livedo reticularis is appreciated. Atherosclerosis Atherosclerosis of intracranial vessels can mimic the angiographic findings of PACNS [2,34]. The patient with multiple atherosclerotic risk factors and CNS dysfunction such as evidence of a cerebrovascular accident is much more likely to have atherosclerosis than PACNS. Cerebral emboli Cerebral emboli can result in multifocal vascular occlusions that suggest the diagnosis of vasculitis. As many as 30 to 40 percent of ischemic strokes remain cryptogenic despite the availability of transesophageal echocardiography, carotid ultrasonography, and magnetic resonance angiography (MRA) to help identify embolic sources. (See "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)" and "Overview of the evaluation of stroke", section on 'Embolic stroke'.) Various types of embolic events can create confusion with PACNS. These include paradoxical emboli in patients with patent foramen ovale as well as emboli in patients with atrial fibrillation, atrial myxoma, and nonbacterial thrombotic endocarditis. (See "Nonbacterial thrombotic endocarditis" and "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Prevention of thromboembolism' and "Patent foramen ovale", section on 'Cryptogenic stroke'.) Atheroemboli are another cause of embolic stroke that may be confused with PACNS. Atheroemboli are often released from vessels other than the carotid arteries (especially the aorta), with a predilection for the middle cerebral artery [35]. Systemic signs of atheroembolism (eg, livedo reticularis, acute renal failure), if present, would exclude https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 7/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate PACNS. (See "Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism)".) Intravascular lymphoma Intravascular lymphoma that leads to widespread occlusion of small vessels is an occasional mimicker of PACNS [36-38]. Appropriate immunohistochemistry staining as well as B- and T-cell markers should be performed on biopsy specimens even with the pathologic finding of angiitis, since the presence of vasculitic changes does not exclude an underlying lymphoproliferative condition. Lymph node, bone marrow, and CSF involvement may not be evident at presentation, as delays of up to five years have been reported before the emergence of extracranial disease [3]. (See "Intravascular large cell lymphoma".) Miscellaneous A number of other diseases that can mimic PACNS include: Cerebral artery dissection Cervical internal carotid artery dissection occasionally presents with headache and scintillating scotomata in the ipsilateral visual field. Many patients with carotid or vertebral artery dissections progress to cerebral ischemia. The combination of headache followed by stroke mimics PACNS. (See "Migraine-associated stroke: risk factors, diagnosis, and prevention".) Sarcoidosis Approximately 5 percent of patients with sarcoidosis develop clinically evident neurological involvement. In a manner similar to PACNS, sarcoidosis can be associated with granulomatous brain masses, encephalopathy, and/or meningeal disease. (See "Neurologic sarcoidosis".) Paraneoplastic and autoimmune encephalitis These are inflammatory conditions of the brain with many etiologies. Some are related to cancer and others are associated with antibodies against neuronal cell surface and synaptic protein. (See "Paraneoplastic and autoimmune encephalitis".) Susac syndrome Susac syndrome is a rare, poorly characterized disorder associated with the clinical triad of visual loss caused by branch retinal artery occlusions, sensorineural hearing loss, and subacute encephalopathy [39,40]. The presence of hyperintense lesions in the corpus callosum on T2-weighted MR images may be a clue to the diagnosis [41,42]. CADASIL CADASIL is the acronym for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. This disorder is a heritable, noninflammatory vasculopathy resulting from mutations in the gene for the protein Notch 3. https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 8/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate The simplest way of diagnosing CADASIL and distinguishing it from PACNS is via a skin biopsy of clinically normal skin. The demonstration of granular osmiophilic material within the vascular basal lamina of arteries, arterioles, and precapillaries is diagnostic of CADASIL. (See "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)".) Mitochondrial encephalomyopathy, lactic acidosis, and stroke syndrome (MELAS) is a mitochondrial genetic disorder caused by a point mutation at nucleotide 3243 (A3243G), leading to stroke-like episodes before age 40, seizures, dementia, and ragged-red fibers in muscle [43]. (See "Mitochondrial myopathies: Clinical features and diagnosis", section on 'MELAS'.) Cerebroretinal vasculopathy syndrome is an autosomal dominant retinal vasculopathy with cerebral leukodystrophy, leading to stroke and dementias with middle-age onset [44]. Moyamoya disease Moyamoya disease is a cerebrovascular disease of unknown cause characterized by progressive stenosis of the intracranial internal carotid arteries and their proximal branches. It generally affects adults in the third to fourth decade of life, and in adults it can cause strokes, recurrent transient ischemic attacks, sensorimotor paralysis, seizures, and/or migraine-like headaches. (See "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis".) Other conditions include amyloid angiopathy and inflammatory bowel disease- associated cerebral vasculitis. (See "Cerebral amyloid angiopathy".) Evaluation As part of the diagnostic evaluation, all patients should undergo routine laboratory testing and serological evaluations to rule out systemic disease, whether infectious or inflammatory. Obtaining cerebrospinal fluid is an essential step in the evaluation and should only be omitted if there are contraindications to perform a lumbar puncture. The evaluation also includes cerebrovascular imaging and/or obtaining tissue biopsy of the leptomeninges and brain for either ruling out other etiologies or confirming suspected PACNS. Initial neuroimaging should include MR imaging (MRI), since a normal MRI is very unlikely in PACNS. The selection of additional neuroimaging studies depends upon the initial MRI findings and individual patient characteristics. The results of the various tests must be interpreted in conjunction with each other in order to determine whether to treat the patient with immunosuppressive therapy, even in the setting of a negative brain biopsy. Laboratory testing to exclude alternative diagnoses The purpose of laboratory testing is primarily to exclude an underlying systemic disease or alternative diagnoses. https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 9/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate We perform the following basic laboratory tests in patients suspected of having PACNS: Complete blood count with differential Serum urea nitrogen and creatinine Serum aspartate and alanine aminotransferases Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) Urinalysis Acute phase reactants such as the ESR and CRP are usually normal in PACNS. An elevated ESR and CRP should raise suspicion of systemic involvement by either an infectious or inflammatory process. We also perform the following serologic assays to exclude other underlying systemic rheumatic diseases: Antinuclear antibodies (ANA) Antibodies to the Ro/SSA, La/SSB, Sm, and RNP antigens Antibodies to double-stranded deoxyribonucleic acid (DNA) Antiphospholipid antibodies (lupus anticoagulant [LA], IgG, and IgM anticardiolipin [aCL] antibodies; and IgG and IgM anti-beta2-glycoprotein [GP] I) Antineutrophil cytoplasmic antibodies (ANCA) Serum C3 and C4 Serum cryoglobulins Serum and urine protein electrophoresis with immune electrophoresis Quantitative immunoglobulin levels (IgG, IgM, IgA) Testing for infections appropriate to the clinical circumstances is critical, as the treatment for infectious causes of CNS dysfunction differs radically from the therapy for immune-mediated disorders. A thorough history for any risk factors for immunodeficiency as well as travel history is important in the assessment for any exposure or an immunodeficiency state. In addition to cultures of the blood, CSF, and other body fluids, diagnostic tests for infection may include assays for the following organisms: Treponema pallidum Borrelia burgdorferi Bartonella species Mycobacterium tuberculosis Herpesviruses (varicella zoster virus, cytomegalovirus, others) Hepatitis B and C viruses HIV https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 10/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate Cysticercosis Lumbar puncture Analysis of the CSF is a crucial part of the evaluation of patients with potential PACNS and should be performed in all patients unless there are contraindications. The importance of CSF analysis in excluding any infectious or malignant process and the performance of adequate stains and cultures of the CSF cannot be overemphasized. (See "Molecular diagnosis of central nervous system infections" and "Lumbar puncture: Technique, indications, contraindications, and complications in adults" and "Cerebrospinal fluid: Physiology and utility of an examination in disease states".) The CSF is abnormal in 80 to 90 percent of patients with pathologically documented disease. Normal CSF findings can occur with localized disease and in patients presenting with mass-like lesions. There are no specific abnormalities of the CSF in PACNS; however, the CSF findings in the majority of patients show an aseptic meningitis pattern with modest lymphocytic pleocytosis, normal glucose levels, elevated protein level, and occasionally the presence of oligoclonal bands and elevated IgG synthesis [19]. By contrast, in the RCVS, the most common mimic of PACNS, the CSF analysis is usually normal or reflects findings of subarachnoid hemorrhage if this is present [45]. Neuroimaging Various neuroimaging modalities can be used to assess for both parenchymal and vascular abnormalities in the evaluation of possible PACNS. MRI should be performed in all patients with PACNS. The selection of additional neuroimaging modalities depends on the initial MRI findings and individual patient characteristics. Some clinicians may choose to order an MRA at the same time as the initial MRI out of convenience because the patient is in the scanner, though it lacks both sensitivity and specificity for PACNS. Computed tomography angiography (CTA) may be more sensitive for detecting vascular irregularities than MRA, but is far less sensitive than catheter-based angiography. (See 'MRI' below and 'MR angiography and CT angiography' below.) Conventional angiography remains an important part of the diagnostic testing for suspected PACNS, and our authors obtain angiography in patients who have MRI findings of multiple cortical and subcortical infarcts that are otherwise unexplained. Angiography can detect segmental narrowing in multiple vessels that are typical of, though not pathognomonic for, PACNS, and help further rule out alternative diagnoses such as atherosclerosis, moyamoya, and dissection. These tests may also be helpful in selecting a location for brain biopsy if needed. (See 'Conventional angiography' below.) MRI MRI is sensitive in detecting abnormalities in PACNS and should be performed in all patients suspected to have PACNS. MRI of the brain commonly shows multiple infarcts in https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 11/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate multiple vascular territories, and often in areas of the brain not affected by more common causes of stroke (such as the corpus callosum). However, these findings are not specific for PACNS and the interpretation of MRI findings should be performed by an expert neuroradiologist who is familiar with the findings of CNS vasculitis and its radiologic mimics. In addition, there may rarely be tumor-like lesions [46-48]. Conversely, a negative MRI carries a high negative predictive value for the diagnosis of PACNS [1]. MR angiography and CT angiography In most cases of PACNS, the medium and small intracranial arteries are affected rather than the large proximal arteries. MRA and CTA are most reliable for the assessment of the large proximal arteries and therefore are inadequate for the demonstration of more distal vasculopathy. Notably, the finding of narrowing of multiple large proximal intracranial arteries as detected by MRA or CTA should suggest an alternative diagnosis, such as atherosclerosis, dissection, moyamoya disease, or reversible cerebral vasoconstriction in the appropriate clinical setting. The resolution of conventional angiogram remains superior to MRA and CTA in detecting abnormalities in smaller vessels. Conventional angiography Visualization of the cerebral vasculature with conventional angiography is a common part of the investigation when PACNS is suspected based on the clinical presentation and MRI findings described above. (See 'MRI' above and "Neuroimaging of acute stroke", section on 'Digital subtraction angiography'.) Classic cerebral angiography studies in PACNS reveal findings of segmental narrowing referred to as "beading," usually in the medium and small arteries. Involvement of several sites of the cerebral circulation is typical of PACNS ( picture 1). Other findings include circumferential or eccentric vessel irregularities. While the findings are characteristic of cerebral arteritis, these findings are not specific, and may be encountered in non-vasculitic disorders such as atherosclerosis and vasospasm [43]. PACNS has a host of potential mimickers of its angiographic features (see 'Alternative diagnoses' above). In addition, angiographic findings interpreted as "consistent with vasculitis" greatly outnumber true cases of PACNS. Thus, a positive angiogram does not make the diagnosis of PACNS. In a study of 38 patients with suspected PACNS, 14 patients had typical angiographic findings of vasculitis [49]. None were found to have vasculitic changes at brain biopsy. This study reflects the poor specificity of the angiographic findings and/or the limited sensitivity of brain biopsy. The sensitivity of angiography is also limited, and in two series of patients PACNS, the sensitivity of angiography in biopsy-proven PACNS cases was only 60 percent [50,51]. PACNS may be limited to the small vessels that are below the resolution of conventional angiography, which is particularly common when the pattern of infarction is predominantly subcortical, and thus a negative angiogram cannot be used to exclude the diagnosis of PACNS. https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 12/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate In unusual cases of PACNS, the disease presents radiologically as a CNS mass lesion, manifested on angiography by the presence of an avascular mass effect. Proper interpretation of CNS angiograms requires insight into the clinical context of the specific patient, experience in reading abnormal angiograms, and thorough appreciation of the range of normal findings within the circulation of the internal carotid artery and its intracerebral branches ( image 1). Although it is not common to perform serial angiograms as a way of following response to treatment, repeat angiography is sometimes useful if the diagnosis remains unclear days to weeks after the performance of an initial study. A rapid change in angiographic appearance (eg, evolution from a flagrantly abnormal study to one that is essentially normal within days or weeks) argues compellingly for an RCVS rather than PACNS ( image 2) [29]. (See "Neuroimaging of acute stroke", section on 'Digital subtraction angiography'.) Brain and leptomeningeal biopsy Selecting patients for brain biopsy The gold standard for the diagnosis of PACNS is histopathology. A brain biopsy should be performed in most patients with suspected PACNS. A biopsy will help histologically identify PACNS as well as exclude other lesions or vasculitis mimics, particularly infection or malignancy. Sampling of the leptomeninges as well as the underlying cortex increases the diagnostic yield; however, the test characteristics of the brain biopsy are far from optimal. The sensitivity of brain biopsy for PACNS is approximately 75 percent, thus leaving the clinician with a false negative rate of 25 percent [50]. A meta-analysis revealed a diagnostic yield of 74.7 percent (95% CI 64.0-84.1 percent) for suspected PACNS [52]. Biopsies may also identify a cause other than PACNS in up to 39 to 50 percent of patients [53,54]. In other words, a brain biopsy not only establishes a diagnosis in the setting of suspected PACNS in roughly 70 percent of cases but also may provide an alternative diagnosis in a fair number of patients [55]. There are two settings of particular concern where obtaining tissue is paramount: The presence of a focal lesion on MR with characteristics that suggest an inflammatory or infectious process, but noninvasive approaches to diagnosis have failed. The presence of a mass lesion in the brain for which the principal concern is usually malignancy or abscess. PACNS is occasionally a surprise finding. In such cases, the finding of vasculitis on pathologic exam does not exclude the diagnosis of infection or malignancy, and appropriate stains and markers should be pursued for accurate diagnosis. Biopsy of a radiologically abnormal area heightens the sensitivity of brain/leptomeningeal biopsies. In the absence of a focal lesion within the brain parenchyma, the temporal tip of the https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 13/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate nondominant hemisphere is the preferred biopsy site [56]. Histopathology Histopathologic findings in the brain in patients with PACNS may include the presence of Langerhans or foreign body giant cells, necrotizing vasculitis, or lymphocytic vasculitis. PACNS is referred to as granulomatous angiitis of the CNS (GACNS) if the pathologic findings are those of granulomatous angiitis affecting the small and medium leptomeningeal and cortical arteries ( image 3) [23,57]. However, the classic finding of granulomatous segmental vasculitis with Langerhans or foreign body giant cells is present in less than 50 percent of the biopsies [58]. The biopsy is not granulomatous in most such cases, and only reveals lymphocytic vasculitis. Appropriate stains, viral studies, and cultures should be performed on the biopsies, since the finding of vasculitis does not preclude the diagnosis of an associated infection or a lymphoproliferative process that is causing the vasculitis. Because of the focal and segmental distribution of CNS vasculitis, a positive biopsy is diagnostic, but a single isolated negative biopsy does not exclude primary or secondary CNS vasculitis [58]. Establishing the diagnosis The diagnosis of PACNS is based upon a constellation of symptoms and signs in the setting of supportive studies, and the exclusion of alternative diagnoses. (See 'Alternative diagnoses' above.) The diagnosis of PACNS can usually be made when all of the following are present: An acquired, otherwise unexplained neurological deficit Evidence of either classic angiographic or histopathologic features of angiitis within the CNS No evidence of systemic vasculitis or any other condition that could elicit the angiographic or pathologic findings These clinical findings are consistent with the diagnostic criteria that were proposed in 1988 [34]. There are patients in whom the diagnosis of PACNS is made without meeting all the criteria described above. In such scenarios, the term "atypical/possible PACNS" has been used to describe the uncertainty about the diagnosis or the variation from the typical pathologic findings. This usually includes lymphocytic PACNS, angiographically defined PACNS, and a mass lesion presentation. Lymphocytic PACNS This group of patients is distinguished by lymphocytic infiltration rather than granulomatous findings on the pathologic examination. When the pathologic https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 14/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate findings are predominantly lymphocytic, careful pathologic examination and immunophenotyping should be performed to rule out a lymphomatous CNS process. Angiographically defined PACNS This group is diagnosed by an abnormal cerebrovascular study and CSF examination, but with a normal CNS biopsy. The culprit vessel size involvement is usually medium-sized vessels rather than the small vessel typically seen in PACNS. In this subset, a diligent workup should be performed to rule out other vasculopathies, given the poor specificity of the cerebrovascular imaging study in the diagnosis of PACNS. Moreover, signs of inflammatory brain changes should be present, such as an abnormal CSF finding or enhancement of arterial vessel walls (in the absence of other causes of arterial enhancement). The RCVS, in particular, should be ruled out since this is a major mimic of this category. Mass lesion presentation These patients present with a solitary cerebral mass lesion. The diagnosis is usually a surprise after pathologic findings of a vasculitic process are observed as part of the pathologic evaluation. A complete analysis of the biopsy is mandatory to exclude alternative diagnoses, especially infection and malignancy even with the finding of vasculitis. TREATMENT Immunosuppressive therapy has been associated with success in central nervous system (CNS) vasculitis [1]. However, no prospective studies of any of the therapies described below have been conducted in patients with primary angiitis of the CNS (PACNS). Thus, our suggestions for treatment are influenced by anecdotal evidence related to PACNS and extrapolation of therapeutic strategies from other forms of vasculitis and retrospectively

of angiography in biopsy-proven PACNS cases was only 60 percent [50,51]. PACNS may be limited to the small vessels that are below the resolution of conventional angiography, which is particularly common when the pattern of infarction is predominantly subcortical, and thus a negative angiogram cannot be used to exclude the diagnosis of PACNS. https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 12/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate In unusual cases of PACNS, the disease presents radiologically as a CNS mass lesion, manifested on angiography by the presence of an avascular mass effect. Proper interpretation of CNS angiograms requires insight into the clinical context of the specific patient, experience in reading abnormal angiograms, and thorough appreciation of the range of normal findings within the circulation of the internal carotid artery and its intracerebral branches ( image 1). Although it is not common to perform serial angiograms as a way of following response to treatment, repeat angiography is sometimes useful if the diagnosis remains unclear days to weeks after the performance of an initial study. A rapid change in angiographic appearance (eg, evolution from a flagrantly abnormal study to one that is essentially normal within days or weeks) argues compellingly for an RCVS rather than PACNS ( image 2) [29]. (See "Neuroimaging of acute stroke", section on 'Digital subtraction angiography'.) Brain and leptomeningeal biopsy Selecting patients for brain biopsy The gold standard for the diagnosis of PACNS is histopathology. A brain biopsy should be performed in most patients with suspected PACNS. A biopsy will help histologically identify PACNS as well as exclude other lesions or vasculitis mimics, particularly infection or malignancy. Sampling of the leptomeninges as well as the underlying cortex increases the diagnostic yield; however, the test characteristics of the brain biopsy are far from optimal. The sensitivity of brain biopsy for PACNS is approximately 75 percent, thus leaving the clinician with a false negative rate of 25 percent [50]. A meta-analysis revealed a diagnostic yield of 74.7 percent (95% CI 64.0-84.1 percent) for suspected PACNS [52]. Biopsies may also identify a cause other than PACNS in up to 39 to 50 percent of patients [53,54]. In other words, a brain biopsy not only establishes a diagnosis in the setting of suspected PACNS in roughly 70 percent of cases but also may provide an alternative diagnosis in a fair number of patients [55]. There are two settings of particular concern where obtaining tissue is paramount: The presence of a focal lesion on MR with characteristics that suggest an inflammatory or infectious process, but noninvasive approaches to diagnosis have failed. The presence of a mass lesion in the brain for which the principal concern is usually malignancy or abscess. PACNS is occasionally a surprise finding. In such cases, the finding of vasculitis on pathologic exam does not exclude the diagnosis of infection or malignancy, and appropriate stains and markers should be pursued for accurate diagnosis. Biopsy of a radiologically abnormal area heightens the sensitivity of brain/leptomeningeal biopsies. In the absence of a focal lesion within the brain parenchyma, the temporal tip of the https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 13/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate nondominant hemisphere is the preferred biopsy site [56]. Histopathology Histopathologic findings in the brain in patients with PACNS may include the presence of Langerhans or foreign body giant cells, necrotizing vasculitis, or lymphocytic vasculitis. PACNS is referred to as granulomatous angiitis of the CNS (GACNS) if the pathologic findings are those of granulomatous angiitis affecting the small and medium leptomeningeal and cortical arteries ( image 3) [23,57]. However, the classic finding of granulomatous segmental vasculitis with Langerhans or foreign body giant cells is present in less than 50 percent of the biopsies [58]. The biopsy is not granulomatous in most such cases, and only reveals lymphocytic vasculitis. Appropriate stains, viral studies, and cultures should be performed on the biopsies, since the finding of vasculitis does not preclude the diagnosis of an associated infection or a lymphoproliferative process that is causing the vasculitis. Because of the focal and segmental distribution of CNS vasculitis, a positive biopsy is diagnostic, but a single isolated negative biopsy does not exclude primary or secondary CNS vasculitis [58]. Establishing the diagnosis The diagnosis of PACNS is based upon a constellation of symptoms and signs in the setting of supportive studies, and the exclusion of alternative diagnoses. (See 'Alternative diagnoses' above.) The diagnosis of PACNS can usually be made when all of the following are present: An acquired, otherwise unexplained neurological deficit Evidence of either classic angiographic or histopathologic features of angiitis within the CNS No evidence of systemic vasculitis or any other condition that could elicit the angiographic or pathologic findings These clinical findings are consistent with the diagnostic criteria that were proposed in 1988 [34]. There are patients in whom the diagnosis of PACNS is made without meeting all the criteria described above. In such scenarios, the term "atypical/possible PACNS" has been used to describe the uncertainty about the diagnosis or the variation from the typical pathologic findings. This usually includes lymphocytic PACNS, angiographically defined PACNS, and a mass lesion presentation. Lymphocytic PACNS This group of patients is distinguished by lymphocytic infiltration rather than granulomatous findings on the pathologic examination. When the pathologic https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 14/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate findings are predominantly lymphocytic, careful pathologic examination and immunophenotyping should be performed to rule out a lymphomatous CNS process. Angiographically defined PACNS This group is diagnosed by an abnormal cerebrovascular study and CSF examination, but with a normal CNS biopsy. The culprit vessel size involvement is usually medium-sized vessels rather than the small vessel typically seen in PACNS. In this subset, a diligent workup should be performed to rule out other vasculopathies, given the poor specificity of the cerebrovascular imaging study in the diagnosis of PACNS. Moreover, signs of inflammatory brain changes should be present, such as an abnormal CSF finding or enhancement of arterial vessel walls (in the absence of other causes of arterial enhancement). The RCVS, in particular, should be ruled out since this is a major mimic of this category. Mass lesion presentation These patients present with a solitary cerebral mass lesion. The diagnosis is usually a surprise after pathologic findings of a vasculitic process are observed as part of the pathologic evaluation. A complete analysis of the biopsy is mandatory to exclude alternative diagnoses, especially infection and malignancy even with the finding of vasculitis. TREATMENT Immunosuppressive therapy has been associated with success in central nervous system (CNS) vasculitis [1]. However, no prospective studies of any of the therapies described below have been conducted in patients with primary angiitis of the CNS (PACNS). Thus, our suggestions for treatment are influenced by anecdotal evidence related to PACNS and extrapolation of therapeutic strategies from other forms of vasculitis and retrospectively assessed experience with PACNS [1,21,22]. The suggested approach for the treatment of PACNS is similar to the therapy of severe polyarteritis nodosa. (See "Treatment and prognosis of polyarteritis nodosa", section on 'Moderate and severe PAN'.) Initial therapy of suspected PACNS If the initial clinical evaluation has excluded infection with a reasonable degree of confidence and PACNS remains a diagnostic possibility, empiric therapy with glucocorticoids may be appropriate while the full workup is completed. There have been no controlled trials in selecting the route of glucocorticoids in the management of the acute phase of PACNS. Some experts suggest avoiding intravenous pulse glucocorticoids, since this regimen is more likely to cloud the clinical picture by contributing to steroid-induced mental status changes, and suggest beginning the patient on the equivalent of prednisone 1 https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 15/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate mg/kg per day (to a maximum of 80 mg/day, or its equivalent) until the diagnostic evaluation is complete. Treatment of PACNS Biopsy-confirmed cases with a picture of granulomatous inflammation on pathology, typical of granulomatous angiitis of the CNS (GACNS), should be treated with a combination of glucocorticoids and cyclophosphamide [19,21,22]. Failure to respond to these drugs after an appropriate treatment regimen should prompt the evaluation for an alternative diagnosis before additional treatment with an alternative immunosuppressive drug. Rituximab may be used in patients who are intolerant of cyclophosphamide (see 'Rituximab' below). The glucocorticoid and cyclophosphamide regimens used for PACNS are discussed below. (See 'Glucocorticoids' below and 'Cyclophosphamide' below.) The treatment of atypical/possible PACNS should be tailored according to the severity and the extent of the neurologic involvement. Atypical/possible PACNS patients should be treated initially with a high dose of glucocorticoids [22], and then tapered slowly. The decision of adding cyclophosphamide to the treatment regimen should be individualized according to the extent and the gravity of the neurologic deficits. Glucocorticoids High-dose glucocorticoids are required to achieve disease control in PACNS. We initiate therapy with prednisone at a dose of 1 mg/kg per day to a maximum of 80 mg/day, or its equivalent. Some experts begin with intravenous methylprednisolone, 15 mg/kg each day for three days [59]. Daily prednisone is begun on day 4. Glucocorticoids are associated with many potential treatment-related morbidities (see "Major side effects of systemic glucocorticoids"). Prophylactic approaches to prevent bone loss and opportunistic infections are discussed below. (See 'Prophylactic therapies' below.) Cyclophosphamide Either daily oral or intermittent (usually monthly) intravenous cyclophosphamide is reasonable as part of a remission induction strategy in PACNS [60]. Some clinicians prefer oral cyclophosphamide because of the ability to titrate the dose on a daily basis if necessary, thereby decreasing the likelihood of severe leukopenia. Other clinicians are more familiar with the intermittent administration of cyclophosphamide. Oral cyclophosphamide is begun at a dose of 1.5 to 2 mg/kg per day. In this setting, the white blood cell count (WBC) must be closely monitored and the cyclophosphamide dose adjusted to avoid severe leukopenia. The WBC count should remain above 3500/microL. The duration of the cyclophosphamide therapy is generally between three and six months, depending on when remission occurs and if there are any potential side effects that preclude the use of cyclophosphamide. (See "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Monitoring of oral CYC dosing'.) https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 16/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate 2 The typical regimen for intravenous cyclophosphamide is 600 to 750 mg/m , infused once a month, generally for between three and six months [59]. A reduction in cyclophosphamide dose 2 is necessary if there is significant renal insufficiency with not more than 500 mg/m for patients with an estimated glomerular filtration rate less than 20 mL/min. Rituximab Limited data are available for the use of rituximab in PACNS [61,62]. Three cases were reported that described clinical and radiographic improvement in adults with PACNS after 2 treatment with rituximab (either as two 1 gram infusions separated by 14 days or as 375 mg/m weekly for four weeks) [61,62]. In one case, the diagnosis was made by angiographic findings and an abnormal cerebrospinal fluid (CSF), and rituximab was given as first-line therapy [61]. In another case, the diagnosis of PACNS was pathologically validated with evidence of a lymphocytic vasculitic process in the brain and spinal cord, and rituximab was used after the patient failed to improve with five monthly cyclophosphamide infusions [61]. In the third case, the diagnosis was confirmed by pathologic findings of granulomatous vasculitis, and rituximab was given as first-line therapy [62]. Prophylactic therapies The toxicities of PACNS treatments require the use of several prophylactic therapies to prevent bone loss and opportunistic infections. Osteoporosis prevention All patients treated with high-dose glucocorticoids are at risk for glucocorticoid-induced osteoporosis. The prevention and treatment of glucocorticoid-induced osteoporosis are discussed separately. (See "Prevention and treatment of glucocorticoid-induced osteoporosis".) Opportunistic infections Glucocorticoid and cyclophosphamide therapy are associated with an increased risk for opportunistic infection. Pneumocystis jirovecii, a common pathogen in immunosuppressed hosts, may cause a life-threatening pneumonia. In patients treated with the combination of high-dose prednisone and another immunosuppressive agent, we recommend prophylaxis against Pneumocystis pneumonia (PCP). Options for prophylactic regimens are discussed separately. The optimal duration of Pneumocystis prophylaxis after immunosuppressive therapy is tapered has not been defined. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.) Other Cyclophosphamide is associated with many potential treatment-related morbidities. Prophylactic approaches to these complications are discussed separately. (See "General principles of the use of cyclophosphamide in rheumatic diseases".) https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 17/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate Monitoring treatment The response to treatment is monitored by periodic reassessment of symptoms, neurologic findings, and neuroimaging abnormalities. It is very important to differentiate between disease damage and disease progression. Neurologic deficits due to cerebral or cerebellar infarction may resolve slowly or not at all. Thus, for some patients, a response to treatment may only be indicated by symptomatic improvement (eg, resolution of headache), but not the resolution of magnetic resonance (MR) lesions. A lack of new lesions on MRI is a more reliable way to assess for progression of the disease. With respect to neuroimaging, noninvasive studies are preferred to repeated angiography. A follow-up MR should be obtained four to six weeks after beginning treatment, then every three to six months throughout therapy, and subsequently according to the evolution of the disease. During the use of immunosuppressive treatment, patients require close clinical follow-up and laboratory monitoring in order to avoid preventable adverse effects of therapy. As an example, patients on daily cyclophosphamide should have complete blood counts checked every two weeks. (See "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Monitoring of oral CYC dosing'.) Duration of therapy and management of recurrent disease There are limited data available that address the optimal duration of therapy or the treatment of disease recurrence. The following approaches are based on the authors' experience and extrapolation from the treatment of other forms of vasculitis. Glucocorticoid taper After four to six weeks at the initial dose, prednisone tapering should begin. There is no standard tapering regimen for PACNS, but regimens similar to the one outlined below are appropriate. Assuming that a patient begins prednisone treatment at 60 mg/day and remains on this dose for six weeks, the following taper will require a total of 26 weeks to reach a daily dose of 5 mg: The prednisone dose should be tapered by 10 mg each week until a dose of 40 mg/day is reached. After one week on 40 mg per day, the prednisone dose should be tapered by 5 mg each week until the patient reaches 20 mg/day. After one week on 20 mg/day, the prednisone dose should be tapered by 2.5 mg each week until the patient reaches 10 mg/day. After one week on 10 mg/day, the prednisone dose should be tapered by 1 mg every two weeks until the patient reaches 5 mg/day. After two weeks on 5 mg/day, the daily prednisone dose should be tapered by 1 mg each month until the taper has been completed. https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 18/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate Deviations from this regimen may be necessary if patients develop a significant complication of glucocorticoid therapy or experience disease recurrence. If a flare in symptoms occurs while the glucocorticoid dose is being lowered, the dose should be increased to the lowest amount that previously suppressed the clinical manifestations. Once the patient improves to the level of their prior status or stabilizes, reductions in the dose can be tried again. Discontinuing cyclophosphamide Three to six months of cyclophosphamide is sufficient for many patients. At this time, cyclophosphamide should be discontinued after approximately six months and replaced with a less toxic medication for an additional six to twelve months of maintenance therapy, in a manner that is similar to that of the management of antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis. Some clinicians switch from cyclophosphamide to azathioprine (2 mg/kg) or mycophenolate mofetil, which are favored over methotrexate, given its limited ability to cross the blood brain barrier. Data on the duration of the maintenance therapy is not available, and the decision on the duration of the therapy should be individualized, based upon the response to therapy. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Maintenance therapy'.) In a single-center cohort of 44 patients with PACNS, relapses were reported in up to 59 percent of patients; relapse was defined as a reoccurrence or worsening of neurologic symptoms or worsening of existing and/or evidence of new abnormal neuroimaging findings on MRI consistent with PACNS activity [63]. Male patients were found to have a higher rate of relapse, but other predictors for relapses that had been identified from other case series were not confirmed in this study. Thus, more studies using a more uniform treatment regimen and relapse definition are needed to help identify factors affecting risk of relapse and response to 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: Vasculitis".) SUMMARY AND RECOMMENDATIONS Primary angiitis of the central nervous system (PACNS) most commonly involves small- and medium-sized cerebral blood vessels resulting in symptoms and signs of CNS dysfunction. https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 19/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate It is defined by inflammation of the cerebral vasculature without angiitis in other organs. (See 'Introduction' above.) PACNS is a rare disease, and the cause is unknown. The median age at diagnosis is 50 years, although it can occur at almost every age. (See 'Epidemiology' above and 'Etiopathogenesis' above.) PACNS is characterized by a long prodromal period, with few patients presenting acutely. The vasculitis can affect any part of the CNS, causing the clinical manifestations to be highly variable and nonspecific. The most commonly reported symptom is a subacute and insidious headache. Other symptoms include cognitive impairment, stroke, and transient ischemic attack. Patients with PACNS who develop strokes usually present with more than a single stroke in different anatomic areas. (See 'Clinical manifestations' above.) The diagnosis of PACNS is challenging as the symptoms are generally nonspecific and there is no specific diagnostic test. The workup for patients who may have PACNS must proceed simultaneously with the systematic evaluation and exclusion of other disorders. While there is no characteristic presentation, there are some scenarios that are highly suspicious. PACNS should be suspected when strokes, more often recurrent, occur in young patients with no identifiable cardiovascular or hypercoagulable risk factors; or in the setting of chronic meningitis, recurrent focal neurologic symptoms, unexplained diffuse neurologic dysfunction, abnormal cerebrovascular imaging obtained in the setting of an unexplained neurological deficit, or unexplained spinal cord dysfunction not associated with systemic disease or any other process. (See 'Diagnostic approach' above and 'When to suspect the diagnosis' above.) In patients in whom a diagnosis of PACNS is suspected, an alternative diagnosis is more likely to be correct. As a result, careful exclusion of other disorders is essential. The most common clinical and radiologic mimickers are the reversible cerebral vasoconstriction syndromes (RCVS). Other alternative diagnoses include infection, systemic vasculitides and other systemic rheumatic diseases, atherosclerosis, cerebral emboli, intravascular lymphoma, and moyamoya. (See 'Alternative diagnoses' above.) Laboratory testing and serological assays are used primarily to exclude other etiologies of CNS dysfunction. Analysis of the cerebrospinal fluid (CSF) is a crucial part of the evaluation of patients with potential PACNS and should be performed in all patents unless there are contraindications. The CSF is abnormal in 80 to 90 percent of patients with pathologically documented disease. CSF findings are nonspecific but most commonly include an elevated https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 20/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate CSF protein and a modest lymphocytic pleocytosis. (See 'Evaluation' above and 'Laboratory testing to exclude alternative diagnoses' above and 'Lumbar puncture' above.) Various neuroimaging modalities can be used to assess for both parenchymal and vascular abnormalities in the evaluation of suspected PACNS. MRI should be performed in all patients. The selection of additional neuroimaging modalities depends on the initial MRI findings and individual patient characteristics. Conventional angiography remains an important part of the diagnostic testing for suspected PACNS, and our authors obtain angiography in patients who have MRI findings of multiple cortical and subcortical infarcts that are otherwise unexplained. Angiography can detect segmental narrowing in multiple vessels that are typical of, though not pathognomonic for, PACNS, and help further rule out alternative diagnoses such as atherosclerosis, moyamoya, and dissection. These tests may also be helpful in selecting a location for brain biopsy if needed. (See 'Neuroimaging' above.) A brain biopsy should be performed in most patients with suspected PACNS. A biopsy will help histologically identify PACNS as well as exclude other lesions or vasculitis mimics, particularly infection or malignancy. (See 'Brain and leptomeningeal biopsy' above.) The diagnosis of PACNS is based upon a constellation of symptoms and signs in the setting of supportive studies, and the exclusion of alternative diagnoses. The diagnosis can usually be made when all of the following are present (see 'Establishing the diagnosis' above): An acquired otherwise unexplained neurological deficit Evidence of either classic angiographic or histopathologic features of angiitis within the CNS No evidence of systemic vasculitis or any other condition that could elicit the angiographic or pathologic findings There are patients in whom the diagnosis of PACNS is made without all the meeting the criteria described above. In such scenarios, the term "atypical/possible PACNS" has been used to describe the uncertainty about the diagnosis or the variation from the typical pathologic findings. This usually includes lymphocytic PACNS, angiographically defined PACNS, and a mass lesion presentation. (See 'Establishing the diagnosis' above.) We suggest treating PACNS with a combination of glucocorticoids and cyclophosphamide (Grade 2C). Treatment of atypical PACNS should be individualized according to the severity and the extent of the neurologic deficit. (See 'Treatment of PACNS' above.) https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 21/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate We use measures to prevent osteoporosis and Pneumocystis infections during the treatment of PACNS. (See 'Prophylactic therapies' above.) The response to treatment is monitored by periodic reassessment of symptoms, neurologic findings, and neuroimaging abnormalities. It is important to differentiate between disease damage and disease progression. Neurologic deficits due to cerebral or cerebellar infarction may resolve slowly or not at all. Thus, for some patients, a response to treatment may only be indicated by symptomatic improvement (eg, resolution of headache), but not the resolution of magnetic resonance (MR) lesions. A lack of new lesions on MRI is a more reliable way to assess for progression of the disease. A follow-up MR should be obtained four to six weeks after beginning treatment, then every three to six months throughout therapy, and subsequently according to the evolution of the disease. (See 'Monitoring treatment' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Salvarani C, Brown RD Jr, Calamia KT, et al. Primary central nervous system vasculitis: analysis of 101 patients. Ann Neurol 2007; 62:442. 2. Calabrese LH, Duna GF, Lie JT. Vasculitis in the central nervous system. Arthritis Rheum 1997; 40:1189. 3. Sigal LH. The neurologic presentation of vasculitic and rheumatologic syndromes. A review. Medicine (Baltimore) 1987; 66:157. 4. Thomas L, Davidson M, McCluskey RT. Studies of PPLO infection. I. The production of cerebral polyarteritis by Mycoplasma gallisepticum in turkeys; the neurotoxic property of the Mycoplasma. J Exp Med 1966; 123:897. 5. Alexander JJ, Lasky AS, Graf WD. Stroke associated with central nervous system vasculitis after West Nile virus infection. J Child Neurol 2006; 21:623. 6. Outteryck O, S n chal O, Berteloot D, et al. [Cerebral vasculitis secondary to Varicella-Zoster virus infection]. Rev Neurol (Paris) 2005; 161:836. 7. Bhat G, Mathur DS, Saxena GN, et al. Granulomatous angiitis of the central nervous system associated with herpes zoster. J Assoc Physicians India 2002; 50:977. 8. Brannagan TH 3rd. Retroviral-associated vasculitis of the nervous system. Neurol Clin 1997; 15:927. https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 22/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate 9. Nogueras C, Sala M, Sasal M, et al. Recurrent stroke as a manifestation of primary angiitis of the central nervous system in a patient infected with human immunodeficiency virus. Arch Neurol 2002; 59:468. 10. Kossorotoff M, Touz E, Godon-Hardy S, et al. Cerebral vasculopathy with aneurysm formation in HIV-infected young adults. Neurology 2006; 66:1121. 11. van der Ven AJ, van Oostenbrugge RJ, Kubat B, Tervaert JW. Cerebral vasculitis after initiation antiretroviral therapy. AIDS 2002; 16:2362. 12. Scolding NJ, Joseph F, Kirby PA, et al. Abeta-related angiitis: primary angiitis of the central nervous system associated with cerebral amyloid angiopathy. Brain 2005; 128:500. 13. Hashizume Y, Yoshida M, Suzuki E, Hirayama M. A 65-year-old man with headaches and left homonymous hemianopsia. Neuropathology 2004; 24:350. 14. Harkness KA, Coles A, Pohl U, et al. Rapidly reversible dementia in cerebral amyloid inflammatory vasculopathy. Eur J Neurol 2004; 11:59. 15. Tamargo RJ, Connolly ES Jr, McKhann GM, et al. Clinicopathological review: primary angiitis of the central nervous system in association with cerebral amyloid angiopathy. Neurosurgery 2003; 53:136. 16. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 10-2000. A 63-year-old man with changes in behavior and ataxia. N Engl J Med 2000; 342:957. 17. Salvarani C, Brown RD Jr, Calamia KT, et al. Primary central nervous system vasculitis: comparison of patients with and without cerebral amyloid angiopathy. Rheumatology (Oxford) 2008; 47:1671. 18. Fountain NB, Eberhard DA. Primary angiitis of the central nervous system associated with cerebral amyloid angiopathy: report of two cases and review of the literature. Neurology 1996; 46:190. 19. Hajj-Ali RA, Calabrese LH. Primary angiitis of the central nervous system. Autoimmun Rev 2013; 12:463. 20. Hajj-Ali RA, Calabrese LH. Diagnosis and classification of central nervous system vasculitis. J Autoimmun 2014; 48-49:149. 21. de Boysson H, Zuber M, Naggara O, et al. Primary angiitis of the central nervous system: description of the first fifty-two adults enrolled in the French cohort of patients with primary vasculitis of the central nervous system. Arthritis Rheumatol 2014; 66:1315. 22. Salvarani C, Brown RD Jr, Christianson TJ, et al. Adult primary central nervous system vasculitis treatment and course: analysis of one hundred sixty-three patients. Arthritis https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 23/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate Rheumatol 2015; 67:1637. 23. Giannini C, Salvarani C, Hunder G, Brown RD. Primary central nervous system vasculitis: pathology and mechanisms. Acta Neuropathol 2012; 123:759. 24. Salvarani C, Brown RD Jr, Calamia KT, et al. Primary CNS vasculitis with spinal cord involvement. Neurology 2008; 70:2394. 25. Wilson MR, O'Donovan BD, Gelfand JM, et al. Chronic Meningitis Investigated via Metagenomic Next-Generation Sequencing. JAMA Neurol 2018; 75:947. 26. Nagel MA, Bubak AN. Varicella Zoster Virus Vasculopathy. J Infect Dis 2018; 218:S107. 27. Nagel MA, Gilden D. Neurological complications of varicella zoster virus reactivation. Curr Opin Neurol 2014; 27:356. 28. Barinagarrementeria F, Cant C. Frequency of cerebral arteritis in subarachnoid cysticercosis: an angiographic study. Stroke 1998; 29:123. 29. Calabrese LH, Dodick DW, Schwedt TJ, Singhal AB. Narrative review: reversible cerebral vasoconstriction syndromes. Ann Intern Med 2007; 146:34. 30. Belmont HM, Abramson SB, Lie JT. Pathology and pathogenesis of vascular injury in systemic lupus erythematosus. Interactions of inflammatory cells and activated endothelium. Arthritis Rheum 1996; 39:9. 31. Ellis SG, Verity MA. Central nervous system involvement in systemic lupus erythematosus: a review of neuropathologic findings in 57 cases, 1955 1977. Semin Arthritis Rheum 1979; 8:212. 32. Hanly JG, Walsh NM, Sangalang V. Brain pathology in systemic lupus erythematosus. J Rheumatol 1992; 19:732. 33. Lyons MK, Caselli RJ, Parisi JE. Nonvasculitic autoimmune inflammatory meningoencephalitis as a cause of potentially reversible dementia: report of 4 cases. J Neurosurg 2008; 108:1024. 34. Calabrese LH, Mallek JA. Primary angiitis of the central nervous system. Report of 8 new cases, review of the literature, and proposal for diagnostic criteria. Medicine (Baltimore) 1988; 67:20. 35. Horowitz DR, Tuhrim S, Budd J, Goldman ME. Aortic plaque in patients with brain ischemia: diagnosis by transesophageal echocardiography. Neurology 1992; 42:1602. 36. Lie JT. Malignant angioendotheliomatosis (intravascular lymphomatosis) clinically simulating primary angiitis of the central nervous system. Arthritis Rheum 1992; 35:831. 37. Demirer T, Dail DH, Aboulafia DM. Four varied cases of intravascular lymphomatosis and a literature review. Cancer 1994; 73:1738. https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 24/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate 38. Nakahara T, Saito T, Muroi A, et al. Intravascular lymphomatosis presenting as an ascending cauda equina: conus medullaris syndrome: remission after biweekly CHOP therapy. J Neurol Neurosurg Psychiatry 1999; 67:403. 39. Susac JO, Hardman JM, Selhorst JB. Microangiopathy of the brain and retina. Neurology 1979; 29:313. 40. Kleffner I, Deppe M, Mohammadi S, et al. Diffusion tensor imaging demonstrates fiber impairment in Susac syndrome. Neurology 2008; 70:1867. 41. Do TH, Fisch C, Evoy F. Susac syndrome: report of four cases and review of the literature. AJNR Am J Neuroradiol 2004; 25:382. 42. Susac JO, Murtagh FR, Egan RA, et al. MRI findings in Susac's syndrome. Neurology 2003; 61:1783. 43. Dimauro S, Hirano M. Pedaling from genotype to phenotype. Arch Neurol 2006; 63:1679. 44. Richards A, van den Maagdenberg AM, Jen JC, et al. C-terminal truncations in human 3'-5' DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy. Nat Genet 2007; 39:1068. 45. Singhal AB, Hajj-Ali RA, Topcuoglu MA, et al. Reversible cerebral vasoconstriction syndromes: analysis of 139 cases. Arch Neurol 2011; 68:1005. 46. Alhalabi M, Moore PM. Serial angiography in isolated angiitis of the central nervous system. Neurology 1994; 44:1221. 47. Pomper MG, Miller TJ, Stone JH, et al. CNS vasculitis in autoimmune disease: MR imaging findings and correlation with angiography. AJNR Am J Neuroradiol 1999; 20:75. 48. Molloy ES, Singhal AB, Calabrese LH. Tumour-like mass lesion: an under-recognised presentation of primary angiitis of the central nervous system. Ann Rheum Dis 2008; 67:1732. 49. Kadkhodayan Y, Alreshaid A, Moran CJ, et al. Primary angiitis of the central nervous system at conventional angiography. Radiology 2004; 233:878. 50. Calabrese LH, Furlan AJ, Gragg LA, Ropos TJ. Primary angiitis of the central nervous system: diagnostic criteria and clinical approach. Cleve Clin J Med 1992; 59:293. 51. Vollmer TL, Guarnaccia J, Harrington W, et al. Idiopathic granulomatous angiitis of the central nervous system. Diagnostic challenges. Arch Neurol 1993; 50:925. 52. Bai HX, Zou Y, Lee AM, et al. Diagnostic Value and Safety of Brain Biopsy in Patients With Cryptogenic Neurological Disease: A Systematic Review and Meta-analysis of 831 Cases. Neurosurgery 2015; 77:283. https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 25/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate 53. Alrawi A, Trobe JD, Blaivas M, Musch DC. Brain biopsy in primary angiitis of the central nervous system. Neurology 1999; 53:858. 54. Chu CT, Gray L, Goldstein LB, Hulette CM. Diagnosis of intracranial vasculitis: a multi- disciplinary approach. J Neuropathol Exp Neurol 1998; 57:30. 55. Krawczyk M, Barra LJ, Sposato LA, Mandzia JL. Primary CNS vasculitis: A systematic review on clinical characteristics associated with abnormal biopsy and angiography. Autoimmun Rev 2021; 20:102714. 56. Parisi JE, Moore PM. The role of biopsy in vasculitis of the central nervous system. Semin Neurol 1994; 14:341. 57. Miller DV, Salvarani C, Hunder GG, et al. Biopsy findings in primary angiitis of the central nervous system. Am J Surg Pathol 2009; 33:35. 58. Lie JT. Classification and histopathologic spectrum of central nervous system vasculitis. Neurol Clin 1997; 15:805. 59. Guillevin L, Pagnoux C. When should immunosuppressants be prescribed to treat systemic vasculitides? Intern Med 2003; 42:313. 60. Gayraud M, Guillevin L, Cohen P, et al. Treatment of good-prognosis polyarteritis nodosa and Churg-Strauss syndrome: comparison of steroids and oral or pulse cyclophosphamide in 25 patients. French Cooperative Study Group for Vasculitides. Br J Rheumatol 1997; 36:1290. 61. De Boysson H, Arquizan C, Guillevin L, Pagnoux C. Rituximab for primary angiitis of the central nervous system: report of 2 patients from the French COVAC cohort and review of the literature. J Rheumatol 2013; 40:2102. 62. Salvarani C, Brown RD Jr, Huston J 3rd, et al. Treatment of primary CNS vasculitis with rituximab: case report. Neurology 2014; 82:1287. 63. Schuster S, Ozga AK, Stellmann JP, et al. Relapse rates and long-term outcome in primary angiitis of the central nervous system. J Neurol 2019; 266:1481. Topic 8230 Version 31.0 https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 26/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate GRAPHICS Carotid angiograms in primary angiitis of the central nervous system Left panel: An anteroposterior view of a right carotid angiogram in a patient with primary angiitis of the central nervous system (PACNS) reveals focal narrowing of multiple vessels in both the anterior and posterior systems. Right panel: A lateral view of a right carotid angiogram in PACNS demonstrates beading and multiple irregularities both proximally and distally. Courtesy of Leonard H Sigal, MD. Graphic 52006 Version 2.0 https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 27/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate Normal internal carotid artery angiogram An angiogram showing the normal radiographic appearance of the internal carotid artery and its branches. The internal carotid enters the skull at the carotid foramen, passes anteromedially, and then rises vertically (C6) to pass forward opposite the sella turcica (C4). The artery then passes upward within the dura (C3) and emerges below and medial to the anterior clinoid (C2), giving rise to the ophthalmic artery. The carotid then bifurcates (C1) to form the anterior and middle cerebral arteries. The anterior cerebral artery is directed anteromedially (A1) until it reaches the midline, where it turns upward (A2) to be joined by the anterior communicating artery. The middle cerebral artery extends laterally (M1). Courtesy of Leonard H Sigal, MD. Graphic 63788 Version 3.0

28. Barinagarrementeria F, Cant C. Frequency of cerebral arteritis in subarachnoid cysticercosis: an angiographic study. Stroke 1998; 29:123. 29. Calabrese LH, Dodick DW, Schwedt TJ, Singhal AB. Narrative review: reversible cerebral vasoconstriction syndromes. Ann Intern Med 2007; 146:34. 30. Belmont HM, Abramson SB, Lie JT. Pathology and pathogenesis of vascular injury in systemic lupus erythematosus. Interactions of inflammatory cells and activated endothelium. Arthritis Rheum 1996; 39:9. 31. Ellis SG, Verity MA. Central nervous system involvement in systemic lupus erythematosus: a review of neuropathologic findings in 57 cases, 1955 1977. Semin Arthritis Rheum 1979; 8:212. 32. Hanly JG, Walsh NM, Sangalang V. Brain pathology in systemic lupus erythematosus. J Rheumatol 1992; 19:732. 33. Lyons MK, Caselli RJ, Parisi JE. Nonvasculitic autoimmune inflammatory meningoencephalitis as a cause of potentially reversible dementia: report of 4 cases. J Neurosurg 2008; 108:1024. 34. Calabrese LH, Mallek JA. Primary angiitis of the central nervous system. Report of 8 new cases, review of the literature, and proposal for diagnostic criteria. Medicine (Baltimore) 1988; 67:20. 35. Horowitz DR, Tuhrim S, Budd J, Goldman ME. Aortic plaque in patients with brain ischemia: diagnosis by transesophageal echocardiography. Neurology 1992; 42:1602. 36. Lie JT. Malignant angioendotheliomatosis (intravascular lymphomatosis) clinically simulating primary angiitis of the central nervous system. Arthritis Rheum 1992; 35:831. 37. Demirer T, Dail DH, Aboulafia DM. Four varied cases of intravascular lymphomatosis and a literature review. Cancer 1994; 73:1738. https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 24/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate 38. Nakahara T, Saito T, Muroi A, et al. Intravascular lymphomatosis presenting as an ascending cauda equina: conus medullaris syndrome: remission after biweekly CHOP therapy. J Neurol Neurosurg Psychiatry 1999; 67:403. 39. Susac JO, Hardman JM, Selhorst JB. Microangiopathy of the brain and retina. Neurology 1979; 29:313. 40. Kleffner I, Deppe M, Mohammadi S, et al. Diffusion tensor imaging demonstrates fiber impairment in Susac syndrome. Neurology 2008; 70:1867. 41. Do TH, Fisch C, Evoy F. Susac syndrome: report of four cases and review of the literature. AJNR Am J Neuroradiol 2004; 25:382. 42. Susac JO, Murtagh FR, Egan RA, et al. MRI findings in Susac's syndrome. Neurology 2003; 61:1783. 43. Dimauro S, Hirano M. Pedaling from genotype to phenotype. Arch Neurol 2006; 63:1679. 44. Richards A, van den Maagdenberg AM, Jen JC, et al. C-terminal truncations in human 3'-5' DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy. Nat Genet 2007; 39:1068. 45. Singhal AB, Hajj-Ali RA, Topcuoglu MA, et al. Reversible cerebral vasoconstriction syndromes: analysis of 139 cases. Arch Neurol 2011; 68:1005. 46. Alhalabi M, Moore PM. Serial angiography in isolated angiitis of the central nervous system. Neurology 1994; 44:1221. 47. Pomper MG, Miller TJ, Stone JH, et al. CNS vasculitis in autoimmune disease: MR imaging findings and correlation with angiography. AJNR Am J Neuroradiol 1999; 20:75. 48. Molloy ES, Singhal AB, Calabrese LH. Tumour-like mass lesion: an under-recognised presentation of primary angiitis of the central nervous system. Ann Rheum Dis 2008; 67:1732. 49. Kadkhodayan Y, Alreshaid A, Moran CJ, et al. Primary angiitis of the central nervous system at conventional angiography. Radiology 2004; 233:878. 50. Calabrese LH, Furlan AJ, Gragg LA, Ropos TJ. Primary angiitis of the central nervous system: diagnostic criteria and clinical approach. Cleve Clin J Med 1992; 59:293. 51. Vollmer TL, Guarnaccia J, Harrington W, et al. Idiopathic granulomatous angiitis of the central nervous system. Diagnostic challenges. Arch Neurol 1993; 50:925. 52. Bai HX, Zou Y, Lee AM, et al. Diagnostic Value and Safety of Brain Biopsy in Patients With Cryptogenic Neurological Disease: A Systematic Review and Meta-analysis of 831 Cases. Neurosurgery 2015; 77:283. https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 25/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate 53. Alrawi A, Trobe JD, Blaivas M, Musch DC. Brain biopsy in primary angiitis of the central nervous system. Neurology 1999; 53:858. 54. Chu CT, Gray L, Goldstein LB, Hulette CM. Diagnosis of intracranial vasculitis: a multi- disciplinary approach. J Neuropathol Exp Neurol 1998; 57:30. 55. Krawczyk M, Barra LJ, Sposato LA, Mandzia JL. Primary CNS vasculitis: A systematic review on clinical characteristics associated with abnormal biopsy and angiography. Autoimmun Rev 2021; 20:102714. 56. Parisi JE, Moore PM. The role of biopsy in vasculitis of the central nervous system. Semin Neurol 1994; 14:341. 57. Miller DV, Salvarani C, Hunder GG, et al. Biopsy findings in primary angiitis of the central nervous system. Am J Surg Pathol 2009; 33:35. 58. Lie JT. Classification and histopathologic spectrum of central nervous system vasculitis. Neurol Clin 1997; 15:805. 59. Guillevin L, Pagnoux C. When should immunosuppressants be prescribed to treat systemic vasculitides? Intern Med 2003; 42:313. 60. Gayraud M, Guillevin L, Cohen P, et al. Treatment of good-prognosis polyarteritis nodosa and Churg-Strauss syndrome: comparison of steroids and oral or pulse cyclophosphamide in 25 patients. French Cooperative Study Group for Vasculitides. Br J Rheumatol 1997; 36:1290. 61. De Boysson H, Arquizan C, Guillevin L, Pagnoux C. Rituximab for primary angiitis of the central nervous system: report of 2 patients from the French COVAC cohort and review of the literature. J Rheumatol 2013; 40:2102. 62. Salvarani C, Brown RD Jr, Huston J 3rd, et al. Treatment of primary CNS vasculitis with rituximab: case report. Neurology 2014; 82:1287. 63. Schuster S, Ozga AK, Stellmann JP, et al. Relapse rates and long-term outcome in primary angiitis of the central nervous system. J Neurol 2019; 266:1481. Topic 8230 Version 31.0 https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 26/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate GRAPHICS Carotid angiograms in primary angiitis of the central nervous system Left panel: An anteroposterior view of a right carotid angiogram in a patient with primary angiitis of the central nervous system (PACNS) reveals focal narrowing of multiple vessels in both the anterior and posterior systems. Right panel: A lateral view of a right carotid angiogram in PACNS demonstrates beading and multiple irregularities both proximally and distally. Courtesy of Leonard H Sigal, MD. Graphic 52006 Version 2.0 https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 27/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate Normal internal carotid artery angiogram An angiogram showing the normal radiographic appearance of the internal carotid artery and its branches. The internal carotid enters the skull at the carotid foramen, passes anteromedially, and then rises vertically (C6) to pass forward opposite the sella turcica (C4). The artery then passes upward within the dura (C3) and emerges below and medial to the anterior clinoid (C2), giving rise to the ophthalmic artery. The carotid then bifurcates (C1) to form the anterior and middle cerebral arteries. The anterior cerebral artery is directed anteromedially (A1) until it reaches the midline, where it turns upward (A2) to be joined by the anterior communicating artery. The middle cerebral artery extends laterally (M1). Courtesy of Leonard H Sigal, MD. Graphic 63788 Version 3.0 https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 28/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate Cerebral angiography of a patient with reversible cerebral vasoconstriction syndrome Note the multiple areas of stenosis (arrows) and dilatation in multiple vessels (arrowheads) of the M2 branch of the middle cerebral artery (A) and their resolution after one month (B). Reproduced with permission from: Hajj-Ali RA, Furlan A, Abou-Chebel A, Calabrese LH. Benign angiopathy of the central nervous system: cohort of 16 patients with clinical course and long-term followup. Arthritis Rheum 2002; 47:662. Copyright 2002 John Wiley & Sons, Inc. Graphic 66139 Version 4.0 https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 29/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate Histopathologic findings of primary angiitis of the CNS Histopathologic findings of a patient with primary angiitis of the central nervous system (PACNS). Granuloma changes are present in the vessel wall. Reproduced from: Hajj-Ali RA, Langford CA. Primary angiitis of the central nervous system. In: Kelley's Textbook of Rheumatology, 9th e GS, Budd RC, Gabriel SE, et al (Eds), Saunders, Philadelphia 2013. Vol 2, p.1519. Illustration used with the permission of Elsevier Inc. All reserved. Graphic 101671 Version 2.0 https://www.uptodate.com/contents/primary-angiitis-of-the-central-nervous-system-in-adults/print 30/31 7/7/23, 11:18 AM Primary angiitis of the central nervous system in adults - UpToDate Contributor Disclosures Rula A Hajj-Ali, MD Consultant/Advisory Boards: GlaxoSmithKline [EGPA]. All of the relevant financial relationships listed have been mitigated. Leonard H Calabrese, DO No relevant financial relationship(s) with ineligible companies to disclose. Gene G Hunder, 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. Philip Seo, MD, MHS 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/primary-angiitis-of-the-central-nervous-system-in-adults/print 31/31

7/7/23, 11:20 AM Treatment and prognosis of polyarteritis nodosa - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Treatment and prognosis of polyarteritis nodosa : Peter A Merkel, MD, MPH : Kenneth J Warrington, MD : Philip Seo, MD, MHS 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: Dec 16, 2021. INTRODUCTION Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis that predominantly affects medium-sized muscular arteries and often involves small muscular arteries [1]. The approach to treatment of PAN depends upon the following variables, which require assessment before beginning therapy: The level of disease severity The presence of isolated cutaneous PAN or other isolated/single-organ disease The presence or absence of viral hepatitis The optimal therapy of PAN remains uncertain, and studies of treatment for PAN have been complicated by the admixture of patients with PAN, microscopic polyangiitis (MPA), and sometimes eosinophilic granulomatosis with polyangiitis (Churg-Strauss) within study cohorts [2-4]. The efficacy of glucocorticoids in the majority of patients with mild disease, and of glucocorticoids plus cyclophosphamide in patients with more severe disease, has been well- demonstrated in observational studies in PAN, but there are few randomized trials [2,3,5-9]. The treatment approach in PAN is also derived from indirect evidence of the efficacy of various medications and drug regiments in other forms of necrotizing vasculitis, particularly MPA and granulomatosis with polyangiitis. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy".) The treatment and prognosis of polyarteritis nodosa will be reviewed here. The clinical manifestations, diagnosis, and classification of PAN are presented separately (see "Clinical https://www.uptodate.com/contents/treatment-and-prognosis-of-polyarteritis-nodosa/print 1/25 7/7/23, 11:20 AM Treatment and prognosis of polyarteritis nodosa - UpToDate manifestations and diagnosis of polyarteritis nodosa in adults"). The diagnosis and management of cutaneous-only PAN is also discussed elsewhere. (See "Cutaneous polyarteritis nodosa".) PRETREATMENT EVALUATION Baseline evaluation Prior to treatment for polyarteritis nodosa (PAN), patients should undergo a careful history, physical examination, and laboratory evaluation; this diagnostic evaluation includes determination of the extent and severity of organ system involvement, testing for viral hepatitis (serum hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core antibody, and hepatitis C antibody), and confirmation of the diagnosis with a tissue biopsy or angiography. Laboratory testing should also include tests of renal function and disease (urinalysis, serum creatinine) and baseline complete blood count. Patients in whom the diagnosis was established without a detailed examination and testing still require such testing to obtain the information needed to determine the extent of disease, to evaluate for comorbidities, and to select the most appropriate therapeutic interventions. (See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults".) In anticipation of use of glucocorticoids and other immunosuppressive medications, clinicians may choose to test for diabetes mellitus, latent tuberculosis, human immunodeficiency virus (HIV) infection and also ensure patients are up-to-date with age-appropriate vaccinations, although the use of live vaccines may be contraindicated depending on their timing relative to initiations of therapy with immunosuppressive drugs ( table 1). Severity of disease Mild versus more severe disease An important factor in determining which medications will be used and the doses employed is whether the patient has only mild disease or disease that is of greater severity. We use the following definitions, which correspond to distinctions made in clinical trials that have examined the benefits of different agents [3,4,7,10]: Mild disease Patients with mild disease include those with constitutional symptoms, arthritis, anemia, and skin lesions, but with normal renal function and an absence of significant cardiac, neurologic, gastrointestinal, or other organ- or life-threatening manifestations. Patients with mild disease should generally be treated initially with glucocorticoids alone. (See 'Mild PAN' below.) Moderate to severe disease Patients with moderate to severe disease include those who typically exhibit more serious disease manifestations than patients with mild disease, such as any degree of renal insufficiency, new or worsened hypertension considered secondary https://www.uptodate.com/contents/treatment-and-prognosis-of-polyarteritis-nodosa/print 2/25 7/7/23, 11:20 AM Treatment and prognosis of polyarteritis nodosa - UpToDate to the vasculitis, symptomatic arterial stenosis, aneurysms, or any ischemic disease (eg, limb, cardiac, gastrointestinal, and central nervous system ischemia). These patients are generally treated initially with glucocorticoids plus a second immunosuppressive agent, typically cyclophosphamide. Subsequent management for the maintenance of remission usually involves switching from cyclophosphamide to an alternative, less toxic, immunosuppressive agent. (See 'Moderate and severe PAN' below.) The goals of therapy are the same in both mild and moderate to severe disease. The aim is to achieve remission, defined as the absence of active disease, including the resolution of potentially reversible symptoms and findings and the prevention of further progression of arterial lesions or organ damage. Our approach to therapy is generally consistent with guidelines developed by professional organizations including the American College of Rheumatology (ACR)/Vasculitis Foundation [11,12]. Isolated versus multi-organ disease The approach to isolated or single-organ PAN may differ from the approach to multisystem disease, depending upon the affected organ or tissue. Cutaneous PAN PAN confined to the skin is generally treated similarly to mild systemic PAN. (See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults", section on 'Skin disease' and 'Isolated cutaneous PAN' below.) Isolated/single-organ PAN Patients with isolated or single-organ involvement, sometimes identified at the time of an operative procedure, may not require further therapy, but should be evaluated for evidence of other manifestations and monitored subsequently. (See 'Isolated/single-organ PAN' below.) ASSOCIATED HEPATITIS B OR C INFECTION Patients with both vasculitis and hepatitis virus infection also benefit from treatment with antivirals, but the timing of therapy relative to the use of immunosuppressive agents depends upon the severity of the vasculitis. In patients in whom polyarteritis nodosa (PAN) is associated with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, the major focus of therapy is the use of antiviral agents for treatment of the underlying viral disorder. PAN continues to be associated with HBV in a substantial minority of cases, although this rate is decreasing in countries with comprehensive HBV vaccination programs. Many fewer cases of PAN are associated with HCV, which should be differentiated from HCV-associated cryoglobulinemic vasculitis. (See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults", section https://www.uptodate.com/contents/treatment-and-prognosis-of-polyarteritis-nodosa/print 3/25 7/7/23, 11:20 AM Treatment and prognosis of polyarteritis nodosa - UpToDate on 'Etiology' and "Overview of the management of chronic hepatitis C virus infection" and "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis" and "Hepatitis B virus: Overview of management" and "Hepatitis B virus: Overview of management", section on 'Indications for antiviral therapy'.) In patients with mild PAN and evidence of infection with HBV or HCV, we suggest treating initially with antivirals rather than using immunosuppressive medications. Some patients with severe manifestations of hepatitis virus-associated PAN may benefit from short-term treatment with glucocorticoids and plasma exchange until antiviral therapy becomes effective [13]. There are no randomized trials or large case series to guide decision-making in such patients; we base our approach upon the available trials in viral hepatitis and clinical experience. The treatment of HBV and HCV and the treatment of renal disease due to PAN in patients with one of these infections are discussed in detail separately. (See "Kidney disease associated with hepatitis B virus infection", section on 'Polyarteritis nodosa (PAN)' and "Overview of the management of chronic hepatitis C virus infection" and "Overview of kidney disease associated with hepatitis C virus infection", section on 'Polyarteritis nodosa' and "Hepatitis B virus: Overview of management" and "Hepatitis B virus: Overview of management", section on 'Indications for antiviral therapy'.) In patients with persistent manifestations of PAN who have an inadequate response of the PAN to treatment for viral hepatitis alone or are intolerant of such treatment, we treat the manifestations of the vasculitis with glucocorticoids and other immunosuppressive medications, depending upon the severity of the vasculitis, using the regimens that would be employed in patients without viral infection (see 'Mild PAN' below and 'Moderate and severe PAN' below). In patients with viral infection who are treated with glucocorticoids and immunosuppressive medications, particular attention should be given to the need for close monitoring of the status of the underlying viral infection and the potential for added toxicity from the immunosuppressive therapies. MILD PAN Patients with mild disease, and without evidence of hepatitis, can usually be treated initially with glucocorticoids alone, although about half of these patients will require an additional agent at some point during their treatment. The treatment approach in patients with hepatitis B or C infection is discussed separately. (See 'Initial treatment of mild PAN' below and 'Disease resistant to treatment with glucocorticoids alone' below and 'Associated hepatitis B or C infection' above.) Initial treatment of mild PAN In patients with relatively mild disease and those with isolated cutaneous disease, we suggest initial monotherapy with oral glucocorticoid as a single morning https://www.uptodate.com/contents/treatment-and-prognosis-of-polyarteritis-nodosa/print 4/25 7/7/23, 11:20 AM Treatment and prognosis of polyarteritis nodosa - UpToDate daily dose (eg, prednisone 1 mg/kg daily, up to a maximum of 60 to 80 mg daily). The initial dose should usually be continued for four weeks, at which time tapering of the glucocorticoids should begin if substantial improvement has occurred. In such patients, substantial improvement would be characterized by findings such as resolution of arthritis/arthralgia, skin lesions, and constitutional symptoms; and by the absence of new disease manifestations and of progression of neuropathy, renal disease, or other arterial lesions. We then taper the dose of prednisone steadily, but fairly slowly as long as the response is maintained, until a dose of 20 mg/day is reached by approximately month three to four. The tapering schedule is then slowed (eg, dose reduction by 2.5 mg daily every 14 days). This results in an overall course of approximately six to eight months until glucocorticoids are discontinued. (See 'Mild versus more severe disease' above and 'Isolated cutaneous PAN' below.) This approach is based upon the potential benefit of glucocorticoids alone seen in retrospective studies [6-8] and in patients with mild polyarteritis nodosa (PAN) and microscopic polyangiitis in the nonrandomized initial phase of a randomized trial [2]. As examples: A retrospective analysis of patients with PAN that was not limited to those with mild disease found that patients treated with glucocorticoids alone, when compared with clinically similar patients who did not received glucocorticoids, experienced substantially longer median survival (63 versus 3 months) and five-year survival (53 versus 12 percent) [8]. Glucocorticoids have not been compared with treatment with placebo alone in a randomized trial. In a randomized trial of patients with mild PAN or microscopic polyangiitis designed to compare cyclophosphamide and azathioprine in patients who had sustained disease or relapse despite glucocorticoid therapy, 79 percent of patients achieved remission with initial glucocorticoid therapy prior to the randomized trial period [2]; half of these patients had a sustained remission without requiring additional immunosuppression. Alternatively, some experts advocate longer treatment courses with glucocorticoids, especially if no other immunosuppressive agent is prescribed concurrently, but trials have not been performed to prospectively compare the long-term outcomes of different durations of therapy. Some patients may require a slower taper. Those who respond to glucocorticoids alone are spared the risk of adverse effects associated with the use of cyclophosphamide or other immunosuppressive drugs. However, treatment with glucocorticoids may be associated with multiple adverse effects. The risks of systemic glucocorticoids and prophylaxis for glucocorticoid-induced osteoporosis are discussed in detail https://www.uptodate.com/contents/treatment-and-prognosis-of-polyarteritis-nodosa/print 5/25 7/7/23, 11:20 AM Treatment and prognosis of polyarteritis nodosa - UpToDate separately. (See "Major side effects of systemic glucocorticoids" and "Prevention and treatment of glucocorticoid-induced osteoporosis".) Disease resistant to treatment with glucocorticoids alone In patients with mild disease or isolated cutaneous PAN who are resistant to or intolerant of the dose of glucocorticoids required for disease control, we suggest the addition of either azathioprine (2 mg/kg daily) or methotrexate (20 to 25 mg once weekly) to glucocorticoid therapy to allow use of a lower dose of glucocorticoids while achieving or maintaining disease control. Such patients include those who do not respond to glucocorticoids alone within three months, whose glucocorticoid dose cannot be tapered to an acceptable level (eg, prednisone 10 mg/day) without experiencing a relapse of disease, who are at high risk of adverse effects for the expected treatment course with glucocorticoids, or in whom the adverse effects of continued glucocorticoids in the dose being used are unacceptable. The choice between methotrexate and azathioprine depends upon the individual toxicity profiles, and patient and clinician preferences regarding dosing and administration of the drugs. Methotrexate is likely faster-acting, but should be avoided in patients with renal disease or hepatitis. We thus prefer azathioprine in patients with renal disease and in patients with hepatic disease, who should be closely monitored for hepatotoxicity. In patients with mild disease who require an immunosuppressive agent in addition to glucocorticoids, we suggest treatment with the added immunosuppressive agent for at least one year following attainment of clinical remission, based upon our clinical experience in patients with PAN and other forms of systemic vasculitis. As with other systemic vasculitides, some patients may require an extended course of treatment or resumption of treatment with low-dose glucocorticoids ( 10 mg/day of prednisone) to prevent recurrence of mild symptoms; low-dose glucocorticoids may be required even in patients also receiving another immunosuppressive agent. The approach to tapering of the glucocorticoids is the same as in patients who do not require an additional immunosuppressive agent. (See 'Initial treatment of mild PAN' above.) There are few randomized trials in patients with PAN that have directly compared the efficacy of azathioprine, methotrexate, cyclophosphamide, and mycophenolate, but we generally avoid the use of cyclophosphamide in patients with mild PAN. One small randomized trial has shown similar benefit but lower toxicity with azathioprine compared with cyclophosphamide in such patients [2]. Additionally, cyclophosphamide has greater toxicity compared with azathioprine or methotrexate in our experience in PAN and in trials in other forms of systemic necrotizing vasculitis, as well as in observational studies [5,8,9]. Another small trial of 95 patients with a case mix of PAN, eosinophilic granulomatosis with polyangiitis (Churg-Strauss), and microscopic polyangiitis compared the addition of azathioprine or placebo to standard daily oral https://www.uptodate.com/contents/treatment-and-prognosis-of-polyarteritis-nodosa/print 6/25 7/7/23, 11:20 AM Treatment and prognosis of polyarteritis nodosa - UpToDate glucocorticoids for patients classified as having nonsevere disease (as defined by a Five-Factor Score [FFS] of zero) [14] (see 'Morbidity and mortality' below). The trial found no benefit of azathioprine in terms of rates of attaining remission, risk of relapse, or cumulative dose of glucocorticoids. However, the admixture of patients with three forms of vasculitis, of which only 19 out of 51 (37 percent) had PAN, makes interpretation and implementation of these results difficult for the treatment of PAN. The small sample size of patients with PAN precluded disease- specific subset efficacy analysis. More data are needed on the efficacy of azathioprine and methotrexate as "steroid-sparing" agents for patients with mild PAN to guide therapy. We prefer to use either methotrexate or azathioprine over mycophenolate (2000 to 3000 mg/day) [15-19]. Mycophenolate has been shown to be less efficacious than azathioprine for maintenance of remission in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis [19], but there are no trial data in PAN to directly inform practice. MODERATE AND SEVERE PAN We generally treat patients with moderate to severe polyarteritis nodosa (PAN) with both high- dose glucocorticoids and a second immunosuppressive drug, such as cyclophosphamide, followed by azathioprine or methotrexate for remission maintenance. (See 'Initial treatment of moderate and severe PAN' below and 'Remission-maintenance immunosuppression' below.) Patients with concomitant viral hepatitis and moderate to severe PAN may require an initial course of glucocorticoid and immunosuppressive therapy before or concurrently with initiation antiviral medications. The goal of the glucocorticoid and immunosuppressive treatment in this setting is to treat the acute inflammatory process and stabilize the patient until the antiviral therapy becomes effective. The treatment approach in patients with hepatitis B or C infection is discussed separately. (See 'Initial treatment of mild PAN' above and 'Disease resistant to treatment with glucocorticoids alone' above and 'Associated hepatitis B or C infection' above.) Initial treatment of moderate and severe PAN In patients with moderate to severe disease (eg, any evidence of renal insufficiency, significant proteinuria, gastrointestinal, cardiac, or neurologic involvement) we recommend treatment with both glucocorticoids and cyclophosphamide. (See 'Glucocorticoid regimen' below and 'Cyclophosphamide regimen' below.) This approach is supported by observations from long-term follow-up studies in several cohorts of patients with PAN and other vasculitides that patients with more serious disease manifestations (eg, renal insufficiency, cardiac disease, mesenteric artery ischemia) had better outcomes, including rates of survival, when treated with an initial combination of https://www.uptodate.com/contents/treatment-and-prognosis-of-polyarteritis-nodosa/print 7/25 7/7/23, 11:20 AM Treatment and prognosis of polyarteritis nodosa - UpToDate cyclophosphamide and glucocorticoids compared with those who were treated with glucocorticoids alone [3,4,6,8]. In our experience, use of oral and intravenous cyclophosphamide results in a similar degree of benefit. While the comparative efficacy of treatment with oral and intravenous cyclophosphamide has been studied in antineutrophil cytoplasmic antibody (ANCA)- associated vasculitis, similar comparisons in patients with PAN have not been performed [20-22]. Additionally, one randomized trial of patients with moderate to severe disease, involving 18 patients with PAN and 47 with microscopic polyangiitis compared treatment with 12 or 6 monthly pulses of cyclophosphamide, in addition to glucocorticoid therapy; the group treated with 12 monthly pulses of cyclophosphamide had a reduced risk of relapse and a higher event free survival rate compared with those receiving only six monthly pulses over a mean follow-up period of 32 months (hazard ratios 0.34 and 0.44, respectively) [23]. Mortality between the groups did not differ. This study did not include a remission-maintenance regimen with an alternative immunosuppressive regimen, and some toxicities of cyclophosphamide only become apparent several years after treatment (eg, premature ovarian failure or bladder cancer). Further support for the use of cyclophosphamide for remission-induction is more indirect and is based upon randomized trials using these medications in patients with other forms of necrotizing vasculitis. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy" and "Eosinophilic granulomatosis with polyangiitis (Churg- Strauss): Treatment and prognosis".) Glucocorticoid regimen We use the following glucocorticoid regimens, together with the use of cyclophosphamide, which depend upon the severity of disease: In patients with moderate to severe disease, but without organ- or life-threatening involvement or progressive mononeuritis multiplex, we initiate therapy with orally administered glucocorticoids (prednisone 1 mg/kg), using the same treatment regimen as outlined for patients with mild disease, with a gradual taper over six to eight months. (See 'Initial treatment of mild PAN' above.) In patients with severe disease, manifested by organ- or life-threatening disease or progressively worsening mononeuritis multiplex, we initiate glucocorticoid therapy with intravenous methylprednisolone (7 to 15 mg/kg to a maximum of 500 to 1000 mg administered intravenously once daily for three days), followed by the oral prednisone regimen. Pulse therapy provides more rapid control of disease, in our experience. This approach is also supported by other experts, but there are no randomized trials comparing pulse with high-dose oral glucocorticoid therapy in patients with PAN [24]. https://www.uptodate.com/contents/treatment-and-prognosis-of-polyarteritis-nodosa/print 8/25 7/7/23, 11:20 AM Treatment and prognosis of polyarteritis nodosa - UpToDate Cyclophosphamide regimen The optimal route, dose, or duration of treatment with cyclophosphamide for PAN is uncertain, and there are no randomized trials comparing intravenous and oral routes of therapy for PAN. Given that current practice for the use of cyclophosphamide in vasculitis is to limit treatment with drug to four to six months, the route of administration is now less of deciding factor since the differences between potential toxicities between oral and intravenous administration is lessened with reduced exposure. Theoretically, compared with oral therapy, intravenous therapy may be associated with lower cumulative dose and potentially reduced risk of bone marrow, bladder, ovarian, and testicular toxicity. However, oral therapy with cyclophosphamide is an alternative preferred by some patients for its convenience and by some experts because of the long experience with this approach in ANCA- associated vasculitis, such as granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). (See "General principles of the use of cyclophosphamide in rheumatic diseases" and "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy".) When intravenous cyclophosphamide is used, we prefer the regimen employed in the CYCLOPS trial consisting of cyclophosphamide 15 mg/kg administered at weeks 0, 2, and 4, and then every 3 weeks [20]. Based upon data in other forms of vasculitis and our experience, we generally avoid courses of cyclophosphamide longer than four months if remission has been achieved by that time. An alternative regimen is intravenous pulse therapy with 2 cyclophosphamide (600 mg/m ) every two weeks for three doses, in addition to the glucocorticoid regimen, then every four weeks for at least four months and until a stable remission has been achieved, but for no greater than six months. The data supporting the use of cyclophosphamide are limited, and come from several observational studies [3,7,10,23,25]. All the recommended doses of cyclophosphamide, both by oral and intravenous routes, must be adjusted for renal function, age, and in response to possibly neutropenia or other hematologic toxicities. The use of cyclophosphamide, including monitoring and prevention of adverse effects, and strategies for dose adjustments are discussed in detail separately. (See "General principles of the use of cyclophosphamide in rheumatic diseases".) Treatment with cyclophosphamide (oral or intravenous) is associated with a number of potential adverse effects, including cytopenias, gastrointestinal upset, alopecia, amenorrhea, infertility (in males and females) and premature ovarian failure, myelodysplasia, cardiomyopathy, hemorrhagic cystitis, and an increase in the risk of malignancy, especially bladder cancer. (See "General toxicity of cyclophosphamide in rheumatic diseases".) Resistant disease Infrequently, patients may not respond adequately to glucocorticoids and cyclophosphamide treatment. In patients with moderate to severe PAN who have ongoing https://www.uptodate.com/contents/treatment-and-prognosis-of-polyarteritis-nodosa/print 9/25 7/7/23, 11:21 AM Treatment and prognosis of polyarteritis nodosa - UpToDate severe or worsening disease that is not controlled by treatment with glucocorticoids and cyclophosphamide within two to three months, we treat with pulse glucocorticoids (eg, 1000 mg methylprednisolone administered intravenously daily for three days), followed by prednisone (1 mg/kg daily taken orally), and switch from cyclophosphamide to a different immunosuppressive agent. This approach is based upon the evidence supporting use of this strategy in patients with ANCA-associated vasculitis and our experience in patients with PAN, as there are no direct comparisons of different treatment options in patients with resistant PAN. We base the choice of alternative immunosuppressive agent on the patient's history of medication use and comorbidities. We usually prescribe an agent not previously used by the patient from among the following: azathioprine, methotrexate, or mycophenolate (see 'Disease resistant to treatment with glucocorticoids alone' above). Rituximab is an option for the treatment of patients without hepatitis B virus (HBV) infection whose disease is resistant to control with cyclophosphamide and subsequent use for at least three months each of one or two of these alternative immunosuppressive agents. It has not been formally evaluated in this setting, with only a few case reports published of this approach, but the use of rituximab in PAN is possibly supported by the efficacy of this approach in patients with ANCA-associated vasculitis [26,27]. In patients treated with rituximab, we use the same regimen as is utilized in patients with granulomatosis with polyangiitis (see "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy"). An extremely small number of case reports have been published describing treatment of PAN with anti-tumor necrosis factor alpha agents [28], tocilizumab [29], and tofacitinib [30], but, as is common when reviewing such small series, publication bias and other factors make interpretation and application of these results difficult. Remission-maintenance immunosuppression In patients who have completed a course of therapy with cyclophosphamide, we switch to another immunosuppressive agent, such as azathioprine (2 mg/kg daily) or methotrexate (20 to 25 mg once weekly), for a total duration of immunosuppressive therapy (including cyclophosphamide and the subsequent agent) of 18 months. (See 'Cyclophosphamide regimen' above.) We avoid the continued use of cyclophosphamide for remission maintenance due to its toxicity and prefer to use either azathioprine or methotrexate over mycophenolate for this purpose [15- 19]. The choice between methotrexate and azathioprine often depends on the individual toxicity profiles and dosing regimens. Methotrexate is likely faster-acting, but should be avoided in patients with renal disease or hepatitis. In patients with poor tolerance of, or contraindications to, azathioprine or methotrexate, we use mycophenolate mofetil (2000 to 3000 mg daily). The highest tolerated dose of a given agent, up to the recommended maximum, should be used for several months before presuming it is insufficient, and that another medication is required. https://www.uptodate.com/contents/treatment-and-prognosis-of-polyarteritis-nodosa/print 10/25 7/7/23, 11:21 AM Treatment and prognosis of polyarteritis nodosa - UpToDate This approach is supported indirectly by randomized trials and experience in patients with ANCA-associated vasculitis, but there are no randomized trials or observational studies that have formally examined this approach or compared azathioprine, cyclophosphamide, methotrexate, and mycophenolate in patients with PAN in this setting [2]. Nonetheless, use of this strategy in patients with PAN has been effective in our experience. The use of this approach in ANCA- associated vasculitis is discussed in detail separately. (See "Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): Treatment and prognosis" and "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Maintenance therapy'.) The monitoring and potential adverse effects of azathioprine, methotrexate, and mycophenolate mofetil are discussed in detail separately. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases" and "Major side effects of low-dose methotrexate" and "Use of methotrexate in the treatment of rheumatoid arthritis" and "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases" and "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Maintenance therapy'.) Hypertension As with most forms of hypertension, especially in the setting of renal insufficiency, obtaining adequate control of the blood pressure is a key goal of treatment. Hypertension can be a major therapeutic issue in patients with polyarteritis nodosa. The elevation in blood pressure may be severe and is often mediated by ischemia-induced activation of the renin-angiotensin system [31]. The intrarenal large vessel disease in PAN may, therefore, be the functional equivalent of extrarenal vascular disease in bilateral renal artery stenosis. (See "Renal effects of ACE inhibitors in hypertension".) We suggest the use of angiotensin-converting enzyme (ACE) inhibitors in PAN because they are generally effective in this setting [32]. However, they may worsen renal function due to removal of the effect of angiotensin II on autoregulation and maintenance of the glomerular filtration rate. Switching to other antihypertensive agents (such as calcium channel blockers) may be required if an ACE inhibitor induces a clinically significant elevation (30 percent or greater) in the plasma creatinine concentration. (See "Renal effects of ACE inhibitors in hypertension", section on 'Renovascular hypertension'.) Limited role of plasma exchange Plasma exchange has not been shown to be beneficial for the treatment of PAN that is not associated with HBV infection [25,33,34]; however, it may have a role in the acute management of HBV-associated PAN [13]. The treatment of HBV-associated PAN is discussed separately. (See 'Associated hepatitis B or C infection' above and "Kidney disease associated with hepatitis B virus infection", section on 'Polyarteritis nodosa (PAN)'.) https://www.uptodate.com/contents/treatment-and-prognosis-of-polyarteritis-nodosa/print 11/25 7/7/23, 11:21 AM Treatment and prognosis of polyarteritis nodosa - UpToDate Pneumocystis jirovecii (PCP) prophylaxis Prophylaxis for Pneumocystis jirovecii (PCP) infection should be employed in patients being treated for PAN using the regimens associated with such risk in patients with granulomatosis with polyangiitis, such as a significant dose of glucocorticoids (eg, 20 mg of prednisone daily for one month or longer) in combination with a second immunosuppressive drug, particularly a cytotoxic agent (eg, cyclophosphamide). (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Indications'.) ISOLATED AND SINGLE-ORGAN PAN The approach to isolated or single-organ polyarteritis nodosa (PAN) depends upon the affected organ or tissue. Cutaneous PAN is generally treated similarly to mild systemic PAN (see 'Isolated cutaneous PAN' below), while isolated organ involvement, sometimes identified at the time of an operative procedure, may not require further therapy. (See 'Isolated/single-organ PAN' below.) Isolated cutaneous PAN The treatment for isolated cutaneous PAN varies depending on the severity of the cutaneous manifestations and associated symptoms. A detailed discussion on the diagnosis and treatment of cutaneous PAN is presented elsewhere. (See "Cutaneous polyarteritis nodosa".) Patients with isolated cutaneous disease when first seen and initially treated may relapse with disease in other organs, and should be monitored periodically as are other patients with mild disease. (See 'Monitoring of disease' below.) Isolated/single-organ PAN Isolated single-organ PAN, other than isolated cutaneous disease, is usually a monocyclic disease, which typically does not relapse, that is diagnosed by histological examination of surgical specimens. Treatment beyond surgical excision (eg, of isolated PAN of the gallbladder) is usually not necessary [35]. However, we fully evaluate such patients initially and provide regular clinical follow-up (every three months in the first year and every 6 to 12 months thereafter) to determine if additional anatomic areas or other clinical features are present or developing. (See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults" and 'Monitoring of disease' below.) MONITORING OF DISEASE Patients with polyarteritis nodosa (PAN) require regular, long-term follow-up to monitor the disease and drug safety by a clinician familiar with the disease and its treatments. Patients must be monitored for the possibility of disease relapse, particularly in organ systems involved at https://www.uptodate.com/contents/treatment-and-prognosis-of-polyarteritis-nodosa/print 12/25 7/7/23, 11:21 AM Treatment and prognosis of polyarteritis nodosa - UpToDate disease onset. However, it is important to recognize that patients with PAN may have relapses of disease that include clinical manifestations of vasculitis not present at diagnosis [36]. We generally see patients at least monthly during the initial phase of therapy, until clinically stable, then at least every three months during the first two years of treatment. We continue to follow patients who have been in remission for two years every three to six months. Even after two years of remission, all patients should be followed indefinitely at some reasonable frequency (eg, every 6 to 12 months) since relapses may occur years after initial presentation and attainment of remission, which may be defined for patients with PAN as the absence of any evidence of active disease. In addition to routine physical examinations, including blood pressure testing, a review of systems, and laboratory monitoring for drug toxicities, a serum creatinine and urinalysis should be obtained. New symptoms or findings should be evaluated for their potential to represent recurrent vasculitis, even if such symptoms or findings are different from the original presenting manifestations of disease. Additionally, patients must be followed and treated for the medium- and long-term clinical sequelae of both treatment toxicities and disease-related long-term organ damage. Patients with cutaneous-only PAN or other single-organ presentations of PAN must also be followed regularly for the possible development of disease in new organ systems. In addition to clinical examinations and appropriate follow-up of patient-reported symptoms, periodic testing of serum creatinine and a urinalysis can help monitor for asymptomatic renal disease. Follow-up angiography is not required unless there are signs or symptoms suggestive of new disease, concerns for ischemia that may require intervention, or aneurysms that are at risk for expansion or rupture and may require intervention. Depending on the anatomic location and size of affected arteries, magnetic resonance imaging (MRI) or computed tomographic (CT) angiography may be substituted for catheter-based angiography. The choice of which imaging modality (MR, CT, or catheter-based) to use will depend upon the availability of equipment and expertise at a medical center and may be influenced by an interest in utilizing the same approach used for prior evaluations to allow for direct comparisons. Some complications of PAN can occur when the disease is clinically inactive, since healing of inflamed vessels can lead to progressive narrowing of the vascular lumina and resultant organ ischemia. Such changes should be distinguished from active disease, as they require appropriate supportive care rather than immunosuppression. As an example, a slowly progressive elevation in the serum creatinine concentration occurs in some patients in whom the signs of active vasculitis (such as systemic symptoms and an active urine sediment) have abated. The primary problem in this situation is diminished glomerular flow, not vascular inflammation. Sometimes serial angiograms or a renal biopsy is required to help differentiate active from inactive disease. https://www.uptodate.com/contents/treatment-and-prognosis-of-polyarteritis-nodosa/print 13/25 7/7/23, 11:21 AM Treatment and prognosis of polyarteritis nodosa - UpToDate RECURRENT DISEASE The treatment of recurrent disease depends upon the severity of the flare and whether recurrence occurs on or off immunosuppressive treatment. Mild disease recurrence may be treated by use of glucocorticoids alone, and/or an increase in dose of immunosuppressive drug, depending upon the patient's treatment at the time of disease exacerbation or recurrence. Moderate to severe relapse requires reinitiation of remission-induction treatment (see 'Initial

"Renal effects of ACE inhibitors in hypertension".) We suggest the use of angiotensin-converting enzyme (ACE) inhibitors in PAN because they are generally effective in this setting [32]. However, they may worsen renal function due to removal of the effect of angiotensin II on autoregulation and maintenance of the glomerular filtration rate. Switching to other antihypertensive agents (such as calcium channel blockers) may be required if an ACE inhibitor induces a clinically significant elevation (30 percent or greater) in the plasma creatinine concentration. (See "Renal effects of ACE inhibitors in hypertension", section on 'Renovascular hypertension'.) Limited role of plasma exchange Plasma exchange has not been shown to be beneficial for the treatment of PAN that is not associated with HBV infection [25,33,34]; however, it may have a role in the acute management of HBV-associated PAN [13]. The treatment of HBV-associated PAN is discussed separately. (See 'Associated hepatitis B or C infection' above and "Kidney disease associated with hepatitis B virus infection", section on 'Polyarteritis nodosa (PAN)'.) https://www.uptodate.com/contents/treatment-and-prognosis-of-polyarteritis-nodosa/print 11/25 7/7/23, 11:21 AM Treatment and prognosis of polyarteritis nodosa - UpToDate Pneumocystis jirovecii (PCP) prophylaxis Prophylaxis for Pneumocystis jirovecii (PCP) infection should be employed in patients being treated for PAN using the regimens associated with such risk in patients with granulomatosis with polyangiitis, such as a significant dose of glucocorticoids (eg, 20 mg of prednisone daily for one month or longer) in combination with a second immunosuppressive drug, particularly a cytotoxic agent (eg, cyclophosphamide). (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Indications'.) ISOLATED AND SINGLE-ORGAN PAN The approach to isolated or single-organ polyarteritis nodosa (PAN) depends upon the affected organ or tissue. Cutaneous PAN is generally treated similarly to mild systemic PAN (see 'Isolated cutaneous PAN' below), while isolated organ involvement, sometimes identified at the time of an operative procedure, may not require further therapy. (See 'Isolated/single-organ PAN' below.) Isolated cutaneous PAN The treatment for isolated cutaneous PAN varies depending on the severity of the cutaneous manifestations and associated symptoms. A detailed discussion on the diagnosis and treatment of cutaneous PAN is presented elsewhere. (See "Cutaneous polyarteritis nodosa".) Patients with isolated cutaneous disease when first seen and initially treated may relapse with disease in other organs, and should be monitored periodically as are other patients with mild disease. (See 'Monitoring of disease' below.) Isolated/single-organ PAN Isolated single-organ PAN, other than isolated cutaneous disease, is usually a monocyclic disease, which typically does not relapse, that is diagnosed by histological examination of surgical specimens. Treatment beyond surgical excision (eg, of isolated PAN of the gallbladder) is usually not necessary [35]. However, we fully evaluate such patients initially and provide regular clinical follow-up (every three months in the first year and every 6 to 12 months thereafter) to determine if additional anatomic areas or other clinical features are present or developing. (See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults" and 'Monitoring of disease' below.) MONITORING OF DISEASE Patients with polyarteritis nodosa (PAN) require regular, long-term follow-up to monitor the disease and drug safety by a clinician familiar with the disease and its treatments. Patients must be monitored for the possibility of disease relapse, particularly in organ systems involved at https://www.uptodate.com/contents/treatment-and-prognosis-of-polyarteritis-nodosa/print 12/25 7/7/23, 11:21 AM Treatment and prognosis of polyarteritis nodosa - UpToDate disease onset. However, it is important to recognize that patients with PAN may have relapses of disease that include clinical manifestations of vasculitis not present at diagnosis [36]. We generally see patients at least monthly during the initial phase of therapy, until clinically stable, then at least every three months during the first two years of treatment. We continue to follow patients who have been in remission for two years every three to six months. Even after two years of remission, all patients should be followed indefinitely at some reasonable frequency (eg, every 6 to 12 months) since relapses may occur years after initial presentation and attainment of remission, which may be defined for patients with PAN as the absence of any evidence of active disease. In addition to routine physical examinations, including blood pressure testing, a review of systems, and laboratory monitoring for drug toxicities, a serum creatinine and urinalysis should be obtained. New symptoms or findings should be evaluated for their potential to represent recurrent vasculitis, even if such symptoms or findings are different from the original presenting manifestations of disease. Additionally, patients must be followed and treated for the medium- and long-term clinical sequelae of both treatment toxicities and disease-related long-term organ damage. Patients with cutaneous-only PAN or other single-organ presentations of PAN must also be followed regularly for the possible development of disease in new organ systems. In addition to clinical examinations and appropriate follow-up of patient-reported symptoms, periodic testing of serum creatinine and a urinalysis can help monitor for asymptomatic renal disease. Follow-up angiography is not required unless there are signs or symptoms suggestive of new disease, concerns for ischemia that may require intervention, or aneurysms that are at risk for expansion or rupture and may require intervention. Depending on the anatomic location and size of affected arteries, magnetic resonance imaging (MRI) or computed tomographic (CT) angiography may be substituted for catheter-based angiography. The choice of which imaging modality (MR, CT, or catheter-based) to use will depend upon the availability of equipment and expertise at a medical center and may be influenced by an interest in utilizing the same approach used for prior evaluations to allow for direct comparisons. Some complications of PAN can occur when the disease is clinically inactive, since healing of inflamed vessels can lead to progressive narrowing of the vascular lumina and resultant organ ischemia. Such changes should be distinguished from active disease, as they require appropriate supportive care rather than immunosuppression. As an example, a slowly progressive elevation in the serum creatinine concentration occurs in some patients in whom the signs of active vasculitis (such as systemic symptoms and an active urine sediment) have abated. The primary problem in this situation is diminished glomerular flow, not vascular inflammation. Sometimes serial angiograms or a renal biopsy is required to help differentiate active from inactive disease. https://www.uptodate.com/contents/treatment-and-prognosis-of-polyarteritis-nodosa/print 13/25 7/7/23, 11:21 AM Treatment and prognosis of polyarteritis nodosa - UpToDate RECURRENT DISEASE The treatment of recurrent disease depends upon the severity of the flare and whether recurrence occurs on or off immunosuppressive treatment. Mild disease recurrence may be treated by use of glucocorticoids alone, and/or an increase in dose of immunosuppressive drug, depending upon the patient's treatment at the time of disease exacerbation or recurrence. Moderate to severe relapse requires reinitiation of remission-induction treatment (see 'Initial treatment of moderate and severe PAN' above). If moderate-severe recurrence occurs when the patient is on immunosuppressive treatment, a different immunosuppressive agent should be used. (See 'Resistant disease' above.) PROGNOSIS Morbidity and mortality Untreated polyarteritis nodosa (PAN) is associated with a poor prognosis (13 percent five-year survival) [5,6]. The outcome of PAN has improved in patients receiving treatment; five-year survival is approximately 80 percent [7]. The survival rates for patients with hepatitis B virus (HBV)-associated PAN are lower than for patients with non-HBV- associated disease. In one large cohort, the one- and five-year survival rates were substantially higher among patients diagnosed after 1995 compared with prior to 1995, possibly indicative of more rapid and widespread use of cyclophosphamide for more severe disease [7]. Whether prognosis of HBV-associated PAN has improved with the introduction of newer antiviral treatments is not known. Most deaths in patients with PAN due to active disease occur within 18 months of disease onset [4,7]. Survival is better among those with limited organ involvement. Renal failure and mesenteric, cardiac, or cerebral infarction are the major causes of death. Some of these complications can occur at a time when the disease is clinically inactive, since healing of inflamed vessels can lead to progressive narrowing of the vascular lumina and resultant organ ischemia. Preservation of tissue function is most likely if treatment is instituted early in the course of the disease. Improvement in renal function may be seen even in patients who initially require dialysis. In this setting, sufficient recovery to allow the patient to be maintained off dialysis for one to two years or more occurs in up to 60 percent of cases [37] and in approximately 10 percent who undergo dialysis for as long as three to six months [38]. The French Vasculitis Study Group (FVSG) has established a large, well-characterized longitudinal cohort of patients with PAN and reported a comprehensive series of studies on the natural history and treatment of this disorder [7]. Using regression analytic techniques, this group https://www.uptodate.com/contents/treatment-and-prognosis-of-polyarteritis-nodosa/print 14/25 7/7/23, 11:21 AM Treatment and prognosis of polyarteritis nodosa - UpToDate derived the "Five-Factor Score" (FFS) in 1996 as a simple prognostic tool for clinicians to use when evaluating patients with various forms of vasculitis, including PAN [4,10,25]. The FFS was revised in 2011 based upon additional data and for PAN now only includes four factors associated with increased mortality: i) age >65 years, ii) cardiac symptoms, iii) gastrointestinal involvement, and iv) renal insufficiency (plasma creatinine >1.7 mg/dL [150 micromol/L]) [10]. The original FFS had included central nervous system disease (dropped from the score in 2011) but did not include age (included in 2011). The FFS has been used to stratify patients in treatment studies; this tool is helpful in both interpreting the data and formulating an approach to treatment of PAN. However, the FFS is based upon mortality and is not designed to predict either relapse or long-term morbidity, both of which are also important outcomes that influence treatment decisions in PAN. Relapse rates Although the proportion of patients with PAN with monocyclic disease courses (ie, a single episode of disease activity without a subsequent relapse) is substantially higher than in many other forms of vasculitis, especially the antineutrophil cytoplasmic antibody (ANCA)- associated diseases (granulomatosis with polyangiitis, microscopic polyangiitis [MPA], and eosinophilic granulomatosis with polyangiitis [Churg-Strauss]), the relapse rate in PAN is still substantial. For example, in a series of 348 patients, the one and five-year relapse rates for patients with non-HBV-associated PAN were at least 9.2 percent and 24 percent, respectively; the relapse rates for HBV-associated PAN were lower [7]. Renal transplantation Few data exist concerning the outcome of patients with PAN and end- stage kidney disease who undergo renal transplantation. Among 112 patients with PAN reported in the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) registry, transplantation was associated with significantly lower patient (77 versus 91 percent) and first cadaveric allograft (60 versus 69 percent) survival rates compared with those diagnosed with other renal diseases (eg, glomerulonephritis, interstitial nephritis, toxic nephropathies, and cystic kidney disease) [39]. Thirteen percent of graft failures were reportedly due to recurrent 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: Vasculitis" and "Society guideline links: Polyarteritis nodosa".) INFORMATION FOR PATIENTS https://www.uptodate.com/contents/treatment-and-prognosis-of-polyarteritis-nodosa/print 15/25 7/7/23, 11:21 AM Treatment and prognosis of polyarteritis nodosa - 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: Polyarteritis nodosa (The Basics)") SUMMARY AND RECOMMENDATIONS For patients with polyarteritis nodosa (PAN) with relatively mild disease (constitutional symptoms, arthritis, anemia, but normal renal function and no gastrointestinal, cardiac, or neurologic manifestations), we suggest initial treatment with oral glucocorticoid monotherapy, rather than combining glucocorticoids and another immunosuppressive medication (Grade 2C). We use an initial dose of prednisone of 1 mg/kg per day (maximum 60 to 80 mg daily), typically for approximately four weeks, at which time slow tapering of the glucocorticoids (over approximately six to eight months) can be started if substantial improvement has occurred. We also employ this approach in patients with isolated cutaneous disease. (See 'Mild PAN' above.) In patients with mild disease who are resistant to or intolerant of the dose of glucocorticoids required for disease control, we suggest the addition of azathioprine or methotrexate, rather than adding cyclophosphamide (Grade 2C). Such patients include those who do not respond to glucocorticoids alone, whose glucocorticoid dose cannot be tapered to an acceptable level (eg, prednisone 10 mg/day) without experiencing a relapse of disease, who are at high risk of adverse effects for the expected treatment course with glucocorticoids, or in whom the adverse effects of continued glucocorticoids in the dose being used are unacceptable. The usual doses are azathioprine, 2 mg/kg daily; or methotrexate, 20 to 25 mg once weekly. Mycophenolate mofetil (2000 to 3000 mg daily) is an alternative in patients unable to use azathioprine or methotrexate. (See 'Disease resistant to treatment with glucocorticoids alone' above.) https://www.uptodate.com/contents/treatment-and-prognosis-of-polyarteritis-nodosa/print 16/25 7/7/23, 11:21 AM Treatment and prognosis of polyarteritis nodosa - UpToDate In patients with moderate to severe disease (eg, any evidence of renal insufficiency, significant proteinuria, gastrointestinal, cardiac, or neurologic involvement), we recommend treatment with both glucocorticoids and cyclophosphamide rather than glucocorticoids alone (Grade 1B). (See 'Initial treatment of moderate and severe PAN' above.) In most patients prednisone is administered orally (1 mg/kg daily to a maximum of 60 to 80 mg daily), but in patients with severe, life-threatening manifestations or worsening mononeuritis multiplex we usually administer intravenous methylprednisolone initially (7 to 15 mg/kg to a maximum of 500 to 1000 mg administered intravenously once daily for three days) prior to the oral prednisone regimen. The initial oral prednisone dose is continued for two to four weeks, until significant improvement is observed. The dose should then be tapered slowly, for an overall course of approximately six to eight months. (See 'Glucocorticoid regimen' above.) Cyclophosphamide may be administered by either intravenous or oral administration. We prefer the use of intravenous pulse therapy with cyclophosphamide 15 mg/kg administered at weeks 0, 2, and 4, and then every 3 weeks for at least 4 months and until a stable remission has been achieved, but for no greater than 6 months. (See 'Moderate and severe PAN' above.) In patients treated with cyclophosphamide, we switch for remission maintenance to another immunosuppressive agent, such as azathioprine (2 mg/kg daily) or methotrexate (20 to 25 mg once weekly), for a total duration of immunosuppressive therapy of 18 months. (See 'Remission-maintenance immunosuppression' above.) In the infrequent patient with moderate to severe PAN who has ongoing severe or worsening disease that is not controlled by treatment with glucocorticoids and cyclophosphamide within two to three months, we treat with pulse glucocorticoids (eg, 1000 mg methylprednisolone administered intravenously daily for 3 days), followed by prednisone (1 mg/kg daily taken orally) and switch from cyclophosphamide to a different immunosuppressive agent, azathioprine (2 mg/kg daily) or methotrexate (20 to 25 mg once weekly). Alternatives in patients unresponsive to or intolerant of these agents are mycophenolate mofetil (2000 to 3000 mg daily) or rituximab. (See 'Resistant disease' above.) In patients with mild PAN and evidence of infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), we suggest treating most patients initially with antivirals only, rather than https://www.uptodate.com/contents/treatment-and-prognosis-of-polyarteritis-nodosa/print 17/25 7/7/23, 11:21 AM Treatment and prognosis of polyarteritis nodosa - UpToDate also treating initially with immunosuppressive medications (Grade 2C). Some patients with severe manifestations of hepatitis virus-associated PAN may benefit from short-term treatment with glucocorticoids and plasma exchange until antiviral therapy becomes effective. We do not use plasma exchange in patients with idiopathic PAN that is not HBV- related. In patients with persistent manifestations of PAN who are unresponsive to or intolerant of treatment for viral hepatitis alone, we cautiously treat the manifestations of the vasculitis with glucocorticoids and other immunosuppressive medication depending upon the severity of the vasculitis. (See 'Associated hepatitis B or C infection' above.) In patients with hypertension, we suggest treatment with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor antagonist, rather than using another type of antihypertensive (Grade 2B). Such patients should be monitored closely for worsening of renal function. (See 'Hypertension' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 2013; 65:1. 2. Ribi C, Cohen P, Pagnoux C, et al. Treatment of polyarteritis nodosa and microscopic polyangiitis without poor-prognosis factors: A prospective randomized study of one hundred twenty-four patients. Arthritis Rheum 2010; 62:1186. 3. Gayraud M, Guillevin L, le Toumelin P, et al. Long-term followup of polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome: analysis of four prospective trials including 278 patients. Arthritis Rheum 2001; 44:666. 4. Bourgarit A, Le Toumelin P, Pagnoux C, et al. Deaths occurring during the first year after treatment onset for polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome: a retrospective analysis of causes and factors predictive of mortality based on 595 patients. Medicine (Baltimore) 2005; 84:323. 5. Balow JE. Renal vasculitis. Kidney Int 1985; 27:954. 6. Frohnert PP, Sheps SG. Long-term follow-up study of periarteritis nodosa. Am J Med 1967; 43:8. 7. Pagnoux C, Seror R, Henegar C, et al. Clinical features and outcomes in 348 patients with polyarteritis nodosa: a systematic retrospective study of patients diagnosed between 1963 and 2005 and entered into the French Vasculitis Study Group Database. Arthritis Rheum 2010; 62:616. https://www.uptodate.com/contents/treatment-and-prognosis-of-polyarteritis-nodosa/print 18/25 7/7/23, 11:21 AM Treatment and prognosis of polyarteritis nodosa - UpToDate 8. Leib ES, Restivo C, Paulus HE. Immunosuppressive and corticosteroid therapy of polyarteritis nodosa. Am J Med 1979; 67:941. 9. Fauci AS, Katz P, Haynes BF, Wolff SM. Cyclophosphamide therapy of severe systemic necrotizing vasculitis. N Engl J Med 1979; 301:235. 10. Guillevin L, Pagnoux C, Seror R, et al. The Five-Factor Score revisited: assessment of prognoses of systemic necrotizing vasculitides based on the French Vasculitis Study Group (FVSG) cohort. Medicine (Baltimore) 2011; 90:19. 11. Chung SA, Gorelik M, Langford CA, et al. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Polyarteritis Nodosa. Arthritis Care Res (Hoboken) 2021; 73:1061. 12. Chung SA, Gorelik M, Langford CA, et al. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Polyarteritis Nodosa. Arthritis Rheumatol 2021; 73:1384. 13. Guillevin L, Mahr A, Cohen P, et al. Short-term corticosteroids then lamivudine and plasma exchanges to treat hepatitis B virus-related polyarteritis nodosa. Arthritis Rheum 2004; 51:482. 14. Pu chal X, Pagnoux C, Baron G, et al. Adding Azathioprine to Remission-Induction Glucocorticoids for Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss), Microscopic Polyangiitis, or Polyarteritis Nodosa Without Poor Prognosis Factors: A Randomized, Controlled Trial. Arthritis Rheumatol 2017; 69:2175. 15. Jayne D, Rasmussen N, Andrassy K, et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med 2003; 349:36. 16. De Groot K, Rasmussen N, Bacon PA, et al. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2005; 52:2461. 17. Wegener's Granulomatosis Etanercept Trial (WGET) Research Group. Etanercept plus standard therapy for Wegener's granulomatosis. N Engl J Med 2005; 352:351. 18. Pagnoux C, Mahr A, Hamidou MA, et al. Azathioprine or methotrexate maintenance for ANCA-associated vasculitis. N Engl J Med 2008; 359:2790. 19. Hiemstra TF, Walsh M, Mahr A, et al. Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial. JAMA 2010; 304:2381. https://www.uptodate.com/contents/treatment-and-prognosis-of-polyarteritis-nodosa/print 19/25 7/7/23, 11:21 AM Treatment and prognosis of polyarteritis nodosa - UpToDate 20. de Groot K, Harper L, Jayne DR, et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med 2009; 150:670. 21. Harper L, Morgan MD, Walsh M, et al. Pulse versus daily oral cyclophosphamide for induction of remission in ANCA-associated vasculitis: long-term follow-up. Ann Rheum Dis 2012; 71:955. 22. de Groot K, Adu D, Savage CO, EUVAS (European vasculitis study group). The value of pulse cyclophosphamide in ANCA-associated vasculitis: meta-analysis and critical review. Nephrol Dial Transplant 2001; 16:2018. 23. Guillevin L, Cohen P, Mahr A, et al. Treatment of polyarteritis nodosa and microscopic polyangiitis with poor prognosis factors: a prospective trial comparing glucocorticoids and six or twelve cyclophosphamide pulses in sixty-five patients. Arthritis Rheum 2003; 49:93. 24. Guillevin L, Pagnoux C. When should immunosuppressants be prescribed to treat systemic vasculitides? Intern Med 2003; 42:313. 25. Guillevin L, Lhote F, Gayraud M, et al. Prognostic factors in polyarteritis nodosa and Churg- Strauss syndrome. A prospective study in 342 patients. Medicine (Baltimore) 1996; 75:17. 26. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA- associated vasculitis. N Engl J Med 2010; 363:221. 27. Jones RB, Tervaert JW, Hauser T, et al. Rituximab versus cyclophosphamide in ANCA- associated renal vasculitis. N Engl J Med 2010; 363:211. 28. Matsuo S, Hayashi K, Morimoto E, et al. The Successful Treatment of Refractory Polyarteritis Nodosa Using Infliximab. Intern Med 2017; 56:1435. 29. Krusche M, Ruffer N, K tter I. Tocilizumab treatment in refractory polyarteritis nodosa: a case report and review of the literature. Rheumatol Int 2019; 39:337. 30. Rimar D, Alpert A, Starosvetsky E, et al. Tofacitinib for polyarteritis nodosa: a tailored therapy. Ann Rheum Dis 2016; 75:2214. 31. Stockigt JR, Topliss DJ, Hewett MJ. High-renin hypertension in necrotizing vasculitis. N Engl J Med 1979; 300:1218. 32. Cohen L, Guillevin L, Meyrier A, et al. [Malignant arterial hypertension in periarteritis nodosa. Incidence, clinicobiologic parameters and prognosis based on a series of 165 cases]. Arch Mal Coeur Vaiss 1986; 79:773. 33. Bhimma R, Coovadia HM. Hepatitis B virus-associated nephropathy. Am J Nephrol 2004; 24:198. https://www.uptodate.com/contents/treatment-and-prognosis-of-polyarteritis-nodosa/print 20/25 7/7/23, 11:21 AM Treatment and prognosis of polyarteritis nodosa - UpToDate 34. Guillevin L, Lhote F, Cohen P, et al. Corticosteroids plus pulse cyclophosphamide and plasma exchanges versus corticosteroids plus pulse cyclophosphamide alone in the treatment of polyarteritis nodosa and Churg-Strauss syndrome patients with factors predicting poor prognosis. A prospective, randomized trial in sixty-two patients. Arthritis Rheum 1995; 38:1638. 35. Hern ndez-Rodr guez J, Hoffman GS. Updating single-organ vasculitis. Curr Opin Rheumatol 2012; 24:38. 36. Grayson PC, Cuthbertson D, Carette S, et al. New features of disease after diagnosis in 6 forms of systemic vasculitis. J Rheumatol 2013; 40:1905. 37. Hind CR, Paraskevakou H, Lockwood CM, et al. Prognosis after immunosuppression of patients with crescentic nephritis requiring dialysis. Lancet 1983; 1:263. 38. Nissenson AR, Port FK. Outcome of end-stage renal disease in patients with rare causes of renal failure. III. Systemic/vascular disorders. Q J Med 1990; 74:63. 39. Briggs JD, Jones E. Renal transplantation for uncommon diseases. Scientific Advisory Board of the ERA-EDTA Registry. European Renal Association-European Dialysis and Transplant Association. Nephrol Dial Transplant 1999; 14:570. Topic 8244 Version 21.0 https://www.uptodate.com/contents/treatment-and-prognosis-of-polyarteritis-nodosa/print 21/25 7/7/23, 11:21 AM Treatment and prognosis of polyarteritis nodosa - UpToDate GRAPHICS Vaccinations for adults with autoimmune inflammatory rheumatic conditions [1-5] Vaccine type Vaccine target Indications Nonlive (inactivated, Pneumococcus All patients who have not previously received a conjugate pneumococcal vaccine*. PCV15 killed, subunit, or recombinant) followed by PPSV23 OR PCV20 Annually for all patients . Seasonal influenza virus Hepatitis A virus At-risk patients who have not been previously vaccinated. All patients 19 to 59 years old and at-risk patients 60 years old (eg, those with occupational or lifestyle risk factors) who have not been previously vaccinated; antibody titers should be checked following completion of vaccine series to ensure response. Hepatitis B virus Meningococcus At-risk patients who have not been previously vaccinated, including those treated with eculizumab and those with impaired splenic function. Haemophilus in uenzae At-risk patients who have not been previously vaccinated, including those with impaired splenic function. Human papillomavirus (HPV) At-risk patients 19 to 26 years old who have not been previously vaccinated. Tetanus, diphtheria, pertussis (Tdap) or tetanus, diphtheria (Td) All patients per guidelines for healthy adults (eg, single dose of Tdap followed by Td booster every 10 years). Recombinant Recommended prior to immunosuppression and for those zoster vaccine (RZV; Shingrix) on immunosuppression. COVID-19 vaccines All patients per guidelines for immunocompromised adults . https://www.uptodate.com/contents/treatment-and-prognosis-of-polyarteritis-nodosa/print 22/25 7/7/23, 11:21 AM Treatment and prognosis of polyarteritis nodosa - UpToDate Live, attenuated Zoster vaccine, live (ZVL; Zostavax) Can be given prior to immunosuppression and for those on low-dose immunosuppression if RZV is not available. Contraindicated for those receiving moderately to highly immunosuppressive medications. Measles, mumps, rubella Patients who have not been previously vaccinated and/or lack evidence of measles immunity (measles IgG seronegative) or who may have potential for measles exposure (eg, through work or travel) when the vaccine can be given prior to immunosuppression. Contraindicated for immunosuppressed patients. Varicella Patients who have not been previously vaccinated and/or lack evidence of varicella immunity (varicella IgG seronegative) or who may have potential for varicella exposure (eg, through work or family) when the vaccine can be given prior to immunosuppression. Contraindicated for immunosuppressed patients. Yellow fever Patients residing in or traveling to endemic areas prior to immunosuppression. Contraindicated for immunosuppressed patients. As part of our routine initial evaluation of patients with AIIRD, we review each patient's vaccination history and ensure that the above vaccinations have been received when appropriate. For maximal protection, vaccinations should be given prior to the start of immunosuppressive therapy. This increases the likelihood of developing a protective immune response, particularly for rituximab, which substantially impairs the humoral immune response. Vaccinating prior to immunosuppressive therapy also allows for administration of any needed live vaccines, which are generally contraindicated once immunosuppressive therapy has started. For complete information on timing of vaccine administration and vaccine schedules, including revaccination (booster dosing), refer to the UpToDate topic on vaccinations in patients with AIIRD. For more detailed description of at-risk populations, refer to the UpToDate topics regarding each vaccine. PCV20: 20-valent pneumococcal conjugate vaccine; PCV15: 15-valent pneumococcal conjugate vaccine; PPSV23: 23-valent pneumococcal polysaccharide vaccine; IgG: immunoglobulin G; AIIRD: autoimmune inflammatory rheumatic disease; COVID-19: coronavirus disease 2019. Patients with AIIRD who are planning to receive or are receiving immunosuppressive medications should receive either PCV20 alone or PCV15 followed by PPSV23 at least eight weeks later. Dosing intervals and schedule may vary if either one of these vaccines has been given previously. Please refer to the UpToDate topic on pneumococcal vaccination in adults for more detail. No formulation of the (nonlive) influenza vaccine is preferred over another, although some clinicians prefer to avoid the adjuvant-containing vaccine to avoid any potential risk of worsening autoimmune disease activity. https://www.uptodate.com/contents/treatment-and-prognosis-of-polyarteritis-nodosa/print 23/25 7/7/23, 11:21 AM Treatment and prognosis of polyarteritis nodosa - UpToDate Patients aged 27 to 45 years may also receive the vaccine based on shared clinical decision-making. Refer to UpToDate topic on HPV vaccination for further details. For vaccine selection and timing of administration, refer to the UpToDate content on COVID-19 vaccines in adults in autoimmune inflammatory rheumatic conditions. Other live attenuated vaccines include the influenza nasal spray, rotavirus, oral typhoid, and some formulations of the Japanese encephalitis vaccine. For most adults, these are not indicated. ZVL is no longer available in the United States. References: 1. Murthy N, Wodi AP, Bernstein H, et al. Advisory Committee on Immunization Practices Recommended Immunization Schedule for Adults Aged 19 Years or Older United States, 2022. MMWR Morb Mortal Wkly Rep 2022; 71:229. 2. Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid ahritis. Arthritis Rheumatol 2016; 68:1. 3. van Assen S, Agmon-Levin N, Elkayam O, et al. EULAR recommendations for vaccination in adult patients with autoimmune in ammatory rheumatic diseases. Ann Rheum Dis 2011; 70:414. 4. Kobayashi M, Farrar JL, Gierke R, et al. Use of 15-Valent Pneumococcal Conjugate Vaccine and 20-Valent Pneumococcal Conjugate Vaccine Among U.S. Adults: Updated Recommendations of the Advisory Committee on Immunization Practices United States, 2022. MMWR Morb Mortal Wkly Rep 2022; 71:109. 5. Anderson TC, Masters NB, Guo A, et al. Use of Recombinant Zoster Vaccine in Immunocompromised Adults Aged 19 Years: Recommendations of the Advisory Committee on Immunization Practices United States, 2022. MMWR Morb Mortal Wkly Rep 2022; 71:80. Graphic 119665 Version 4.0 https://www.uptodate.com/contents/treatment-and-prognosis-of-polyarteritis-nodosa/print 24/25 7/7/23, 11:21 AM Treatment and prognosis of polyarteritis nodosa - UpToDate Contributor Disclosures Peter A Merkel, MD, MPH Equity Ownership/Stock Options: Kyverna [Systemic lupus erythematosus]. Grant/Research/Clinical Trial Support: AbbVie [Vasculitis]; AstraZeneca [Vasculitis]; Boehringer Ingelheim [Scleroderma]; Bristol-Myers Squibb [Vasculitis]; ChemoCentryx [Vasculitis]; Electra [Vasculitis]; Genentech/Roche [Vasculitis]; GlaxoSmithKline [Vasculitis]; InflaRx [Vasculitis]; Sanofi [Vasculitis]; Takeda [Vasculitis]. Consultant/Advisory Boards: AbbVie [Vasculitis]; AstraZeneca [Vasculitis]; Boehringer Ingelheim [Scleroderma]; Bristol-Myers Squibb [Vasculitis]; ChemoCentryx [Vasculitis]; CSL Behring [Scleroderma, vasculitis]; Dynacure [Vasculitis]; EMDSerono [Vasculitis]; GlaxoSmithKline [Vasculitis]; InflaRx [Vasculitis]; Janssen [Vasculitis]; Kyverna [Scleroderma, vasculitis]; MiroBio [Vasculitis]; Neutrolis [Vasculitis]; Novartis [Vasculitis]; NS Pharma [Vasculitis]; Otsuka [Vasculitis]; Q32 [Vasculitis]; Regeneron [Vasculitis]; Sparrow [Vasculitis]; Takeda [Vasculitis]. All of the relevant financial relationships listed have been mitigated. Kenneth J Warrington, MD Grant/Research/Clinical Trial Support: Eli Lilly [Giant cell arteritis]; GSK [Giant cell arteritis]; Kiniksa [Giant cell arteritis]. Other Financial Interest: Chemocentryx [Honoraria ANCA-associated vasculitis]. All of the relevant financial relationships listed have been mitigated. Philip Seo, MD, MHS 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/treatment-and-prognosis-of-polyarteritis-nodosa/print 25/25

7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Treatment of giant cell arteritis : Carlo Salvarani, MD, Francesco Muratore, MD : Jonathan Trobe, MD, Kenneth J Warrington, MD : Philip Seo, MD, MHS 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 01, 2023. INTRODUCTION Giant cell arteritis (GCA, also known as Horton disease, cranial arteritis, and temporal arteritis) is the most common systemic vasculitis in North America and Europe [1,2]. GCA affects only older adults, with a peak incidence between ages 70 and 79 [3]. Many of the clinical features of the disease result from vascular inflammation of the small extracranial branches of the carotid arteries. One of the most concerning potential complications of GCA is that of sight loss, which serves as the rationale for prompt initiation of glucocorticoids as soon as the diagnosis is suspected. The disease can be generalized, however, and involve the aorta, leading to aneurysms of the thoracic aorta, and may cause stenoses in the large arteries, resulting in ischemic symptoms of the extremities. The treatment and prognosis of GCA are reviewed here. The clinical manifestations and diagnosis of this disorder are discussed separately. (See "Clinical manifestations of giant cell arteritis" and "Diagnosis of giant cell arteritis".) INITIAL MANAGEMENT No visual loss at diagnosis Glucocorticoids For all patients with giant cell arteritis (GCA), we recommend initial treatment with high-dose glucocorticoids rather than a moderate dose of glucocorticoids. The specific dose and route of administration of glucocorticoids for newly diagnosed GCA varies https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 1/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate depending on whether the patient presents with or without threatened or established visual loss at diagnosis. (See 'Threatened or established visual loss at diagnosis' below.) For patients without signs of ischemic organ damage (eg, visual loss), we initiate glucocorticoid therapy with prednisone 40 to 60 mg/day (or equivalent) administered in a single daily dose, with the goal of relieving symptoms and preventing visual loss. In selected cases in which reversible symptoms persist or worsen, the dose can be increased until symptomatic control is achieved (up to a maximum of prednisone 80 mg or equivalent). We do not use lower doses of glucocorticoids (ie, prednisone <40 mg/day) as initial therapy in any patients with newly diagnosed GCA. In patients at high risk of developing glucocorticoid toxicity, we also use high doses of glucocorticoids and add a glucocorticoid-sparing agent. The approach to using a glucocorticoid-sparing agent and glucocorticoid tapering is discussed in detail below. (See 'Glucocorticoid-sparing agent in selected patients' below and 'Glucocorticoid tapering' below.) Patients usually report dramatic improvements of many GCA-related symptoms (eg, headache, fever, malaise) within 24 to 48 hours of glucocorticoid administration. The diagnosis of GCA should be reevaluated in patients who are resistant to adequate glucocorticoid therapy, especially in situations where temporal artery biopsy and imaging studies have been negative. (See "Diagnosis of giant cell arteritis", section on 'Diagnosis'.) Efficacy Though never studied in a randomized trial, the role of glucocorticoids for the prevention of visual loss is supported by observational data and decades of clinical experience [4-6]. In a retrospective study of 245 patients with biopsy-proven GCA, all of whom were treated with glucocorticoids, permanent visual loss was found in 34 patients (14 percent) [5]. However, vision loss occurred in 32 of the 34 patients before the initiation of glucocorticoids. Of the two cases of de novo visual loss that developed after glucocorticoids were started, one occurred eight days into treatment, and the other occurred three years after glucocorticoids were first administered and one year after their discontinuation when the erythrocyte sedimentation rate (ESR) was normal and was therefore unlikely related to GCA. In another study of 144 patients with biopsy-proven GCA described in the ophthalmologic literature, none of the 53 patients with normal vision at presentation lost vision after initiation of glucocorticoids [6]. Of the 91 patients with sight loss at presentation, 9 experienced further visual loss after beginning glucocorticoids, all within 5 days of the start of treatment. Thus, if vision is intact at the time of the diagnosis of GCA, treatment with glucocorticoids appears to reduce the risk of sight loss to less than 1 percent. https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 2/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate Data regarding initial dose There are no clinical trials comparing different initial oral glucocorticoid doses for newly diagnosed GCA; however, clinical experience and observational data suggest that almost all patients with GCA respond symptomatically within 1 to 7 days to a 40 to 60 mg of oral prednisone (or equivalent) [4,7-10]. As an example, a population-based study with 120 patients with GCA found that all patients responded rapidly to a median initial dose of 60 mg of prednisone daily [7]. Our approach to the initial glucocorticoid dose is consistent with the European Alliance of Associations for Rheumatology (EULAR; formerly European League Against Rheumatism) guidelines, which recommend a fixed starting dose of prednisone 40 to 60 mg daily (or equivalent) [11]. By contrast, the American College of Rheumatology (ACR) guidelines recommend a starting dose of 1 mg/kg of prednisone or equivalent, up to a maximum of 80 mg daily [12,13]. Our preference is based on the fact that the majority of clinical trials have used fixed starting doses of prednisone 60 mg daily, and that additional high-quality data on the optimal starting dose of glucocorticoids in GCA are lacking. We do not use starting doses of <40 mg/day, as the use of such doses have not been systematically studied. There is insufficient evidence to justify the upfront use of intravenous pulse glucocorticoids in all patients with GCA, although they are recommended in patients with visual loss at presentation (see 'Threatened or established visual loss at diagnosis' below). A randomized trial with 164 patients with GCA (without ocular involvement at presentation) found no differences in the cumulative glucocorticoid doses or the number of GCA complications when comparing three different glucocorticoid protocols, two of which consisted of different pulse glucocorticoid regimens on a background of oral prednisone (240 mg intravenous pulse of methylprednisolone followed by 0.7 mg/kg/day oral prednisone or 240 mg intravenous pulse methylprednisolone followed by 0.5 mg/kg/day) and the other of which consisted of only oral prednisone (0.7 mg/kg/day) [14]. Another small randomized study of 27 patients without ocular involvement found that adding initial pulse glucocorticoid therapy resulted in a reduced total exposure to glucocorticoids and a lower relapse rate [15]. Neither of these randomized trials, however, was designed to assess the outcome of ocular complications. No role for alternate-day dosing Treatment of GCA requires daily glucocorticoid administration. The importance of daily dosing was demonstrated in the course of a study on the use of methotrexate for the management of GCA in which a rapid glucocorticoid taper to an alternate-day dose was associated with new sight loss in 8 of 98 patients [16]. In another study of regimens for glucocorticoid dosing, daily doses were more effective than alternate-day doses for symptomatic management [17]. https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 3/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate The risks of high-dose and of chronic glucocorticoid therapy are well known and include cataracts, fractures, infections, hypertension, diabetes, osteoporosis, and osteonecrosis [7]. Other side effects of glucocorticoids include weight gain; hair loss; and capillary fragility, which can be especially problematic in older adults on antiplatelet or anticoagulant therapies. (See "Major side effects of systemic glucocorticoids".) Glucocorticoid-sparing agent in selected patients Indications and rationale For patients with newly diagnosed GCA with increased risk of glucocorticoid-related adverse effects, we suggest the addition of tocilizumab to glucocorticoids. Patients who are at increased risk of developing glucocorticoid-related side effects or complications include those with osteoporosis, diabetes, hypertension, or glaucoma. We also add tocilizumab at first disease relapse, which is discussed further below. (See 'Tocilizumab' below and 'Management' below.) Methotrexate may be used as an alternative glucocorticoid-sparing agent for patients who are unable to use tocilizumab due to factors such as availability, cost, recurrent infections, or a history of gastrointestinal perforations or diverticulitis. (See 'Methotrexate' below.) Our approach to the use of a glucocorticoid-sparing agent is consistent with the EULAR guidelines [11] but differs from those of the ACR [12,13], in which tocilizumab use is recommended for all newly diagnosed patients with GCA. Despite the glucocorticoid-sparing effects of tocilizumab and its beneficial effects of remission rates, our caution with the use of tocilizumab is based on the lack of definitive data confirming the safety of long-term exposure of tocilizumab in an older adult population with multiple comorbidities. Furthermore, there are no definitive data showing that tocilizumab is able to reduce glucocorticoid-related side effects or definitively alter the inflammation in patients with large vessel disease. (See 'Tocilizumab' below.) Tocilizumab Tocilizumab is administered as a 162 mg subcutaneous weekly injection or as a monthly intravenous infusion in combination with glucocorticoids. When tocilizumab is administered intravenously, we typically dose it at 8 mg/kg once every four weeks (with a maximum of 800 mg/infusion). The dose more commonly used in the United States is 6 mg/kg based on regulatory approval. Tocilizumab may be administered as monotherapy following discontinuation of glucocorticoids. In patients who develop an adverse event (eg, cytopenias or abnormal liver function tests) with the standard initial dose, the tocilizumab dose should be adjusted and injections can be administered every other week or the intravenous dose can be reduced to 4 mg/kg. The risks of tocilizumab include opportunistic infection, neutropenia, abnormal liver function tests, increased serum cholesterol, diverticulitis, and gastrointestinal perforation. Additional https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 4/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate information regarding dose adjustments and adverse effects are described separately as well as in the Lexicomp drug information topic within UpToDate. (See "Interleukin 6 inhibitors: Biology, principles of use, and adverse effects", section on 'Adverse effects'.) The optimal duration of therapy with tocilizumab is unknown. We generally continue treatment for 12 to 18 months. If clinical remission is maintained, and glucocorticoids are successfully tapered off, we attempt complete discontinuation of tocilizumab. In some patients with relapsing disease who achieve sustained remission with tocilizumab, we try spacing out the tocilizumab injections to every other week (or reduce the dose of the intravenous infusion) for a period of 6 to 12 months before complete discontinuation. A pragmatic concern with the use of tocilizumab in the management of GCA pertains to its effects on the acute phase reactants. Interleukin (IL) 6 is a major driver of the acute phase response through its induction of hepatic synthesis of acute phase proteins (see "Acute phase reactants"). Blockade of IL-6 activity completely normalizes the ESR and C-reactive protein (CRP), with the result that the assessment of GCA in a patient on tocilizumab must rely on clinical evaluation and, in the case of large vessel involvement, periodic imaging studies. There continues to be an unfulfilled need for a reliable marker of active disease in GCA. (See 'Routine monitoring of disease activity' below and 'Imaging surveillance for patients with large vessel involvement' below.) The beneficial effects of tocilizumab as a glucocorticoid-sparing intervention have been demonstrated in two randomized trials [18,19]. In an industry-sponsored Giant Cell Arteritis Actemra (GiACTA) trial, 251 patients with newly diagnosed or relapsing GCA were randomly assigned to receive either weekly or every-other-week subcutaneous tocilizumab injections, combined with a 26-week prednisone taper, or placebo combined with a prednisone taper over a period of either 26 or 52 weeks [19]. Patients with evidence of critical optic ischemia were not enrolled in the study. Sustained remission at 52 weeks occurred in 56 percent of the weekly tocilizumab group and in 53 percent of the every-other-week tocilizumab group, compared with 14 percent of the placebo group who tapered over 26 weeks and 18 percent of the placebo (prednisone-only) group who tapered over 52 weeks. When normalization of the CRP concentration was excluded from the definition, sustained remission at 52 weeks occurred in 59 percent of the weekly tocilizumab group and in 55 percent of the every-other-week tocilizumab group, compared with 20 percent of the placebo group, who tapered over 26 weeks, and 33 percent of the placebo (prednisone-only) group, who tapered over 52 weeks. The cumulative median prednisone dose over the 52-week period in each tocilizumab group was 1862 mg, as compared with 3296 mg in the placebo group on the 26-week taper and 3818 mg in the placebo group on the 52-week taper. Serious adverse events were more common in the placebo groups, most of which were related to infection. One patient in the group receiving tocilizumab every https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 5/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate other week had an episode of anterior ischemic optic neuropathy (AION) that resolved with glucocorticoid treatment. Information about long-term effects of tocilizumab treatment on the disease course are limited [18,19]. In the two-year extension study of the GiACTA trial, after tocilizumab discontinuation, relapses were common, occurring in over half of patients enrolled [20]. Restarting tocilizumab (with or without glucocorticoids) was effective in restoring clinical remission in most patients. The glucocorticoid-sparing effect of tocilizumab demonstrated in the initial trial was maintained through year 3. Cumulative glucocorticoid doses over three years were significantly lower in patients originally randomized to tocilizumab compared with those originally randomized to placebo (median cumulative prednisone dose 2647 mg for tocilizumab once a week, 3948 mg for tocilizumab every other week, 5277 mg for placebo with a 26-week prednisone taper, and 5323 mg for placebo with a 52-week prednisone taper). No new or unexpected safety findings were reported over the full three years of the study. It remains to be seen whether tocilizumab definitively resolves vessel inflammation and consequently prevents the long-term development of aortic aneurysm and supra-aortic vessels stenosis. In a case report, a patient with GCA in apparent remission on tocilizumab died of a postoperative myocardial infarction and was found on postmortem examination to have active arteritis of the aorta, subclavian arteries, and right superficial temporal artery [21]. Methotrexate When used, methotrexate is typically initiated at a dose of 10 to 15 mg/week, with increases in dose every two to eight weeks of 5 mg/week up to 25 mg/week. We use the same regimen and approach to titration as that used in rheumatoid arthritis. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Dosing and administration'.) Limited data suggest that methotrexate is, at best, only moderately effective for reducing cumulative glucocorticoid dose and the rate of relapses [22]. Three randomized trials comparing methotrexate with placebo in patients with GCA treated with glucocorticoids reached divergent conclusions [16,23,24]. Of note, the doses of methotrexate used in the trials were low by contemporary standards, only 10 to 15 mg per week. A meta-analysis of the individual patient- level data of 161 patients from these three trials suggested that the add-on use of methotrexate resulted in a statistically significant reduction in the cumulative dose of glucocorticoids over the 48 weeks following randomization (cumulative dose reduction of prednisone or equivalent of 842 mg), a decreased rate of first and second relapse, and a higher probability of achieving a glucocorticoid-free remission [25]. Adverse effects between the two treatment groups were similar. The superiority of methotrexate over placebo appeared only after 24 to 36 weeks. https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 6/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate There are no randomized trials comparing methotrexate with tocilizumab in GCA. In an observational study on patients with new-onset, active, large vessel GCA starting treatment with either glucocorticoid monotherapy or combination with methotrexate or tocilizumab, all three treatment regimens controlled the clinical and biochemical signs of GCA and vascular inflammation evaluated by the positron emission tomography/computed tomography (PET/CT) [26]. Mean cumulative prednisone doses, however, were higher with glucocorticoid monotherapy (5637 mg), intermediate with methotrexate (4478 mg), and significantly lower with tocilizumab (2984 mg). Threatened or established visual loss at diagnosis Patients who present with visual manifestations (amaurosis fugax or unilateral visual loss) or with cerebrovascular events (eg, stroke or transient ischemic attack) potentially attributed to GCA require a higher initial dose of glucocorticoids, which should be administered promptly. We use either 500 to 1000 mg/day of intravenous methylprednisolone daily for three days (followed by 40 to 60 mg/day of oral prednisone) or 1 mg/kg/day of oral prednisone (if intravenous pulse cannot be rapidly initiated). While the association between diplopia and visual loss in patients with GCA has not been confirmed in all studies, we treat patients with GCA who present with diplopia with an initial course of intravenous glucocorticoids [27]. Though not validated in rigorous studies, this approach is used because of the crucial importance of preventing visual impairment due to GCA, which, once established, is rarely reversible [15]. The stark reality of such visual loss is that patients seldom recover useful vision in an affected eye [28-30]. In a retrospective review of 84 patients (114 eyes) with variable degrees of GCA-associated visual loss (due to AION in over 90 percent of patients), there were no differences in improvement in visual acuity when comparing patients who received intravenous glucocorticoids followed by oral therapy (41 patients) with patients who received only oral glucocorticoids (43 patients). Improvement in visual acuity was only observed in 4 percent of eyes (three patients treated with intravenous glucocorticoids and two with oral glucocorticoids), as judged by improvement in both visual acuity and central visual field (by kinetic perimetry and Amsler grid) [28]. Of note, improvement perceived by patients and noted on visual acuity tests may not reflect true recovery of retinal or optic nerve function but rather eccentric compensation for acquired, permanent visual deficits. Limited data suggest that the timing of glucocorticoid therapy may be more important than the route of administration for the prevention of future severe ischemic events [31]. A retrospective multicenter study of 29 patients with GCA with permanent visual loss is the only study that used a cut-off interval time of 24 hours from diagnosis to treatment onset to define early treatment. Early treatment was the only significant predictor of improvement of visual acuity (odds ratio https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 7/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate [OR] 17.7); the therapeutic regimen (intravenous pulse versus oral prednisone) did not influence visual outcome [32]. Preexisting sight loss can progress, despite initiation of glucocorticoid therapy, in approximately 10 percent of patients, usually within the first week of treatment [6]. If untreated, the second eye is likely to become affected in up to 30 percent of patients, and more than half of these patients develop bilateral loss of vision within the first two weeks [33]. Patients with large vessel involvement Large vessel GCA refers to involvement of the aorta and the great vessels, most commonly the subclavian arteries and distally to the axillary and brachial arteries. Patients with large vessel GCA are managed in a manner similar to those without large vessel involvement. It remains uncertain whether large vessel involvement may require more protracted or intensive treatment. In one retrospective cohort study comparing 120 patients with large vessel GCA with 240 patients with cranial GCA, the patients with large vessel GCA had a higher cumulative glucocorticoid dose after one year of treatment, relapsed more frequently, and received more adjunctive immunosuppressant therapies [34]. Additional information regarding the clinical features of large vessel involvement is presented separately. (See "Clinical manifestations of giant cell arteritis", section on 'Large vessel involvement'.) Additional management considerations for patients with large vessel include the following: Antiplatelet therapy for selected patients For patients who have critical or flow-limiting involvement of the cerebral or carotid arteries, we add low-dose aspirin to glucocorticoid and glucocorticoid-sparing therapy. If low-dose aspirin is used, a proton pump inhibitor should also be administered as aspirin, age, and high-dose glucocorticoids are all risk factors for gastrointestinal bleeding (see "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity", section on 'Proton pump inhibitors'). The rationale for low-dose aspirin use in this setting is for prevention of ischemic events in patients with vascular narrowing resulting in decreased cerebral flow. Otherwise, there are limited data supporting the role of antiplatelet therapy for the prevention of ischemic events in patients with GCA [35-39]. Vascular complications For patients with vascular complications such as aortic aneurysms or stenosis resulting in limb or organ ischemia, management decisions regarding potential surgical intervention should involve collaboration of the vascular surgeon and the rheumatologist. https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 8/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate For patients with GCA who require vascular surgical intervention and have clinical evidence of active disease, we typically use high-dose glucocorticoids in the periprocedural period. Clinical studies that would inform the management of complications such as limb ischemia or aortic aneurysms in GCA are lacking, and the approach to management is largely based on clinical experience and extrapolated from experience with Takayasu arteritis. Additional considerations regarding specific vascular complications include: Ischemic limb symptoms Most ischemic limb symptoms from stenosis improve or stabilize with medical management in GCA, and revascularization of arteries to the extremities (eg, angioplasty, stent placement, or bypass surgery) is seldom required. Vasculitic narrowing of large arteries, such as the subclavian artery, is usually gradual and accompanied by the development of an extensive web of collateral vessels ( image 1). With treatment of the underlying inflammatory process, the collateral circulation is commonly adequate to maintain the viability of distal tissues, even though there is some incident limb ischemia or diminished or absent peripheral arterial pulsations (brachial, radial, and ulnar). In 1 report of 53 treated patients with subclavian involvement due to GCA, symptoms and signs of ischemia resolved in 15 (27 percent), improved in 30 (55 percent), and were unchanged in 8 (15 percent) [40]. If indicated, stenting or angioplasty should be undertaken when clinical evidence for inflammation has been suppressed with treatment. Restenosis is not infrequent [40]. Aortic aneurysms Patients with aortic aneurysms related to GCA should be carefully evaluated for the presence of ongoing active vascular inflammation with laboratory (ESR, CRP) and imaging studies (magnetic resonance angiography [MRA], PET). Patients with active disease are treated with resumption or an increase in glucocorticoid therapy. If patients are not taking a glucocorticoid-sparing agent, this could be added. Additional information regarding medical and surgical management of thoracic aortic aneurysm and dissections is presented separately. (See "Management of thoracic aortic aneurysm in adults" and "Management of acute type B aortic dissection".) SUBSEQUENT MANAGEMENT Glucocorticoid tapering Symptoms and signs of giant cell arteritis (GCA) usually respond quickly to glucocorticoids, permitting a taper after two to four weeks. The approach to glucocorticoid tapering generally depends on whether patients are also receiving tocilizumab. https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 9/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate Patients on glucocorticoid monotherapy For patients who are not on tocilizumab, we use a more standard, slower tapering regimen similar to that used in the Giant Cell Arteritis Actemra (GiACTA) trial ( table 1). The initial dose of prednisone 60 mg/day can generally be reduced to 50 mg/day after two weeks and to 40 mg/day at the end of four weeks, assuming symptoms and signs have receded and the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) have declined to normal or near-normal ranges. Subsequently, the dose can gradually be reduced by 5 mg every two weeks to 20 mg/day and then by 2.5 mg every two weeks to 10 mg/day if there are no flares of disease activity. After achieving a daily dose of 10 mg, the prednisone taper should be slowed, such that patients remain on progressively decreasing doses over the ensuing 6 to 12 months. Tapering by 1 mg decrements each month once the daily dose is less than 10 mg can be considered, particularly in patients with concomitant polymyalgia rheumatica (PMR). In selected patients with significant risk for severe glucocorticoid toxicity and contraindications to tocilizumab and methotrexate, we use an accelerated taper regimen consistent with the taper used for patients on tocilizumab. Patients on glucocorticoids plus tocilizumab For most patients with GCA receiving glucocorticoids in combination with tocilizumab, we use an accelerated glucocorticoid- tapering regimen. We use the accelerated tapering regimen used in the trial demonstrating the glucocorticoid-sparing effect of tocilizumab (GiACTA) [19]. Patients are initiated on prednisone 60 mg daily and tapered off over 26 weeks as indicated in the table ( table 2). The details of this study presented above. (See 'Tocilizumab' above.) Routine monitoring of disease activity Monthly follow-up visits for the first six months of treatment are ideal, though their frequency will be subject to the exigencies of logistical issues. In stable patients, subsequent follow-up visits can be spaced out to every three months. Ultimately, all matters of follow-up (the interval between clinician visits, the frequency of laboratory monitoring, and the speed of the glucocorticoid taper) are governed by the clinical course of the given patient and must be individualized accordingly. The goal of these visits is to evaluate the patient's response to therapy and assess for toxicity of the treatment regimen. Patients should be counseled to be watchful for symptoms of PMR or GCA and should be encouraged to seek medical attention immediately if any symptoms are noted. The following data are obtained during follow-up visits: History and physical examination At each visit, patients should routinely be asked about cranial symptoms (eg, headache, visual symptoms, jaw claudication) and PMR https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 10/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate symptoms (eg, proximal musculoskeletal symptoms and/or signs), as well as any new or worsening symptoms and signs of large vessel involvement (eg, limb claudication, aortic murmur, peripheral loss of pulses). Patients should also be monitored for adverse effects from glucocorticoids (eg, osteoporosis, infection, diabetes, cataracts, and glaucoma) [7] and tocilizumab. (See "Major side effects of systemic glucocorticoids" and "Interleukin 6 inhibitors: Biology, principles of use, and adverse effects", section on 'Adverse effects'.) ESR and CRP For patients who are not on tocilizumab, the ESR and CRP can be useful adjuncts to clinical decision making. Blockade of interleukin (IL) 6 activity with tocilizumab completely normalizes the ESR and CRP levels, with the result that these inflammatory makers are not useful for monitoring disease activity. Unfortunately, there are no useful alternative markers for monitoring disease activity in patients on tocilizumab, and clinicians must rely on clinical evaluation and, in the case of large vessel involvement, periodic imaging studies. For most patients on glucocorticoid monotherapy, the ESR and CRP usually improve substantially within a few days of the institution of therapy; the CRP declines much more rapidly than the ESR. Elevations of the ESR and CRP should be accompanied by other clinical findings suggestive of recrudescent GCA if changes in glucocorticoid doses are to be made. As markers of disease activity for large vessel GCA, the ESR and CRP have the same value and are accompanied by the same caveats as they do for the cranial phenotype. Both the ESR and CRP, however, are imperfect biomarkers in GCA. The ESR usually rises with age (a value of 40 mm/hour may be normal for an 80-year-old), and, in some patients, abnormalities of serum proteins unrelated to GCA can spuriously elevate the ESR. Examples include monoclonal gammopathies and hypergammaglobulinemia secondary to liver disease. Though the ESR and CRP have not been directly compared for the assessment of disease activity in GCA, clinical experience suggests that the CRP is more useful. (See "Clinical manifestations of giant cell arteritis", section on 'Erythrocyte sedimentation rate and C-reactive protein' and "Acute phase reactants", section on 'Clinical use'.) Imaging surveillance for patients with large vessel involvement Different imaging modalities (CT, CT angiography [CTA], magnetic resonance imaging [MRI], MR angiography [MRA], and ultrasound) may be used for long-term monitoring of structural damage, particularly to detect stenosis, occlusion, dilatation, and/or aneurysms. The frequency of surveillance, as well as the imaging method applied, should be decided on an individual basis. Repeat imaging of a https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 11/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate newly discovered or enlarging aortic aneurysm should be considered at six months of follow-up; if stable, the interval between imaging studies can be lengthened to an annual basis. The choice of an imaging modality will vary by institution and individual patient (see "Diagnosis of giant cell arteritis", section on 'Imaging modalities'). There are not enough data to recommend the routine use of any of the different imaging modalities for monitoring disease activity during follow-up of patients with large vessel GCA. As an example, in a large retrospective cohort study of patients diagnosed with large vessel GCA, positron emission tomography (PET)/CT grading showed moderate accuracy in distinguishing between clinically active and inactive disease, with a sensitivity of 51 and specificity of 83 percent [41]. Furthermore, PET/CT was not able to predict subsequent relapse. However, in selected cases in which a flare is suspected, imaging might be helpful to confirm or exclude it. Prevention of treatment-associated toxicity Immunosuppressive therapy with high-dose glucocorticoids with or without a glucocorticoid-sparing agent has both infectious and noninfectious toxicities that warrant additional prophylactic measures. The specific regimens are discussed in detail separately: Prevention of opportunistic infections Reports of Pneumocystis jirovecii pneumonia (PCP) in GCA are rare [42,43]. In a retrospective cohort study of 1168 patients with GCA, no cases of PCP were identified over 547 patient-years of follow-up [44]. However, prednisone use at 16 mg daily or more for eight weeks has been shown to be associated with an increased risk of PCP [45], and to date, the risk of PCP in patients on prednisone and tocilizumab is unknown. While the absolute risk of PCP in GCA is small, some experts recommend PCP prophylaxis for patients with GCA given the risk of morbidity and mortality associated with PCP pneumonia. Ultimately, the decision to prescribe PCP prophylaxis should be individualized based on patient risk factors and preference and following a careful discussion of risks and benefit. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Indications'.) Osteoporosis prevention Because of the length of the course of glucocorticoid treatment for GCA, osteoporosis prevention should be aggressively pursued at the start of therapy. Adequate dietary calcium and vitamin D intake should be encouraged. Determination of bone mineral density near the time that treatment is begun is essential for guiding management of bone loss. (See "Prevention and treatment of glucocorticoid- induced osteoporosis".) Age-appropriate vaccinations Age-appropriate vaccinations should be up to date in immunosuppressed patients. (See "Immunizations in autoimmune inflammatory rheumatic disease in adults".) https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 12/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate Screening for latent tuberculosis Screening tests of latent tuberculosis should be performed at the start of therapy. (See "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)".) DISEASE RELAPSE Incidence and clinical features Reports on the incidence of relapses in giant cell arteritis (GCA) vary widely, from 34 to 74 percent [46-50]. This range is due in part to a lack of consensus regarding the definition of what constitutes a relapse. In some analyses, asymptomatic rises in the acute phase reactants were counted as a flare of GCA and in others, a recrudescence of symptoms only, unaccompanied by rises in the acute phase reactants, was included. All studies construed the appearance of polymyalgia rheumatica (PMR) as a relapse of GCA. Late relapses (and recurrences) of GCA are described, leading to protracted glucocorticoid treatment. In one study, one-half of patients were still on treatment after five years [49]. Other estimates of the total duration of glucocorticoid treatment are in the range of one to two years [51,52], which is more consonant with clinical practice. The majority of relapses in GCA occur at doses of prednisone below 20 mg/day and are most prevalent during the first year of treatment. Headache and PMR are the most common symptomatic expressions of relapse. Other symptoms include jaw claudication, the development of ischemic limb symptoms, and the recurrence of constitutional symptoms. Elevations of the erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) do not always indicate a disease flare, but their occurrence should trigger close clinical follow-up and questioning of patients about symptoms of recurring disease. In addition, if elevations in ESR and CRP are accompanied by constitutional symptoms, diagnostic imaging for underlying large vessel vasculitis may be considered. The occurrence of sight loss after an initial course of high-dose glucocorticoid treatment, administered daily, is exceptional. Management Increase glucocorticoid dose For patients who experience a relapse of GCA, we increase the glucocorticoid dose appropriate to the nature of the relapse. For visual symptoms attributable to GCA (generally occurring within the first weeks of the initial diagnosis of disease), an increase of the prednisone dose to 40 to 60 mg/day and even pulse doses may be needed. For other symptoms, an increase of the daily dose of glucocorticoids to the last effective dose or 5 to 15 mg above this dose is appropriate. Smaller increments in the daily dose of prednisone, between 5 to 7.5 mg/day, are usually appropriate for PMR symptoms. https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 13/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate Addition of a glucocorticoid-sparing agent For patients who are not already on a glucocorticoid-sparing agent at the time of relapse, a glucocorticoid-sparing agent, preferably tocilizumab, should be added. The rationale for this approach is based on data from the clinical trials of tocilizumab for GCA that included patients with relapsing disease. These trials are discussed in detail above. (See 'Tocilizumab' above.) For patients with relapsing disease while already on tocilizumab, in addition to increasing the glucocorticoid dose, some experts may modify the tocilizumab dose or route of administration when possible. This approach is based on clinical experience, as there are no data to support this approach. As an example, if a patient relapses while on tocilizumab subcutaneous injections every other week, the dosing frequency may be increased to weekly injections. As another example, if a patient relapses while receiving tocilizumab 6 mg/kg intravenously once every four weeks, they may have their dose increased to 8 mg/kg once every four weeks. Additionally, switching from subcutaneous administration to intravenous administration may be attempted. Entry into an investigational trial may also be an option at some institutions for patients with relapsing disease while already on tocilizumab. UNPROVEN OR INEFFECTIVE AGENTS

and C-reactive protein' and "Acute phase reactants", section on 'Clinical use'.) Imaging surveillance for patients with large vessel involvement Different imaging modalities (CT, CT angiography [CTA], magnetic resonance imaging [MRI], MR angiography [MRA], and ultrasound) may be used for long-term monitoring of structural damage, particularly to detect stenosis, occlusion, dilatation, and/or aneurysms. The frequency of surveillance, as well as the imaging method applied, should be decided on an individual basis. Repeat imaging of a https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 11/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate newly discovered or enlarging aortic aneurysm should be considered at six months of follow-up; if stable, the interval between imaging studies can be lengthened to an annual basis. The choice of an imaging modality will vary by institution and individual patient (see "Diagnosis of giant cell arteritis", section on 'Imaging modalities'). There are not enough data to recommend the routine use of any of the different imaging modalities for monitoring disease activity during follow-up of patients with large vessel GCA. As an example, in a large retrospective cohort study of patients diagnosed with large vessel GCA, positron emission tomography (PET)/CT grading showed moderate accuracy in distinguishing between clinically active and inactive disease, with a sensitivity of 51 and specificity of 83 percent [41]. Furthermore, PET/CT was not able to predict subsequent relapse. However, in selected cases in which a flare is suspected, imaging might be helpful to confirm or exclude it. Prevention of treatment-associated toxicity Immunosuppressive therapy with high-dose glucocorticoids with or without a glucocorticoid-sparing agent has both infectious and noninfectious toxicities that warrant additional prophylactic measures. The specific regimens are discussed in detail separately: Prevention of opportunistic infections Reports of Pneumocystis jirovecii pneumonia (PCP) in GCA are rare [42,43]. In a retrospective cohort study of 1168 patients with GCA, no cases of PCP were identified over 547 patient-years of follow-up [44]. However, prednisone use at 16 mg daily or more for eight weeks has been shown to be associated with an increased risk of PCP [45], and to date, the risk of PCP in patients on prednisone and tocilizumab is unknown. While the absolute risk of PCP in GCA is small, some experts recommend PCP prophylaxis for patients with GCA given the risk of morbidity and mortality associated with PCP pneumonia. Ultimately, the decision to prescribe PCP prophylaxis should be individualized based on patient risk factors and preference and following a careful discussion of risks and benefit. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Indications'.) Osteoporosis prevention Because of the length of the course of glucocorticoid treatment for GCA, osteoporosis prevention should be aggressively pursued at the start of therapy. Adequate dietary calcium and vitamin D intake should be encouraged. Determination of bone mineral density near the time that treatment is begun is essential for guiding management of bone loss. (See "Prevention and treatment of glucocorticoid- induced osteoporosis".) Age-appropriate vaccinations Age-appropriate vaccinations should be up to date in immunosuppressed patients. (See "Immunizations in autoimmune inflammatory rheumatic disease in adults".) https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 12/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate Screening for latent tuberculosis Screening tests of latent tuberculosis should be performed at the start of therapy. (See "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)".) DISEASE RELAPSE Incidence and clinical features Reports on the incidence of relapses in giant cell arteritis (GCA) vary widely, from 34 to 74 percent [46-50]. This range is due in part to a lack of consensus regarding the definition of what constitutes a relapse. In some analyses, asymptomatic rises in the acute phase reactants were counted as a flare of GCA and in others, a recrudescence of symptoms only, unaccompanied by rises in the acute phase reactants, was included. All studies construed the appearance of polymyalgia rheumatica (PMR) as a relapse of GCA. Late relapses (and recurrences) of GCA are described, leading to protracted glucocorticoid treatment. In one study, one-half of patients were still on treatment after five years [49]. Other estimates of the total duration of glucocorticoid treatment are in the range of one to two years [51,52], which is more consonant with clinical practice. The majority of relapses in GCA occur at doses of prednisone below 20 mg/day and are most prevalent during the first year of treatment. Headache and PMR are the most common symptomatic expressions of relapse. Other symptoms include jaw claudication, the development of ischemic limb symptoms, and the recurrence of constitutional symptoms. Elevations of the erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) do not always indicate a disease flare, but their occurrence should trigger close clinical follow-up and questioning of patients about symptoms of recurring disease. In addition, if elevations in ESR and CRP are accompanied by constitutional symptoms, diagnostic imaging for underlying large vessel vasculitis may be considered. The occurrence of sight loss after an initial course of high-dose glucocorticoid treatment, administered daily, is exceptional. Management Increase glucocorticoid dose For patients who experience a relapse of GCA, we increase the glucocorticoid dose appropriate to the nature of the relapse. For visual symptoms attributable to GCA (generally occurring within the first weeks of the initial diagnosis of disease), an increase of the prednisone dose to 40 to 60 mg/day and even pulse doses may be needed. For other symptoms, an increase of the daily dose of glucocorticoids to the last effective dose or 5 to 15 mg above this dose is appropriate. Smaller increments in the daily dose of prednisone, between 5 to 7.5 mg/day, are usually appropriate for PMR symptoms. https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 13/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate Addition of a glucocorticoid-sparing agent For patients who are not already on a glucocorticoid-sparing agent at the time of relapse, a glucocorticoid-sparing agent, preferably tocilizumab, should be added. The rationale for this approach is based on data from the clinical trials of tocilizumab for GCA that included patients with relapsing disease. These trials are discussed in detail above. (See 'Tocilizumab' above.) For patients with relapsing disease while already on tocilizumab, in addition to increasing the glucocorticoid dose, some experts may modify the tocilizumab dose or route of administration when possible. This approach is based on clinical experience, as there are no data to support this approach. As an example, if a patient relapses while on tocilizumab subcutaneous injections every other week, the dosing frequency may be increased to weekly injections. As another example, if a patient relapses while receiving tocilizumab 6 mg/kg intravenously once every four weeks, they may have their dose increased to 8 mg/kg once every four weeks. Additionally, switching from subcutaneous administration to intravenous administration may be attempted. Entry into an investigational trial may also be an option at some institutions for patients with relapsing disease while already on tocilizumab. UNPROVEN OR INEFFECTIVE AGENTS Several other glucocorticoid-sparing agents have been reported as having efficacy as adjunctive treatment for giant cell arteritis (GCA), but their use cannot be endorsed because of small effect, potential toxicity, lack of controls, or small numbers of patients studied. Abatacept A trial of abatacept, a blocker of T-cell costimulation, was proposed on the basis of the presence of activated CD4+ T cells in the typical inflammatory infiltrate of the temporal artery in GCA [53] (see "Pathogenesis of giant cell arteritis"). In a phase 2 randomized, double-blind study of patients with newly diagnosed or relapsing GCA, 49 patients were enrolled and treated with prednisone and intravenous abatacept, administered on days 1, 15, 29, and 56. At week 12, 41 patients were in remission and were randomized to continue treatment with monthly abatacept or placebo. Prednisone was tapered by a standardized schedule and discontinued by week 28. The rate of sustained remission at 12 months in patients treated with abatacept compared with placebo was of borderline statistical significance, 48 versus 31 percent. There was no difference in adverse events, including infection, between the two groups. Further study is needed to determine a possible role for abatacept as adjunctive treatment for GCA. https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 14/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate Baricitinib Preclinical findings and case reports have demonstrated the biologic plausibility that agents selectively targeting Janus kinase (JAK) 1/JAK2 hold potential promise in GCA. In a prospective, open-label, proof-of-concept study with a tiered glucocorticoid entry and accelerated taper in patients with relapsing GCA, the oral selective JAK1/JAK2 inhibitor baricitinib at 4 mg/day was well tolerated and allowed discontinuation of glucocorticoids in most patients [54]. Larger randomized clinical trials are needed to determine the safety and efficacy of JAK inhibition in GCA. Mavrilimumab Preclinical research has implicated granulocyte-macrophage colony- stimulating factor (GM-CSF) in the pathogenesis of GCA. Mavrilimumab, an immunoglobulin (Ig) G4 monoclonal antibody, blocks GM-CSF signaling by binding to the alpha chain of the receptor. In a phase 2 trial enrolling patients with GCA, mavrilimumab plus 26 weeks of prednisone was superior to placebo for time to flare by week 26 and sustained remission [55]. Further studies are needed to define the potential role of mavrilimumab in the treatment of GCA. Azathioprine In a study from a single center of 31 patients with GCA, polymyalgia rheumatica (PMR), or both, a double-blind randomized controlled study of azathioprine, 150 mg/day, versus placebo showed a small but statistically significant reduction in mean prednisolone dose at 52 weeks (1.9 mg/day 0.84 versus 4.2 mg/day 0.58) [56]. Only 20 patients completed the study. Ustekinumab T helper (Th) 1 and Th17 cells are believed to play key roles in the pathogenesis of GCA [57] (see "Pathogenesis of giant cell arteritis"). Ustekinumab blocks interleukin (IL) 12, a Th1-promoting cytokine, and IL-23, a Th17-promoting cytokine, providing a theoretical basis for its use in the treatment of GCA. In an open-label study of ustekinumab in 14 patients with refractory GCA, the prednisolone dose was decreased from a median of 20 mg/day to 5 mg/day; four patients discontinued glucocorticoid therapy entirely [58]. However, a subsequent prospective, open-label trial of ustekinumab in patients with active new-onset or relapsing GCA was closed prematurely after 7 of the initial 10 patients relapsed [59]. Cyclophosphamide Cyclophosphamide has been widely used in the treatment of systemic vasculitis. A few small, uncontrolled studies have suggested that it may be useful in GCA in patients at high risk of glucocorticoid-related adverse effects who have not responded adequately to other immunosuppressive or immunomodulatory glucocorticoid- sparing treatments [60-62]. A systematic review identified 103 published cases for analysis [62]. The major indications for cyclophosphamide, administered either orally or intravenously, included glucocorticoid dependency or relapsing disease. Most of the https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 15/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate reported patients (86 percent) responded, but 22 percent relapsed despite maintenance immunosuppressive therapy. Adverse effects were described in one-third of the patients, and 12.5 percent discontinued the therapy because of infections and cytopenias. One death due to hepatitis was reported. Others Small, uncontrolled, retrospective series have proposed benefit for dapsone [63], leflunomide [64], and IL-1 blockade [65] for the management of GCA. Lack of benefit of anti-TNF therapy Because GCA is characterized by granulomatous inflammation, tumor necrosis factor (TNF) inhibition would appear to be an appropriate approach to treatment. However, several small randomized trials of TNF inhibition have found that infliximab, etanercept, and adalimumab are ineffective in patients with GCA [66- 68]. As an example, 44 patients were studied in a multicenter, randomized, placebo- controlled trial of infliximab for the maintenance of remission [66]. After prednisone- induced remission, patients were randomly assigned in a 2:1 ratio to infliximab 5 mg/kg or placebo. An interim analysis at week 22 demonstrated that infliximab did not reduce the proportion of patients with relapses (43 versus 50 percent on placebo). In addition, infliximab did not increase the proportion of patients whose prednisone dose could be tapered to 10 mg/day without relapse (61 versus 75 percent). Consequently, the trial was stopped early. Through the follow-up period, no differences between the treatment groups were observed in the proportion of relapse-free patients, the cumulative dose of prednisone, or the incidence of adverse events. PROGNOSIS Giant cell arteritis (GCA) is a disease of variable duration. In some, it may have a course of one to two years, while in many others, the disease is more chronic. The glucocorticoid dose can eventually be reduced and discontinued in the majority of patients, although some patients require low doses of prednisone for a number of years to control symptoms. GCA does not adversely affect overall survival, excepting the subset of patients with aortic involvement and dissection [69-71]. 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: Giant cell arteritis and polymyalgia rheumatica".) https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 16/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - 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 topic (see "Patient education: Polymyalgia rheumatica and giant cell arteritis (The Basics)") Beyond the Basics topics (see "Patient education: Vasculitis (Beyond the Basics)" and "Patient education: Polymyalgia rheumatica and giant cell arteritis (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS Initial management Systemic glucocorticoids For all patients with giant cell arteritis (GCA), we recommend initial treatment with high-dose systemic glucocorticoids to preserve vision (Grade 1C), as well as to treat other clinical symptoms associated with GCA (Grade 2B). Treatment should be initiated promptly once the diagnosis is confirmed or there is a high index of suspicion for GCA. Our practice regarding the specific dose and route of administration of glucocorticoids for newly diagnosed GCA is as follows (see 'Glucocorticoids' above): No visual loss at diagnosis Prednisone 40 to 60 mg/day or equivalent, given in a single daily dose. Threatened or established visual loss at diagnosis Methylprednisolone 500 to 1000 mg intravenous daily, for three days (followed by 40 to 60 mg/day of oral prednisone). https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 17/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate Glucocorticoid-sparing agent in selected patients For patients with newly diagnosed GCA with an increased risk of glucocorticoid-related adverse effects, we suggest the addition of tocilizumab to glucocorticoid therapy (Grade 2B). Patients who are at increased risk of developing glucocorticoid-related side effects or complications include those with osteoporosis, diabetes, cardiovascular disease, or glaucoma. Tocilizumab has demonstrated a glucocorticoid-sparing effect in clinical trials. (See 'Glucocorticoid-sparing agent in selected patients' above and 'Indications and rationale' above and 'Tocilizumab' above.) Whether a glucocorticoid-sparing agent should be used in the routine care of all patients with GCA is uncertain. The American College of Rheumatology (ACR) recommends the use of adjunctive tocilizumab for all patients with GCA. Methotrexate may be used as an alternative to tocilizumab for patients who are unable to use the medication due to factors such as availability, cost, recurrent infections, or a history of gastrointestinal perforations or diverticulitis; however, limited available data and clinical experience suggest methotrexate is less effective. (See 'Methotrexate' above.) Patients with large vessel involvement Patients with large vessel GCA are managed in a manner similar to those without large vessel involvement. Additional considerations include antiplatelet therapy in selected patients as well as possible surgical interventions for patients with vascular complications. (See 'Patients with large vessel involvement' above.) Subsequent management Glucocorticoid tapering Symptoms and signs of GCA usually respond quickly to glucocorticoids, permitting the initiation of a taper after one to two weeks. The approach to glucocorticoid tapering varies generally depends on whether patients are also receiving tocilizumab. (See 'Glucocorticoid tapering' above.) Patients on glucocorticoid monotherapy For patients with GCA receiving monotherapy with glucocorticoids, we use a standard glucocorticoid tapering regimen ( table 1). Patients on glucocorticoids plus tocilizumab For most patients with GCA receiving glucocorticoids in combination with tocilizumab (or another glucocorticoid-sparing agent), we use an accelerated glucocorticoid-tapering regimen ( table 2). https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 18/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate Routine monitoring of disease activity Monitoring of disease activity requires careful clinical follow-up to evaluate the patient's response to therapy and assess for toxicity of the treatment regimen. For patients who are not on tocilizumab, the erythrocyte sedimentation rate (ESR) and the C-reactive protein (CRP) can be useful adjuncts to clinical decision making. Tocilizumab completely normalizes the ESR and CRP levels, and they are thus not useful for monitoring disease activity in such patients. Clinicians must rely on clinical evaluation and, in the case of large vessel involvement, periodic imaging studies for patients on tocilizumab. (See 'Routine monitoring of disease activity' above.) Imaging surveillance for patients with large vessel involvement Different imaging modalities (CT, CT angiography [CTA], MRI, MR angiography [MRA], and ultrasound) may be used for long-term monitoring of structural damage, particularly to detect stenosis, occlusion, dilatation, and/or aneurysms. The frequency of surveillance, as well as the imaging method applied, should be decided on an individual basis. (See 'Imaging surveillance for patients with large vessel involvement' above.) Prevention of treatment-associated toxicity Immunosuppressive therapy with high- dose glucocorticoids with or without a glucocorticoid-sparing agent has both infectious and noninfectious toxicities that warrant additional prophylactic measures including prevention of opportunistic infections, osteoporosis prevention, age-appropriate vaccinations, and screening for latent tuberculosis. (See 'Prevention of treatment- associated toxicity' above.) Disease relapse Incidence and clinical features Relapses of disease activity are most common at prednisone doses less than 20 mg/day and are most prevalent during the first year of treatment. Headache and polymyalgia rheumatica (PMR) are the most common symptomatic expressions of relapse. Relapses usually do not result in major adverse events such as visual loss. (See 'Incidence and clinical features' above.) Management of relapse For patients who experience a relapse of GCA, we increase the glucocorticoid dose appropriate to the nature of the relapse. For patients who are not already on a glucocorticoid-sparing agent at the time of relapse, we suggest adding tocilizumab (Grade 2B). (See 'Management' above.) https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 19/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate Prognosis GCA is a disease of variable duration. Length of treatment may extend from one to multiple years. Glucocorticoid treatment can eventually be discontinued in the majority of patients. (See 'Prognosis' above.) ACKNOWLEDGMENTS The UpToDate editorial staff acknowledges Gene G Hunder, MD and William P Docken, MD, who contributed to earlier versions of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Crowson CS, Matteson EL, Myasoedova E, et al. The lifetime risk of adult-onset rheumatoid arthritis and other inflammatory autoimmune rheumatic diseases. Arthritis Rheum 2011; 63:633. 2. Gonz lez-Gay MA, Garc a-Porr a C. Systemic vasculitis in adults in northwestern Spain, 1988-1997. Clinical and epidemiologic aspects. Medicine (Baltimore) 1999; 78:292. 3. Gonzalez-Gay MA, Vazquez-Rodriguez TR, Lopez-Diaz MJ, et al. Epidemiology of giant cell arteritis and polymyalgia rheumatica. Arthritis Rheum 2009; 61:1454. 4. BIRKHEAD NC, WAGENER HP, SHICK RM. Treatment of temporal arteritis with adrenal corticosteroids; results in fifty-five cases in which lesion was proved at biopsy. J Am Med Assoc 1957; 163:821. 5. Aiello PD, Trautmann JC, McPhee TJ, et al. Visual prognosis in giant cell arteritis. Ophthalmology 1993; 100:550. 6. Hayreh SS, Zimmerman B. Visual deterioration in giant cell arteritis patients while on high doses of corticosteroid therapy. Ophthalmology 2003; 110:1204. 7. Proven A, Gabriel SE, Orces C, et al. Glucocorticoid therapy in giant cell arteritis: duration and adverse outcomes. Arthritis Rheum 2003; 49:703. 8. Delecoeuillerie G, Joly P, Cohen de Lara A, Paolaggi JB. Polymyalgia rheumatica and temporal arteritis: a retrospective analysis of prognostic features and different corticosteroid regimens (11 year survey of 210 patients). Ann Rheum Dis 1988; 47:733. 9. Kyle V, Hazleman BL. Treatment of polymyalgia rheumatica and giant cell arteritis. II. Relation between steroid dose and steroid associated side effects. Ann Rheum Dis 1989; 48:662. https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 20/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate 10. Hayreh SS, Zimmerman B. Management of giant cell arteritis. Our 27-year clinical study: new light on old controversies. Ophthalmologica 2003; 217:239. 11. Hellmich B, Agueda A, Monti S, et al. 2018 Update of the EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis 2020; 79:19. 12. Maz M, Chung SA, Abril A, et al. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Giant Cell Arteritis and Takayasu Arteritis. Arthritis Care Res (Hoboken) 2021; 73:1071. 13. Maz M, Chung SA, Abril A, et al. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Giant Cell Arteritis and Takayasu Arteritis. Arthritis Rheumatol 2021; 73:1349. 14. Chevalet P, Barrier JH, Pottier P, et al. A randomized, multicenter, controlled trial using intravenous pulses of methylprednisolone in the initial treatment of simple forms of giant cell arteritis: a one year followup study of 164 patients. J Rheumatol 2000; 27:1484. 15. Hayreh SS, Biousse V. Treatment of acute visual loss in giant cell arteritis: should we prescribe high-dose intravenous steroids or just oral steroids? J Neuroophthalmol 2012; 32:278. 16. Hoffman GS, Cid MC, Hellmann DB, et al. A multicenter, randomized, double-blind, placebo- controlled trial of adjuvant methotrexate treatment for giant cell arteritis. Arthritis Rheum 2002; 46:1309. 17. Hunder GG, Sheps SG, Allen GL, Joyce JW. Daily and alternate-day corticosteroid regimens in treatment of giant cell arteritis: comparison in a prospective study. Ann Intern Med 1975; 82:613. 18. Villiger PM, Adler S, Kuchen S, et al. Tocilizumab for induction and maintenance of remission in giant cell arteritis: A phase 2, randomised, double-blind, placebo-controlled trial. Lancet 2016; 387:1921. 19. Stone JH, Tuckwell K, Dimonaco S, et al. Trial of Tocilizumab in Giant-Cell Arteritis. N Engl J Med 2017; 377:317. 20. Stone JH, Han J, Aringer M, et al. Long-term effect of tocilizumab in patients with giant cell arteritis: Open-label extension phase of the Giant Cell Arteritis Actemra (GiACTA) trial. Lancet Rheumatol 2021; 3:E328. 21. Unizony S, Arias-Urdaneta L, Miloslavsky E, et al. Tocilizumab for the treatment of large- vessel vasculitis (giant cell arteritis, Takayasu arteritis) and polymyalgia rheumatica. Arthritis Care Res (Hoboken) 2012; 64:1720. https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 21/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate 22. Buttgereit F, Dejaco C, Matteson EL, Dasgupta B. Polymyalgia Rheumatica and Giant Cell Arteritis: A Systematic Review. JAMA 2016; 315:2442. 23. Jover JA, Hern ndez-Garc a C, Morado IC, et al. Combined treatment of giant-cell arteritis with methotrexate and prednisone. a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001; 134:106. 24. Spiera RF, Mitnick HJ, Kupersmith M, et al. A prospective, double-blind, randomized, placebo controlled trial of methotrexate in the treatment of giant cell arteritis (GCA). Clin Exp Rheumatol 2001; 19:495. 25. Mahr AD, Jover JA, Spiera RF, et al. Adjunctive methotrexate for treatment of giant cell arteritis: an individual patient data meta-analysis. Arthritis Rheum 2007; 56:2789. 26. Sch nau V, Roth J, Tascilar K, et al. Resolution of vascular inflammation in patients with new- onset giant cell arteritis: data from the RIGA study. Rheumatology (Oxford) 2021; 60:3851. 27. Castillejo Becerra CM, Crowson CS, Koster MJ, et al. Population-based Rate and Patterns of Diplopia in Giant Cell Arteritis. Neuroophthalmology 2022; 46:75. 28. Hayreh SS, Zimmerman B, Kardon RH. Visual improvement with corticosteroid therapy in giant cell arteritis. Report of a large study and review of literature. Acta Ophthalmol Scand 2002; 80:355. 29. Danesh-Meyer H, Savino PJ, Gamble GG. Poor prognosis of visual outcome after visual loss from giant cell arteritis. Ophthalmology 2005; 112:1098. 30. Singh AG, Kermani TA, Crowson CS, et al. Visual manifestations in giant cell arteritis: trend over 5 decades in a population-based cohort. J Rheumatol 2015; 42:309. 31. Soriano A, Muratore F, Pipitone N, et al. Visual loss and other cranial ischaemic complications in giant cell arteritis. Nat Rev Rheumatol 2017; 13:476. 32. Gonz lez-Gay MA, Blanco R, Rodr guez-Valverde V, et al. Permanent visual loss and cerebrovascular accidents in giant cell arteritis: predictors and response to treatment. Arthritis Rheum 1998; 41:1497. 33. Hayreh SS, Podhajsky PA, Zimmerman B. Ocular manifestations of giant cell arteritis. Am J Ophthalmol 1998; 125:509. 34. Muratore F, Kermani TA, Crowson CS, et al. Large-vessel giant cell arteritis: a cohort study. Rheumatology (Oxford) 2015; 54:463. 35. Nesher G, Berkun Y, Mates M, et al. Low-dose aspirin and prevention of cranial ischemic complications in giant cell arteritis. Arthritis Rheum 2004; 50:1332. 36. Lee MS, Smith SD, Galor A, Hoffman GS. Antiplatelet and anticoagulant therapy in patients with giant cell arteritis. Arthritis Rheum 2006; 54:3306. https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 22/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate 37. Narv ez J, Bernad B, G mez-Vaquero C, et al. Impact of antiplatelet therapy in the development of severe ischemic complications and in the outcome of patients with giant cell arteritis. Clin Exp Rheumatol 2008; 26:S57. 38. Salvarani C, Della Bella C, Cimino L, et al. Risk factors for severe cranial ischaemic events in an Italian population-based cohort of patients with giant cell arteritis. Rheumatology (Oxford) 2009; 48:250. 39. Berger CT, Wolbers M, Meyer P, et al. High incidence of severe ischaemic complications in patients with giant cell arteritis irrespective of platelet count and size, and platelet inhibition. Rheumatology (Oxford) 2009; 48:258. 40. Amann-Vesti BR, Koppensteiner R, Rainoni L, et al. Immediate and long-term outcome of upper extremity balloon angioplasty in giant cell arteritis. J Endovasc Ther 2003; 10:371. 41. Galli E, Muratore F, Mancuso P, et al. The role of PET/CT in disease activity assessment in patients with large vessel vasculitis. Rheumatology (Oxford) 2022; 61:4809. 42. Kermani TA, Ytterberg SR, Warrington KJ. Pneumocystis jiroveci pneumonia in giant cell arteritis: A case series. Arthritis Care Res (Hoboken) 2011; 63:761. 43. Berger CT, Greiff V, John S, et al. Risk factors for pneumocystis pneumonia in giant cell arteritis: a single-centre cohort study. Clin Exp Rheumatol 2015; 33:S. 44. Anumolu N, Henry K, Sattui SE, Putman M. Is there a role for Pneumocystis jiroveci pneumonia prophylaxis in giant cell arteritis or polymyalgia rheumatica? Semin Arthritis Rheum 2023; 58:152154. 45. Yale SH, Limper AH. Pneumocystis carinii pneumonia in patients without acquired immunodeficiency syndrome: associated illness and prior corticosteroid therapy. Mayo Clin Proc 1996; 71:5. 46. Kermani TA, Warrington KJ, Cuthbertson D, et al. Disease Relapses among Patients with Giant Cell Arteritis: A Prospective, Longitudinal Cohort Study. J Rheumatol 2015; 42:1213. 47. Martinez-Lado L, Calvi o-D az C, Pi eiro A, et al. Relapses and recurrences in giant cell arteritis: a population-based study of patients with biopsy-proven disease from northwestern Spain. Medicine (Baltimore) 2011; 90:186. 48. Alba MA, Garc a-Mart nez A, Prieto-Gonz lez S, et al. Relapses in patients with giant cell arteritis: prevalence, characteristics, and associated clinical findings in a longitudinally followed cohort of 106 patients. Medicine (Baltimore) 2014; 93:194. 49. Labarca C, Koster MJ, Crowson CS, et al. Predictors of relapse and treatment outcomes in biopsy-proven giant cell arteritis: a retrospective cohort study. Rheumatology (Oxford) 2016; 55:347. https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 23/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate 50. Restuccia G, Boiardi L, Cavazza A, et al. Flares in Biopsy-Proven Giant Cell Arteritis in Northern Italy: Characteristics and Predictors in a Long-Term Follow-Up Study. Medicine (Baltimore) 2016; 95:e3524. 51. Hoffman GS. Giant Cell Arteritis. Ann Intern Med 2016; 165:ITC65. 52. Salvarani C, Cantini F, Hunder GG. Polymyalgia rheumatica and giant-cell arteritis. Lancet 2008; 372:234. 53. Langford CA, Cuthbertson D, Ytterberg SR, et al. A Randomized, Double-Blind Trial of Abatacept (CTLA-4Ig) for the Treatment of Giant Cell Arteritis. Arthritis Rheumatol 2017; 69:837. 54. Koster MJ, Crowson CS, Giblon RE, et al. Baricitinib for relapsing giant cell arteritis: a prospective open-label 52-week pilot study. Ann Rheum Dis 2022; 81:861. 55. Cid MC, Unizony SH, Blockmans D, et al. Efficacy and safety of mavrilimumab in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial. Ann Rheum Dis 2022; 81:653. 56. De Silva M, Hazleman BL. Azathioprine in giant cell arteritis/polymyalgia rheumatica: a double-blind study. Ann Rheum Dis 1986; 45:136. 57. Deng J, Younge BR, Olshen RA, et al. Th17 and Th1 T-cell responses in giant cell arteritis. Circulation 2010; 121:906. 58. Conway R, O'Neill L, O'Flynn E, et al. Ustekinumab for the treatment of refractory giant cell arteritis. Ann Rheum Dis 2016; 75:1578. 59. Matza MA, Fernandes AD, Stone JH, Unizony SH. Ustekinumab for the Treatment of Giant Cell Arteritis. Arthritis Care Res (Hoboken) 2021; 73:893. 60. Quartuccio L, Maset M, De Maglio G, et al. Role of oral cyclophosphamide in the treatment of giant cell arteritis. Rheumatology (Oxford) 2012; 51:1677. 61. Henes JC, Mueller M, Pfannenberg C, et al. Cyclophosphamide for large vessel vasculitis: assessment of response by PET/CT. Clin Exp Rheumatol 2011; 29:S43. 62. de Boysson H, Boutemy J, Creveuil C, et al. Is there a place for cyclophosphamide in the treatment of giant-cell arteritis? A case series and systematic review. Semin Arthritis Rheum 2013; 43:105. 63. Ly KH, Dalmay F, Gondran G, et al. Steroid-sparing effect and toxicity of dapsone treatment in giant cell arteritis: A single-center, retrospective study of 70 patients. Medicine (Baltimore) 2016; 95:e4974. 64. Diamantopoulos AP, Hetland H, Myklebust G. Leflunomide as a corticosteroid-sparing agent in giant cell arteritis and polymyalgia rheumatica: a case series. Biomed Res Int 2013; https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 24/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate 2013:120638. 65. Ly KH, Stirnemann J, Liozon E, et al. Interleukin-1 blockade in refractory giant cell arteritis. Joint Bone Spine 2014; 81:76. 66. Hoffman GS, Cid MC, Rendt-Zagar KE, et al. Infliximab for maintenance of glucocorticosteroid-induced remission of giant cell arteritis: a randomized trial. Ann Intern Med 2007; 146:621. 67. Seror R, Baron G, Hachulla E, et al. Adalimumab for steroid sparing in patients with giant- cell arteritis: results of a multicentre randomised controlled trial. Ann Rheum Dis 2014; 73:2074. 68. Mart nez-Taboada VM, Rodr guez-Valverde V, Carre o L, et al. A double-blind placebo controlled trial of etanercept in patients with giant cell arteritis and corticosteroid side effects. Ann Rheum Dis 2008; 67:625. 69. Kermani TA, Warrington KJ, Crowson CS, et al. Large-vessel involvement in giant cell arteritis: a population-based cohort study of the incidence-trends and prognosis. Ann Rheum Dis 2013; 72:1989. 70. Gonz lez-Gay MA, Blanco R, Abraira V, et al. Giant cell arteritis in Lugo, Spain, is associated with low longterm mortality. J Rheumatol 1997; 24:2171. 71. Gran JT, Myklebust G, Wilsgaard T, Jacobsen BK. Survival in polymyalgia rheumatica and temporal arteritis: a study of 398 cases and matched population controls. Rheumatology (Oxford) 2001; 40:1238. Topic 8240 Version 40.0 https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 25/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate GRAPHICS Narrowing of the left subclavian artery in giant cell arteritis Angiogram of the left subclavian artery in GCA, showing several areas of severe vascular narrowing but a proliferation of small blood vessels forming excellent collateral circulation. The long, smooth arterial tapering in large vessel GCA is often not amenable to revascularization interventions such as angioplasty or stent placement. Those types of interventions are rarely necessary. GCA: giant cell arteritis. Courtesy of John H Stone, MD, MPH. Graphic 73553 Version 8.0 https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 26/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate 52-week glucocorticoid tapering regimen for giant cell arteritis Taper week Dose (mg/day) 1 60 2 50 3 40 4 35 5 30 6 25 7 20 8 17.5 9 17.5 10 15 11 15 12 12.5 13 10 14 10 15 10 16 10 17 9 18 9 19 9 20 9 21 8 22 8 23 8 24 8 25 7 26 7 27 7 28 7 29 6 https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 27/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate 30 6 31 6 32 6 33 5 34 5 35 5 36 5 37 4 38 4 39 4 40 4 41 3 42 3 43 3 44 3 45 2 46 2 47 2 48 2 49 1 50 1 51 1 52 1 Tapering doses listed refer to oral prednisone (or equivalent) typically administered once daily in the morning. Data from: Stone JH, Tuckwell K, Dimonaco S, et al. Trial of tocilizumab in giant-cell arteritis. New Engl J Med 2017; 377:317. Graphic 139301 Version 2.0 https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 28/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate Accelerated glucocorticoid tapering regimen for patients with giant cell arteritis on tocilizumab Taper week Dose (mg/day) 1 60 2 50 3 40 4 35 5 30 6 25 7 20 8 15 9 12.5 10 12.5 11 10 12 9 13 8 14 7 15 6 16 6 17 5 18 5 19 4 20 4 21 3 22 3 23 2 24 2 25 1 26 1 Tapering doses listed refer to oral prednisone (or equivalent) typically administered once daily in the morning. https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 29/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate Data from: Stone JH, Tuckwell K, Dimonaco S, et al. Trial of tocilizumab in giant-cell arteritis. New Engl J Med 2017; 377:317. Graphic 139298 Version 2.0 https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 30/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate Contributor Disclosures Carlo Salvarani, MD No relevant financial relationship(s) with ineligible companies to disclose. Francesco Muratore, MD No relevant financial relationship(s) with ineligible companies to disclose. Jonathan Trobe, MD No relevant financial relationship(s) with ineligible companies to disclose. Kenneth J Warrington, MD Grant/Research/Clinical Trial Support: Eli Lilly [Giant cell arteritis]; GSK [Giant cell arteritis]; Kiniksa [Giant cell arteritis]. Other Financial Interest: Chemocentryx [Honoraria ANCA-associated vasculitis]. All of the relevant financial relationships listed have been mitigated. Philip Seo, MD, MHS No relevant financial relationship(s) with ineligible companies to disclose.

arteritis: prevalence, characteristics, and associated clinical findings in a longitudinally followed cohort of 106 patients. Medicine (Baltimore) 2014; 93:194. 49. Labarca C, Koster MJ, Crowson CS, et al. Predictors of relapse and treatment outcomes in biopsy-proven giant cell arteritis: a retrospective cohort study. Rheumatology (Oxford) 2016; 55:347. https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 23/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate 50. Restuccia G, Boiardi L, Cavazza A, et al. Flares in Biopsy-Proven Giant Cell Arteritis in Northern Italy: Characteristics and Predictors in a Long-Term Follow-Up Study. Medicine (Baltimore) 2016; 95:e3524. 51. Hoffman GS. Giant Cell Arteritis. Ann Intern Med 2016; 165:ITC65. 52. Salvarani C, Cantini F, Hunder GG. Polymyalgia rheumatica and giant-cell arteritis. Lancet 2008; 372:234. 53. Langford CA, Cuthbertson D, Ytterberg SR, et al. A Randomized, Double-Blind Trial of Abatacept (CTLA-4Ig) for the Treatment of Giant Cell Arteritis. Arthritis Rheumatol 2017; 69:837. 54. Koster MJ, Crowson CS, Giblon RE, et al. Baricitinib for relapsing giant cell arteritis: a prospective open-label 52-week pilot study. Ann Rheum Dis 2022; 81:861. 55. Cid MC, Unizony SH, Blockmans D, et al. Efficacy and safety of mavrilimumab in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial. Ann Rheum Dis 2022; 81:653. 56. De Silva M, Hazleman BL. Azathioprine in giant cell arteritis/polymyalgia rheumatica: a double-blind study. Ann Rheum Dis 1986; 45:136. 57. Deng J, Younge BR, Olshen RA, et al. Th17 and Th1 T-cell responses in giant cell arteritis. Circulation 2010; 121:906. 58. Conway R, O'Neill L, O'Flynn E, et al. Ustekinumab for the treatment of refractory giant cell arteritis. Ann Rheum Dis 2016; 75:1578. 59. Matza MA, Fernandes AD, Stone JH, Unizony SH. Ustekinumab for the Treatment of Giant Cell Arteritis. Arthritis Care Res (Hoboken) 2021; 73:893. 60. Quartuccio L, Maset M, De Maglio G, et al. Role of oral cyclophosphamide in the treatment of giant cell arteritis. Rheumatology (Oxford) 2012; 51:1677. 61. Henes JC, Mueller M, Pfannenberg C, et al. Cyclophosphamide for large vessel vasculitis: assessment of response by PET/CT. Clin Exp Rheumatol 2011; 29:S43. 62. de Boysson H, Boutemy J, Creveuil C, et al. Is there a place for cyclophosphamide in the treatment of giant-cell arteritis? A case series and systematic review. Semin Arthritis Rheum 2013; 43:105. 63. Ly KH, Dalmay F, Gondran G, et al. Steroid-sparing effect and toxicity of dapsone treatment in giant cell arteritis: A single-center, retrospective study of 70 patients. Medicine (Baltimore) 2016; 95:e4974. 64. Diamantopoulos AP, Hetland H, Myklebust G. Leflunomide as a corticosteroid-sparing agent in giant cell arteritis and polymyalgia rheumatica: a case series. Biomed Res Int 2013; https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 24/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate 2013:120638. 65. Ly KH, Stirnemann J, Liozon E, et al. Interleukin-1 blockade in refractory giant cell arteritis. Joint Bone Spine 2014; 81:76. 66. Hoffman GS, Cid MC, Rendt-Zagar KE, et al. Infliximab for maintenance of glucocorticosteroid-induced remission of giant cell arteritis: a randomized trial. Ann Intern Med 2007; 146:621. 67. Seror R, Baron G, Hachulla E, et al. Adalimumab for steroid sparing in patients with giant- cell arteritis: results of a multicentre randomised controlled trial. Ann Rheum Dis 2014; 73:2074. 68. Mart nez-Taboada VM, Rodr guez-Valverde V, Carre o L, et al. A double-blind placebo controlled trial of etanercept in patients with giant cell arteritis and corticosteroid side effects. Ann Rheum Dis 2008; 67:625. 69. Kermani TA, Warrington KJ, Crowson CS, et al. Large-vessel involvement in giant cell arteritis: a population-based cohort study of the incidence-trends and prognosis. Ann Rheum Dis 2013; 72:1989. 70. Gonz lez-Gay MA, Blanco R, Abraira V, et al. Giant cell arteritis in Lugo, Spain, is associated with low longterm mortality. J Rheumatol 1997; 24:2171. 71. Gran JT, Myklebust G, Wilsgaard T, Jacobsen BK. Survival in polymyalgia rheumatica and temporal arteritis: a study of 398 cases and matched population controls. Rheumatology (Oxford) 2001; 40:1238. Topic 8240 Version 40.0 https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 25/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate GRAPHICS Narrowing of the left subclavian artery in giant cell arteritis Angiogram of the left subclavian artery in GCA, showing several areas of severe vascular narrowing but a proliferation of small blood vessels forming excellent collateral circulation. The long, smooth arterial tapering in large vessel GCA is often not amenable to revascularization interventions such as angioplasty or stent placement. Those types of interventions are rarely necessary. GCA: giant cell arteritis. Courtesy of John H Stone, MD, MPH. Graphic 73553 Version 8.0 https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 26/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate 52-week glucocorticoid tapering regimen for giant cell arteritis Taper week Dose (mg/day) 1 60 2 50 3 40 4 35 5 30 6 25 7 20 8 17.5 9 17.5 10 15 11 15 12 12.5 13 10 14 10 15 10 16 10 17 9 18 9 19 9 20 9 21 8 22 8 23 8 24 8 25 7 26 7 27 7 28 7 29 6 https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 27/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate 30 6 31 6 32 6 33 5 34 5 35 5 36 5 37 4 38 4 39 4 40 4 41 3 42 3 43 3 44 3 45 2 46 2 47 2 48 2 49 1 50 1 51 1 52 1 Tapering doses listed refer to oral prednisone (or equivalent) typically administered once daily in the morning. Data from: Stone JH, Tuckwell K, Dimonaco S, et al. Trial of tocilizumab in giant-cell arteritis. New Engl J Med 2017; 377:317. Graphic 139301 Version 2.0 https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 28/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate Accelerated glucocorticoid tapering regimen for patients with giant cell arteritis on tocilizumab Taper week Dose (mg/day) 1 60 2 50 3 40 4 35 5 30 6 25 7 20 8 15 9 12.5 10 12.5 11 10 12 9 13 8 14 7 15 6 16 6 17 5 18 5 19 4 20 4 21 3 22 3 23 2 24 2 25 1 26 1 Tapering doses listed refer to oral prednisone (or equivalent) typically administered once daily in the morning. https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 29/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate Data from: Stone JH, Tuckwell K, Dimonaco S, et al. Trial of tocilizumab in giant-cell arteritis. New Engl J Med 2017; 377:317. Graphic 139298 Version 2.0 https://www.uptodate.com/contents/treatment-of-giant-cell-arteritis/print 30/31 7/7/23, 11:22 AM Treatment of giant cell arteritis - UpToDate Contributor Disclosures Carlo Salvarani, MD No relevant financial relationship(s) with ineligible companies to disclose. Francesco Muratore, MD No relevant financial relationship(s) with ineligible companies to disclose. Jonathan Trobe, MD No relevant financial relationship(s) with ineligible companies to disclose. Kenneth J Warrington, MD Grant/Research/Clinical Trial Support: Eli Lilly [Giant cell arteritis]; GSK [Giant cell arteritis]; Kiniksa [Giant cell arteritis]. Other Financial Interest: Chemocentryx [Honoraria ANCA-associated vasculitis]. All of the relevant financial relationships listed have been mitigated. Philip Seo, MD, MHS 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/treatment-of-giant-cell-arteritis/print 31/31

7/7/23, 11:21 AM Treatment of Takayasu arteritis - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Treatment of Takayasu arteritis : Peter A Merkel, MD, MPH : Kenneth J Warrington, MD : Philip Seo, MD, MHS 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 10, 2022. INTRODUCTION Takayasu arteritis (TAK) is a large-vessel vasculitis of unknown etiology, primarily affecting the aorta and its primary branches. The inflammatory processes cause thickening of the walls of the affected arteries. The proximal aorta (eg, aortic root) may become dilated secondary to inflammatory injury. Narrowing, occlusion, or dilation of involved portions of the arteries in varying degrees results in a wide variety of symptoms. The treatment of TAK will be reviewed here. The pathogenesis, pathology, clinical manifestations, and diagnosis of this disorder are discussed separately. (See "Clinical features and diagnosis of Takayasu arteritis".) PHARMACOLOGIC MANAGEMENT Overall approach The mainstay of therapy for Takayasu arteritis (TAK) is systemic glucocorticoids. However, given the chronic, relapsing nature of the disease and the imperative to avoid glucocorticoid-related toxicities, patients are often prescribed a nonglucocorticoid immunosuppressive agent in an attempt to provide both a "steroid-sparing" benefit and longer- term disease control. No specific agent has been well-proven to be effective, and it is common that patients are prescribed a series of medications, sometimes in combination. Endovascular interventions or other surgical procedures may be necessary once irreversible arterial stenosis leading to critical ischemia has occurred or large aneurysms develop. However, both https://www.uptodate.com/contents/treatment-of-takayasu-arteritis/print 1/21 7/7/23, 11:21 AM Treatment of Takayasu arteritis - UpToDate endovascular intervention and surgical procedures should generally be avoided when the disease is active. (See 'Surgical management of vascular complications' below.) Because the disease process in TAK often remains active in the absence of clinical symptoms, it is important that patients undergo regularly scheduled imaging to assess for progression of arterial disease. (See 'Monitoring disease activity and routine follow-up' below.) It is recommended that patients with TAK be evaluated and managed by centers and physicians with experience treating this rare disease. Our management approach is generally consistent with guidelines developed by professional organizations [1-3]. Initial management Systemic glucocorticoids plus glucocorticoid-sparing agent For most patients with active TAK, we suggest initial treatment with high-dose, orally administered glucocorticoids in combination with a glucocorticoid-sparing agent rather than glucocorticoids alone. Some clinicians reserve the addition of a glucocorticoid-sparing agent for patients whose disease relapses after treatment with an extended course of glucocorticoids alone. Given the adverse effects associated with glucocorticoids and the high rate of relapse during tapering, we prefer to initiate additional immunosuppressive agents at the time prednisone therapy is prescribed. This approach is largely based on data from case series along with expert opinion and experience. There are no randomized trials evaluating the role of glucocorticoids alone, and there are no substantive comparative effective analyses to help guide the use of one agent over another. (See 'Choice of glucocorticoid-sparing agent' below.) The initial dose of glucocorticoids depends on the nature and severity of the disease activity. In patients with new-onset arterial stenosis and/or symptoms of involvement of critical region (eg, aortitis or carotidynia), the dose of oral prednisone is typically 1 mg/kg per day, up to a maximum daily dose of 60 to 80 mg, and should be continued for two to four weeks, at which time tapering of the dose should begin if patients demonstrate clinical improvement. Glucocorticoids are administered as a single daily morning dose. We taper the dose of prednisone steadily with an attempt to achieve a dose of 20 mg/day by no later than the end of month 3 of therapy. Long-term, low-dose daily prednisone therapy is commonly prescribed to prevent minor constitutional symptoms, although some centers aim to discontinue all glucocorticoids when sustained remission is obtained. Whether low-dose glucocorticoids prevent progression of arterial stenosis is not clear. https://www.uptodate.com/contents/treatment-of-takayasu-arteritis/print 2/21 7/7/23, 11:21 AM Treatment of Takayasu arteritis - UpToDate Occasionally, it may be appropriate to initiate treatment with daily high-dose "pulse" intravenous glucocorticoids (500 to 1000 mg doses) for one to three days to treat perceived immediately organ-threatening disease such as involvement of the coronary arteries or critical stenosis of the carotid or vertebral arteries. This is then typically followed by the oral prednisone regimen described above. Observational data from case series suggest that glucocorticoids help many patients achieve remission, but that patients frequently relapse and are then treated with additional courses of glucocorticoids plus additional immunosuppressive (glucocorticoid-sparing) agents. More than one-half of all patients with TAK have chronic active disease for which glucocorticoid therapy alone does not provide sustained remissions [4,5]. The normochromic anemia and elevated acute phase reactants typically return to normal with use of glucocorticoids [6]. Arterial stenosis may rarely reverse, and ischemic symptoms may improve in early cases. However, the vascular response is diminished once fibrous tissue has formed in the involved vessels or once thrombosis has occurred. Ischemia may also improve over time with the development of new collateral arteries. Choice of glucocorticoid-sparing agent The choice of an additional agent in combination with glucocorticoids depends on several factors including considerations regarding comorbidities, a patient's plans for conceiving a child, cost of treatments, and availability of specific agents. For most patients with active TAK, we suggest the addition of either methotrexate (20 to 25 mg once weekly) or azathioprine (2 mg/kg daily) to therapy with glucocorticoids, to allow use of a lower dose of glucocorticoids while achieving or maintaining disease control. While these drugs are suggested because of overall greater clinical experience, ease of use, and familiarity, reasonable alternatives include mycophenolate and leflunomide. There are no data available to clearly favor one glucocorticoid-sparing agent over another. However, depending on patient-specific circumstances, access to biologic agents, and severity of disease at presentation, it is also reasonable to start with an anti-tumor necrosis factor (TNF) agent alone, or use it as additional treatment to methotrexate, azathioprine, or leflunomide. (See 'Combination therapy' below.) As mentioned above, there are no randomized trials comparing the efficacy of different immunosuppressive therapies, and practice patterns typically reflect the results of observational data and expert opinion. A meta-analysis provides insight into the range of small studies involved and relatively weak evidence base from which to make decisions [7]. The meta-analysis was limited to observational studies and found that approximately 60 percent of patients achieved remission with glucocorticoids combined with either nonbiologic or biologic agents, and that these rates of remission were similar between the two groups (ie, nonbiologic versus https://www.uptodate.com/contents/treatment-of-takayasu-arteritis/print 3/21 7/7/23, 11:21 AM Treatment of Takayasu arteritis - UpToDate biologic). The nonbiologic agents included in the studies were methotrexate, azathioprine, mycophenolate, leflunomide, and cyclophosphamide and the biologic agents included anti-TNF agents, tocilizumab, and rituximab. There was a trend towards higher relapse rates for nonbiologic agents, but this was not statistically significant. Nonbiologic DMARDs The typical dosing and available data for the use of the nonbiologic disease-modifying antirheumatic drugs (DMARDs) used for the treatment of TAK are discussed below: Methotrexate Methotrexate is typically initiated at a dose of 15 mg/week, with increases in dose every week of 5 mg/week up to 25 mg/week. We use the same regimen and approach to titration as that used for rheumatoid arthritis and prefer to administer the drug subcutaneously. (See "Use of methotrexate in the treatment of rheumatoid arthritis" and "Major side effects of low-dose methotrexate".) The data for the use of methotrexate for the treatment of TAK are mostly limited to a few case reports and small open-label trials [4,8-10]. In one study, the use of methotrexate was evaluated in an open-label study of 18 patients, 16 of whom were followed for a mean of almost three years [4]. Weekly administration of methotrexate (mean stable dose 17.1 mg) plus glucocorticoids resulted in remissions in 13 of 16 patients (81 percent). Relapse occurred in seven (44 percent) when the glucocorticoids were tapered near or to discontinuation. Retreatment again led to remission, and three of seven patients in this group successfully stopped glucocorticoid therapy. Of those patients who achieved remission, eight (50 percent) sustained the remission at a mean of 18 months of follow-up; four patients in this group had not required either drug for a mean of 11 months. Disease progression occurred in three patients in spite of treatment. Azathioprine Azathioprine is typically initiated at a dose of 50 mg/day and gradually increased. If this dose is tolerated well at one week, the daily dose can be increased over several weeks to the range of 1.5 to 2 mg/kg per day. The maximum dose should typically not exceed 200 mg/day. Additional information regarding dosing, adverse effects, and the role of testing for thiopurine methyltransferase (TMPT) deficiency can be found separately. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases" and "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Adverse effects' and "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Pharmacogenetics and azathioprine toxicity'.) Aside from case reports, there is only one open study evaluating the use of azathioprine in patients with TAK. In an uncontrolled series of 15 young women in India, all of whom had https://www.uptodate.com/contents/treatment-of-takayasu-arteritis/print 4/21 7/7/23, 11:21 AM Treatment of Takayasu arteritis - UpToDate angiographic evidence of disease and in whom follow-up angiograms were performed, the combination of glucocorticoids and azathioprine was evaluated [11]. Remission occurred in all patients within 12 weeks during treatment with prednisolone (1 mg/kg/day for six weeks followed by a taper to 5 to 10 mg/day by 12 weeks) and azathioprine (2 mg/kg/day). Azathioprine was continued for one year, at which time repeat angiography revealed no new arterial lesions and no worsening of the previously noted stenoses or aneurysms. The combination was well tolerated, and no adverse effects were reported. Leflunomide Leflunomide is typically administered at a dose of 20 mg daily. We use the same regimen as used in rheumatoid arthritis. (See "Pharmacology, dosing, and adverse effects of leflunomide in the treatment of rheumatoid arthritis".) A favorable response to leflunomide was observed in several case series totaling 83 patients with TAK [12,13]. These series included patients whose disease had been refractory to therapy with glucocorticoids and other immunosuppressive agents [12]. Approximately 50 percent of patients remained on leflunomide after 12 months and were in remission; however, relapses, including with new angiographic lesions, also occurred in many patients. Mycophenolate mofetil The target dose of mycophenolate mofetil is generally the same as that used for other systemic rheumatic diseases, which is generally between 1.5 and 3 grams daily, in divided doses. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases".) There are limited data supporting mycophenolate mofetil as a safe and effective glucocorticoid-sparing agent in the treatment of TAK [14-16]. In an observational study of 21 TAK patients followed for a mean of 9.6 months, 20 patients demonstrated improvement in disease activity [15]. Although all of the patients required use of concomitant glucocorticoids, there was a significant decrease in total glucocorticoid dose at the time of follow-up. Cyclophosphamide There is limited published experience with cyclophosphamide and TAK [17-19], and it is generally reserved for patients with TAK with severe life- or vital organ-threatening conditions; patients receiving cyclophosphamide are later switched, usually after three to six months, to another less toxic conventional immunosuppressive agent. Many patients with TAK are young women, and the substantial risk of cyclophosphamide inducing ovarian failure or reduced fertility makes use of this drug in this disease particularly problematic. Additional information regarding dosing and adverse effects of cyclophosphamide administration can be found separately. (See "General https://www.uptodate.com/contents/treatment-of-takayasu-arteritis/print 5/21 7/7/23, 11:21 AM Treatment of Takayasu arteritis - UpToDate principles of the use of cyclophosphamide in rheumatic diseases" and "General toxicity of cyclophosphamide in rheumatic diseases".) Biologic DMARDs The typical dosing and available data for the use of biologic DMARDs used for the treatment of TAK are discussed below. Among the biologic agents used for this indication, the most experience is with TNF inhibitors. TNF inhibitor Experience with anti-TNF-alpha agents in difficult-to-treat patients with TAK is growing, and there have now been several case series published supporting this class of drugs as efficacious in the treatment of TAK [20,21]. There are more published data on the use of anti-TNF agents than for any other biologic agent. The first published report was of an uncontrolled series of 15 patients who required high doses of glucocorticoids to maintain remission and who relapsed while treated with other agents (or who refused retreatment with glucocorticoids) and were treated with either etanercept (seven patients received an initial dose of 25 mg twice weekly) or infliximab (eight patients received 3 to 5 mg/kg initially, at two weeks, at six weeks, and every four to eight weeks thereafter) [20]. Improvement was noted in 14 of 15 patients. Sustained remission was achieved in 10 patients who were able to discontinue glucocorticoids. Nine of the 14 patients required dose escalation to maintain disease control. Subsequent case series mostly demonstrated positive effects of the drugs, with some series reporting higher rates of relapse despite use of the anti-TNF agent. A metaanalysis of nonbiologic and biologic therapies suggested that anti-TNFs may be more effective in maintaining remission in patients with TAK, but effect sizes were small and risk of channeling bias was high [7]. Tocilizumab Several cases of successful use of tocilizumab have been reported in patients with TAK [22-26]. In most, but not all, cases, there was an improvement in disease activity and the glucocorticoid doses were tapered. A randomized trial of tocilizumab as adjuvant therapy to standard doses of glucocorticoids for patients with active TAK did not demonstrate benefit for the use of the study drug [27]. However, this trial had a sample size of 36 (18 per treatment group) and thus was underpowered to show a modest to moderate benefit, and the "trend" was seemingly encouraging in favor of the group receiving tocilizumab. Thus, given the evidence that interleukin (IL)-6 may be involved in the pathogenesis of TAK, treatment interfering with the action of IL-6 remains of interest in TAK, although the evidence of efficacy to date is mixed. Although it is tempting to extrapolate data generated in the study of giant cell arteritis to the treatment of TAK given that these two diseases are both forms of large-vessel vasculitis with similar characteristics, such a comparison is tempered by trials that use the same https://www.uptodate.com/contents/treatment-of-takayasu-arteritis/print 6/21 7/7/23, 11:21 AM Treatment of Takayasu arteritis - UpToDate agent to treat both diseases but demonstrate efficacy in giant cell arteritis but not in TAK [27-31]. (See "Treatment of giant cell arteritis", section on 'Tocilizumab'.) There are several other biologic therapies that have been studied for the treatment of TAK; however, we do not routinely use any of the following therapies given the lack of data to support their efficacy: Abatacept The first-ever randomized controlled trial conducted in TAK tested the efficacy of abatacept (CTLA4-Ig) to prevent relapse [28]. This trial enrolled 34 patients with TAK. The trial did not demonstrate efficacy of abatacept for TAK. Abatacept is therefore not recommended for use in the treatment of TAK. Interestingly, a trial with the same design among patients with giant cell arteritis was conducted in parallel and found benefit for this agent in that disease [29], providing additional evidence of important differences in the pathophysiology of these two forms of large-vessel vasculitis. Ustekinumab Only a few cases of patients with TAK being treated with ustekinumab have been reported with initially encouraging results [32,33]. Rituximab A case series of seven patients with TAK treated with rituximab reported positive results, but no trials or additional cases have been reported [34]. Resistant to initial therapy Combination therapy For patients with progressive disease despite the initial therapeutic approach, we often combine an oral nonbiologic agent with a biologic agent, in addition to treatment as needed with glucocorticoids. The combination may depend on both the perceived benefit, if any, of initial therapy and other patient-related factors (eg, patient preferences, comorbidities, cost barriers to drug access). The most common combination of oral nonbiologic DMARD and biologic DMARD involves adding a TNF inhibitor to either methotrexate, azathioprine, or leflunomide. Another reasonable approach would be to combine tocilizumab with either methotrexate, azathioprine, or leflunomide. Mycophenolate and cyclophosphamide should not be combined with the biologic DMARDs discussed above (ie, TNF inhibitor and mycophenolate used together), as this could result in excessive immunosuppression with related adverse events without clear evidence of additional benefit. Monitoring disease activity and routine follow-up Monitoring disease activity and response to therapy may be challenging for clinicians, given the absence of specific laboratory https://www.uptodate.com/contents/treatment-of-takayasu-arteritis/print 7/21 7/7/23, 11:21 AM Treatment of Takayasu arteritis - UpToDate tests or validated assessment criteria for disease activity. Factors that should be taken into account when assessing disease activity include patient symptoms, physical findings, acute phase reactants, and findings on imaging. Clinical evaluation During treatment, we monitor for a decrease and eventual disappearance of constitutional symptoms and arthralgias, accompanied by a decrease in acute phase reactants such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels. However, these blood tests do not reliably reflect disease activity and can be normal in the setting of active disease. Some patients may also experience an improvement in limb claudication either due to reduction in stenosis (not common) or development of collateral vessels (common). (See "Clinical features and diagnosis of Takayasu arteritis", section on 'Laboratory findings'.) Imaging Although there is increasing accumulation of data and experience with various imaging modalities for the assessment of disease activity in TAK, much about this area remains both controversial and dependent on expert opinion [35,36]. We suggest obtaining an magnetic resonance (MR) or computed tomography (CT) angiography at the time of diagnosis and then repeating the test at least annually and more often if new signs or symptoms of active disease or arterial stenosis occur. We prefer to use serial MR angiography over serial CT angiography whenever possible to avoid the additive exposure to radiation and iodinated contrast dye. Serial MR imaging (MRI) or CT scans can be used to follow the response to treatment [37,38]. The potential efficacy of this approach was evaluated in 31 patients in whom repeat CT angiography was performed over a median period of three years [38]. Thoracic or abdominal aortic aneurysms were initially noted in 12 patients (approximately 40 percent) and subsequently developed in two during follow-up. Rapidly increasing aneurysmal size (more than 1 cm/year) occurred in three patients despite glucocorticoid therapy ( image 1A-B); this was accompanied by mural thickening (suggestive of continued disease activity), eventually culminating in aortic rupture. Vascular wall edema demonstrated by MRI, in the absence of other clinical evidence of active disease, does not appear to be a sufficient reason for more aggressive therapy. This point was illustrated by a study in which there was poor correlation between the appearance of MRI- detected vessel wall edema and the presence or absence of active vasculitis, as determined clinically by subsequent development of stenotic or aneurysmal dilation or by pathologic examination of resected vessel walls [39]. Ultrasound may have a role in following specific arterial regions, but this modality is impractical for monitoring the entire aorta and its main branches. Doppler ultrasound studies of the carotid https://www.uptodate.com/contents/treatment-of-takayasu-arteritis/print 8/21 7/7/23, 11:21 AM Treatment of Takayasu arteritis - UpToDate and vertebral arteries may provide important functional data complementary to MRI or CT. Positron emission tomography (PET) scanning, usually in combination with either CT or MRI, is increasingly being investigated as a potentially useful measure of disease activity in TAK [40,41]. There is ongoing controversy regarding whether to base treatment on results of PET scans or whether these tests can assess response to therapy. This modality remains experimental but will likely soon find a role in disease management of TAK once greater standardization and refinement of indications occur. Additionally, information obtained from MRI or CT is complementary to that obtained by PET [42]. It should be recognized that not all active arterial disease will result in changes on imaging. For example, carotidynia from arterial wall inflammation may occur with no change on MRI, CT, or ultrasound. Furthermore, the finding of a new stenosis in a new arterial territory implies disease activity was present since the last image was obtained but may not inform the clinician of current disease status. It is also important to realize that expansion of an aneurysm or even further occlusion at the site of a previously recognized lesion may not be due to active inflammation but may be the progression of the original lesion. Other general measures Additional monitoring and interventions to prevent complications of disease and therapy should be implemented at the beginning of treatment. Screening tests for tuberculosis and immunizations against influenza and pneumococcal pneumonia must be up to date. Blood pressure management Patients with TAK are at risk for severe or even malignant hypertension from renovascular hypertension secondary to either stenosis of the renal arteries or stenosis of the aorta proximal to the take-off of the renal arteries. It is imperative that clinicians and patients be aware of which of the patient's limbs do not have substantial arterial occlusions, provide accurate blood pressure readings, and only use these limbs for assessment and management of blood pressure. This approach may mean only a lower extremity is used for blood pressure readings. In some cases, it may be necessary for patients to undergo a catheter-based angiogram to determine the accuracy of blood pressure readings. Blood pressure management in a patient with TAK may be even more complicated by reduced cerebral blood flow due to stenosis of the innominate, carotid, or vertebral arteries. Prevention of osteoporosis All patients treated with high-dose glucocorticoids are at risk for glucocorticoid-induced osteoporosis. Prevention of glucocorticoid-induced osteoporosis https://www.uptodate.com/contents/treatment-of-takayasu-arteritis/print 9/21 7/7/23, 11:21 AM Treatment of Takayasu arteritis - UpToDate is discussed in detail elsewhere. (See "Prevention and treatment of glucocorticoid-induced osteoporosis".) Prevention of opportunistic infections Prophylaxis against Pneumocystis jirovecii is indicated for patients treated with the combination of high-dose glucocorticoids and other immunosuppressive agents. A common prophylactic strategy for Pneumocystis involves the daily use of one single-strength tablet daily of trimethoprim-sulfamethoxazole (TMP/SMZ), which contains trimethoprim 80 mg and 400 mg of sulfamethoxazole. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.) Antiplatelet therapy We limit the use of low-dose aspirin (75 to 81 mg/day) to patients with critical stenosis of carotid or vertebral arteries, especially if more than one artery is involved, thus limiting reserve cerebral circulation. However, such treatment is purely empiric and is associated with the usual risks of aspirin. (See "Aspirin: Mechanism of action, major toxicities, and use in rheumatic diseases", section on 'Major side effects and other concerns'.) SURGICAL MANAGEMENT OF VASCULAR COMPLICATIONS Vascular intervention may be necessary for the treatment of stenosed or occluded arteries leading to organ ischemia or hypertension and for the management of aneurysmal disease [43- 48]. Progressive aneurysmal dilation at risk for dissection or rupture, severe aortic regurgitation (AR), and aortic coarctation also require surgery. Revascularization procedures, however, should be avoided during the active phase of the disease [49]. Revascularization Endovascular surgery including percutaneous transluminal angioplasty (PTA) and stent graft placement are preferable for short segment arterial stenotic lesions. Percutaneous intervention is less likely to be successful when stenoses or occlusions affect lengthy portions of an artery or when the artery is heavily scarred. Open surgical revascularization procedures, such as bypass grafts, may be necessary for long-segment stenosis with extensive periarterial fibrosis or occlusion [50]. Continued inflammation in a treated segment may result in restenosis following angioplasty, with or without stenting; restenosis is less likely following bypass grafting than angioplasty, when performed after initiation of treatment or when revascularization is followed by antiinflammatory therapy [51,52]. Given the substantial difficulty assessing disease activity in Takayasu arteritis (TAK), perioperative or periprocedural treatment of patients with glucocorticoids in an effort to prevent restenosis may be appropriate. https://www.uptodate.com/contents/treatment-of-takayasu-arteritis/print 10/21 7/7/23, 11:21 AM Treatment of Takayasu arteritis - UpToDate When safe and feasible, obtaining tissue, even if only a small arterial sample during revascularization, may be quite helpful in determining if active arterial inflammation is present [53,54]. An important consideration when planning surgical arterial bypass procedures on patients with TAK is the condition of the "touchdown" artery. The surgeon needs to avoid attaching a repositioned artery or a graft onto an inflamed artery, including the aorta, to prevent postsurgical occlusion at the attachment site. Additionally, the condition of the distal flow of the destination artery needs to be considered, given that many patients with TAK have multiple arterial lesions. Thus, whenever possible, it is important to have a full assessment of the patient's current state of disease and arterial anatomy prior to planned surgery. Aortic valve surgery Progressive AR may require surgical therapy, either with valve replacement or with valve repair. Surgery is more difficult in this disorder since the tissue is fragile and inflamed. The general indications for surgery for AR and the available options are discussed separately. (See "Natural history and management of chronic aortic regurgitation in adults".) The long-term outcome after surgery for AR in TAK was evaluated in a series of 90 consecutive patients (mean age 49) [55]. Sixty-three patients underwent aortic valve replacement, and 27 underwent composite graft repair. The study was not designed to compare the two approaches, and the two groups had significant baseline differences. The overall 15-year survival was 76 percent. Late dilation of the residual ascending aorta occurred in 8.9 percent (in 11.1 percent with valve replacement and in 3.7 percent with valve repair, a difference that was not significant). Outcomes appeared to be worse with aortic-valve-sparing reimplantation, as three of four patients required subsequent aortic valve replacement for recurrent AR. PROGNOSIS Takayasu arteritis (TAK) is a chronic disease characterized by a fluctuating course, with apparent exacerbations and reductions (or remissions) in the intensity of the inflammatory processes [56]. Only approximately one-fifth of patients have a monophasic and self-limited course, while the majority of patients show a progressive or relapsing and remitting arteritis and require long- term immunosuppressive therapies [43]. Vascular involvement tends to be progressive, although the short-term prognosis is favorable. In several follow-up studies, 80 to 90 percent of five-year survivals have been reported [57-60]. One study investigating prognostic factors associated with this disease found two major predictors of outcome: the incidence of complications (Takayasu retinopathy, hypertension, aortic https://www.uptodate.com/contents/treatment-of-takayasu-arteritis/print 11/21 7/7/23, 11:21 AM Treatment of Takayasu arteritis - UpToDate regurgitation [AR], and aneurysm) and the presence of a progressive course [46]. The 15-year survival was 66 and 96 percent for patients with and without a major complication, respectively, and was 68 and 93 percent for those with and without a progressive course, respectively. The presence of both a major complication and progressive course was the worst prognostic indicator (43 percent survival at 15 years). By contrast, no patient died who had neither of these manifestations. These variables may identify a subset of patients who require more aggressive medical and/or surgical 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: Takayasu arteritis".) 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.) Beyond the Basics topics (see "Patient education: Vasculitis (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS The mainstay of therapy for Takayasu arteritis (TAK) is systemic glucocorticoids. However, given the chronic, relapsing nature of the disease and the imperative to avoid glucocorticoid-related toxicities, patients are often prescribed a nonglucocorticoid immunosuppressive agent in an attempt to provide both a "steroid-sparing" benefit and longer-term disease control. No specific agent has been well-proven to be effective, and it https://www.uptodate.com/contents/treatment-of-takayasu-arteritis/print 12/21 7/7/23, 11:21 AM Treatment of Takayasu arteritis - UpToDate is common that patients are prescribed a series of medications, sometimes in combination. Endovascular interventions or other surgical procedures may be necessary once irreversible arterial stenosis leading to critical ischemia has occurred or large aneurysms develop. (See 'Overall approach' above.) For most patients with active TAK, we suggest initial treatment with high-dose glucocorticoids in combination with a glucocorticoid-sparing agent rather than glucocorticoids alone (Grade 2C). The choice of an additional agent in combination with glucocorticoids depends on several factors including considerations regarding comorbidities, a patient's plans for conceiving a child, cost of treatments, and availability of specific agents. (See 'Choice of glucocorticoid-sparing agent' above.) For most patients, we add either methotrexate (20 to 25 mg once weekly) or azathioprine (2 mg/kg daily) to therapy with glucocorticoids, to allow use of a lower dose of glucocorticoids while achieving or maintaining disease control. While these medications are suggested because of overall greater clinical experience, ease of use, and familiarity, reasonable alternatives include mycophenolate and leflunomide. There are no data available to clearly favor one nonbiologic disease-modifying antirheumatic drug (DMARD) over another. (See 'Nonbiologic DMARDs' above.) In selected cases, it would be reasonable to add a tumor necrosis factor (TNF) inhibitor to initial therapy with glucocorticoids. This approach depends on patient-specific preferences and circumstances, access to biologic agents, and severity of disease at presentation. (See 'Biologic DMARDs' above.) For patients with progressive disease despite initial therapy, we often combine an oral nonbiologic DMARD with a biologic DMARD, in addition to treatment as needed with glucocorticoids. The combination depends on both the perceived benefit, if any, of initial therapy and the patient's individual situation. (See 'Combination therapy' above.) Monitoring disease activity and response to therapy may be challenging for clinicians, given the absence of specific laboratory tests or validated assessment criteria for disease activity. Factors that should be taken into account when assessing disease activity include patient symptoms, physical findings, acute phase reactants, and findings on imaging. (See 'Monitoring disease activity and routine follow-up' above.) We suggest obtaining a magnetic resonance (MR) or computed tomography (CT) angiography at the time of diagnosis and then repeating the test at least annually and more often if new signs or symptoms of active disease or arterial stenosis occur. We prefer https://www.uptodate.com/contents/treatment-of-takayasu-arteritis/print 13/21 7/7/23, 11:21 AM Treatment of Takayasu arteritis - UpToDate to use serial MR angiography over serial CT angiography whenever possible to avoid the additive exposure to radiation and iodinated contrast dye. (See 'Imaging' above.) Vascular intervention may be necessary for the treatment of stenosed or occluded arteries leading to organ ischemia or hypertension and for the management of aneurysmal disease. Progressive aneurysmal dilation at risk for dissection or rupture, severe aortic regurgitation (AR), and aortic coarctation also require surgery. Revascularization procedures, however, should be avoided during the active phase of the disease. (See 'Surgical management of vascular complications' above.) TAK is a chronic disease characterized by a fluctuating course, with apparent exacerbations and reductions (or remissions) in the intensity of the inflammatory processes. Only approximately one-fifth of patients have a monophasic and self-limited course, while the majority of patients show a progressive or relapsing and remitting arteritis and require long-term immunosuppressive therapies. (See 'Prognosis' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Gene G Hunder, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Maz M, Chung SA, Abril A, et al. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Giant Cell Arteritis and Takayasu Arteritis. Arthritis Rheumatol 2021; 73:1349. 2. Maz M, Chung SA, Abril A, et al. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Giant Cell Arteritis and Takayasu Arteritis. Arthritis Care Res (Hoboken) 2021; 73:1071. 3. Hellmich B, Agueda A, Monti S, et al. 2018 Update of the EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis 2020; 79:19. 4. Hoffman GS, Leavitt RY, Kerr GS, et al. Treatment of glucocorticoid-resistant or relapsing Takayasu arteritis with methotrexate. Arthritis Rheum 1994; 37:578. 5. Kerr GS, Hallahan CW, Giordano J, et al. Takayasu arteritis. Ann Intern Med 1994; 120:919. 6. Kerr GS. Takayasu's arteritis. Rheum Dis Clin North Am 1995; 21:1041. https://www.uptodate.com/contents/treatment-of-takayasu-arteritis/print 14/21 7/7/23, 11:21 AM Treatment of Takayasu arteritis - UpToDate 7. Barra L, Yang G, Pagnoux C, Canadian Vasculitis Network (CanVasc). Non-glucocorticoid drugs for the treatment of Takayasu's arteritis: A systematic review and meta-analysis. Autoimmun Rev 2018; 17:683. 8. Mevorach D, Leibowitz G, Brezis M, Raz E. Induction of remission in a patient with Takayasu's arteritis by low dose pulses of methotrexate. Ann Rheum Dis 1992; 51:904. 9. Nakamura S, Morishita M, Yang CL, et al. An elderly female who survived more than 30 years following a diagnosis of Takayasu's arteritis, complicated by fatal intestinal amyloidosis. Clin Rheumatol 2006; 25:907. 10. Shetty AK, Stopa AR, Gedalia A. Low-dose methotrexate as a steroid-sparing agent in a child with Takayasu's arteritis. Clin Exp Rheumatol 1998; 16:335. 11. Valsakumar AK, Valappil UC, Jorapur V, et al. Role of immunosuppressive therapy on clinical,

medical and/or surgical 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: Takayasu arteritis".) 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.) Beyond the Basics topics (see "Patient education: Vasculitis (Beyond the Basics)") SUMMARY AND RECOMMENDATIONS The mainstay of therapy for Takayasu arteritis (TAK) is systemic glucocorticoids. However, given the chronic, relapsing nature of the disease and the imperative to avoid glucocorticoid-related toxicities, patients are often prescribed a nonglucocorticoid immunosuppressive agent in an attempt to provide both a "steroid-sparing" benefit and longer-term disease control. No specific agent has been well-proven to be effective, and it https://www.uptodate.com/contents/treatment-of-takayasu-arteritis/print 12/21 7/7/23, 11:21 AM Treatment of Takayasu arteritis - UpToDate is common that patients are prescribed a series of medications, sometimes in combination. Endovascular interventions or other surgical procedures may be necessary once irreversible arterial stenosis leading to critical ischemia has occurred or large aneurysms develop. (See 'Overall approach' above.) For most patients with active TAK, we suggest initial treatment with high-dose glucocorticoids in combination with a glucocorticoid-sparing agent rather than glucocorticoids alone (Grade 2C). The choice of an additional agent in combination with glucocorticoids depends on several factors including considerations regarding comorbidities, a patient's plans for conceiving a child, cost of treatments, and availability of specific agents. (See 'Choice of glucocorticoid-sparing agent' above.) For most patients, we add either methotrexate (20 to 25 mg once weekly) or azathioprine (2 mg/kg daily) to therapy with glucocorticoids, to allow use of a lower dose of glucocorticoids while achieving or maintaining disease control. While these medications are suggested because of overall greater clinical experience, ease of use, and familiarity, reasonable alternatives include mycophenolate and leflunomide. There are no data available to clearly favor one nonbiologic disease-modifying antirheumatic drug (DMARD) over another. (See 'Nonbiologic DMARDs' above.) In selected cases, it would be reasonable to add a tumor necrosis factor (TNF) inhibitor to initial therapy with glucocorticoids. This approach depends on patient-specific preferences and circumstances, access to biologic agents, and severity of disease at presentation. (See 'Biologic DMARDs' above.) For patients with progressive disease despite initial therapy, we often combine an oral nonbiologic DMARD with a biologic DMARD, in addition to treatment as needed with glucocorticoids. The combination depends on both the perceived benefit, if any, of initial therapy and the patient's individual situation. (See 'Combination therapy' above.) Monitoring disease activity and response to therapy may be challenging for clinicians, given the absence of specific laboratory tests or validated assessment criteria for disease activity. Factors that should be taken into account when assessing disease activity include patient symptoms, physical findings, acute phase reactants, and findings on imaging. (See 'Monitoring disease activity and routine follow-up' above.) We suggest obtaining a magnetic resonance (MR) or computed tomography (CT) angiography at the time of diagnosis and then repeating the test at least annually and more often if new signs or symptoms of active disease or arterial stenosis occur. We prefer https://www.uptodate.com/contents/treatment-of-takayasu-arteritis/print 13/21 7/7/23, 11:21 AM Treatment of Takayasu arteritis - UpToDate to use serial MR angiography over serial CT angiography whenever possible to avoid the additive exposure to radiation and iodinated contrast dye. (See 'Imaging' above.) Vascular intervention may be necessary for the treatment of stenosed or occluded arteries leading to organ ischemia or hypertension and for the management of aneurysmal disease. Progressive aneurysmal dilation at risk for dissection or rupture, severe aortic regurgitation (AR), and aortic coarctation also require surgery. Revascularization procedures, however, should be avoided during the active phase of the disease. (See 'Surgical management of vascular complications' above.) TAK is a chronic disease characterized by a fluctuating course, with apparent exacerbations and reductions (or remissions) in the intensity of the inflammatory processes. Only approximately one-fifth of patients have a monophasic and self-limited course, while the majority of patients show a progressive or relapsing and remitting arteritis and require long-term immunosuppressive therapies. (See 'Prognosis' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Gene G Hunder, MD, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Maz M, Chung SA, Abril A, et al. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Giant Cell Arteritis and Takayasu Arteritis. Arthritis Rheumatol 2021; 73:1349. 2. Maz M, Chung SA, Abril A, et al. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Giant Cell Arteritis and Takayasu Arteritis. Arthritis Care Res (Hoboken) 2021; 73:1071. 3. Hellmich B, Agueda A, Monti S, et al. 2018 Update of the EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis 2020; 79:19. 4. Hoffman GS, Leavitt RY, Kerr GS, et al. Treatment of glucocorticoid-resistant or relapsing Takayasu arteritis with methotrexate. Arthritis Rheum 1994; 37:578. 5. Kerr GS, Hallahan CW, Giordano J, et al. Takayasu arteritis. Ann Intern Med 1994; 120:919. 6. Kerr GS. Takayasu's arteritis. Rheum Dis Clin North Am 1995; 21:1041. https://www.uptodate.com/contents/treatment-of-takayasu-arteritis/print 14/21 7/7/23, 11:21 AM Treatment of Takayasu arteritis - UpToDate 7. Barra L, Yang G, Pagnoux C, Canadian Vasculitis Network (CanVasc). Non-glucocorticoid drugs for the treatment of Takayasu's arteritis: A systematic review and meta-analysis. Autoimmun Rev 2018; 17:683. 8. Mevorach D, Leibowitz G, Brezis M, Raz E. Induction of remission in a patient with Takayasu's arteritis by low dose pulses of methotrexate. Ann Rheum Dis 1992; 51:904. 9. Nakamura S, Morishita M, Yang CL, et al. An elderly female who survived more than 30 years following a diagnosis of Takayasu's arteritis, complicated by fatal intestinal amyloidosis. Clin Rheumatol 2006; 25:907. 10. Shetty AK, Stopa AR, Gedalia A. Low-dose methotrexate as a steroid-sparing agent in a child with Takayasu's arteritis. Clin Exp Rheumatol 1998; 16:335. 11. Valsakumar AK, Valappil UC, Jorapur V, et al. Role of immunosuppressive therapy on clinical, immunological, and angiographic outcome in active Takayasu's arteritis. J Rheumatol 2003; 30:1793. 12. de Souza AW, da Silva MD, Machado LS, et al. Short-term effect of leflunomide in patients with Takayasu arteritis: an observational study. Scand J Rheumatol 2012; 41:227. 13. de Souza AW, de Almeida Agustinelli R, de Cinque Almeida H, et al. Leflunomide in Takayasu arteritis - A long term observational study. Rev Bras Reumatol 2016. 14. Daina E, Schieppati A, Remuzzi G. Mycophenolate mofetil for the treatment of Takayasu arteritis: report of three cases. Ann Intern Med 1999; 130:422. 15. Goel R, Danda D, Mathew J, Edwin N. Mycophenolate mofetil in Takayasu's arteritis. Clin Rheumatol 2010; 29:329. 16. Shinjo SK, Pereira RM, Tizziani VA, et al. Mycophenolate mofetil reduces disease activity and steroid dosage in Takayasu arteritis. Clin Rheumatol 2007; 26:1871. 17. Edwards KK, Lindsley HB, Lai CW, Van Veldhuizen PJ. Takayasu arteritis presenting as retinal and vertebrobasilar ischemia. J Rheumatol 1989; 16:1000. 18. Rodr guez-Hurtado FJ, Sabio JM, Lucena J, Jim nez-Alonso J. Ocular involvement in Takayasu's arteritis: response to cyclophosphamide therapy. Eur J Med Res 2002; 7:128. 19. Shelhamer JH, Volkman DJ, Parrillo JE, et al. Takayasu's arteritis and its therapy. Ann Intern Med 1985; 103:121. 20. Hoffman GS, Merkel PA, Brasington RD, et al. Anti-tumor necrosis factor therapy in patients with difficult to treat Takayasu arteritis. Arthritis Rheum 2004; 50:2296. 21. Della Rossa A, Tavoni A, Merlini G, et al. Two Takayasu arteritis patients successfully treated with infliximab: a potential disease-modifying agent? Rheumatology (Oxford) 2005; 44:1074. https://www.uptodate.com/contents/treatment-of-takayasu-arteritis/print 15/21 7/7/23, 11:21 AM Treatment of Takayasu arteritis - UpToDate 22. Salvarani C, Magnani L, Catanoso M, et al. Tocilizumab: a novel therapy for patients with large-vessel vasculitis. Rheumatology (Oxford) 2012; 51:151. 23. Unizony S, Arias-Urdaneta L, Miloslavsky E, et al. Tocilizumab for the treatment of large- vessel vasculitis (giant cell arteritis, Takayasu arteritis) and polymyalgia rheumatica. Arthritis Care Res (Hoboken) 2012; 64:1720. 24. Seitz M, Reichenbach S, Bonel HM, et al. Rapid induction of remission in large vessel vasculitis by IL-6 blockade. A case series. Swiss Med Wkly 2011; 141:w13156. 25. Salvarani C, Magnani L, Catanoso MG, et al. Rescue treatment with tocilizumab for Takayasu arteritis resistant to TNF- blockers. Clin Exp Rheumatol 2012; 30:S90. 26. Bredemeier M, Rocha CM, Barbosa MV, Pitrez EH. One-year clinical and radiological evolution of a patient with refractory Takayasu's arteritis under treatment with tocilizumab. Clin Exp Rheumatol 2012; 30:S98. 27. Nakaoka Y, Isobe M, Takei S, et al. Efficacy and safety of tocilizumab in patients with refractory Takayasu arteritis: results from a randomised, double-blind, placebo-controlled, phase 3 trial in Japan (the TAKT study). Ann Rheum Dis 2018; 77:348. 28. Langford CA, Cuthbertson D, Ytterberg SR, et al. A Randomized, Double-Blind Trial of Abatacept (CTLA-4Ig) for the Treatment of Takayasu Arteritis. Arthritis Rheumatol 2017; 69:846. 29. Langford CA, Cuthbertson D, Ytterberg SR, et al. A Randomized, Double-Blind Trial of Abatacept (CTLA-4Ig) for the Treatment of Giant Cell Arteritis. Arthritis Rheumatol 2017; 69:837. 30. Villiger PM, Adler S, Kuchen S, et al. Tocilizumab for induction and maintenance of remission in giant cell arteritis: A phase 2, randomised, double-blind, placebo-controlled trial. Lancet 2016; 387:1921. 31. Stone JH, Tuckwell K, Dimonaco S, et al. Trial of Tocilizumab in Giant-Cell Arteritis. N Engl J Med 2017; 377:317. 32. Terao C, Yoshifuji H, Nakajima T, et al. Ustekinumab as a therapeutic option for Takayasu arteritis: from genetic findings to clinical application. Scand J Rheumatol 2016; 45:80. 33. Yachoui R, Kreidy M, Siorek M, Sehgal R. Successful treatment with ustekinumab for corticosteroid- and immunosuppressant-resistant Takayasu's arteritis. Scand J Rheumatol 2018; 47:246. 34. Pazzola G, Muratore F, Pipitone N, et al. Rituximab therapy for Takayasu arteritis: a seven patients experience and a review of the literature. Rheumatology (Oxford) 2018; 57:1151. https://www.uptodate.com/contents/treatment-of-takayasu-arteritis/print 16/21 7/7/23, 11:21 AM Treatment of Takayasu arteritis - UpToDate 35. Dejaco C, Ramiro S, Duftner C, et al. EULAR recommendations for the use of imaging in large vessel vasculitis in clinical practice. Ann Rheum Dis 2018; 77:636. 36. Barra L, Kanji T, Malette J, et al. Imaging modalities for the diagnosis and disease activity assessment of Takayasu's arteritis: A systematic review and meta-analysis. Autoimmun Rev 2018; 17:175. 37. Hata A, Numano F. Magnetic resonance imaging of vascular changes in Takayasu arteritis. Int J Cardiol 1995; 52:45. 38. Sueyoshi E, Sakamoto I, Hayashi K. Aortic aneurysms in patients with Takayasu's arteritis: CT evaluation. AJR Am J Roentgenol 2000; 175:1727. 39. Tso E, Flamm SD, White RD, et al. Takayasu arteritis: utility and limitations of magnetic resonance imaging in diagnosis and treatment. Arthritis Rheum 2002; 46:1634. 40. Grayson PC, Alehashemi S, Bagheri AA, et al. 18 F-Fluorodeoxyglucose-Positron Emission Tomography As an Imaging Biomarker in a Prospective, Longitudinal Cohort of Patients With Large Vessel Vasculitis. Arthritis Rheumatol 2018; 70:439. 41. Banerjee S, Quinn KA, Gribbons KB, et al. Effect of Treatment on Imaging, Clinical, and Serologic Assessments of Disease Activity in Large-vessel Vasculitis. J Rheumatol 2020; 47:99. 42. Quinn KA, Ahlman MA, Malayeri AA, et al. Comparison of magnetic resonance angiography and 18F-fluorodeoxyglucose positron emission tomography in large-vessel vasculitis. Ann Rheum Dis 2018; 77:1165. 43. Serra R, Butrico L, Fugetto F, et al. Updates in Pathophysiology, Diagnosis and Management of Takayasu Arteritis. Ann Vasc Surg 2016; 35:210. 44. Keser G, Direskeneli H, Aksu K. Management of Takayasu arteritis: a systematic review. Rheumatology (Oxford) 2014; 53:793. 45. Rao SA, Mandalam KR, Rao VR, et al. Takayasu arteritis: initial and long-term follow-up in 16 patients after percutaneous transluminal angioplasty of the descending thoracic and abdominal aorta. Radiology 1993; 189:173. 46. Ishikawa K, Maetani S. Long-term outcome for 120 Japanese patients with Takayasu's disease. Clinical and statistical analyses of related prognostic factors. Circulation 1994; 90:1855. 47. Jeong HS, Jung JH, Song GG, et al. Endovascular balloon angioplasty versus stenting in patients with Takayasu arteritis: A meta-analysis. Medicine (Baltimore) 2017; 96:e7558. 48. Mason JC. Takayasu arteritis: Surgical interventions. Curr Opin Rheumatol 2015; 27:45. https://www.uptodate.com/contents/treatment-of-takayasu-arteritis/print 17/21 7/7/23, 11:21 AM Treatment of Takayasu arteritis - UpToDate 49. Fields CE, Bower TC, Cooper LT, et al. Takayasu's arteritis: operative results and influence of disease activity. J Vasc Surg 2006; 43:64. 50. Ogino H, Matsuda H, Minatoya K, et al. Overview of late outcome of medical and surgical treatment for Takayasu arteritis. Circulation 2008; 118:2738. 51. Liang P, Tan-Ong M, Hoffman GS. Takayasu's arteritis: vascular interventions and outcomes. J Rheumatol 2004; 31:102. 52. Park MC, Lee SW, Park YB, et al. Post-interventional immunosuppressive treatment and vascular restenosis in Takayasu's arteritis. Rheumatology (Oxford) 2006; 45:600. 53. Morrissey NJ, Goldman J, Fallon JT, et al. Endovascular aortic biopsy in the diagnosis of takayasu arteritis. J Endovasc Ther 2003; 10:136. 54. Singh V, Naik S, Robert J, et al. Endovascular biopsy in Takayasu arteritis. Eur J Rheumatol 2019; 6:155. 55. Matsuura K, Ogino H, Kobayashi J, et al. Surgical treatment of aortic regurgitation due to Takayasu arteritis: long-term morbidity and mortality. Circulation 2005; 112:3707. 56. Maksimowicz-McKinnon K, Clark TM, Hoffman GS. Limitations of therapy and a guarded prognosis in an American cohort of Takayasu arteritis patients. Arthritis Rheum 2007; 56:1000. 57. Hall S, Barr W, Lie JT, et al. Takayasu arteritis. A study of 32 North American patients. Medicine (Baltimore) 1985; 64:89. 58. Ishikawa K. Natural history and classification of occlusive thromboaortopathy (Takayasu's disease). Circulation 1978; 57:27. 59. Eichhorn J, Sima D, Thiele B, et al. Anti-endothelial cell antibodies in Takayasu arteritis. Circulation 1996; 94:2396. 60. Schmidt J, Kermani TA, Bacani AK, et al. Diagnostic features, treatment, and outcomes of Takayasu arteritis in a US cohort of 126 patients. Mayo Clin Proc 2013; 88:822. Topic 8219 Version 24.0 https://www.uptodate.com/contents/treatment-of-takayasu-arteritis/print 18/21 7/7/23, 11:21 AM Treatment of Takayasu arteritis - UpToDate GRAPHICS Fusiform aneurysm and wall thickening in a patient with Takayasu arteritis Enlargement of the descending thoracic aorta and thickening of the vessel wall (arrows) is apparent in this contrast-enhanced CT scan. These findings suggest an active inflammatory process. CT: computed tomography. Reproduced with permission from: Sueyoshi E, Sakamoto I, Hayashi K. Aortic aneurysms in patients with Takayasu's arteritis: CT evaluation. Am J Roentgenology 2000; 175:1727. Copyright 2000 American Roentgen Ray Society. Graphic 62264 Version 6.0 https://www.uptodate.com/contents/treatment-of-takayasu-arteritis/print 19/21 7/7/23, 11:21 AM Treatment of Takayasu arteritis - UpToDate Fusiform aneurysm Enlargement of the contrast-filled descending thoracic aneurysm has occurred despite treatment with glucocorticoids. Reproduced with permission from: Sueyoshi E, Sakamoto I, Hayashi K. Aortic aneurysms in patients with Takayasu's arteritis: CT evaluation. Am J Roentgenology 2000; 175:1727. Copyright 2000 American Roentgen Ray Society. Graphic 70960 Version 5.0 https://www.uptodate.com/contents/treatment-of-takayasu-arteritis/print 20/21 7/7/23, 11:21 AM Treatment of Takayasu arteritis - UpToDate Contributor Disclosures Peter A Merkel, MD, MPH Equity Ownership/Stock Options: Kyverna [Systemic lupus erythematosus]. Grant/Research/Clinical Trial Support: AbbVie [Vasculitis]; AstraZeneca [Vasculitis]; Boehringer Ingelheim [Scleroderma]; Bristol-Myers Squibb [Vasculitis]; ChemoCentryx [Vasculitis]; Electra [Vasculitis]; Genentech/Roche [Vasculitis]; GlaxoSmithKline [Vasculitis]; InflaRx [Vasculitis]; Sanofi [Vasculitis]; Takeda [Vasculitis]. Consultant/Advisory Boards: AbbVie [Vasculitis]; AstraZeneca [Vasculitis]; Boehringer Ingelheim [Scleroderma]; Bristol-Myers Squibb [Vasculitis]; ChemoCentryx [Vasculitis]; CSL Behring [Scleroderma, vasculitis]; Dynacure [Vasculitis]; EMDSerono [Vasculitis]; GlaxoSmithKline [Vasculitis]; InflaRx [Vasculitis]; Janssen [Vasculitis]; Kyverna [Scleroderma, vasculitis]; MiroBio [Vasculitis]; Neutrolis [Vasculitis]; Novartis [Vasculitis]; NS Pharma [Vasculitis]; Otsuka [Vasculitis]; Q32 [Vasculitis]; Regeneron [Vasculitis]; Sparrow [Vasculitis]; Takeda [Vasculitis]. All of the relevant financial relationships listed have been mitigated. Kenneth J Warrington, MD Grant/Research/Clinical Trial Support: Eli Lilly [Giant cell arteritis]; GSK [Giant cell arteritis]; Kiniksa [Giant cell arteritis]. Other Financial Interest: Chemocentryx [Honoraria ANCA-associated vasculitis]. All of the relevant financial relationships listed have been mitigated. Philip Seo, MD, MHS 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/treatment-of-takayasu-arteritis/print 21/21

Guideline sources The following summarized guidelines for the evaluation and management of abdominal aortic aneurysm are prepared by our editorial team based on guidelines from the American Heart Association (AHA/ACC 2022), the European Society for Vascular Surgery (ESVS 2019), the U.S. Preventive Services Task Force (USPSTF 2019), the Society for Vascular Surgery (SVS 2018), the European Society of Cardiology (ESC 2014), and the Society for Cardiovascular Angiography and https://web.pathway.md/diseases/recAViRuLGldn39TW 1/15 6/22/23, 11:39 PM Abdominal aortic aneurysm Pathway Interventions (SCAI/STS/SVM/AATS/SCA/AHA/ACR/ACC/ASA/SIR 2010). 1 2 3 4 5 6 8 8 9 9 10 Definition An AAA is a structural disease of the abdominal aorta characterized by a pathological, localized dilatation of > 30 mm or > 50% of the original aortic size. 8 Epidemiology Multiple environmental factors (including smoking, hypertension, coronary artery disease, and collagen diseases) and genetic factors can induce and accelerate degeneration of the layers of the aortic wall. An inflammatory response in the aortic vessel wall leads to destruction of elastin and collagen in the media and adventitia, loss of smooth muscle cells, thinning of the media, and neovascularization. 9 Pathophysiology In the United States, the overall prevalence of AAA is estimated at 2200 persons per 100,000 population. 8 Disease course The majority of AAAs are asymptomatic and are detected as an incidental finding on diagnostic imaging performed for other purposes. AAAs can also present with abdominal pain or complications such as thrombosis, embolization and rupture. 10 Prognosis and risk of recurrence The overall mortality associated with ruptured AAA is approximately 85-90%. 9 Guidelines 1. Screening and diagnosis Indications for screening: As per AHA 2022 guidelines, obtain ultrasound screening for AAA in 65 years old male individuals who have ever smoked. Show 4 more As per ESVS 2019 guidelines, screen for AAA with one-time ultrasound in all men at 65 years of age. A Show 3 more Landmark trials: MASS https://web.pathway.md/diseases/recAViRuLGldn39TW 2/15 6/22/23, 11:39 PM Abdominal aortic aneurysm Pathway In men aged 65-74 years, ultrasound screening for AAA was superior to no ultrasound screening with respect to death related to AAA at 10 years. Thompson SG et al. BMJ. 2009 Jun 24. As per USPSTF 2019 guidelines, obtain one-time screening for AAA with ultrasound in 65-75 years old males who have ever smoked. Show 3 more As per SVS 2018 guidelines, screen for AAA with one-time ultrasound in men or women 65-75 years of age who have ever smoked. A Show 2 more As per ESC 2014 guidelines, screen for AAA with ultrasound in all males > 65 years old. A Show 5 more Indications for rescreening: As per ESVS 2019 guidelines, consider re-screening men with an aortic diameter 2.5-2.9 cm after 5-10 years. C As per SVS 2018 guidelines, consider re-screening patients with an aortic diameter 2.6-2.9 cm after 10 years. C As per ESC 2014 guidelines, consider re-screening patients with an abdominal aortic diameter of 2.5-2.9 cm after 4 years. C 2. Diagnostic investigations Physical examination: perform a physical examination in patients with a suspected or known AAA, including an assessment of femoral and popliteal arteries. Evaluate for an AAA in patients with a popliteal or femoral artery aneurysm. A Diagnostic imaging: As per AHA 2022 guidelines, measure aortic diameters at reproducible anatomic landmarks perpendicular to axis of blood flow in patients with known or suspected aortic disease. Report the longest diameter and its perpendicular diameter in case of asymmetric or oval contour. Show 6 more As per ESVS 2019 guidelines, use ultrasound as the first-line test for the diagnosis and surveillance of small AAAs. Show 3 more As per SVS 2018 guidelines, obtain a CT scan in patients thought to have an AAA who present with recent-onset abdominal or back pain, particularly in the presence of a pulsatile epigastric mass or significant risk factors for AAA. Evaluation for carotid artery stenosis: avoid routine screening for asymptomatic carotid artery stenosis prior to AAA repair. D Psychosocial assessment: consider screening for anxiety, depression, and posttraumatic stress disorder in patients with clinically significant aortic disease and provide resources for support https://web.pathway.md/diseases/recAViRuLGldn39TW 3/15 6/22/23, 11:39 PM Abdominal aortic aneurysm Pathway when indicated. Consider providing education and resources to minimize patients' concerns, support optimal decision-making, and enhance the quality of life. C 3. Medical management General principles: consider initiating antihypertensive, antiplatelet, and statin therapy in all patients with AAA. C Setting of care: Determine the most suitable intervention in patients with acute aortic disease requiring urgent repair by a multidisciplinary team. Consider referring asymptomatic patients with extensive aortic disease, patients likely to benefit from complex open and endovascular aortic repairs, and patients with multiple comorbidities eligible for an intervention to a high-volume center (performing at least 30-40 aortic procedures annually) with experienced surgeons in a multidisciplinary aortic team to optimize treatment outcomes. C Shared decision-making: Ensure shared decision-making when determining the appropriate thresholds for intervention, deciding on the type of surgical repair, choosing between open surgical versus endovascular approaches, and in medical management and surveillance in patients with aortic disease. Ensure shared decision-making when considering the cardiovascular risks of pregnancy, the diameter thresholds for prophylactic aortic surgery, and the mode of delivery in patients with aortic disease contemplating pregnancy or who are pregnant. Beta-blockers: As per ESVS 2019 guidelines, avoid initiating -blockers prior to AAA repair. D As per SVS 2018 guidelines, avoid administering -blocker therapy for the sole purpose of reducing the risk of AAA expansion and rupture. D Antithrombotic therapy: As per AHA 2022 guidelines, consider initiating low-dose aspirin in patients with AAA with concomitant atheroma and/or penetrating atherosclerotic ulcer, unless contraindicated. C As per ESVS 2019 guidelines, continue antiplatelet therapy with aspirin or a thienopyridine (e.g. clopidogrel) during the perioperative period after open and endovascular AAA repair. Statins: As per AHA 2022 guidelines, initiate statin therapy at moderate or high intensity in patients with AAA and evidence of aortic atherosclerosis. Consider initiating statin therapy also in patients with AAA with no evidence of atherosclerosis. As per ESVS 2019 guidelines, initiate statins one month before operative intervention for AAA, in order to reduce cardiovascular morbidity. A As per ESC 2014 guidelines, consider statins to reduce aortic complications in patients with small AAA. C https://web.pathway.md/diseases/recAViRuLGldn39TW 4/15 6/22/23, 11:39 PM Abdominal aortic aneurysm Pathway Antihypertensive therapy: initiate antihypertensive therapy to reduce the risk of cardiovascular events in patients with AAA and an average systolic BP of 130 mmHg or an average diastolic BP of 80 mmHg. Other medical therapies: As per ESVS 2019 guidelines, avoid initiating medical therapy to slow the expansion rate of an AAA, as no such treatment option has been proven to be effective. D As per SVS 2018 guidelines, consider not using statins, doxycycline, roxithromycin, ACEIs, or ARBs for the sole purpose of reducing the risk of AAA expansion and rupture. D As per ESC 2014 guidelines, consider ACEIs to reduce aortic complications in patients with small AAA. C 4. Inpatient care Setting of care: Admit patients having undergone AAA repair to an ICU for postoperative monitoring and management in the following clinical scenarios: patients with significant cardiac, pulmonary, or renal disease patients requiring postoperative mechanical ventilation patients who developed a significant arrhythmia or hemodynamic instability during operative treatment. A Nutritional considerations: Use nasogastric decompression intraoperatively for all patients undergoing open aneurysm repair, but only for those with nausea and abdominal distention in the postoperative setting. A Provide parenteral nutrition to patients who are unable to tolerate enteral nutrition within 7 days of AAA repair. A Pain management: As per ESVS 2019 guidelines, consider perioperative epidural analgesia in patients undergoing open AAA repair, in order to maximize pain relief and minimize early postoperative complications. C As per SVS 2018 guidelines, provide multimodality treatment, including epidural analgesia, for postoperative pain control after open surgical repair of an AAA. A Thromboprophylaxis: As per ESVS 2019 guidelines, consider administering prolonged DVT prophylaxis with LMWH prophylaxis (up to 4 weeks) in patients with malignancy who have undergone AAA repair. C As per SVS 2018 guidelines: Providing thromboprophylaxis, including intermittent pneumatic compression and early ambulation, in all patients undergoing open surgical repair or endovascular aneurysm repair. A Consider administering thromboprophylaxis with unfractionated or LMWH for patients undergoing AAA repair at moderate to high risk for VTE and low risk for bleeding. C https://web.pathway.md/diseases/recAViRuLGldn39TW 5/15 6/22/23, 11:39 PM Abdominal aortic aneurysm Pathway Monitoring for abdominal compartment syndrome: monitor intra-abdominal pressure in all patients undergoing open or endovascular treatment for ruptured AAA, in order to achieve early diagnosis and management of intra-abdominal hypertension/abdominal compartment syndrome. Show 2 more Monitoring for myocardial injury: Monitor ST-segment changes postoperatively in all patients undergoing open aneurysm repair and in those undergoing endovascular aneurysm repair who are at high cardiac risk. Measure troponin levels postoperatively in all patients with electrocardiographic changes or chest pain after AAA repair. A 5. Nonpharmacologic interventions Smoking cessation: As per AHA 2022 guidelines, advise smoking cessation in smoker patients with AAA. As per ESVS 2019 guidelines, advise smoking cessation in patients with a small AAA, in order to reduce the risk of AAA growth and rupture, and provide assistance towards that goal. As per SVS 2018 guidelines, advise smoking cessation in patients an AAA, in order to reduce the risk of AAA growth and rupture. As per ESC 2014 guidelines, advise smoking cessation to slow growth of the AAA. Physical activity: As per AHA 2022 guidelines: Provide education and guidance on avoiding intense isometric exercises (such as heavy weightlifting or activities requiring the Valsalva maneuver), burst exertion and activities, and collision sports in patients with significant aortic disease. Consider encouraging 30-60 minutes of mild-to-moderate intensity aerobic activity at least 3-4 days per week in patients with AAA and adequately controlled BP. C As per ESVS 2019 guidelines, consider advising strategies targeted at a healthy lifestyle, including exercise and a healthy diet, in all patients with AAA. C 6. Therapeutic procedures Endovascular aneurysm repair: as per AHA 2022 guidelines, perform US-guided percutaneous closure over open cutdown for endovascular AAA repair to reduce operative time, blood loss, length of stay, time to wound healing, and pain in patients with suitable common femoral artery anatomy. Aortic balloon occlusion: consider performing aortic balloon occlusion for proximal control in hemodynamically unstable patients with a ruptured AAA undergoing open or endovascular repair. C Preoperative renal/mesenteric angioplasty: https://web.pathway.md/diseases/recAViRuLGldn39TW 6/15 6/22/23, 11:39 PM Abdominal aortic aneurysm Pathway Consider performing renal artery angioplasty and stenting in selected patients with symptomatic renal artery stenosis before endovascular aneurysm repair or open surgical repair. C Consider superior mesenteric artery angioplasty and stenting in selected patients with symptomatic superior mesenteric artery stenosis before endovascular aneurysm repair or open surgical repair. C 7. Perioperative care Preoperative counseling: consider informing patients contemplating open repair or endovascular aneurysm repair of their perioperative mortality risk score (Vascular Quality Initiative score). C Preoperative pulmonary function testing: As per ESVS 2019 guidelines, consider obtaining pulmonary function testing with spirometry in all patients prior to elective AAA repair. C Show 2 more As per SVS 2018 guidelines, consider obtaining preoperative pulmonary function testing, including room air arterial blood gas determinations, in patients scheduled to undergo AAA repair in whom there is a history of symptomatic COPD, long-standing tobacco use, or inability to climb one flight of stairs. C Preoperative cardiac risk assessment: As per ESVS 2019 guidelines: Avoid routine referral for cardiac work up, coronary angiography or cardiopulmonary exercise testing prior to AAA repair. D Refer patients with poor functional capacity (defined as < 4 metabolic equivalents) or with significant clinical risk factors (such as unstable angina, decompensated HF, severe valvular disease, and significant arrhythmia) for cardiac work up and optimization prior to elective AAA repair. As per SVS 2018 guidelines, obtain a preoperative cardiology consultation before endovascular aneurysm repair or open surgical repair in patients with active cardiac conditions (including unstable angina, decompensated HF, severe valvular disease, and significant arrhythmia). Show 2 more Preoperative renal function testing: assess preoperative kidney function by measuring serum creatinine and estimated GFR in patients scheduled to undergo AAA repair, and refer patients with severe renal impairment (estimated GFR < 30 mL/min/1.73 m ) for specialist assessment. Preoperative nutritional assessment: measure serum albumin to assess preoperative nutritional status in patients undergoing elective AAA repair, and use an albumin level of < 2.8 g/dL as a threshold for preoperative correction. Preoperative hematologic assessment: consider referring patients for a hematologic assessment if the preoperative platelet count is < 150 10 . C Preoperative cardiac optimization: https://web.pathway.md/diseases/recAViRuLGldn39TW 7/15 6/22/23, 11:39 PM Abdominal aortic aneurysm Pathway As per ESVS 2019 guidelines, avoid routinely performing routine coronary revascularization before elective AAA repair in patients with stable coronary artery disease. D Show 3 more As per SVS 2018 guidelines, consider performing coronary revascularization before aneurysm repair in patients with acute ST-segment or non-ST segment elevation myocardial infarction, unstable angina, or stable angina with left main coronary artery or three-vessel disease. C Show 4 more Preoperative renal optimization: Administer preoperative hydration in nondialysis dependent patients with renal insufficiency before AAA repair. A Administer preprocedure and postprocedure hydration with normal saline or 5% dextrose/sodium bicarbonate for patients at increased risk of contrast-induced nephropathy undergoing endovascular aneurysm repair. A Preoperative pulmonary optimization: Advise smoking cessation for at least 2 weeks before aneurysm repair. Consider initiating pulmonary bronchodilators for at least 2 weeks before aneurysm repair in patients with a history of COPD or abnormal pulmonary function testing results. C Preoperative nutritional optimization: optimize preoperative nutritional status before elective open aneurysm repair if repair will not be unduly delayed. A Preoperative dental optimization: eliminate any potential source of dental sepsis at least 2 weeks before implantation of an aortic prosthesis. E Considerations for anesthesia: As per ESVS 2019 guidelines, consider using local anesthesia as the anesthetic modality of choice for endovascular repair of ruptured AAA, whenever tolerated by the patient. C As per SVS 2018 guidelines, use general endotracheal anesthesia for patients undergoing open aneurysm repair. A Show 2 more Preoperative antibiotic prophylaxis: As per ESVS 2019 guidelines, administer perioperative systemic antibiotic prophylaxis in all patients undergoing open or endovascular AAA repair. A As per SVS 2018 guidelines, administer perioperative systemic antibiotic prophylaxis in all patients undergoing open surgical repair or endovascular aneurysm repair, using an intravenous first-generation cephalosporin given within 30 minutes of surgery (or vancomycin in patients with a penicillin allergy). Avoid continuing prophylactic antibiotics for > 24 hours. A Perioperative transfusions: As per ESVS 2019 guidelines, consider intraoperative cell salvage and re-transfusion in patients undergoing open AAA repair. C As per SVS 2018 guidelines, transfuse packed blood cells along with FFP and platelets in a ratio of 1:1:1, in patients with an intraoperative Hgb level < 10 g/dL and ongoing blood loss. https://web.pathway.md/diseases/recAViRuLGldn39TW 8/15 6/22/23, 11:39 PM Abdominal aortic aneurysm Pathway Show 2 more Intraoperative temperature management: as per SVS 2018 guidelines, maintain core body temperature at or above 36 C during AAA repair. A Intraoperative anticoagulation: administer IV heparin (50-100 IU/kg) before aortic cross clamping. Management of beta-blockers: Consider continuing -blocker therapy during the perioperative period, if already established, in patients undergoing AAA repair. C Consider initiating -blocker therapy well in advance of surgery, if indicated for the management of a patient's comorbidities, to allow sufficient time to assess safety and tolerability. C Management of antiplatelet agents: As per ESVS 2019 guidelines, consider delaying AAA repair in patients on dual antiplatelet therapy after interventional coronary revascularization, until reduction to monotherapy can be safely performed. Alternatively, if AAA repair becomes necessary, EVAR may be considered under dual antiplatelet therapy. C As per SVS 2018 guidelines, discontinue P2Y12 platelet receptor inhibitor therapy 10 days preoperatively and continue aspirin in patients with a drug-eluting coronary stent requiring open aneurysm repair. Restart the P2Y12 inhibitor as soon as possible after surgery. Discuss the relative risks and benefits of perioperative bleeding and stent thrombosis with the patient. Management of antihypertensives and antihyperglycemics: consider holding ACEIs and angiotensin receptor antagonists on the morning of surgery and restarting these agents after the procedure once euvolemia has been achieved. C Show 2 more Preoperative imaging: obtain CT for preoperative planning in patients with an AAA meeting criteria for repair. 8. Surgical interventions General principles: As per ESVS 2019 guidelines: Refer patients with incidentally detected AAA to a vascular surgeon for evaluation, except for patients with very limited life expectancy. Consider performing aortic aneurysm repair only in centres with a minimum yearly caseload of 30 repairs. C As per SVS 2018 guidelines, consider referring the patient to a vascular surgeon at the time of initial diagnosis of an aortic aneurysm. E Show 2 more Indications for surgery, symptomatic AAA: https://web.pathway.md/diseases/recAViRuLGldn39TW 9/15 6/22/23, 11:39 PM Abdominal aortic aneurysm Pathway As per AHA 2022 guidelines, perform aneurysm repair in patients with unruptured AAA with a maximal aneurysm diameter of 5.5 cm in male patients and 5.0 cm in female patients. A Show 3 more As per ESC 2014 guidelines, perform surgical repair of AAA if: AAA diameter is > 5.5 cm aneurysm growth is > 1.0 cm/year. Show 3 more Timing of surgery: target an 8 week delay as the maximal reasonable waiting time between surgical referral and elective treatment of AAAs. Choice of surgical approach: As per AHA 2022 guidelines, ensure a shared decision-making process weighing the risks and benefits of each approach in patients with unruptured AAA with low-to-moderate operative risk and having anatomy suitable for either open or endovascular AAA repair. A Show 2 more As per ESVS 2019 guidelines, avoid routinely performing laparoscopic AAA repair outside of highly specialized centres, registries or trials. D Indications for tube graft placement: as per SVS 2018 guidelines, use straight tube grafts for open surgical repair of AAA in the absence of significant disease of the iliac arteries. A Management of enlarging AAA post-repair: As per ESVS 2019 guidelines, consider obtaining further diagnostic evaluation with alternative imaging modalities to exclude the presence of an unidentified endoleak in patients with aneurysm sac growth after endovascular AAA repair, without visible endoleak on standard imaging. C As per SVS 2018 guidelines, consider treating ongoing aneurysm expansion, even in the absence of a visible endoleak. C Management of endoleaks: As per ESVS 2019 guidelines, perform re-intervention (primarily by endovascular means) to achieve a seal in patients with type I endoleak after endovascular AAA repair. Show 2 more As per SVS 2018 guidelines, treat patients with type I endoleaks. Show 4 more 9. Specific circumstances Patients with ruptured AAA: As per AHA 2022 guidelines, obtain CT to evaluate whether the AAA is amenable to endovascular repair in hemodynamically stable patients presenting with ruptured AAA. Show 3 more https://web.pathway.md/diseases/recAViRuLGldn39TW 10/15 6/22/23, 11:39 PM Abdominal aortic aneurysm Pathway As per ESVS 2019 guidelines, implement a policy of permissive hypotension in conscious patients with ruptured AAA, by restricting fluid resuscitation. As per SVS 2018 guidelines, implement hypotensive hemostasis with restriction of fluid resuscitation in the conscious patient. Patients with carotid artery stenosis: Perform preoperative carotid artery intervention in patients with an AAA and carotid artery stenosis that was symptomatic within the last 6 months. Avoid routinely performing prophylactic carotid intervention for asymptomatic carotid artery stenosis prior to AAA repair. D Patients with gastrointestinal bleeding: As per ESVS 2019 guidelines, assess for aortoenteric fistula promptly in any patient with an aortic prosthesis presenting with gastrointestinal bleeding. Show 2 more As per SVS 2018 guidelines, assess for possible aortoenteric fistula promptly in patients presenting with gastrointestinal bleeding after AAA repair. A Patients with heparin-induced thrombocytopenia: use a thrombin inhibitor, such as bivalirudin or argatroban, as an alternative to heparin in patients with a history of heparin-induced thrombocytopenia. Patients with an infected AAA graft: assess for possible graft infection promptly in patients presenting with generalized sepsis, groin drainage, pseudoaneurysm formation, or ill-defined pain after AAA repair. A Show 4 more Patients with common iliac artery aneurysm: Perform elective repair of both abdominal and iliac aneurysms in patients with asymptomatic small AAA and concomitant common iliac artery aneurysms 3.5 cm. Preserve at least one hypogastric artery, if anatomically feasible, to decrease the risk of pelvic ischemia when treating common iliac artery aneurysms or ectasia as part of AAA repair. Patients with thoracoabdominal aortic aneurysm (indications for repair): perform aneurysm repair in patients with intact degenerative thoracoAAA of 6.0 cm. Show 2 more Patients with thoracoabdominal aortic aneurysm, open repair: As per AHA/ACC 2022 guidelines, perform open repair in patients with ruptured thoracoAAA requiring intervention. Show 5 more As per SVM/STS/SIR/SCAI/SCA/ASA/ACR/AATS/AHA/ACC 2010 guidelines, perform elective surgery in patients with thoracoabdominal aneurysms with a diameter of > 6.0 cm (or less in patients with a connective tissue disorder, such as Marfan or Loeys- Dietz syndrome) if endovascular stent graft options are limited and surgical morbidity is elevated. https://web.pathway.md/diseases/recAViRuLGldn39TW 11/15 6/22/23, 11:39 PM Abdominal aortic aneurysm Pathway Patients with thoracoabdominal aortic aneurysm (endovascular repair): consider performing endovascular repair in hemodynamically stable patients with ruptured thoracoAAA requiring intervention in centers with endovascular expertise and access to appropriate endovascular stent grafts. C Show 3 more Patients with Marfan syndrome: Consider obtaining surveillance imaging every 3-5 years for potential AAA in patients with Marfan syndrome undergone aortic root replacement. C Consider performing surgery to replace the aneurysmal segment in patients with Marfan syndrome and a nondissected AAA of 5.0 cm. C Patients with Loeys-Dietz syndrome: consider performing surgery to replace the intact aortic arch, descending aorta, or abdominal aorta at a diameter of 4.5 cm based on the specific genetic variant, patient age, aortic growth rate, family history, presence of high-risk features, and surgical risk in patients with Loeys-Dietz syndrome attributable to a pathogenic variant in TGFBR1, TGFBR2, or SMAD3. C 10. Preventative measures Preprocedural antibiotic prophylaxis: As per ESVS 2019 guidelines: Avoid routinely administering antibiotic prophylaxis for the prevention of graft infection in patients with previous AAA repair undergoing dental or other surgical procedures. D Consider administering antibiotic prophylaxis for the prevention of graft infection in patients with previous AAA repair undergoing high-risk procedures, including abscess drainage, dental procedures requiring manipulation of the gingival or peri-apical region of the teeth or breaching the oral mucosa, as well as in immunocompromised patients undergoing surgical or interventional procedures. C As per SVS 2018 guidelines: Administer antibiotic prophylaxis for the prevention of graft infection in patients with an aortic prosthesis undergoing any dental procedure involving the manipulation of the gingival or periapical region of teeth or perforation of the oral mucosa, including scaling and root canal procedures. Consider administering antibiotic prophylaxis before respiratory tract procedures, gastrointestinal or genitourinary procedures, and dermatologic or musculoskeletal procedures for any patient with an aortic prosthesis if the potential for infection exists or the patient is immunocompromised. C 11. Follow-up and surveillance Serial clinical assessment: https://web.pathway.md/diseases/recAViRuLGldn39TW 12/15 6/22/23, 11:39 PM Abdominal aortic aneurysm Pathway As per SVS 2018 guidelines: Perform thorough lower extremity pulse examination or ABI in follow-up visits of patients after aneurysm repair. Assess for possible graft limb occlusion in patients who develop new-onset lower extremity claudication, ischemia, or reduction in ABI after aneurysm repair. A Serial imaging assessment: As per AHA 2022 guidelines, obtain surveillance ultrasound every 3 years to assess for interval change in patients with an AAA of 3.0-3.9 cm. Show 3 more As per ESVS 2019 guidelines, schedule follow-up ultrasound is recommended for aneurysm surveillance: every three years for aneurysms 3-3.9 cm in size annually for aneurysms 4.0-4.9 cm in size every 3-6 month for aneurysms 5.0 cm in size. As per SVS 2018 guidelines, consider performing surveillance imaging at 3-year intervals for patients with an AAA of 3.0-3.9 cm diameter. C Show 2 more As per ESC 2014 guidelines: Obtain surveillance imaging in patients with AAA with a maximum diameter of < 5.5 cm and slow (< 1.0 cm/year) growth. A Consider obtaining surveillance imaging at following time intervals in patients with small (3.0- 5.5 cm) AAA: every 3 years for AAA of 3.0-3.9 cm diameter every 2 years for AAA of 4.0-4.4 cm diameter annually for AAA > 4.5 cm diameter. C Postoperative rehabilitation: offer postoperative cardiac rehabilitation in patients after surgery for aortic aneurysm. Early postoperative imaging: As per ESVS 2019 guidelines, schedule early postoperative follow up (within 30 days) after endovascular aortic repair, including imaging of the stent graft to assess for the presence of endoleak, component overlap and sealing zone length. As per SVS 2018 guidelines, obtain baseline imaging in the first month after endovascular aneurysm repair with contrast-enhanced CT and color duplex ultrasound imaging. Repeat imaging in 12 months in the absence of an endoleak or sac enlargement. Show 4 more Late postoperative imaging: As per AHA 2022 guidelines, obtain baseline surveillance CT at 1 month postoperatively in patients with after endovascular AAA repair. Obtain continued surveillance with duplex https://web.pathway.md/diseases/recAViRuLGldn39TW 13/15 6/22/23, 11:39 PM Abdominal aortic aneurysm Pathway ultrasound at 12 months and then annually thereafter, if there is no evidence of endoleak or sac enlargement. Show 4 more As per ESVS 2019 guidelines, consider obtaining follow-up imaging of the aorta and peripheral arteries every 5 years in all patients having undergone open repair for AAA. C As per SVS 2018 guidelines, consider obtaining noncontrast CT imaging of the entire aorta at 5- year intervals after open repair or endovascular aneurysm repair. C Likelihood Ratios Pertinent positives The following findings increase the probability of abdominal aortic aneurysm in adults. -1 Finding LR+ Value Increased aortic width (> 4.0 cm) 16 (8.6-29) Increased aortic width (> 3.0 cm) 12 (7.4-20) Pertinent negatives The following findings decrease the probability of abdominal aortic aneurysm in adults. -1 Finding LR- Value aortic width not increased ( 4.0 cm) 0.51 (0.38-0.67) aortic width not increased ( 3.0 cm) 0.72 (0.65-0.81) References 1. Eric M Isselbacher, Ourania Preventza, James Hamilton Black rd et al. 2022 ACC/AHA Guideline for the Diagnosis and Management of Aortic Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation. 2022 Nov 2. Open 2. Elliot L Chaikof, Ronald L Dalman, Mark K Eskandari et al. The Society for Vascular Surgery practice guidelines on the care of patients with an abdominal aortic aneurysm. J Vasc Surg. 2018 Jan;67 1 2 77.e2. Open 3. Wanhainen A, Verzini F, Van Herzeele I et al. European Society for Vascular Surgery ESVS 2019 Clinical Practice Guidelines on the Management of Abdominal Aorto-iliac Artery Aneurysms. Eur J Vasc Endovasc Surg. 2019 Jan;57 1 8 93. Open 4. Hiratzka LF, Bakris GL, Beckman JA et al. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with Thoracic Aortic Disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine. Circulation. 2010 Apr 6;121 13):e266 369. Open https://web.pathway.md/diseases/recAViRuLGldn39TW 14/15 6/22/23, 11:39 PM Abdominal aortic aneurysm Pathway 5. Erbel R, Aboyans V, Boileau C et al. 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases: Document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology ESC . Eur Heart J. 2014 Nov 1;35 41 2873 926. Open 6. US Preventive Services Task Force, Douglas K Owens, Karina W Davidson et al. Screening for Abdominal Aortic Aneurysm: US Preventive Services Task Force Recommendation Statement. JAMA. 2019 Dec 10;322 22 2211 2218. Open 7. Gloviczki P, Lawrence PF, Forbes TL. Update of the Society for Vascular Surgery abdominal aortic aneurysm guidelines. J Vasc Surg. 2018 Jan;67 1 1. Open 8. Li X, Zhao G, Zhang J et al. Prevalence and trends of the abdominal aortic aneurysms epidemic in general population a meta-analysis. PLoS One. 2013 Dec 2;8 12):e81260. Open 9. Kent KC. Clinical practice. Abdominal aortic aneurysms. N Engl J Med. 2014 Nov 27;371 22 2101 8. Open 10. Aggarwal S, Qamar A, Sharma V et al. Abdominal aortic aneurysm: A comprehensive review. Exp Clin Cardiol. 2011 Spring;16 1 11 5. Open 11. Moll FL, Powell JT, Fraedrich G et al. Management of abdominal aortic aneurysms clinical practice guidelines of the European society for vascular surgery. Eur J Vasc Endovasc Surg. 2011 Jan;41 Suppl 1 S1 S58. Open 12. Canadian Task Force on Preventive Health Care. Recommendations on screening for abdominal aortic aneurysm in primary care. CMAJ. 2017 Sep 11;189 36 E1137 E1145. Open 13. N Sakalihasan, R Limet, O D Defawe. Abdominal aortic aneurysm. Lancet. 2005 Apr 30 May 6;365 9470 1577 89. Open 14. V Tchana-Sato, N Sakalihasan, J O Defraigne. Ruptured abdominal aortic aneurysm. Rev Med Liege. 2018 May;73 5 6 296 299. Open 15. Brant W Ullery, Richard L Hallett, Dominik Fleischmann. Epidemiology and contemporary management of abdominal aortic aneurysms. Abdom Radiol NY . 2018 May;43 5 1032 1043. Open 16. Matthew Mell. Screening for Abdominal Aortic Aneurysm-A Call to Arms?. JAMA Netw Open. 2019 Dec 2;2 12):e1917168. Open 17. Regitz-Zagrosek V, Roos-Hesselink JW, Bauersachs J et al. 2018 ESC Guidelines for the management of cardiovascular diseases during pregnancy. Eur Heart J. 2018 Sep 7;39 34 3165 3241. Open https://web.pathway.md/diseases/recAViRuLGldn39TW 15/15

Guideline sources The following summarized guidelines for the evaluation and management of abdominal compartment syndrome are prepared by our editorial team based on guidelines from the World Society of Emergency Surgery (WSES 2018), the European Society for Vascular Surgery (ESVS 2017), and the World Society of the Abdominal Compartment Syndrome (WSACS 2013). 1 2 3 Guidelines 1. Diagnostic investigations Measurement of intra-abdominal pressure: As per WSES 2018 guidelines, obtain intra-abdominal pressure measurement in critically ill patients at risk for intra-abdominal hypertension/abdominal compartment syndrome. B As per ESVS 2017 guidelines, obtain intra-abdominal pressure monitoring to prevent non- occlusive mesenteric ischemia in patients with known risk factors for intraabdominal hypertension/abdominal compartment syndrome. B As per WSACS 2013 guidelines, obtain intra-abdominal pressure measurement when any known risk factor for intra-abdominal hypertension/abdominal compartment syndrome is present in a critically ill or trauma patient. B https://web.pathway.md/diseases/recGaFLYS9MVjCahO 1/3 6/23/23, 1:18 AM Abdominal compartment syndrome Pathway 2. Medical management Supportive care: consider providing optimal pain and anxiety relief in critically ill or trauma patients. C Neuromuscular blocking agents: consider administering brief trials of neuromuscular blockade as a temporizing measure in the treatment of intra-abdominal hypertension/abdominal compartment syndrome. C Fluid resuscitation: consider using a protocol to try and avoid a positive cumulative fluid balance in critically ill or trauma patients with or at risk of intra-abdominal hypertension/abdominal compartment syndrome after the acute resuscitation has been completed and the inciting issues have been addressed. C Neostigmine: consider administering neostigmine for the treatment of established colonic ileus not responding to other simple measures and associated with intra-abdominal hypertension. C 3. Therapeutic procedures Blood product transfusion: consider using an enhanced ratio of plasma/packed RBCs for resuscitation of massive hemorrhage. C Enteral decompression: consider performing enteral decompression with nasogastric or rectal tubes when the stomach or colon are dilated in the presence of intra-abdominal hypertension/abdominal compartment syndrome. B Percutaneous catheter drainage: Consider performing percutaneous catheter drainage, if technically possible, to remove fluid (in the setting of obvious intraperitoneal fluid) in patients with intra-abdominal hypertension/abdominal compartment syndrome. C Consider performing percutaneous catheter drainage, technically possible, to remove fluid (in the setting of obvious intraperitoneal fluid) in patients with intra-abdominal hypertension/abdominal compartment syndrome rather than immediate decompressive laparotomy, as this may alleviate the need for decompressive laparotomy. C 4. Surgical interventions Decompressive laparotomy: As per WSES 2018 guidelines, recognize that risk factors for abdominal compartment syndrome, such as damage control surgery, injuries requiring packing and planned reoperation, extreme visceral or retroperitoneal swelling, obesity, elevated bladder pressure when abdominal closure is attempted, abdominal wall tissue loss, and aggressive resuscitation, are predictors of the necessity for open abdomen in patients with trauma. B Show 6 more https://web.pathway.md/diseases/recGaFLYS9MVjCahO 2/3 6/23/23, 1:18 AM Abdominal compartment syndrome Pathway As per ESVS 2017 guidelines, perform decompression laparotomy to prevent non-occlusive mesenteric ischemia in patients with abdominal compartment syndrome (defined as an intra- abdominal pressure > 20 mmHg and newly developed organ dysfunction or failure). B As per WSACS 2013 guidelines, perform decompressive laparotomy in critically ill adult patients with overt abdominal compartment syndrome. B Show 3 more 5. Specific circumstances Patients with open abdominal wounds: Utilize negative pressure wound therapy in critically ill/injured patients with open abdominal wounds. B Attempt to perform an early or at least same-hospital-stay abdominal fascial closure in ICU patients with open abdominal wounds. B References 1. Andrew W Kirkpatrick, Derek J Roberts, Jan De Waele et al. Intra-abdominal hypertension and the abdominal compartment syndrome: updated consensus definitions and clinical practice guidelines from the World Society of the Abdominal Compartment Syndrome. Intensive Care Med. 2013 Jul;39 7 1190 206. Open 2. Federico Coccolini, Derek Roberts, Luca Ansaloni et al. The open abdomen in trauma and non-trauma patients: WSES guidelines. World J Emerg Surg. 2018 Feb 2;13 7. Open 3. M Bj rck, M Koelemay, S Acosta et al. Editor's Choice Management of the Diseases of Mesenteric Arteries and Veins: Clinical Practice Guidelines of the European Society of Vascular Surgery ESVS . Eur J Vasc Endovasc Surg. 2017 Apr;53 4 460 510. Open https://web.pathway.md/diseases/recGaFLYS9MVjCahO 3/3

Guideline sources The following summarized guidelines for the evaluation and management of abdominal vascular injury are prepared by our editorial team based on guidelines from the Pan-European Multidisciplinary Task Force for Advanced Bleeding Care in Trauma (ABC-T 2023; 2019), the American Heart Association (AHA/ACC 2022), the Society of Interventional Radiology (SIR 2020), the World Society of Emergency Surgery (WSES/AAST 2020), the World Society of Emergency Surgery (WSES 2020; 2017), and the Eastern Association for the Surgery of Trauma (EAST 2012; 2011). 1 2 3 4 5 6 7 8 9 10 11 Guidelines 1. Diagnostic investigations FAST ultrasound: As per EAST 2011 guidelines: Avoid relying on FAST results to exclude intraperitoneal bleeding in the presence of a pelvic fracture. D Rely on FAST results in patients with unstable vital signs and pelvic fracture to decide on laparotomy to control bleeding. A https://web.pathway.md/diseases/recM34Nf88iI65Wd8 1/5 6/23/23, 1:19 AM Abdominal vascular injury Pathway Angiography: As per EAST 2012 guidelines, consider obtaining angiography in patients with AAST grade > III injuries, presence of a contrast blush, moderate hemoperitoneum, or evidence of ongoing splenic bleeding. C As per EAST 2011 guidelines: Consider obtaining pelvic angiography in patients with pelvic fracture and hemodynamic instability or signs of ongoing bleeding after non-pelvic sources of blood loss have been ruled out. B Consider obtaining pelvic angiography in > 60 years old patients with a major pelvic fracture (open book, butterfly segment, or vertical shear), regardless of hemodynamic status. C As per EAST 2011 guidelines: Obtain CT of the abdomen and pelvis with IV contrast to evaluate for intra-abdominal and pelvic bleeding in hemodynamically stable patients with pelvic fracture, regardless of FAST results. B Avoid relying on the absence of contrast extravasation on CT to exclude active bleeding. D 2. Medical management Non-operative management: as per ACC 2022 guidelines, initiate anti-impulse therapy, if clinically tolerated, and obtain repeat imaging within 24-48 hours of the initial imaging to reduce the risk of injury progression in patients with grade 1-2 blunt traumatic abdominal aortic injury without malperfusion. B 3. Therapeutic procedures Pelvic packing: As per ABC-T 2023 guidelines, perform temporary extraperitoneal packing when bleeding is ongoing and/or when angioembolization cannot be achieved promptly. Consider combining extraperitoneal packing with open abdominal surgery when necessary. B As per EAST 2011 guidelines: Perform retroperitoneal pelvic packing as a salvage technique to control hemorrhage after angioembolization in patients with pelvic hemorrhage. B Perform retroperitoneal pelvic packing to control hemorrhage as part of a multidisciplinary clinical pathway including a pelvic orthotic device/C-clamp. B Angioembolization: As per SIR 2020 guidelines: Perform angioembolization as first-line therapy and the standard of care over surgery in patients with pelvic trauma. B Consider performing angioembolization in patients with blunt hepatic injury with ongoing bleeding, identification of an arterial source of bleeding on imaging, or suspicion of a persistent https://web.pathway.md/diseases/recM34Nf88iI65Wd8 2/5 6/23/23, 1:19 AM Abdominal vascular injury Pathway source of arterial bleeding despite operative intervention. C As per WSES 2020 guidelines, consider performing angioembolization as a first-line intervention in hemodynamically stable patients with liver trauma with an arterial blush on CT. C Show 3 more As per ABC-T 2019 guidelines, perform angiographic embolization and/or preperitoneal packing and/or early surgical bleeding control in patients with pelvic trauma and ongoing hemodynamic instability despite adequate pelvic ring stabilization. B As per WSES 2017 guidelines, consider performing angioembolization in patients with pelvic fracture and hemodynamic instability or evidence of ongoing bleeding, after pelvic stabilization, initiation of aggressive hemostatic resuscitation, and exclusion of extra-pelvic sources of blood loss. B Show 3 more As per EAST 2012 guidelines: Consider performing angioembolization as a first-line intervention in patients with liver trauma transiently responding to resuscitation as an adjunct to potential operative intervention. C Consider performing angioembolization in hemodynamically stable patients with liver trauma with evidence of active extravasation (a contrast blush) on abdominal CT. C As per EAST 2011 guidelines, consider performing pelvic angioembolization in patients with pelvic fracture and hemodynamic instability or signs of ongoing bleeding after non-pelvic sources of blood loss have been ruled out. B Show 4 more Resuscitative endovascular balloon occlusion of the aorta: As per ABC-T 2023 guidelines, consider performing REBOA in patients with non-compressible life-threatening traumatic hemorrhage to bridge the gap between hemodynamic collapse and hemorrhage control. C As per ACC 2022 guidelines, insufficient evidence regarding the usefulness of the routine use of REBOA for hemorrhage control in patients with blunt traumatic abdominal aortic injury, and even it may cause harm in some cases. I As per WSES 2020 guidelines, consider performing REBOA as a bridge to other more definitive procedures for hemorrhage control in hemodynamically unstable patients with liver trauma. C As per WSES 2017 guidelines, consider performing REBOA in zone 3 in hemodynamically unstable patients (systolic BP < 90 mmHg or lack of hemodynamic response to blood product transfusion) with suspected pelvic hemorrhage. C Show 3 more 4. Perioperative care Perioperative prophylactic antibiotics: administer a single preoperative dose of prophylactic antibiotics with broad-spectrum aerobic and anaerobic coverage in all patients with penetrating abdominal trauma. A https://web.pathway.md/diseases/recM34Nf88iI65Wd8 3/5 6/23/23, 1:19 AM Abdominal vascular injury Pathway Show 3 more 5. Surgical interventions Damage-control surgery: As per WSES 2017 guidelines: Perform resuscitative thoracotomy with aortic cross-clamping to achieve temporary control of hemorrhage in patients with pelvic trauma and exsanguinating hemorrhage. A Consider performing REBOA as an alternative to aortic cross-clamping. C Definitive repair: as per ACC 2022 guidelines, consider performing repair in patients with grade 2 blunt traumatic abdominal aortic injury and associated malperfusion. C Show 3 more 6. Follow-up and surveillance Serial imaging assessment: Consider obtaining surveillance imaging at intervals appropriate for the repair approach and location in patients with blunt traumatic aortic injury undergone aortic repair. C Consider obtaining surveillance CT at 1 month, 6 months, and 12 months after the diagnosis and, if stable, at appropriate intervals thereafter (depending on the type and extent of the injury) in patients with blunt traumatic aortic injury not undergone repair. C References 1. Goldberg SR, Anand RJ, Como JJ et al. Prophylactic antibiotic use in penetrating abdominal trauma: an Eastern Association for the Surgery of Trauma practice management guideline. J Trauma Acute Care Surg. 2012 Nov;73 5 Suppl 4 S321 5. Open 2. Donat R Spahn, Bertil Bouillon, Vladimir Cerny et al. The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition. Crit Care. 2019 Mar 27;23 1 98. Open 3. Siddharth A Padia, Christopher R Ingraham, John M Moriarty et al. Society of Interventional Radiology Position Statement on Endovascular Intervention for Trauma. J Vasc Interv Radiol. 2020 Mar;31 3 363 369.e2. Open 4. Cullinane DC, Schiller HJ, Zielinski MD et al. Eastern Association for the Surgery of Trauma practice management guidelines for hemorrhage in pelvic fracture update and systematic review. J Trauma. 2011 Dec;71 6 1850 68. Open 5. Leslie Kobayashi, Raul Coimbra, Adenauer M O Goes Jr et al. American Association for the Surgery of Trauma-World Society of Emergency Surgery guidelines on diagnosis and management of abdominal vascular injuries. J Trauma Acute Care Surg. 2020 Dec;89 6 1197 1211. Open 6. Nicole A Stassen, Indermeet Bhullar, Julius D Cheng et al. Nonoperative management of blunt hepatic injury: an Eastern Association for the Surgery of Trauma practice management guideline. J Trauma Acute https://web.pathway.md/diseases/recM34Nf88iI65Wd8 4/5 6/23/23, 1:19 AM Abdominal vascular injury Pathway Care Surg. 2012 Nov;73 5 Suppl 4 S288 93. Open 7. Federico Coccolini, Raul Coimbra, Carlos Ordonez et al. Liver trauma: WSES 2020 guidelines. World J Emerg Surg. 2020 Mar 30;15 1 24. Open 8. Coccolini F, Stahel PF, Montori G et al. Pelvic trauma: WSES classification and guidelines. World J Emerg Surg. 2017 Jan 18;12 5. Open 9. Eric M Isselbacher, Ourania Preventza, James Hamilton Black rd et al. 2022 ACC/AHA Guideline for the Diagnosis and Management of Aortic Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation. 2022 Nov 2. Open 10. Rolf Rossaint, Arash Afshari, Bertil Bouillon et al. The European guideline on management of major bleeding and coagulopathy following trauma: sixth edition. Crit Care. 2023 Mar 1;27 1 80. Open 11. Nicole A Stassen, Indermeet Bhullar, Julius D Cheng et al. Selective nonoperative management of blunt splenic injury: an Eastern Association for the Surgery of Trauma practice management guideline. J Trauma Acute Care Surg. 2012 Nov;73 5 Suppl 4 S294 300. Open 12. Expert Panel on Major Trauma Imaging, Jeffrey Y Shyu, Bharti Khurana et al. ACR Appropriateness Criteria Major Blunt Trauma. J Am Coll Radiol. 2020 May;17 5S S160 S174. Open https://web.pathway.md/diseases/recM34Nf88iI65Wd8 5/5

Guideline sources The following summarized guidelines for the evaluation and management of abnormal uterine bleeding (AUB) are prepared by our editorial team based on guidelines from the American College of Radiology (ACR 2020), the American Association of Family Physicians (AAFP 2019), the American College of Obstetricians and Gynecologists (ACOG 2019; 2013; 2012), the Society of Obstetricians and Gynaecologists of Canada (SOGC 2019; 2018; 2015), and the Society of Gynecologic Surgeons (SGS 2012). 1 2 3 4 5 6 7 8 9 10 Guidelines 1. Classification and risk stratification Classification: As per AAFP 2019 guidelines, use the International Federation of Gynecology and Obstetrics classification system to characterize AUB. B As per SOGC 2018 guidelines, consider adopting standardized international terminology for AUB. C As per ACOG 2013 guidelines, classify etiologies of AUB based on the PALM-COEIN system: https://web.pathway.md/diseases/recyVq825NSm4QU51 1/7 6/23/23, 1:24 AM Abnormal uterine bleeding Pathway s pe COG 0 3 gu de es, c ass y et o og es o U based o t e CO syste polyp adenomyosis leiomyoma malignancy and hyperplasia coagulopathy ovulatory dysfunction endometrial iatrogenic not otherwise classified. E 2. Diagnostic investigations History and physical examination: elicit history and perform physical examination to determine the cause of AUB and direct the need for further investigation and treatment. B Pregnancy testing: As per AAFP 2019 guidelines, obtain pregnancy testing in all patients with AUB. B As per SOGC 2018 guidelines, obtain a sensitive urine or serum pregnancy test in patients with AUB if there is any possibility of pregnancy. B Ultrasound: As per ACR 2020 guidelines, obtain transabdominal and transvaginal ultrasound (including Doppler ultrasound) as initial imaging in patients with AUB. B Show 2 more As per AAFP 2019 guidelines, obtain transvaginal ultrasound as first-line imaging for the evaluation of AUB in most patients. B As per SOGC 2018 guidelines, obtain imaging to acquire additional information to assist in patient assessment and treatment in indicated circumstances. A Show 2 more Magnetic resonance imaging: As per ACR 2020 guidelines: Obtain contrast-enhanced pelvic MRI for subsequent imaging of AUB if the initial ultrasound is inconclusive or further imaging characterization is needed. B Obtain contrast-enhanced pelvic MRI for follow-up imaging of AUB when surveillance is appropriate given findings from the initial ultrasound. B Laboratory testing: As per AAFP 2019 guidelines, obtain testing for anemia in all patients with AUB. B As per SOGC 2018 guidelines, obtain a CBC in patients with heavy or prolonged bleeding. B Show 2 more https://web.pathway.md/diseases/recyVq825NSm4QU51 2/7 6/23/23, 1:24 AM Abnormal uterine bleeding Pathway 3. Diagnostic procedures Hysteroscopy: Perform hysteroscopy to acquire additional information to assist in patient assessment and treatment in indicated circumstances. A Perform hysteroscopy for the diagnosis and characterization of discrete intrauterine abnormalities, such as submucosal fibroids. A Endometrial biopsy: As per AAFP 2019 guidelines, perform endometrial biopsy in all patients with AUB with any of the following: age 45 years younger patients with a significant history of unopposed estrogen exposure persistent bleeding failed medical management. B As per SOGC 2018 guidelines, consider performing endometrial biopsy in patients with AUB with any of the following: age > 40 years bleeding not responsive to medical therapy younger patients with risk factors from endometrial cancer. B Show 2 more 4. Medical management General principles: Initiate medical treatment as first-line therapy in patients with AUB once malignancy and significant pelvic pathology is ruled out. A Tailor medical treatment to individual patient's therapeutic goals, desire for contraception, underlying medical conditions and tolerance of side effects to encourage compliance and maximize the likelihood of treatment success. B Initiate medical management with the following agents as the initial treatment in most patients with AUB, if clinically appropriate, with choice of agent based on the patient's medical history and contraindications to therapies: IV conjugated equine estrogen multi-dose regimens of oral contraceptives or oral progestins tranexamic acid. E Consider offering any of the following treatment options in patients with AUB presumed caused by predominately ovulatory disorders or endometrial hemostatic disorders, with choice of treatment based on the patient's values and preferences: hysterectomy https://web.pathway.md/diseases/recyVq825NSm4QU51 3/7 6/23/23, 1:24 AM Abnormal uterine bleeding Pathway endometrial ablation systemically administered medical therapies levonorgestrel intrauterine system. C Show 2 more Management of acute bleeding: As per SOGC 2018 guidelines, recognize that acute heavy menstrual bleeding may result in significant anemia and require emergent care. B Show 2 more As per ACOG 2013 guidelines, initiate long-term maintenance therapy once acute bleeding episode has been controlled. E Hormone therapy: as per SOGC 2018 guidelines, offer combined oral contraceptive pills, depot medroxyprogesterone acetate, or levonorgestrel-releasing intrauterine systems to reduce menstrual bleeding in patients with AUB desiring effective contraception. A Show 3 more Antifibrinolytics: consider offering antifibrinolytics for the treatment of patients with heavy menstrual bleeding being mainly cyclic or predictable in timing. B Nonsteroidal anti-inflammatory drugs: consider offering NSAIDs for the treatment of patients with heavy menstrual bleeding being mainly cyclic or predictable in timing. B 5. Therapeutic procedures Intrauterine devices: As per AAFP 2019 guidelines, offer 20 g/day formulation of the levonorgestrel releasing intrauterine system over other medical therapies for reducing heavy menstrual bleeding. A As per SOGC 2018 guidelines, consider placing progestin intrauterine system before surgical intervention in patients with heavy menstrual bleeding due to outcomes similar to endometrial ablation. B As per SGS 2012 guidelines: Consider placing levonorgestrel intrauterine system rather than performing hysterectomy if the patient's main preference is to avoid adverse events. C Consider either performing hysterectomy or placing levonorgestrel intrauterine system if the patient's main preference is improvement in overall quality of life or sexual health, with choice of treatment based on additional patient preferences. C Endometrial ablation: As per SOGC 2018 guidelines, prefer non-hysteroscopic ablation techniques over traditional hysteroscopic ablation due to similar patient satisfaction results with fewer risks of complications, less anesthetic requirement, and higher efficacy and safety. A As per SOGC 2015 guidelines, obtain comprehensive preoperative assessment to rule out any contraindication to endometrial ablation. B https://web.pathway.md/diseases/recyVq825NSm4QU51 4/7 6/23/23, 1:24 AM Abnormal uterine bleeding Pathway Show 8 more As per SGS 2012 guidelines: Consider performing endometrial ablation rather than hysterectomy if the patient's main preference is for shorter hospitalization and for lower operative and postoperative procedural risk. C Consider performing either hysterectomy or endometrial ablation if the patient's main preference is for improvement in overall quality of life or sexual health, with choice of treatment based on additional patient preferences. C 6. Surgical interventions General principles: Decide on performing surgery based on the following factors: clinical stability severity of bleeding contraindications to medical management lack of response to medical management underlying medical condition patient's desire for future fertility. E Hysterectomy: As per AAFP 2019 guidelines, perform hysterectomy as the most effective treatment for reducing heavy menstrual bleeding. A As per SOGC 2018 guidelines, perform hysterectomy as the definitive treatment in patients with AUB. A As per SGS 2012 guidelines, consider performing hysterectomy rather than endometrial ablation if the patient's main preference is for amenorrhea or avoiding additional therapy or experiencing less pain. C Show 5 more Myomectomy: consider performing hysteroscopic myomectomy in patients with AUB secondary to submucosal fibroids. B 7. Specific circumstances Adolescent patients, evaluation: As per ACOG 2019 guidelines, recognize that heavy menstrual bleeding at menarche and in adolescence may be an important sentinel for an underlying bleeding disorder. E Show 6 more As per SOGC 2018 guidelines: Recognize that AUB in adolescents most commonly represents ovulatory dysfunction related to immaturity of the hypothalamic-pituitary-ovarian axis. B https://web.pathway.md/diseases/recyVq825NSm4QU51 5/7 6/23/23, 1:24 AM Abnormal uterine bleeding Pathway Obtain assessment for an underlying bleeding disorder in adolescent patients presenting with heavy menstrual bleeding at or in close approximation to menarche. B Adolescent patients (management): initiate medical management as first-line approach to acute bleeding in the adolescent patients. Reserve surgery for patients not responding to medical therapy. E Show 9 more Patients with inherited bleeding disorders: recognize that inherited bleeding disorders may be an underlying cause of AUB, with von Willebrand's disease present in the majority of cases. B Show 3 more Patients undergoing cancer treatment: Consider obtaining a gynecologic consultation before initiation of treatment in all premenopausal patients at risk for AUB from chemotherapy. B Consider offering leuprolide acetate or combined hormonal contraceptives before cancer treatment to preven AUB in premenopausal patients at risk for thrombocytopenia. B References 1. No authors listed. ACOG committee opinion no. 557 Management of acute abnormal uterine bleeding in nonpregnant reproductive-aged women. Obstet Gynecol. 2013 Apr;121 4 891 896. Open 2. Sukhbir Singh, Carolyn Best, Sheila Dunn et al. No. 292 Abnormal Uterine Bleeding in Pre-Menopausal Women. J Obstet Gynaecol Can. 2018 May;40 5):e391-e415. Open 3. No authors listed. Practice bulletin no. 136 management of abnormal uterine bleeding associated with ovulatory dysfunction. Obstet Gynecol. 2013 Jul;122 1 176 185. Open 4. Philippe Laberge, Nicholas Leyland, Ally Murji et al. Endometrial ablation in the management of abnormal uterine bleeding. J Obstet Gynaecol Can. 2015 Apr;37 4 362 79. Open 5. Committee on Practice Bulletins Gynecology. Practice bulletin no. 128 diagnosis of abnormal uterine bleeding in reproductive-aged women. Obstet Gynecol. 2012 Jul;120 1 197 206. Open 6. Noah Wouk, Margaret Helton. Abnormal Uterine Bleeding in Premenopausal Women. Am Fam Physician. 2019 Apr 1;99 7 435 443. Open 7. Thomas L Wheeler nd, Miles Murphy, Rebecca G Rogers et al. Clinical practice guideline for abnormal uterine bleeding: hysterectomy versus alternative therapy. J Minim Invasive Gynecol. Jan-Feb 2012;19 1 81 8. Open 8. Expert Panel on GYN and OB Imaging, Jessica B Robbins, Elizabeth A Sadowski et al. ACR Appropriateness Criteria Abnormal Uterine Bleeding. J Am Coll Radiol. 2020 Nov;17 11S S336 S345. Open 9. No authors listed. Screening and Management of Bleeding Disorders in Adolescents With Heavy Menstrual Bleeding: ACOG COMMITTEE OPINION, Number 785. Obstet Gynecol. 2019 Sep;134 3):e71-e83. Open https://web.pathway.md/diseases/recyVq825NSm4QU51 6/7 6/23/23, 1:24 AM Abnormal uterine bleeding Pathway 10. Yolanda A Kirkham, Melanie P Ornstein, Anjali Aggarwal et al. No. 313 Menstrual Suppression in Special Circumstances. J Obstet Gynaecol Can. 2019 Feb;41 2):e7-e17. Open https://web.pathway.md/diseases/recyVq825NSm4QU51 7/7

Guideline sources The following summarized guidelines for the evaluation and management of accidental hypothermia are prepared by our editorial team based on guidelines from the American Heart Association (AHA 2020) and the Wilderness Medical Society (WMS 2019). 1 2 Guidelines 1. Diagnostic investigations Field assessment: Classify hypothermia as mild, moderate, severe and profound on the bases of clinical observations, recognizing that: shivering can occur below 32 C, usually with altered mental status patients can have detectable vital signs with core temperatures below 24 C core temperature can overlap between classification categories. B Show 5 more Core temperature measurement: place an esophageal temperature probe, if available, in patients with protected and secured airways. Recognize that esophageal temperature is the preferred method of core temperature measurement. B https://web.pathway.md/diseases/recWvNGvunIameK26 1/4 6/23/23, 1:26 AM Accidental hypothermia Pathway Show 6 more 2. Respiratory support Airway management: Recognize that advantages of advanced airway management outweigh the risk of causing VF. B Place a nasogastric or orogastric tube after the airway is secured to decompress the stomach. B Ventilation: deliver ventilation at the same rate as in normothermic patients in the absence of end-tidal CO monitoring, unless an advanced airway is in place. B Show 5 more 3. Medical management Fluid resuscitation: place intraosseous catheter, if immediate peripheral IV catheter cannot be placed. Use femoral line for the central venous access, if no other option is available. B Show 3 more Vasopressors: do not administer vasoactive drugs until the patient has been rewarmed to 30 C. D Extend dosing intervals twice as long as usual while keeping the usual doses in patients with a core temperature of 30-35 C, to minimize the potential toxic accumulation of medication. D Glucose and insulin: administer glucose for the management of hypoglycemia in patients with hypothermia. A Show 2 more 4. Nonpharmacologic interventions Out-of-hospital management (safety of the rescuer): ensure that the scene is secure and safe to enter and make an evaluation before the decision to rescue or resuscitate a patient. A Out-of-hospital management (patient handling): keep a hypothermic patient horizontal, especially during rescue from water or a crevasse B and limit physical effort by the patient during rescue. Encourage conscious patients to be attentive and focused on survival. B Show 2 more Out-of-hospital management (protection from cold): use insulation and vapor barriers to protect patients from further cooling until they have reached a warm environment, such as the warmed interior of an ambulance. Remove wet clothes, preferably by cutting them off, only when patients have been protected from the cold. B Show 2 more Out-of-hospital management (passive rewarming): encourage shivering in patients with cold- stress or mild hypothermia for rewarming. Ensure adequate insulation of patients with https://web.pathway.md/diseases/recWvNGvunIameK26 2/4 6/23/23, 1:26 AM Accidental hypothermia Pathway hypothermia from the environment to retain the generated heat. A Show 3 more Out-of-hospital management (active rewarming): use active sources of heat. Use rewarming devices in conjunction with vapor barriers and insulation. Use the Heat Pac only outdoors or with proper ventilation carefully monitored to prevent CO accumulation. B Show 11 more Out-of-hospital management (rewarming during transport): use forced air warming during air or ground transport, if available. A Consider continuing other heat sources, if forced air warming is not available. B Show 2 more Out-of-hospital management (non-hypothermic cold-stressed patients): keep cold-stressed patients without hypothermia horizontal. Show 2 more Out-of-hospital management (patients with severe trauma): initiate early and aggressive active rewarming during all phases of out-of-hospital care to prevent hypothermia in severely injured patients. B Transportation: Undertake the following measures when preparing patients for transport: stabilize potential spinal injuries reduce fractures and dislocations to the normal anatomic configuration as much as possible cover open wounds. B Show 6 more 5. Therapeutic procedures Cardiopulmonary resuscitation: attempt CPR unless contraindications exist. Recognize that fixed, dilated pupils, apparent rigor mortis, and dependent lividity are not contraindications to resuscitation in patients with severe hypothermia. A Show 9 more Automated external defibrillation: attempt defibrillation and initiate CPR if shock is advised by an automated external defibrillator. B Show 2 more Transcutaneous pacing: consider performing transcutaneous pacing in patients with hypothermia in the setting of bradycardia with hypotension disproportionate to the core temperature. C 6. Specific circumstances Patients in cardiac arrest: undertake full resuscitative measures, including extracorporeal rewarming when available, in all victims of accidental hypothermia without characteristics suggesting that they are unlikely to survive and without any obviously lethal traumatic injury. B https://web.pathway.md/diseases/recWvNGvunIameK26 3/4 6/23/23, 1:26 AM Accidental hypothermia Pathway Show 3 more References 1. Ashish R Panchal, Jason A Bartos, Jos G Caba as et al. Part 3 Adult Basic and Advanced Life Support: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2020 Oct 20;142 16_suppl_2 S366 S468. Open 2. Dow J, Giesbrecht GG, Danzl DF et al. Wilderness Medical Society Clinical Practice Guidelines for the Out-of-Hospital Evaluation and Treatment of Accidental Hypothermia: 2019 Update. Wilderness Environ Med. 2019 Dec;30 4S S47 S69. Open https://web.pathway.md/diseases/recWvNGvunIameK26 4/4

Guideline sources The following summarized guidelines for the evaluation and management of acetaminophen poisoning are prepared by our editorial team based on guidelines from the American Association for the Study of Liver Diseases (AASLD 2022), the Treatment of Paracetamol Poisoning Writing Group (TPPWG 2020), the Extracorporeal Treatments in Poisoning Workgroup (EXTRIP 2014), and the American Association of Poison Control Centers (AAPCC 2006). 1 2 3 4 Calculator King's College Criteria for aceta Guidelines https://web.pathway.md/diseases/recy8dq98BY2MASYn 1/5 6/23/23, 1:27 AM Acetaminophen poisoning Pathway 1. Screening and diagnosis Diagnosis: As per AASLD 2022 guidelines, recognize that acetaminophen is a dose-dependent hepatotoxin causing acute pericentral liver injury when doses of > 4 g are ingested within a 24-hour period or excessive doses over several days. E Show 2 more As per AAPCC 2006 guidelines, set > 4 g or 100 mg/kg (whichever is less) per day of acetaminophen as repeated supratherapeutic ingestion of acetaminophen in patients with conditions purported to increase susceptibility to acetaminophen toxicity (AUD, isoniazid use, prolonged fasting). B 2. Classification and risk stratification Prognosis: recognize that the prognosis in acetaminophen-related ALF is related to the degree of encephalopathy, coagulopathy, and acidosis. E 3. Diagnostic investigations History of ingestion: elicit history including the patient's age and intent, B specific formulation and dose of acetaminophen, ingestion pattern, duration of ingestion, B and concomitant medications ingested. B 4. Medical management Setting of care: refer patients with stated or suspected self-harm or recipients of a potentially malicious administration of acetaminophen to an emergency department regardless of the amount ingested. B Show 7 more N-acetylcysteine: As per AASLD 2022 guidelines, administer IV or PO N-acetylcysteine to prevent liver injury, nearly completely if administered within 12 hours of acetaminophen ingestion. E As per TPPWG 2020 guidelines, administer N-acetylcysteine as a two-bag regimen (200 mg/kg over 4 hours followed by 100 mg/kg over 16 hours). B Show 8 more Cimetidine: do not use cimetidine as an antidote in patients with acetaminophen poisoning. D 5. Nonpharmacologic interventions Gastrointestinal decontamination: https://web.pathway.md/diseases/recy8dq98BY2MASYn 2/5 6/23/23, 1:27 AM Acetaminophen poisoning Pathway As per AASLD 2022 guidelines, perform gastric lavage and administer activated charcoal in all patients presenting within 4 hours of a single-time-point acetaminophen overdose. E As per TPPWG 2020 guidelines, administer activated charcoal 50 g in cooperative, awake adult patients presenting within 2 hours of ingestion of a toxic dose of immediate-release acetaminophen, or within 4 hours of immediate-release acetaminophen overdoses > 30 g. B As per AAPCC 2006 guidelines: Consider administering activated charcoal if local poison center policies support its prehospital use, a toxic dose of acetaminophen has been taken, and fewer than 2 hours have elapsed since the ingestion. B Do not perform gastrointestinal decontamination in patients with repeated supratherapeutic ingestion of acetaminophen. D 6. Therapeutic procedures Extracorporeal treatment: Consider initiating ECTR in patients with any of the following: acetaminophen concentration > 1,000 mg/L (1D) or > 800 mg/L, if N-acetylcysteine is not administered acetaminophen concentration > 700 mg/L (1D) or > 500 mg/L, (2D) presenting with altered mental status, metabolic acidosis, elevated lactate, if N-acetylcysteine is not administered acetaminophen concentration > 900 mg/L (1D) or > 800 mg/L, (2D) presenting with altered mental status, metabolic acidosis, elevated lactate, if N-acetylcysteine is administered. C Show 4 more 7. Surgical interventions Liver transplantation: Consult a liver transplant unit if any of the following criteria are met: INR > 3.0 at 48 hours or > 4.5 at any time oliguria or creatinine > 200 mcmol/L persistent acidosis (pH < 7.3) or arterial lactate > 3 mmol/L systolic hypotension with BP < 80 mmHg, despite resuscitation hypoglycemia, severe thrombocytopenia, or encephalopathy of any degree any alteration of consciousness (GCS < 15) not associated with sedative co-ingestions. E Do not administer clotting factors unless the patient is bleeding or after discussion with a liver transplant unit. D 8. Specific circumstances Pediatric patients: https://web.pathway.md/diseases/recy8dq98BY2MASYn 3/5 6/23/23, 1:27 AM Acetaminophen poisoning Pathway As per TPPWG 2020 guidelines, measure serum acetaminophen concentration at least 2 hours after ingestion in < 6 years old pediatric patients with suspected ingestion of > 200 mg/kg of liquid acetaminophen. Do not administer N-acetylcysteine if the 2-4-hour acetaminophen concentration is < 150 mg/L. Repeat measurement of acetaminophen concentration 4 hours after ingestion if the 2-hour acetaminophen concentration is > 150 mg/L and administer N- acetylcysteine if the 4-hour concentration is 150 mg/L. B Show 2 more As per AAPCC 2006 guidelines, refer < 6 years old pediatric patients to an emergency department if the estimated acute ingestion amount is unknown or is 200 mg/kg. Consider monitoring patients at home if the dose ingested is < 200 mg/kg. B Show 3 more 9. Follow-up and surveillance Indications for poison center consultation: Consult a poisons information center in the following situations: very large overdoses - immediate-release or modified-release acetaminophen overdoses of 50 g or 1 g/kg (whichever is less) high acetaminophen concentration, more than triple the nomogram line IV acetaminophen errors or overdoses, as the treatment threshold is lower patients with hepatotoxicity (ALT > 1,000 IU/L) neonatal acetaminophen poisonings. E Assessment of treatment response: measure ALT levels near the completion of N-acetylcysteine (2 hours before completion of the infusion) in all patients. Measure acetaminophen concentration in patients with an initial acetaminophen level > 2 the nomogram line. Continue N-acetylcysteine if the acetaminophen concentration is > 10 mg/L or ALT is elevated (> 50 U/L) and increasing (if baseline ALT > 50 U/L). Repeat ALT measurement in all cases as there is a small (< 1%) risk of developing acute liver injury despite treatment with acetylcysteine within 8 hours. B Show 3 more References 1. Richard C Dart, Andrew R Erdman, Kent R Olson et al. Acetaminophen poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol Phila). 2006;44 1 1 18. Open 2. Robert J Fontana, Iris Liou, Adrian Reuben et al. AASLD practice guidance on drug, herbal, and dietary supplement-induced liver injury. Hepatology. 2022 Jul 27. Open 3. S Gosselin, D N Juurlink, J T Kielstein et al. Extracorporeal treatment for acetaminophen poisoning: recommendations from the EXTRIP workgroup. Clin Toxicol Phila). Sep-Oct 2014;52 8 856 67. Open 4. Angela L Chiew, David Reith, Adam Pomerleau et al. Updated guidelines for the management of paracetamol poisoning in Australia and New Zealand. Med J Aust. 2020 Mar;212 4 175 183. Open https://web.pathway.md/diseases/recy8dq98BY2MASYn 4/5 6/23/23, 1:27 AM Acetaminophen poisoning Pathway 5. McNeil Consumer Healthcare. Guidelines for the Management of Acetaminophen Overdose. McNeil Consumer Healthcare. 2018 Sep 8. Open 6. No authors listed. NCPDP recommendations for dose accumulation monitoring in the inpatient setting: Acetaminophen case model, version 1.0. Am J Health Syst Pharm. 2016 Aug 1;73 15 1144 65. Open 7. J G O'Grady, G J Alexander, K M Hayllar et al. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989 Aug;97 2 439 45. Open https://web.pathway.md/diseases/recy8dq98BY2MASYn 5/5

Guideline sources The following summarized guidelines for the evaluation and management of achalasia are prepared by our editorial team based on guidelines from the European Society of Gastrointestinal Endoscopy (ESGE 2020), the American Society for Gastrointestinal Endoscopy (ASGE 2020; 2014), the International Society for Diseases of the Esophagus (ISDE 2018), and the American College of Gastroenterology (ACG 2013). 1 2 3 4 5 6 7 8 9 Definition Achalasia is an esophageal motility disorder defined by loss of esophageal peristalsis and incomplete relaxation of lower esophageal sphincter. 6 Epidemiology Proposed causes of achalasia include GEJ obstruction, neuronal degeneration, viral infection, genetic inheritance, and autoimmune disease. 7 Disease course https://web.pathway.md/diseases/rec1RhD8XTnEbi1MA 1/8 6/23/23, 1:27 AM Achalasia Pathway Disease course Inflammatory neurodegenerative insult with possible viral involvement within the esophagus results in achalasia, which causes the clinical manifestation of progressive dysphagia, regurgitation, chest pain, heartburn, nocturnal cough, aspiration, and weight loss. The progression of the disease may result in aspiration-pneumonia, Barrett's esophagus, and esophageal cancer. 8 Prognosis and risk of recurrence Achalasia is not associated with an increase in mortality. 9 Calculator Calculator Pathway Diagnostic criteria for achalasia Eckardt clinical staging of achal Achalasia Investigatio Guidelines 1. Screening and diagnosis Diagnosis: suspect achalasia in patients with dysphagia to solids and liquids, and in patients with regurgitation unresponsive to an adequate trial of PPI therapy. B 2. Classification and risk stratification Disease classification: Use the Chicago classification of esophageal motility disorders to assign patients with achalasia to one of three disease subclasses: Situation Guidance Elevated median integrated relaxation pressure (> 15 mmHg) Type I (classic) 100% failed peristalsis Distal contractile integral < 100 mmHg Premature contractions with distal contractile integral < 450 mmHg cm/sec satisfy criteria for failed peristalsis Elevated median integrated relaxation pressure (> 15 mmHg) Type II (with esophageal compression) 100% failed peristalsis Panesophageal pressurization with 20% of swallows https://web.pathway.md/diseases/rec1RhD8XTnEbi1MA 2/8 6/23/23, 1:27 AM Achalasia Pathway Contractions may be masked by esophageal pressurization and distal contractile integral should not be calculated Elevated median integrated relaxation pressure (> 15 mmHg) Type III (spastic) No normal peristalsis Premature (spastic) contractions with distal contractile integral > 450 mmHg cm/sec with 20% of swallows May be mixed with panesophageal pressurization. E Severity grading: use the Eckardt score to assess the severity of achalasia symptoms as part of the initial evaluation and follow-up assessment. E 3. Diagnostic investigations Esophageal manometry: As per ISDE 2018 guidelines, consider obtaining high-resolution esophageal manometry as first- line investigation for the diagnosis of achalasia. C As per ACG 2013 guidelines, obtain esophageal manometry in all patients with suspected achalasia without evidence of mechanical obstruction on endoscopy or esophagram. B Barium esophagram: As per ISDE 2018 guidelines: Consider obtaining a timed barium esophagram as part of the diagnostic evaluation and follow-up assessment of patients with achalasia. C Obtain a timed barium esophagram in patients with suspected end-stage achalasia. E As per ACG 2013 guidelines: Obtain a timed barium esophagram to assess esophageal emptying and esophagogastric junction morphology in patients with equivocal results on esophageal manometry. B Look for esophagram findings supporting the diagnosis of achalasia, such as dilation of the esophagus, a narrow esophagogastric junction with "bird-beak" appearance, aperistalsis, and poor emptying of barium. B Upper gastrointestinal endoscopy: As per ISDE 2018 guidelines, perform upper gastrointestinal endoscopy in adult patients with suspected achalasia to exclude neoplastic pseudoachalasia. E As per ACG 2013 guidelines, obtain endoscopic assessment of the GEJ and gastric cardia to rule out pseudoachalasia. B https://web.pathway.md/diseases/rec1RhD8XTnEbi1MA 3/8 6/23/23, 1:27 AM Achalasia Pathway 4. Medical management Pharmacologic therapy: As per ISDE 2018 guidelines, avoid using nitrates, calcium blockers or phosphodiesterase inhibitors for symptomatic relief in patients with achalasia. D As per ACG 2013 guidelines, initiate pharmacologic therapy (CCBs or long-acting nitrates) in patients with achalasia unwilling or unable to undergo definitive treatment with either pneumatic dilatation or surgical myotomy, and failed botulinum toxin therapy. B 5. Therapeutic procedures Choice of initial therapy: As per ASGE 2020 guidelines, offer laparoscopic Heller myotomy, pneumatic dilation, and POEM as effective therapeutic modalities in patients with achalasia. Decide between these treatment options based on achalasia type, local expertise, and patient preference. A Show 3 more As per ASGE 2014 guidelines, discuss both endoscopic and surgical treatment options in patients with achalasia. A As per ACG 2013 guidelines: Individualize the choice of initial therapy according to the patient's age, gender, personal preferences, and local institutional expertise. B Perform pneumatic dilation and surgical myotomy at high-volume centers of excellence. B Pneumatic dilatation: As per ESGE 2020 guidelines, use a graded pneumatic dilation protocol in achalasia, starting with a 30-mm dilation and followed by a 35-mm dilation at a planned interval of 2 - 4 weeks, with a subsequent 40-mm dilation when there is insufficient relief, over both a single balloon dilation procedure or the use of a larger balloon from the outset. A As per ISDE 2018 guidelines, perform graded pneumatic dilatations as an effective treatment in patients with esophageal achalasia. B Show 3 more As per ASGE 2014 guidelines, perform pneumatic dilatation with large-caliber balloon dilators in patients being good candidates and desiring endoscopic management. A As per ACG 2013 guidelines, perform either graded pneumatic dilatation or laparoscopic surgical myotomy with a partial fundoplication as initial therapy for the surgical treatment of patients with achalasia fitting and willing to undergo surgery. B Peroral endoscopic myotomy: As per ASGE 2020 guidelines, consider performing POEM as the preferred treatment in patients with type III achalasia. C Show 2 more https://web.pathway.md/diseases/rec1RhD8XTnEbi1MA 4/8 6/23/23, 1:27 AM Achalasia Pathway As per ESGE 2020 guidelines, perform POEM using low-flow CO insufflation. B Show 3 more As per ISDE 2018 guidelines, consider performing POEM as an effective treatment option in patients with achalasia, with results comparable to Heller myotomy for symptom improvement C and to pneumatic dilation for symptom control. C Show 4 more Updated evidence: POEM for achalasia In patients with symptomatic achalasia, POEM was noninferior to laparoscopic Heller's myotomy with respect to clinical success at 2 years. Werner YB et al. N Engl J Med. 2019 Dec 5. Botulinum toxin injection: As per ASGE 2020 guidelines, do not perform botulinum toxin injection as definitive therapy in patients with achalasia. Reserve botulinum toxin injection for patients unfit for other definitive therapies. D As per ESGE 2020 guidelines: Administer botulinum toxin injection (100 units of the toxin diluted in preservative-free saline injected in aliquots of 0.5 -1 mL) using an injection needle in forward view just above the squamocolumnar junction in at least 4 quadrants. A Avoid administering routine injections of botulinum toxin in the esophageal body in addition to injection in the lower esophageal sphincter in patients with type III achalasia. D As per ISDE 2018 guidelines, do not perform botulinum toxin injection in patients < 50 years old. D Show 4 more As per ASGE 2014 guidelines, perform endoscopic botulinum toxin injection for the treatment of patients with achalasia being poor candidates for surgery or pneumatic dilatation. A As per ACG 2013 guidelines, perform endoscopic botulinum toxin injection for the treatment of patients with achalasia being poor candidates for surgery or pneumatic dilatation. B Other endoscopic therapies: Do not perform implantation of retrievable or absorbable temporary stents for the treatment of patients with achalasia. D Do not perform intrasphincteric injection of ethanolamine oleate or polidocanol for the treatment of patients with achalasia. D 6. Perioperative care https://web.pathway.md/diseases/rec1RhD8XTnEbi1MA 5/8 6/23/23, 1:27 AM Achalasia Pathway Perioperative antibiotic prophylaxis: administer perioperative antibiotic prophylaxis for POEM. Adapt the choice and duration of antibiotics according to national or local protocols. B 7. Surgical interventions Surgical myotomy: As per ISDE 2018 guidelines, perform laparoscopic Heller myotomy for symptom control in patients with Chicago type I and type II achalasia. B Show 3 more As per ACG 2013 guidelines, perform either laparoscopic surgical myotomy or graded pneumatic dilatation as initial therapy for the treatment of patients with achalasia fitting and willing to undergo surgery. B Esophagectomy: consider performing esophagectomy in patients with end-stage achalasia failed other interventions. C 8. Specific circumstances Pediatric patients: obtain the same work-up in pediatric patients with a provisional diagnosis of achalasia as in adult patients. E Show 3 more Patients with Chagas disease esophagopathy: consider obtaining the same work-up and offering the same treatments for symptom relief in patients with Chagas disease esophagopathy as in patients with idiopathic achalasia, due to the similarities in manometric and clinical features. C Patients with other spastic motility disorders: Be cautious when treating spastic motility disorders other than achalasia with POEM. B Do not use botulinum toxin injections routinely for the treatment of patients with non-achalasia hypercontractile esophageal motility disorders (Jackhammer esophagus, distal esophageal spasm). Administer injections into 4 quadrants of the lower esophageal sphincter and in the lower 1/3 of the esophagus in individual patients, if endoscopic injection of botulinum toxin is chosen. D 9. Patient education General counseling: inform male patients with achalasia about the moderately increased risk of esophageal cancer after 10 years from the initial treatment. E 10. Follow-up and surveillance Post-treatment follow-up: https://web.pathway.md/diseases/rec1RhD8XTnEbi1MA 6/8 6/23/23, 1:27 AM Achalasia Pathway As per ISDE 2018 guidelines: Assess patients for symptomatic improvement after treatment for achalasia. E Consider obtaining a timed barium esophagram to assess for recurrence of achalasia. C As per ACG 2013 guidelines, assess patients for symptomatic improvement after treatment for achalasia, and consider obtaining a timed barium esophagram to assess esophageal emptying. B Management of disease recurrence: As per ASGE 2020 guidelines, consider performing pneumatic dilation or redo myotomy using either the same or an alternative myotomy technique (POEM or laparoscopic Heller myotomy) in patients failed initial myotomy. C As per ISDE 2018 guidelines, obtain objective testing in patients with recurrent symptoms after treatment of achalasia, including upper gastrointestinal endoscopy, barium swallow, manometry, and 24-hour pH monitoring. E Show 3 more Surveillance endoscopy: do not perform routine surveillance endoscopy to screen for esophageal cancer. D References 1. Vaezi MF, Pandolfino JE, Vela MF. ACG clinical guideline: diagnosis and management of achalasia. Am J Gastroenterol. 2013 Aug;108 8 1238 49. Open 2. Zaninotto G, Bennett C, Boeckxstaens G et al. The 2018 ISDE achalasia guidelines. Dis Esophagus. 2018 Sep 1;31 9 . Open 3. Bas L A M Weusten, Maximilien Barret, Albert J Bredenoord et al. Endoscopic management of gastrointestinal motility disorders - part 1 European Society of Gastrointestinal Endoscopy ESGE Guideline. Endoscopy. 2020 Jun;52 6 498 515. Open 4. Mouen A Khashab, Marcelo F Vela, Nirav Thosani et al. ASGE guideline on the management of achalasia. Gastrointest Endosc. 2020 Feb;91 2 213 227.e6. Open 5. Pasha SF, Acosta RD, Chandrasekhara V et al. The role of endoscopy in the evaluation and management of dysphagia. Gastrointest Endosc. 2014 Feb;79 2 191 201. Open 6. Dhyanesh A Patel, Hannah P Kim, Jerry S Zifodya et al. Idiopathic (primary) achalasia: a review. 2015 Jul 22;10 89.2015 Jul 22;10 89. Open 7. Woosuk Park, Michael F Vaezi. Etiology and pathogenesis of achalasia: the current understanding. 2005 Jun;100 6 1404 14.2005 Jun;100 6 1404 14. Open 8. Orla M O'Neill, Brian T Johnston, Helen G Coleman. Achalasia: a review of clinical diagnosis, epidemiology, treatment and outcomes. 2013 Sep 21;19 35 5806 12.2013 Sep 21;19 35 5806 12. Open 9. Volker F Eckardt, Tom Hoischen, Gudrun Bernhard. Life expectancy, complications, and causes of death in patients with achalasia: results of a 33-year follow-up investigation. 2008 Oct;20 10 956 60.2008 https://web.pathway.md/diseases/rec1RhD8XTnEbi1MA 7/8 6/23/23, 1:27 AM Achalasia Pathway Oct;20 10 956 60. Open 10. Werner YB, Hakanson B, Martinek J et al. Endoscopic or Surgical Myotomy in Patients with Idiopathic Achalasia. N Engl J Med. 2019 Dec 5;381 23 2219 2229. Open 11. Ines Gockel, Michaela M ller, Johannes Schumacher. Achalasia a Disease of Unknown Cause That Is Often Diagnosed Too Late. Dtsch Arztebl Int. 2012 Mar; 109 12 209 214. Open 12. Zubin Arora, Prashanthi N Thota, Madhusudhan R Sanaka. Achalasia: current therapeutic options. Ther Adv Chronic Dis. 2017 Jun;8 6 7 101 108. Open 13. Dhyanesh A Patel, Brian M Lappas, Michael F Vaezi. An Overview of Achalasia and Its Subtypes. Gastroenterol Hepatol N Y . 2017 Jul;13 7 411 421. Open 14. Fehmi Ates, Michael F Vaezi. The Pathogenesis and Management of Achalasia: Current Status and Future Directions. Gut Liver. 2015 Jul;9 4 449 63. Open 15. Orla M O Neill, Brian T Johnston, and Helen G Coleman. Achalasia: A review of clinical diagnosis, epidemiology, treatment and outcomes. World J Gastroenterol. 2013 Sep 21; 19 35 5806 5812. Open 16. H D Allescher, M Storr, M Seige et al. Treatment of achalasia: botulinum toxin injection vs. pneumatic balloon dilation. A prospective study with long-term follow-Up. Endoscopy. 2001 Dec;33 12 1007 17. Open 17. Maura Torres-Aguilera and Jos Mar a Remes Troche. Achalasia and esophageal cancer: risks and links. Clin Exp Gastroenterol. 2018; 11 309 316. Open 18. Alexander J Eckardt, Volker F Eckardt. Treatment and surveillance strategies in achalasia: an update. Nat Rev Gastroenterol Hepatol. 2011 Jun;8 6 311 9. Open https://web.pathway.md/diseases/rec1RhD8XTnEbi1MA 8/8

Guideline sources The following summarized guidelines for the evaluation and management of achilles tendinopathy are prepared by our editorial team based on guidelines from the Dutch Multidisciplinary Guideline (DMG 2021), the American College of Rheumatology (ACR 2018), and the American Physical Therapy Association (APTA 2018). 1 2 3 Guidelines 1. Screening and diagnosis Diagnosis: Diagnose midportion Achilles tendinopathy based on the presence of all the following findings: symptoms localized 2-7 cm proximal to the Achilles tendon insertion painful Achilles tendon midportion on (sports) loading https://web.pathway.md/diseases/reczZeUKisuY7l3bF 1/7 6/23/23, 1:27 AM Achilles tendinopathy Pathway local thickening of the Achilles tendon midportion (may be absent in cases with short symptom duration) pain on local palpation of the Achilles tendon midportion. E Show 2 more Differential diagnosis: Suspect alternative diagnoses in patients with posterior ankle pain: Situation Guidance Plantaris tendinopathy or rupture Musculotendinous disorders Plantar fasciopathy or fascia rupture Tendinopathy of the flexor tendons of the toes or ankle Rupture of the crural fascia Accessory soleus muscle Exercise-related compartment syndrome of the deep flexor compartment Soft tissue tumor Stress fracture of the calcaneus Bone disorders Bone tumor of the calcaneus Infectious pathology of the calcaneus (such as Brodies abscess) Posterior ankle impingement Joint disorders Chondral pathology of the subtalar joint Neuropathy of the sural nerve Neurological disorders Tarsal tunnel syndrome. E Take into account underlying causes and associated pathologies in patients with a clinical diagnosis of Achilles tendinopathy: Situation Guidance Achilles tendon rupture (partial or complete) Mechanical causes Calcifying Achilles tendinopathy Plantaris tendon mediated Achilles tendinopathy (medially localized Achilles tendinopathy due to invagination of the plantaris tendon) Retrocalcaneal bursitis with or without Haglund's morphology https://web.pathway.md/diseases/reczZeUKisuY7l3bF 2/7 6/23/23, 1:27 AM Achilles tendinopathy Pathway Paratendinopathy of the Achilles tendon Subcutaneous Achilles bursitis Sever's disease (children and adolescents) Axial spondyloartritis Inflammatory causes Reactive arthritis Psoriatic arthritis Diabetes mellitus, hypercholesterolemia, gout Metabolic causes Familial hypercholesterolemia (tendon xanthomas) Fluoroquinolone antibiotics. E Medications 2. Diagnostic investigations History and physical examination: consider using a subjective report of pain located 2-6 cm proximal to the Achilles tendon insertion that began gradually and pain with palpation of the midportion of the tendon, in addition to the arc sign and Royal London Hospital test, for the diagnosis of midportion Achilles tendinopathy. C Show 3 more Diagnostic imaging: As per DMG 2021 guidelines, consider obtaining additional imaging (X-ray of the calcaneus, ultrasound of the Achilles tendon, or MRI of the ankle) in the following situations: symptoms do not fit with all 4 diagnostic criteria symptoms match all 4 diagnostic criteria but there is an unexpected course or change of symptoms during follow-up surgery is being considered. E Show 7 more As per ACR 2018 guidelines: Obtain an X-ray of the ankle as the initial imaging in patients with chronic ankle pain. E Obtain either ankle MRI without IV contrast or ankle ultrasound when tendon abnormality is suspected and ankle radiographs are normal in patients with chronic ankle pain. E 3. Medical management Nonsteroidal anti-inflammatory drugs: be cautious when using NSAIDs in patients with Achilles tendinopathy. E https://web.pathway.md/diseases/reczZeUKisuY7l3bF 3/7 6/23/23, 1:27 AM Achilles tendinopathy Pathway 4. Nonpharmacologic interventions Exercise: As per DMG 2021 guidelines, advise progressive calf muscle strengthening exercises for at least 12 weeks in patients with Achilles tendinopathy. Ensure the form of exercise therapy is suitable for the individual patient. Take into consideration the role of motivation, time constraints, pain monitoring, and availability of facilities and resources. Consider advising performing exercises initially on a flat surface in patients with insertional Achilles tendinopathy. E As per APTA 2018 guidelines, advise mechanical loading either in the form of eccentric exercise or a heavy-load, slow-speed (concentric/eccentric) exercise program to decrease pain and improve function in patients with midportion Achilles tendinopathy without presumed frailty of the tendon structure. A Show 3 more Footwear and ankle support: As per DMG 2021 guidelines, consider offering night splint and inlays in case of insufficient effectiveness of patient education and loading advice in combination with continued exercise therapy. E As per APTA 2018 guidelines, insufficient evidence to support the use of heel lifts or orthoses in patients with midportion Achilles tendinopathy. I Show 3 more Manual therapy: As per DMG 2021 guidelines, consider offering application of ultrasound and friction massages in case of insufficient effectiveness of patient education and loading advice in combination with continued exercise therapy. E As per APTA 2018 guidelines, consider offering joint mobilization to improve mobility and function and soft tissue mobilization to increase ROM in patients with midportion Achilles tendinopathy. C Acupuncture: As per DMG 2021 guidelines, consider offering acupuncture or intratendinous needling in case of insufficient effectiveness of patient education and loading advice in combination with continued exercise therapy. E As per APTA 2018 guidelines, consider offering combined therapy of dry needling with injection under ultrasound guidance and eccentric exercise to decrease pain in patients with symptoms > 3 months and increased tendon thickness. C Collagen supplements: consider offering collagen supplements in case of insufficient effectiveness of patient education and loading advice in combination with continued exercise therapy. E 5. Therapeutic procedures https://web.pathway.md/diseases/reczZeUKisuY7l3bF 4/7 6/23/23, 1:27 AM Achilles tendinopathy Pathway Injection therapy: consider offering injection therapies (polidocanol, lidocaine, autologous blood, platelet-rich plasma, stromal vascular fraction, hyaluronic acid, prolotherapy, or high-volume injection) in case of insufficient effectiveness of patient education and loading advice in combination with continued exercise therapy. Be cautious when using corticosteroid injections. E Updated evidence: Corticosteroid injection for AT In adult patients with ultrasound-verified Achilles tendinopathy for 3 months, US-guided corticosteroid injection was superior to US-guided placebo injection with respect to improvement in Victorian Institute of Sports Assessment-Achilles score at 6 months. Finn Johannsen et al. JAMA Netw Open. 2022 Jul 1. Iontophoresis: offer iontophoresis with dexamethasone to decrease pain and improve function in patients with acute midportion Achilles tendinopathy. B Laser and light therapy: As per DMG 2021 guidelines, consider offering laser and light therapies in case of insufficient effectiveness of patient education and loading advice in combination with continued exercise therapy. E As per APTA 2018 guidelines, insufficient evidence to recommend low-level laser therapy in patients with midportion Achilles tendinopathy. I Extracorporeal shockwave therapy: consider offering extracorporeal shockwave therapy in case of insufficient effectiveness of patient education and loading advice in combination with continued exercise therapy. E 6. Surgical interventions Indications for surgery: consider performing surgery only in patients not recovering after at least 6 months of active treatment. Discuss the expected effectiveness of surgical intervention compared with active non-surgical treatments and the potential surgical complications. E 7. Patient education General counseling: As per DMG 2021 guidelines, discuss the initial active treatment options together with the patient. Assess specific patient characteristics (such as activity level and the presence of comorbidities) to personalize treatment. E Show 7 more As per APTA 2018 guidelines: https://web.pathway.md/diseases/reczZeUKisuY7l3bF 5/7 6/23/23, 1:27 AM Achilles tendinopathy Pathway Avoid advising complete rest in patients with non-acute midportion Achilles tendinopathy, rather advise continuing their recreational activity within their pain tolerance while participating in rehabilitation. D Consider counseling patients with midportion Achilles tendinopathy regarding the following key elements: theories supporting the use of physical therapy and the role of mechanical loading modifiable risk factors, including BMI and footwear typical time course for recovery from symptoms. C 8. Preventative measures Avoidance of fluoroquinolone: consider advising the avoidance of fluoroquinolone antibiotics if alternative antibiotics are available and the clinical picture allows in the context of the importance of preventing Achilles tendinopathy. E Secondary prevention: advise that sufficient time should be spent on active treatment before starting with provocative (sports) loading. E Show 3 more 9. Follow-up and surveillance Indications for specialist referral: consider referring patients to a sports medicine physician or an orthopedic surgeon if there is continued uncertainty about the diagnosis or there is an unexpected course or change of symptoms during follow-up. E Show 2 more Assessment of treatment response: Consider using the Victorian Institute of Sports Assessment-Achilles (VISA-A) questionnaire to evaluate the course of Achilles tendinopathy. E Do not obtain imaging to monitor treatment response and/or predict the course of symptoms of Achilles tendinopathy. D References 1. Robert-Jan de Vos, Arco C van der Vlist, Johannes Zwerver et al. Dutch multidisciplinary guideline on Achilles tendinopathy. Br J Sports Med. 2021 Oct;55 20 1125 1134. Open 2. Expert Panel on Musculoskeletal Imaging:, Eric Y Chang, Anthony S Tadros et al. ACR Appropriateness Criteria Chronic Ankle Pain. J Am Coll Radiol. 2018 May;15 5S S26 S38. Open 3. Robroy L Martin, Ruth Chimenti, Tyler Cuddeford et al. Achilles Pain, Stiffness, and Muscle Power Deficits: Midportion Achilles Tendinopathy Revision 2018. J Orthop Sports Phys Ther. 2018 May;48 5 A1 A38. Open https://web.pathway.md/diseases/reczZeUKisuY7l3bF 6/7 6/23/23, 1:27 AM Achilles tendinopathy Pathway 4. Finn Johannsen, Jens Lykkegaard Olesen, Tommy Frisgaard hlenschl ger et al. Effect of Ultrasonography-Guided Corticosteroid Injection vs Placebo Added to Exercise Therapy for Achilles Tendinopathy: A Randomized Clinical Trial. JAMA Netw Open. 2022 Jul 1;5 7):e2219661. Open https://web.pathway.md/diseases/reczZeUKisuY7l3bF 7/7

Guideline sources The following summarized guidelines for the evaluation and management of acne vulgaris are prepared by our editorial team based on guidelines from the British Photodermatology Group (BPG/BAD 2019), the Global Alliance to Improve Outcomes in Acne (GAIOA 2018), the French Working Group on Acne (FWG-A 2017), the American Academy of Dermatology (AAD 2016), the European Dermatology Forum (EDF 2016), the Canadian Working Group on Acne (CWG-A 2016), and the American Acne and Rosacea Society (AARS 2013). 1 2 3 4 5 6 7 Guidelines 1. Diagnostic investigations Microbiological testing: Consider microbiological testing in patients who exhibit acne-like lesions suggestive of Gram- negative folliculitis. C Do not routinely obtain microbiological testing in the evaluation and management of patients with acne. D Endocrinological testing: Obtain laboratory evaluation for patients who have acne and additional signs of androgen excess. B https://web.pathway.md/diseases/rec9pxWO3pKKNJQ7A 1/5 6/23/23, 1:35 AM Acne vulgaris Pathway Do not routinely obtain endocrinological evaluation (such as for androgen excess) for the majority of patients with acne. D 2. Medical management Topical therapies: As per AAD 2016 guidelines, offer benzoyl peroxide as monotherapy for mild acne, or in conjunction with a topical retinoid, or systemic antibiotic therapy for moderate-to-severe acne. B Show 8 more As per CWG-A 2016 guidelines, offer the following options in patients with comedonal acne: topical retinoids benzoyl peroxide fixed-dose combinations of adapalene-benzoyl peroxide and clindamycin-benzoyl peroxide. B Show 3 more As per EDF 2016 guidelines, consider offering topical retinoids C , benzoyl peroxide, or azelaic acid in patients with comedonal acne. C Show 10 more Systemic antibiotics: As per AAD 2016 guidelines, offer systemic antibiotics for the management of moderate and severe acne and forms of inflammatory acne that are resistant to topical treatments. B Show 5 more As per CWG-A 2016 guidelines: Add systemic antibiotics to the topical therapy in patients with more extensive moderate papulopustular acne. B Offer systemic antibiotics in combination with benzoyl peroxide, with or without topical retinoids, in patients with severe acne. B As per EDF 2016 guidelines, do not use systemic antibiotics in patients with comedonal or mild- to-moderate papulopustular acne. D Show 10 more Systemic retinoids: As per AAD 2016 guidelines, offer oral isotretinoin for the treatment of patients with severe nodular acne. B Show 7 more As per CWG-A 2016 guidelines, offer oral isotretinoin in patients with severe acne. A As per EDF 2016 guidelines, do not use systemic isotretinoin in patients with comedonal or mild-to-moderate papulopustular acne. D Show 2 more https://web.pathway.md/diseases/rec9pxWO3pKKNJQ7A 2/5 6/23/23, 1:35 AM Acne vulgaris Pathway Hormonal agents: As per AAD 2016 guidelines, offer estrogen-containing combined oral contraceptives for the treatment of inflammatory acne in female patients. A Show 3 more Updated evidence: SAFA In adult women with facial acne for at least 6 months, judged to warrant oral antibiotics, spironolactone was superior to placebo with respect to improvement in Acne-Specific Quality of Life symptom subscale score at week 12. Miriam Santer et al. BMJ. 2023 May 16. As per CWG-A 2016 guidelines: Consider offering combined oral contraceptives in female patients with comedonal acne. C Add combined oral contraceptives to the topical therapy in female patients with more extensive moderate papulopustular acne. B As per EDF 2016 guidelines, do not use anti-androgens in patients with comedonal or mild-to- moderate papulopustular acne. D Show 4 more Oral zinc: consider offering oral zinc in patients with mild-to-moderate papulopustular acne. C Show 2 more Chemical peels: insufficient evidence to support the use and of glycolic and salicylic acid peels in patients with acne. I 3. Nonpharmacologic interventions Dietary modifications: As per FWG-A 2017 guidelines, do not offer any dietary restrictions to attenuate acne. D As per AAD 2016 guidelines, insufficient evidence to support specific dietary changes in the management of patients with acne. I Show 2 more Alternative and complementary therapies: insufficient evidence to support herbal and alternative therapies for the treatment of patients with acne. I 4. Therapeutic procedures Intralesional corticosteroid injections: consider performing intralesional corticosteroid injections for the treatment of individual acne nodules. C Laser and light therapy: https://web.pathway.md/diseases/rec9pxWO3pKKNJQ7A 3/5 6/23/23, 1:35 AM Acne vulgaris Pathway As per BAD 2019 guidelines, consider offering photodynamic therapy as a treatment option in patients with acne, if standard treatments are ineffective or contraindicated. C As per AAD 2016 guidelines, insufficient evidence to recommend physical modalities, including pulsed dye laser, for the routine treatment of patients with acne. I As per EDF 2016 guidelines, insufficient evidence to recommend for or against laser, intense pulsed light or photodynamic therapy in patients with comedonal, papulopustular, nodular or conglobate acne. I Show 7 more 5. Patient education General counseling: Counsel patients with acne regarding the following in order to improve adherence: treatment (except isotretinoin) is not curative treatment efficacy is not immediate, regular application and/or intake over several weeks is needed to obtain lesion improvement maintenance therapy is mandatory once remission has been obtained by the induction regimen local irritation frequently induced by topical treatments can be prevented by starting with application on alternating days and using moisturizers. B Show 2 more References 1. Zaenglein AL, Pathy AL, Schlosser BJ et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016 May;74 5 945 73.e33. Open 2. Lawrence F Eichenfield, Andrew C Krakowski, Caroline Piggott et al. Evidence-based recommendations for the diagnosis and treatment of pediatric acne. Pediatrics. 2013 May;131 Suppl 3 S163 86. Open 3. Diane M Thiboutot, Brigitte Dr no, Abdullah Abanmi et al. Practical management of acne for clinicians: An international consensus from the Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol. 2018 Feb;78 2 Suppl 1 S1 S23.e1. Open 4. A Nast, B Dr no, V Bettoli et al. European evidence-based S3 guideline for the treatment of acne - update 2016 short version. J Eur Acad Dermatol Venereol. 2016 Aug;30 8 1261 8. Open 5. Yuka Asai, Akerke Baibergenova, Maha Dutil et al. Management of acne: Canadian clinical practice guideline. CMAJ. 2016 Feb 2;188 2 118 126. Open 6. L Le Cleach, B Lebrun-Vignes, A Bachelot et al. Guidelines for the management of acne: recommendations from a French multidisciplinary group. Br J Dermatol. 2017 Oct;177 4 908 913. Open 7. T H Wong, C A Morton, N Collier et al. British Association of Dermatologists and British Photodermatology Group guidelines for topical photodynamic therapy 2018. Br J Dermatol. 2019 Apr;180 4 730 739. Open https://web.pathway.md/diseases/rec9pxWO3pKKNJQ7A 4/5 6/23/23, 1:35 AM Acne vulgaris Pathway 8. American Academy of Dermatology. Choosing Wisely AAD recommendations. Choosing Wisely. 2015. Open 9. Hywel C Williams, Robert P Dellavalle, Sarah Garner. Acne vulgaris. Lancet. 2012 Jan 28;379 9813 361 72. Open 10. Siri Knutsen-Larson, Annelise L Dawson, Cory A Dunnick et al. Acne vulgaris: pathogenesis, treatment, and needs assessment. Dermatol Clin. 2012 Jan;30 1 99 106, viii-ix. Open 11. Yuka Asai, Akerke Baibergenova, Maha Dutil et al. Management of acne: Canadian clinical practice guideline. CMAJ. 2016 Feb 2;188 2 118 126. Open 12. J K L Tan, K Bhate. A global perspective on the epidemiology of acne. Br J Dermatol. 2015 Jul;172 Suppl 1 3 12. Open 13. Anna Hwee Sing Heng, Fook Tim Chew. Systematic review of the epidemiology of acne vulgaris. Sci Rep. 2020 Apr 1;10 1 5754. Open 14. Nevena Skroza, Ersilia Tolino, Alessandra Mambrin et al. Adult Acne Versus Adolescent Acne: A Retrospective Study of 1,167 Patients. J Clin Aesthet Dermatol. 2018 Jan;11 1 21 25. Open 15. A C Perkins, C E Cheng, G G Hillebrand et al. Comparison of the epidemiology of acne vulgaris among Caucasian, Asian, Continental Indian and African American women. J Eur Acad Dermatol Venereol. 2011 Sep;25 9 1054 60. Open 16. A U Tan, B J Schlosser, A S Paller. A review of diagnosis and treatment of acne in adult female patients. Int J Womens Dermatol. 2017 Dec 23;4 2 56 71. Open 17. Miriam Santer, Megan Lawrence, Susanne Renz et al. Effectiveness of spironolactone for women with acne vulgaris SAFA in England and Wales: pragmatic, multicentre, phase 3, double blind, randomised controlled trial. BMJ. 2023 May 16;381:e074349. Open https://web.pathway.md/diseases/rec9pxWO3pKKNJQ7A 5/5

Guideline sources The following summarized guidelines for the evaluation and management of acromegaly are prepared by our editorial team based on guidelines from the European Society of Endocrinology (ESE 2021), the Pituitary Society (PS 2021), the Endocrine Society (ES 2020; 2014), the Acromegaly Consensus Conference (ACC 2018), and the European Thyroid Association (ETA 2018). 1 2 3 4 5 6 7 8 9 9 Definition Acromegaly is a chronic, debilitating disease caused by chronic GH hypersecretion, which results in chronic medical comorbidities, poor quality of life and high mortality rates. 7 Epidemiology Acromegaly is caused by excess GH from a pituitary adenoma (90%). 8 Disease course Chronic excess of GH and insulin-like growth factor 1 results in acromegaly, which causes clinical manifestations of soft-tissue overgrowth, bone and joint disease, impaired glucose tolerance and https://web.pathway.md/diseases/recMfZl2zvw4mzEbH 1/8 6/23/23, 1:35 AM Acromegaly Pathway diabetes, hypertension and cardiovascular complications, gonadal dysfunction, sleep apnea, impaired respiratory function, and colonic neoplasms. 9 Prognosis and risk of recurrence The mortality rate in untreated acromegaly is two to three times higher than that for the general population. 9 Pathway Acromegaly Perioperative management Guidelines 1. Classification and risk stratification Prognostic factors: Use biochemical control as the strongest predictor of patient outcomes, reflecting improvements in glucose metabolism, obstructive sleep apnea, CVD, and vertebral fractures, recognizing that structural heart and joint changes are unlikely to resolve. B Do not use patient age as a predictor of surgical outcomes, recognizing that it does not impact the favorable effects of postsurgical remission on alleviating disease comorbidities. D 2. Diagnostic investigations Insulin-like growth factor-1: obtain IGF-1 level measurement to rule out acromegaly in patients with a pituitary mass. B Show 2 more Growth hormone: Obtain an oral glucose load test to confirm the diagnosis of acromegaly (by finding a lack of suppression of GH to < 1 g/L following documented hyperglycemia) in patients with elevated or equivocal serum IGF-1 levels. B Do not rely on random GH levels to diagnose acromegaly. D Brain imaging: Obtain diagnostic imaging to assess for the presence of a pituitary tumor in patients with biochemical evidence of acromegaly. A Consider obtaining MRI as the imaging modality of choice. Consider obtaining CT if MRI is contraindicated or unavailable. C https://web.pathway.md/diseases/recMfZl2zvw4mzEbH 2/8 6/23/23, 1:35 AM Acromegaly Pathway Visual field testing: consider obtaining formal visual field testing if the pituitary tumor abuts the optic chiasm identified on imaging. C Evaluation of thyroid abnormalities: As per ETA 2018 guidelines, obtain screening for central hypothyroidism in patients with acromegaly and hypothyroid manifestations. A As per ES 2014 guidelines, consider obtaining a thyroid ultrasound if there is palpable thyroid nodularity. C Screening for vertebral fractures: screen for vertebral fractures with the morphometric approach at diagnosis and annually thereafter. A Screening for comorbidities: As per ES 2020 guidelines, consider obtaining a usual lipid profile before and after treatment of GH excess in adult patients with acromegaly. C As per ACC 2018 guidelines: Evaluate for acromegaly-associated comorbidities, such as hypertension, cardiac hypertrophy, diabetes mellitus, glucose intolerance, sleep apnea, and osteopathy, in all patients with acromegaly. A Use screening questionnaires for obstructive sleep apnea and obtain sleep studies to confirm the diagnosis. A As per PS 2014 guidelines, consider obtaining evaluation for associated comorbidities, including hypertension, diabetes mellitus, CVD, OA, and sleep apnea, in all patients presenting with acromegaly. C Screening for cancer: As per PS 2021 guidelines, obtain appropriate evaluations after screening colonoscopy at diagnosis similar to the general population. B As per ACC 2018 guidelines, obtain screening for cancer as recommended for the general population. B As per PS 2014 guidelines, consider obtaining screening for colon neoplasia with colonoscopy at diagnosis of acromegaly. C 3. Medical management Setting of care: manage patients with acromegaly at pituitary tumor centers of excellence to ensure the best and most cost-effective care. A Indications for medical therapy: As per ACC 2018 guidelines, initiate medical therapy in patients with persistent disease after surgical resection of the adenoma or if surgery is not appropriate. A Show 2 more https://web.pathway.md/diseases/recMfZl2zvw4mzEbH 3/8 6/23/23, 1:35 AM Acromegaly Pathway As per ES 2014 guidelines, initiate medical therapy in patients with persistent disease following surgery. A Therapeutic targets: As per ACC 2018 guidelines, monitor biochemical control by measuring GH and IGF-1 levels. A Show 3 more As per PS 2014 guidelines, consider targeting a normal age-adjusted serum IGF-1 level. C Show 2 more Somatostatin receptor ligands: As per PS 2021 guidelines, initiate oral octreotide capsules in patients demonstrated complete or partial biochemical response to injectable octreotide or lanreotide. A Insufficient evidence to recommend oral octreotide capsules in patients with tumor characteristics predictive of octreotide resistance. B Show 5 more As per ACC 2018 guidelines, consider initiating primary medical therapy with a first-generation long-acting somatostatin receptor ligand if surgery is contraindicated or if a poor likelihood of success is expected owing to patient-specific and/or tumor-specific factors. C Show 3 more As per ES 2014 guidelines, consider initiating somatostatin receptor ligands as primary therapy in patients ineligible for surgery (unable to be cured or poor surgical candidates), having extensive cavernous sinus invasion, or not having chiasmal compression. C Growth hormone receptor antagonists: As per PS 2021 guidelines, initiate pegvisomant at higher doses and undertake more rapid up- titration to achieve IGF-1 normalization in patients with diabetes mellitus or a higher BMI. Recognize that pegvisomant improves glucose metabolism in patients with diabetes mellitus independent of IGF-1 control, but does not affect glycemic endpoints in patients without diabetes mellitus. B As per ACC 2018 guidelines, consider initiating pegvisomant (at doses of 10-30 mg/day, increased to the recommended highest dose as needed) as an alternative option in patients with impaired glucose metabolism and/or experiencing worsening hyperglycemia on somatostatin receptor ligand therapy. C Show 2 more As per ES 2014 guidelines: Consider initiating either a somatostatin receptor ligand or pegvisomant as initial adjuvant medical therapy in patients with moderate-to-severe signs and symptoms of GH excess without local mass effects. C Consider adding pegvisomant in patients with inadequate response to somatostatin receptor ligands. C Combination therapy: initiate low-dose octreotide long-acting release or lanreotide with weekly pegvisomant in patients requiring combination therapy. A https://web.pathway.md/diseases/recMfZl2zvw4mzEbH 4/8 6/23/23, 1:35 AM Acromegaly Pathway Show 2 more Dopamine agonists: As per ACC 2018 guidelines: Consider initiating cabergoline as first-line medical therapy in patients with acromegaly and mildly elevated IGF-1 levels (< 2.5 the ULN). C Consider initiating cabergoline as an alternative option in patients with impaired glucose metabolism and/or experiencing worsening hyperglycemia on somatostatin receptor ligand therapy. C As per ES 2014 guidelines: Consider initiating a trial of a dopamine agonist, usually cabergoline, as initial adjuvant medical therapy in patients with only modest elevations of serum IGF-1 and mild signs and symptoms of GH excess. C Consider adding cabergoline to somatostatin receptor ligand therapy in patients with moderate-to-severe signs and symptoms of GH excess without local mass effects exhibiting inadequate response to somatostatin receptor ligands. C Temozolomide: initiate temozolomide only in patients with unusually aggressive or proven malignant pituitary tumors. Ensure close cooperation with a neuro-oncologist for such treatment. B Pituitary hormone replacement: assess patients with acromegaly for hypopituitarism and replace hormone deficits. B Management of comorbidities: manage disease-associated comorbidities, specifically hypertension, cardiac hypertrophy, glucose intolerance, diabetes mellitus, sleep apnea, and osteopathy. A Show 3 more 4. Therapeutic procedures Radiotherapy: consider offering radiotherapy in patients with residual tumor mass following surgery, or if medical therapy is unavailable, unsuccessful, or not tolerated. C Show 3 more 5. Perioperative care Preoperative somatostatin receptor ligands: As per ACC 2018 guidelines, avoid administering somatostatin receptor ligands preoperatively to reduce the tumor size and improve surgical cure rates in patients with macroadenomas. D As per ES 2014 guidelines: Avoid administering routine preoperative medical therapy to improve biochemical control after surgery. D https://web.pathway.md/diseases/recMfZl2zvw4mzEbH 5/8 6/23/23, 1:35 AM Acromegaly Pathway Consider administering preoperative somatostatin receptor ligands to reduce surgical risk from severe comorbidities in patients with severe pharyngeal thickness and sleep apnea, or high- output HF. C 6. Surgical interventions Surgical resection: As per ACC 2018 guidelines, perform surgical resection of the pituitary adenoma, where possible, by an experienced neurosurgeon as the primary treatment for acromegaly. A As per PS 2014 guidelines: Perform transsphenoidal surgery as the primary treatment in most patients with acromegaly. B Consider performing repeat surgery in patients with residual intrasellar disease following initial surgery. C Surgical debulking: consider performing surgical debulking to improve subsequent response to medical therapy in patients with parasellar disease making total surgical resection unlikely. C 7. Specific circumstances Pregnant patients, preconception care: As per ESE 2021 guidelines, manage female patients of reproductive age contemplating pregnancy with a diagnosis of pituitary adenoma, functioning or nonfunctioning, by an endocrinologist. B Show 7 more As per ES 2014 guidelines, consider discontinuing long-acting somatostatin receptor ligands formulations and pegvisomant approximately 2 months before attempting to conceive, with the use of short-acting octreotide as necessary until conception. C Pregnant patients (evaluation): Obtain MRI without contrast during pregnancy in case of symptoms of tumor progression or apoplexy. B Obtain neuro-ophthalmologic evaluation during pregnancy for adenomas impinging visual pathways or in case of suspected tumor progression or pituitary apoplexy. B Pregnant patients, management: As per ESE 2021 guidelines, consider discontinuing drugs for acromegaly once pregnancy is established. B Show 3 more As per ES 2014 guidelines, discontinue medical therapy for acromegaly during pregnancy. Initiate or re-initiate treatment only for tumor and headache control. B Pregnant patients, monitoring: https://web.pathway.md/diseases/recMfZl2zvw4mzEbH 6/8 6/23/23, 1:35 AM Acromegaly Pathway As per ESE 2021 guidelines, monitor pregnant patients with a known pituitary adenoma, particularly in large sizes (> 1 cm) and with acromegaly, by an endocrinologist and an advanced nurse practitioner where relevant. Decide on the frequency based on the underlying condition and individualized needs. B Show 2 more As per ES 2014 guidelines: Consider obtaining serial visual field testing during pregnancy in patients with macroadenomas. C Avoid obtaining monitoring GH and/or IGF-1 levels during pregnancy. D Pregnant patients (delivery and breastfeeding): consider providing standard obstetrical care with close maternal and fetal surveillance in pregnant patients with pituitary adenomas. C Show 3 more Patients with gigantism: follow the standard approaches to normalizing GH and IGF-1 hypersecretion in patients with the rare presentation of gigantism. B 8. Follow-up and surveillance Serial laboratory assessment, after surgery: As per PS 2021 guidelines, consider obtaining IGF-1 level measurement 6 weeks after surgery to assess remission in most patients with acromegaly, recognizing that patients with mildly elevated IGF-1 may yet normalize by 3-6 months. B As per ES 2014 guidelines, obtain IGF-1 and a random GH level measurement at 12 weeks or later following surgery. B Show 2 more Serial laboratory assessment (after radiotherapy): Obtain annual GH/IGF-1 reassessment following medication withdrawal to monitor the efficacy of radiotherapy. B Obtain annual hormonal testing following radiotherapy to monitor for hypopituitarism and other delayed radiation effects. A Serial imaging assessment (after surgery): obtain imaging at least 12 weeks after surgery to visualize the residual tumor and adjacent structures. B Consider obtaining MRI as the imaging modality of choice. Obtain CT if MRI is contraindicated or unavailable. B Serial imaging assessment, on medical therapy: As per ACC 2018 guidelines, obtain ongoing imaging surveillance in patients with notable residual tumor treated with pegvisomant. A As per ES 2014 guidelines: Consider obtaining serial MRI to evaluate tumor size in patients receiving pegvisomant. C Avoid obtaining routine abdominal ultrasound to monitor for gallstone disease in patients receiving somatostatin receptor ligands. Obtain an ultrasound in patients with signs and https://web.pathway.md/diseases/recMfZl2zvw4mzEbH 7/8 6/23/23, 1:35 AM Acromegaly Pathway symptoms of gallstone disease. D Management of postoperative residual disease (repeat surgery): consider performing repeat surgery in patients with residual intrasellar disease following initial surgery. C Management of postoperative residual disease (radiotherapy): Consider offering radiotherapy in patients with residual tumor mass following surgery, or if medical therapy is unavailable, unsuccessful, or not tolerated. C Consider offering stereotactic radiotherapy over conventional radiotherapy in patients with acromegaly unless the technique is not available, there is significant residual tumor burden, or the tumor is too close to the optic chiasm resulting in exposure of > 8 Gy. C Management of incomplete treatment response: initiate additional therapies if first-line medical therapy is not successful in normalizing levels of IGF-1. A Show 7 more References 1. Katznelson L, Laws ER Jr, Melmed S et al. Acromegaly: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014 Nov;99 11 3933 51. Open 2. Melmed S, Bronstein MD, Chanson P et al. A Consensus Statement on acromegaly therapeutic outcomes. Nat Rev Endocrinol. 2018 Sep;14 9 552 561. Open 3. Connie B Newman, Michael J Blaha, Jeffrey B Boord et al. Lipid Management in Patients with Endocrine Disorders: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2020 Dec 1;105 12):dgaa674. Open 4. Persani L, Brabant G, Dattani M et al. 2018 European Thyroid Association ETA Guidelines on the Diagnosis and Management of Central Hypothyroidism. Eur Thyroid J. 2018 Oct;7 5 225 237. Open 5. A Luger, L H A Broersen, N R Biermasz et al. ESE Clinical Practice Guideline on functioning and nonfunctioning pituitary adenomas in pregnancy. Eur J Endocrinol. 2021 Aug 23;185 3 G1 G33. Open 6. Maria Fleseriu Beverly M. K. Biller Pamela U. Freda Monica R. Gadelha Andrea Giustina Laurence Katznelson Mark E. Molitch Susan L. Samson Christian J. Strasburger A. J. van der Lely Shlomo Melmed. A Pituitary Society update to acromegaly management guidelines. Pituitary. 2021; 24 1 1 13. Open 7. Zachary M Bush, Mary Lee Vance. Management of acromegaly: is there a role for primary medical therapy?. 2008 Mar;9 1 83 94.2008 Mar;9 1 83 94. Open 8. Annamaria Colao, Renata S Auriemma, Rosario Pivonello. The effects of somatostatin analogue therapy on pituitary tumor volume in patients with acromegaly. 2016 Apr;19 2 210 21.2016 Apr;19 2 210 21. Open 9. Daphne T Adelman, Karen Jp Liebert, Lisa B Nachtigall et al. Acromegaly: the disease, its impact on patients, and managing the burden of long-term treatment. 2013;6 31 8.2013;6 31 8. Open 10. A Luger, L H A Broersen, N R Biermasz et al. ESE Clinical Practice Guideline on functioning and nonfunctioning pituitary adenomas in pregnancy. Eur J Endocrinol. 2021 Aug 23;185 3 G1 G33. Open https://web.pathway.md/diseases/recMfZl2zvw4mzEbH 8/8

Guideline sources The following summarized guidelines for the management of actinic keratosis are prepared by our editorial team based on guidelines from the American Academy of Dermatology (AAD 2021). 1 Guidelines 1. Medical management Topical agents: Offer field treatment with 5-fluorouracil or imiquimod for the management of patients with actinic keratosis. B Consider offering topical diclofenac for the management patients with actinic keratosis. C Combination therapy: offer a combination of 5-fluorouracil and cryosurgery for the management of patients with actinic keratosis. B Show 3 more 2. Therapeutic procedures Cryosurgery: Perform cryosurgery for the management of patients with actinic keratosis. E https://web.pathway.md/diseases/recWO47IRjA4MO0mi 1/2 6/23/23, 1:35 AM Actinic keratosis Pathway Consider performing cryosurgery rather than CO laser ablation for the management of patients with actinic keratosis. C Photodynamic therapy: Consider performing photodynamic therapy for the management of patients with actinic keratosis using: ALA-red light C ALA-blue light C aminolevulinic-daylight - it is less painful than but equally effective as ALA-red light. C Show 3 more 3. Preventative measures Ultraviolet protection: advise using UV protection in patients with actinic keratosis. E References 1. Daniel B Eisen, Maryam M Asgari, Daniel D Bennett et al. Guidelines of care for the management of actinic keratosis. J Am Acad Dermatol. 2021 Apr 2;S0190 9622 21 00502 8. Open 2. C A Morton, R M Szeimies, N Basset-Seguin et al. European Dermatology Forum guidelines on topical photodynamic therapy 2019 Part 1 treatment delivery and established indications - actinic keratoses, Bowen's disease and basal cell carcinomas. J Eur Acad Dermatol Venereol. 2019 Dec;33 12 2225 2238. Open https://web.pathway.md/diseases/recWO47IRjA4MO0mi 2/2

Guideline sources The following summarized guidelines for the management of acute altitude sickness are prepared by our editorial team based on guidelines from the Wilderness Medical Society (WMS 2019). 1 Guidelines 1. Respiratory support Supplemental oxygen: Consider administering ongoing supplemental oxygen, if available, sufficient to raise SpO to > 90% or to relieve symptoms while waiting to initiate descent or when descent is not practical. B Administer supplemental oxygen sufficient to achieve SpO of > 90% or to relieve symptoms while waiting to initiate descent when descent is infeasible and during descent in severely ill patients with high altitude pulmonary edema. A Positive airway pressure: Insufficient evidence to support the use of CPAP for the treatment of patients with acute mountain sickness. Consider administering CPAP or EPAP for the treatment of patients with high altitude pulmonary edema when supplemental oxygen or pulmonary vasodilators are not available or as adjunctive therapy in patients not responding to supplemental oxygen alone. C Hyperbaric oxygen therapy: https://web.pathway.md/diseases/rec1cXRcFXHv2p0dW 1/4 6/23/23, 1:40 AM Acute altitude sickness Pathway Use portable hyperbaric chambers, if available, in patients with severe acute mountain sickness or high altitude cerebral edema when descent is infeasible or delayed and supplemental oxygen is unavailable. B Consider using portable hyperbaric chambers in patients with high altitude pulmonary edema when descent is infeasible or delayed or supplemental oxygen is unavailable. B 2. Medical management Acetazolamide: Consider administering acetazolamide for the treatment of patients with acute mountain sickness. B Do not use diuretics or acetazolamide for the treatment of patients with high altitude pulmonary edema. D Dexamethasone: consider administering dexamethasone for the treatment of patients with acute mountain sickness. B Show 2 more Nifedipine: administer nifedipine for the treatment of patients with high altitude pulmonary edema when descent is impossible or delayed and reliable access to supplemental oxygen or portable hyperbaric therapy is unavailable. B Phosphodiesterase inhibitors: consider administering tadalafil or sildenafil for the treatment of patients with high altitude pulmonary edema when descent is impossible or delayed, access to supplemental oxygen or portable hyperbaric therapy is impossible, and nifedipine is unavailable. C Beta-agonists: insufficient evidence to support the use of -agonists for the treatment of patients with high altitude pulmonary edema. I Analgesics: consider offering acetaminophen or ibuprofen for the treatment of headache at high altitude. B 3. Nonpharmacologic interventions Descent: Advise descent in patients with: acute mountain sickness failed to resolve with other measures, or severe acute mountain sickness high altitude cerebral edema high altitude pulmonary edema. A 4. Preventative measures https://web.pathway.md/diseases/rec1cXRcFXHv2p0dW 2/4 6/23/23, 1:40 AM Acute altitude sickness Pathway Gradual ascent: Advise gradual ascent, defined as a slow increase in sleeping elevation, for the prevention of: acute mountain sickness high altitude cerebral edema high altitude pulmonary edema. B Pre-acclimatization: Consider advising staged ascent and prea-aclimatization, when feasible, for the prevention of: acute mountain sickness prevention high altitude pulmonary edema. B Consider offering hypoxic tents to facilitate acclimatization and prevent acute mountain sickness if sufficiently long exposures can be undertaken regularly over an appropriate number of weeks and other factors, such as sleep quality, are not compromised. C Chemoprophylaxis (acetazolamide): consider offering acetazolamide in travelers at moderate or high risk of acute mountain sickness with ascent to high altitude. B Show 3 more Chemoprophylaxis (corticosteroids): consider offering dexamethasone as an alternative to acetazolamide in adult travelers at moderate to high risk of acute mountain sickness. B Show 2 more Chemoprophylaxis (nifedipine): offer nifedipine for the prevention of high altitude pulmonary edema in high altitude pulmonary edema susceptible persons. B Chemoprophylaxis (tadalafil): consider offering tadalafil for the prevention of high altitude pulmonary edema in known susceptible persons not being candidates for nifedipine. B Chemoprophylaxis (salmeterol): do not use salmeterol for the prevention of high altitude pulmonary edema. D Chemoprophylaxis (analgesics): Consider offering ibuprofen for the prevention of acute mountain sickness in persons not wishing to take acetazolamide or dexamethasone or having allergies or intolerance to these medications. C Do not use acetaminophen for the prevention of acute mountain sickness. D Chemoprophylaxis (ginkgo biloba): do not use ginkgo biloba for the prevention of acute mountain sickness. D References 1. Andrew M Luks, Paul S Auerbach, Luanne Freer et al. Wilderness Medical Society Clinical Practice Guidelines for the Prevention and Treatment of Acute Altitude Illness: 2019 Update. Wilderness Environ Med. 2019 Dec;30 4S S3 S18. Open https://web.pathway.md/diseases/rec1cXRcFXHv2p0dW 3/4 6/23/23, 1:40 AM Acute altitude sickness Pathway 2. Luks AM, McIntosh SE, Grissom CK et al. Medical Society Practice Guidelines for the Prevention and Treatment of Acute Altitude Illness: 2019 Update. Wilderness Environ Med. 2010 Jun;21 2 146 55. Open 3. Robert C Roach, Peter H Hackett, Oswald Oelz et al. The 2018 Lake Louise Acute Mountain Sickness Score. High Alt Med Biol. 2018 Mar;19 1 4 6. Open 4. M Yaron, N Waldman, S Niermeyer et al. The diagnosis of acute mountain sickness in preverbal children. Arch Pediatr Adolesc Med. 1998 Jul;152 7 683 7. Open https://web.pathway.md/diseases/rec1cXRcFXHv2p0dW 4/4

Guideline sources The following summarized guidelines for the evaluation and management of acute appendicitis are prepared by our editorial team based on guidelines from the American College of Radiology (ACR 2022), the Pathway (Pathway 2020), the World Society of Emergency Surgery (WSES 2020), the Eastern Association for the Surgery of Trauma (EAST 2019), the American Association of Family Physicians (AAFP 2018), the European Association for Endoscopic Surgery (EAES 2016), and the American College of Surgeons (ACS 2013). 1 2 3 4 5 6 7 8 9 10 11 11 12 Definition Acute appendicitis is a disease resulting from acute inflammation of the vermiform appendix. 8 Epidemiology Acute appendicitis is initiated by a process that causes obstruction of the appendiceal lumen, such as fecaliths, lymphoid hyperplasia, parasites, Crohn's disease, foreign bodies, or neoplasms. 10 Pathophysiology https://web.pathway.md/diseases/recFwDBzssIJqaRqC 1/10 6/23/23, 1:36 AM Acute appendicitis Pathway The incidence of acute appendicitis is estimated at 110 per 100,000 person-years in the United States, with a male predominance. 9 Disease course Progressive luminal obstruction is associated with inflammation and distension of the appendix, leading to suppurative transmural inflammation, ischemia, infarction, and perforation. Perforated appendicitis progresses to generalized peritonitis and intra-abdominal abscess formation. 11 Prognosis and risk of recurrence The mortality rate associated with non-perforated appendicitis is 0.8 per 1,000 individuals, whereas, for perforated appendicitis, it increases to 5.1 per 1000 individuals. The risk of recurrent appendicitis post interval appendicectomy is about 20% within a year. Recurrent appendicitis may also occur in the setting of previous appendicectomy in patients with a long appendiceal stump. 11 12 Calculator Calculator Calculator Acetaminophen dosing calculator Adult Appendicitis score AAS Alvarado s Guidelines 1. Classification and risk stratification Risk stratification: As per WSES 2020 guidelines, adopt a tailored individualized diagnostic approach for stratifying the risk and disease probability and planning an appropriate stepwise diagnostic pathway in patients with suspected acute appendicitis, depending on age, sex, and clinical signs and symptoms of the patient. B Show 4 more As per AAFP 2018 guidelines, consider using the Alvarado score with point-of-care or formal ultrasound and laboratory testing to assist in diagnosing acute appendicitis and reduce the use of CT. C As per EAES 2016 guidelines, use the Alvarado score to determine the likelihood of appendicitis. A 2. Diagnostic investigations Abdominal ultrasound: https://web.pathway.md/diseases/recFwDBzssIJqaRqC 2/10 6/23/23, 1:36 AM Acute appendicitis Pathway As per WSES 2020 guidelines, obtain diagnostic imaging in patients with suspected appendicitis after an initial assessment and risk stratification using clinical scores. B Show 3 more As per AAFP 2018 guidelines, obtain an abdominal ultrasound as first-line imaging in patients with suspected acute appendicitis when skilled sonographers are available, especially in children and pregnant women. B As per EAES 2016 guidelines, obtain an abdominal ultrasound in patients with suspected appendicitis. A Computed tomography and magnetic resonance imaging: As per ACR 2022 guidelines, obtain CT of the abdomen and pelvis with IV contrast for the initial imaging of RLQ pain, including in the presence of fever, leukocytosis, and suspected appendicitis. B As per WSES 2020 guidelines, obtain cross-sectional imaging before surgery in patients with normal investigations but non-resolving right iliac fossa pain. A Show 2 more As per EAES 2016 guidelines, consider second-line imaging studies (either CT or MRI; MRI preferred in children or pregnant patients) in patients in whom the diagnosis of appendicitis remains in question after ultrasound. C As per ACS 2013 guidelines, avoid obtaining CT for evaluation of suspected appendicitis in children until after ultrasound has been considered as an option. D 3. Diagnostic procedures Explorative laparoscopy: Perform explorative laparoscopy in patients with negative imaging but progressive or persistent pain to establish/exclude the diagnosis of acute appendicitis or alternative diagnoses. A Avoid obtaining cross-sectional imaging (CT) in < 40 years old high-risk patients with AIR score 9-12, Alvarado score 9-10 and AAS 16 before proceeding to diagnostic and/or therapeutic laparoscopy. D Histopathology: As per WSES 2020 guidelines, perform routine histopathology after appendectomy. B As per EAES 2016 guidelines, obtain histopathological analysis of all resected appendices. B 4. Medical management Non-operative management: As per WSES 2020 guidelines, consider offering nonoperative management with antibiotics as a safe alternative to surgery in selected patients with uncomplicated acute appendicitis and https://web.pathway.md/diseases/recFwDBzssIJqaRqC 3/10 6/23/23, 1:36 AM Acute appendicitis Pathway absence of appendicolith, recognizing the possibility of failure and misdiagnosing complicated appendicitis. B Show 6 more Landmark trials: CODA In adult patients with appendicitis, antibiotics were noninferior to appendectomy with respect to mean improvement in health status at day 30 as measured by the european quality of life- 5 dimension questionnaire score. CODA Collaborative et al. N Engl J Med. 2020 Nov 12. As per EAST 2019 guidelines: Insufficient evidence to recommend for or against antibiotics-first therapy versus surgery in patients with acute uncomplicated appendicitis. Avoid performing routine interval appendectomy following initial nonoperative management in patients with appendiceal abscess or phlegmon. D As per AAFP 2018 guidelines, consider nonoperative management with intravenous antibiotics as first-line therapy for children and adults with acute appendicitis. B Landmark trials: APPAC In patients with uncomplicated appendicitis confirmed by a CT scan, antibiotic treatment was not noninferior to surgical appendectomy with respect to treatment success. Salminen P et al. JAMA. 2015 Jun 16. As per EAES 2016 guidelines, consider nonoperative treatment for patients with a contained phlegmon or abscess in the absence of diffuse peritonitis. C Show 2 more Landmark trials: APPAC In patients with uncomplicated appendicitis confirmed by a CT scan, antibiotic treatment was not noninferior to surgical appendectomy with respect to treatment success. Salminen P et al. JAMA. 2015 Jun 16. Analgesic therapy: administer analgesic therapy (acetaminophen, NSAIDs, or opioids) for pain control in patients with suspected acute appendicitis. A https://web.pathway.md/diseases/recFwDBzssIJqaRqC 4/10 6/23/23, 1:36 AM Acute appendicitis Pathway 5. Perioperative care Preoperative antibiotics: As per WSES 2020 guidelines, administer a single preoperative dose of broad spectrum antibiotics in patients with acute appendicitis undergoing appendectomy. A As per EAES 2016 guidelines, administer preoperative prophylactic antibiotics in adults undergoing appendectomy. A Intraoperative grading systems: Consider adopting an intraoperative grading system for acute appendicitis based on clinical, imaging and operative findings, such as WSES 2015 grading score (provided below) or AAST EGS grading score: Situation Guidance Normal looking appendix (endoappendicitis/periappendicitis) Grade 0 Inflamed appendix (hyperemia, edema +/- fibrin without or little pericolic fluid) Grade 1 A - segmental necrosis (without or little pericolic fluid) Grade 2 B - base necrosis (without or little pericolic fluid) A - flegmon Grade 3 B - abscess < 5 cm without peritoneal free air C - abscess > 5 cm without peritoneal free air Perforated, diffuse peritonitis with or without peritoneal free air. C Grade 4 Postoperative antibiotics: As per WSES 2020 guidelines: Do not administer postoperative antibiotics in patients with uncomplicated appendicitis. D Do not prolong antibiotics longer than 3-5 days postoperatively in patients with complicated appendicitis with adequate source-control. D Updated evidence: APPIC In patients, aged 8 years, with complex appendicitis, short 2-day course was noninferior to standard 5-day course with respect to the rate of infectious complications and death within 90 days. Elisabeth M L de Wijkerslooth et al. Lancet. 2023 Jan 17. https://web.pathway.md/diseases/recFwDBzssIJqaRqC 5/10 6/23/23, 1:36 AM Acute appendicitis Pathway As per EAES 2016 guidelines, administer postoperative antibiotics in patients with complicated appendicitis. B Postoperative nasogastric tube: avoid routine postoperative nasogastric tube placement. D Postoperative diet: consider avoiding postoperative dietary restrictions after an uncomplicated appendectomy. D 6. Surgical interventions Timing of surgery: As per WSES 2020 guidelines: Plan laparoscopic appendectomy for the next available operating list within 24 hours in patients with uncomplicated acute appendicitis, minimizing the delay wherever possible. B Do not delay appendectomy in patients with acute appendicitis requiring surgery beyond 24 hours from the admission. D As per EAES 2016 guidelines, perform surgery as soon as feasible after the diagnosis of acute appendicitis is established. B Laparoscopic appendectomy: As per WSES 2020 guidelines, prefer laparoscopic appendectomy over open appendectomy in patients with either uncomplicated or complicated acute appendicitis, if laparoscopic equipment and expertise are available. A Show 4 more As per EAES 2016 guidelines, perform laparoscopic appendectomy in adults with uncomplicated appendicitis. B Show 3 more Technical considerations for surgery: As per WSES 2020 guidelines, consider performing appendix removal if the appendix appears "normal" during surgery and no other disease is found in symptomatic patients. C Show 7 more As per EAES 2016 guidelines, perform meticulous suction of intraperitoneal fluid or collections. B Show 6 more 7. Specific circumstances Pediatric patients, diagnosis: As per WSES 2020 guidelines, avoid diagnosing acute appendicitis in pediatric patients solely based on clinical scores. D Show 5 more https://web.pathway.md/diseases/recFwDBzssIJqaRqC 6/10 6/23/23, 1:36 AM Acute appendicitis Pathway As per EAES 2016 guidelines, obtain an abdominal MRI study (rather than an abdominal CT scan) as second-line imaging in children, in order to avoid radiation. B Pediatric patients, management: As per WSES 2020 guidelines, consider offering nonoperative management with antibiotics as a safe and effective alternative to surgery in pediatric patients with uncomplicated acute appendicitis in the absence of an appendicolith, recognizing the possibility of failure and misdiagnosing complicated appendicitis. C Show 8 more As per EAES 2016 guidelines, consider performing laparoscopic appendectomy, if appendectomy is indicated, as the procedure of choice in pediatric patients with acute appendicitis. C Elderly patients: As per WSES 2020 guidelines, consider performing laparoscopic appendectomy in older patients with acute appendicitis. C As per EAES 2016 guidelines, perform laparoscopic appendectomy as the procedure of choice in patients over 65 years of age. B Pregnant patients, diagnosis: As per ACR 2022 guidelines, obtain abdominal ultrasound or MRI of the abdomen and pelvis without IV contrast for the initial imaging in pregnant patients with RLQ pain with fever, leukocytosis, and suspected appendicitis. B As per WSES 2020 guidelines, do not diagnose acute appendicitis in pregnant patients solely based on symptoms and signs, rather always obtain laboratory tests and inflammatory serum parameters (such as CRP). D Show 2 more As per EAES 2016 guidelines, obtain abdominal MRI (rather than CT) as second-line imaging (in case of diagnostic doubt) in pregnant patients, in order to avoid radiation. B Pregnant patients, management: As per WSES 2020 guidelines: Avoid offering nonoperative management in pregnant patients with acute appendicitis. D Consider preferring laparoscopic appendectomy over open appendectomy in pregnant patients, if surgery is indicated, recognizing that it is technically safe and feasible during pregnancy if expertise of laparoscopy is available. C As per EAES 2016 guidelines, consider performing laparoscopic appendectomy as the procedure of choice in pregnant patients (even in the third trimester) with acute appendicitis. C Obese patients: As per WSES 2020 guidelines, consider performing laparoscopic appendectomy in obese patients with acute appendicitis. C As per EAES 2016 guidelines, select laparoscopic appendectomy as the procedure of choice in obese patients with acute appendicitis. B https://web.pathway.md/diseases/recFwDBzssIJqaRqC 7/10 6/23/23, 1:36 AM Acute appendicitis Pathway Immunosuppressed patients: consider treating immunosuppressed patients with appendicitis following the same approach as outlined for immunocompetent patients. C Likelihood Ratios Pertinent positives The following findings increase the probability of acute appendicitis in adults. 1 1 Finding LR+ Value Increased Alvarado score ( 7) 3.1 (1.9-5.0) Presence of rebound tenderness 3.0 (2.3-3.9) Presence of rectal tenderness 2.3 (1.3-4.1) Increased WBC count (> 10,000 cells/ L) 2.0 (1.3-2.9) Show 5 more Pertinent negatives The following findings decrease the probability of acute appendicitis in adults. 1 1 Finding LR- Value WBC count not increased ( 10,000 cells/ L) 0.22 (0.17-0.30) Alvarado score not increased (< 7) 0.26 (0.19-0.35) Absence of rebound tenderness 0.28 (0.14-0.55) Absence of RLQ tenderness 0.45 (0.35-0.59) Show 6 more References 1. L Mullie. Investigation Algorithms. Pathway Editors. Open 2. Salomone Di Saverio, Mauro Podda, Belinda De Simone et al. Diagnosis and treatment of acute appendicitis: 2020 update of the WSES Jerusalem guidelines. World J Emerg Surg. 2020 Apr 15;15 1 27. Open 3. Gorter RR, Eker HH, Gorter-Stam MA et al. Diagnosis and management of acute appendicitis. EAES consensus development conference 2015. Surg Endosc. 2016 Nov;30 11 4668 4690. Open 4. Expert Panel on Gastrointestinal Imaging, Avinash R Kambadakone, Cynthia S Santillan et al. ACR Appropriateness Criteria Right Lower Quadrant Pain: 2022 Update. J Am Coll Radiol. 2022 Nov;19 11S S445 S461. Open 5. Amy Rushing, Nikolay Bugaev, Christian Jones et al. Management of acute appendicitis in adults: A practice management guideline from the Eastern Association for the Surgery of Trauma. J Trauma Acute Care Surg. 2019 Jul;87 1 214 224. Open https://web.pathway.md/diseases/recFwDBzssIJqaRqC 8/10 6/23/23, 1:36 AM Acute appendicitis Pathway 6. Snyder MJ, Guthrie M, Cagle S. Acute Appendicitis: Efficient Diagnosis and Management. Am Fam Physician. 2018 Jul 1;98 1 25 33. Open 7. American College of Surgeons. Choosing Wisely: Recommendations of the American College of Surgeons. Choosing Wisely. 2013 Sept. Open 8. Morgan AC. Unveiling appendicitis. Contemp Nurse. 2003 Aug;15 1 2 114 7. Open 9. Addiss DG, Shaffer N, Fowler BS et al. The epidemiology of appendicitis and appendectomy in the United States. Am J Epidemiol. 1990 Nov;132 5 910 25. Open 10. Hardin DM Jr. Acute appendicitis: review and update. Am Fam Physician. 1999 Nov 1;60 7 2027 34. Open 11. Stringer MD. Acute appendicitis. J Paediatr Child Health. 2017 Nov;53 11 1071 1076. Open 12. Humes DJ, Simpson J. Acute appendicitis. BMJ. 2006 Sep 9;333 7567 530 4. Open 13. Di Saverio S, Birindelli A, Kelly MD et al. WSES Jerusalem guidelines for diagnosis and treatment of acute appendicitis. World J Emerg Surg. 2016 Jul 18;11 34. Open 14. American Academy of Pediatrics. Choosing Wisely AAP recommendations. Choosing Wisely. 2019. Open 15. American College of Rheumatology. Choosing Wisely ACR recommendations. Choosing Wisely. 2017. Open 16. American College of Surgeons. Choosing Wisely ACS recommendations. Choosing Wisely. 2013. Open 17. Aneel Bhangu, Kjetil S reide, Salomone Di Saverio et al. Acute appendicitis: modern understanding of pathogenesis, diagnosis, and management. Lancet. 2015 Sep 26;386 10000 1278 1287. Open 18. Matthew J Snyder, Marjorie Guthrie, Stephen Cagle. Acute Appendicitis: Efficient Diagnosis and Management. Am Fam Physician. 2018 Jul 1;98 1 25 33. Open 19. Michel Wagner, Dustin John Tubre, Juan A Asensio. Evolution and Current Trends in the Management of Acute Appendicitis. Surg Clin North Am. 2018 Oct;98 5 1005 1023. Open 20. Manne Andersson, Roland E Andersson. The Appendicitis Inflammatory Response Score: A Tool for the Diagnosis of Acute Appendicitis that Outperforms the Alvarado Score. World J Surg 2008 Aug;32 8 1843 9. Open 21. Anand Singla, Satpaul Singla, Mohinder Singh et al. A comparison between modified Alvarado score and RIPASA score in the diagnosis of acute appendicitis. Updates Surg. 2016 Dec;68 4 351 355. Open 22. James M. Wagner, MD, W. Paul McKinney et al. Does This Patient Have Appendicitis?. JAMA. 1996;276 19 1589 1594. Open 23. C F Chong, M I W Adi, A Thien et al. Development of the RIPASA score: a new appendicitis scoring system for the diagnosis of acute appendicitis. Singapore Med J. 2010 Mar;51 3 220 5. Open 24. Sohail R Shah, Kelly A Sinclair, Stephanie B Theut et al. Computed Tomography Utilization for the Diagnosis of Acute Appendicitis in Children Decreases With a Diagnostic Algorithm. Ann Surg. 2016 Sep;264 3 474 81. Open 25. Henna E Sammalkorpi, Panu Mentula, Ari Lepp niemi. A new adult appendicitis score improves diagnostic accuracy of acute appendicitis a prospective study. BMC Gastroenterol. 2014 Jun 26;14 114. https://web.pathway.md/diseases/recFwDBzssIJqaRqC 9/10 6/23/23, 1:36 AM Acute appendicitis Pathway Open 26. CODA Collaborative, David R Flum, Giana H Davidson et al. A Randomized Trial Comparing Antibiotics with Appendectomy for Appendicitis. N Engl J Med. 2020 Nov 12;383 20 1907 1919. Open 27. Elisabeth M L de Wijkerslooth, Evert-Jan G Boerma, Charles C van Rossem et al. 2 days versus 5 days of postoperative antibiotics for complex appendicitis: a pragmatic, open-label, multicentre, non-inferiority randomised trial. Lancet. 2023 Jan 17;S0140 6736 22 02588 0. Open https://web.pathway.md/diseases/recFwDBzssIJqaRqC 10/10

Guideline sources The following summarized guidelines for the evaluation and management of acute bacterial meningitis (ABM) are prepared by our editorial team based on guidelines from the Center for Disease Control (CDC 2022; 2019), the European Society for Microbiology and Infectious Diseases (ESCMID 2016), the European Federation of Neurological Societies (EFNS 2008), and the Infectious Diseases Society of America (IDSA 2004). 1 2 3 4 5 7 7 7 Definition ABM is an acute inflammation of the meninges, particularly the arachnoid and the pia mater, associated with the invasion of bacteria into the subarachnoid space. 7 Epidemiology Bacterial meningitis is mostly caused by S. pneumoniae and Neisseria meningitides. [ 21180625]. Disease course https://web.pathway.md/diseases/reclISc8dymrnSrCz 1/7 6/23/23, 1:37 AM Acute bacterial meningitis Pathway Bacterial invasion to the CNS through the bloodstream or direct access leads to ABM, which causes clinical manifestations of fever, malaise, headache, meningismus, photophobia, phonophobia, vomiting, altered mental status, focal neurological signs (epileptic seizures, or paresis of a limb), and coma. 7 Prognosis and risk of recurrence Bacterial meningitis is associated with a 34% mortality rate. 7 Guidelines 1. Screening and diagnosis Diagnostic algorithms: consider the use of diagnostic algorithms to guide the management of patients with suspected ABM, but use clinical judgment in deciding whether to start empiric treatment. C 2. Diagnostic investigations Clinical history: avoid ruling out ABM solely based on the absence of classic symptoms, because such classic clinical characteristics may be absent in adults. D Blood cultures: obtain blood cultures before administering the first dose of antibiotics in patients with suspected ABM. A Cranial imaging: Obtain cranial imaging before lumbar puncture in patients with: focal neurologic deficits new-onset seizures severely altered mental status with a Glasgow Coma Score < 10 severely immunocompromised state. A Initiate empiric treatment immediately on clinical suspicion if lumbar puncture is delayed while awaiting cranial imaging. A LP and CSF analysis: As per ESCMID 2016 guidelines, obtain CSF leukocyte count, protein and glucose concentration, CSF culture, and Gram stain in patients with suspected ABM. A As per EFNS 2008 guidelines: Perform lumbar puncture and obtain CSF analysis as soon as safely possible in patients with suspected ABM. B Postpone diagnostic lumbar puncture in patients with symptoms and signs of raised ICP, or in patients judged to be at high risk of cerebral herniation following lumbar puncture (imaging evidence of intracranial mass lesion, obstructive hydrocephalus or midline shift). A https://web.pathway.md/diseases/reclISc8dymrnSrCz 2/7 6/23/23, 1:37 AM Acute bacterial meningitis Pathway As per IDSA 2004 guidelines, obtain a Gram stain examination of CSF in all patients with suspected meningitis. B CSF lactate: avoid measurement of CSF lactate concentrations for patients with suspected community-acquired bacterial meningitis. D CSF enterovirus PCR: consider enteroviral reverse transcription PCR to establish the diagnosis of enteroviral meningitis. C Serum C-reactive protein: consider obtaining serum CRP in patients with CSF findings consistent with meningitis, but for whom the Gram stain result is negative, and the physician is considering withholding antimicrobial therapy. A normal CRP has a high negative predictive value for the diagnosis of ABM. C Serum procalcitonin: insufficient evidence at the time of guideline writing to make recommendations regarding the use of serum procalcitonin. I 3. Medical management Setting of care: hospitalize all patients with suspected ABM on an emergent basis. B Time to antibiotics: insufficient evidence to set forth specific guidelines on the interval between the initial physician encounter and the administration of the first dose of antimicrobial therapy. I Prehospital antibiotics: initiate pre-hospital antibiotic treatment only for patients with strong suspicion of disseminated meningococcal infection, because of the unpredictable risk of early circulatory collapse from adrenocortical necrosis. Consider rapid pre-admission antibiotic therapy for other patients only if a delay in excess of 90 minutes in hospital transfer is anticipated. B Route of antibiotic administration: administer initial antibiotic therapy via the parenteral route in patients with ABM. A Empiric antibiotics: As per ESCMID 2016 guidelines, use an empiric antibiotic regimen based on patient age and local resistance rates. A As per EFNS 2008 guidelines, administer intravenous ceftriaxone or cefotaxime as part of initial empirical therapy for ABM. B Show 2 more Duration of treatment: complete 5-7 days of antibiotic therapy for meningococcal meningitis. B Show 5 more Definitive antibiotic therapy (cephalosporins): use a third-generation cephalosporin in patients with pneumococcal and meningococcal meningitis caused by strains that are not susceptible to penicillin. B Definitive antibiotic therapy (vancomycin): maintain serum vancomycin trough concentrations of approximately 15-20 mg/mL in patients in whom vancomycin is used for the treatment of meningitis. B https://web.pathway.md/diseases/reclISc8dymrnSrCz 3/7 6/23/23, 1:37 AM Acute bacterial meningitis Pathway Show 2 more Definitive antibiotic therapy (carbapenems): use meropenem as an alternative to cefotaxime or ceftriaxone that has been shown to have similar clinical and microbiologic outcomes. A Definitive antibiotic therapy (fluoroquinolones): use fluoroquinolones only for meningitis caused by multidrug-resistant gram-negative bacilli, or when patients have not responded to or cannot receive standard antimicrobial therapy. B Definitive antibiotic therapy (rifampin): add rifampin only if the organism is shown to be susceptible and there is a delay in the expected clinical or bacteriologic response. B Adjunctive dexamethasone: As per ESCMID 2016 guidelines, administer adjunctive dexamethasone (10 mg IV q6h, for 4 days) to all adults with ABM in high-income countries. A As per EFNS 2008 guidelines, administer adjunctive high-dose dexamethasone before or with the first dose of antibiotics in all patients with clinically suspected pneumococcal (or H. influenzae) meningitis, especially if focal neurological signs are present. B As per IDSA 2004 guidelines, avoid prescribing adjunctive dexamethasone to adult patients who have already received antimicrobial therapy, because administration of dexamethasone in this circumstance is unlikely to improve patient outcome. D Landmark trials: European Dexamethasone Study In adults with bacterial meningitis, dexamethasone was superior to placebo with respect to unfavorable outcome. de Gans J et al. N Engl J Med. 2002 Nov 14. Other adjunctive treatments: Avoid routine adjuvant therapy with mannitol, acetaminophen, antiepileptic drugs, or hypertonic saline. D Avoid hypothermia and glycerol in patients with ABM. D 4. Inpatient care Monitoring for complications: monitor patients with bacterial meningitis for neurologic and systemic complications, and initiate specific treatment when required. A 5. Therapeutic procedures Intrathecal antibiotics: consider intrathecal administration of vancomycin in patients who do not respond to parenteral antibiotics. C https://web.pathway.md/diseases/reclISc8dymrnSrCz 4/7 6/23/23, 1:37 AM Acute bacterial meningitis Pathway 6. Specific circumstances Patients with seizures: Initiate long-term antiepileptic drug therapy in patients with late-onset seizures. For patients with acute symptomatic seizures, consider withdrawing antiepileptic drug therapy after 1 year, in the absence of seizure recurrence and structural brain (cortical) injury as visualized in brain imaging. Consider driving restriction in adult patients if they had seizures, or have functional impairment such as visual field defect and limb weakness. CSF shunt infection: Remove CSF shunts in patients in whom shunt infection is present; administer appropriate antibiotic therapy, and insert an external drainage catheter to accelerate clearance of ventriculitis and facilitate the management of hydrocephalus. B Combine rifampin with vancomycin in patients with CSF shunt infections caused by staphylococci, especially in cases in which the shunt cannot be removed. B 7. Preventative measures Meningococcal and Hib immunization: As per ESCMID 2016 guidelines, provide pneumococcal immunization to patients who have had pneumococcal meningitis. B Show 2 more As per EFNS 2008 guidelines, provide primary immunization against N. meningitidis and H. influenzae type B infection to all groups at risk. B Pneumococcal immunization: Offer 1 dose of pneumococcal conjugate vaccine (either PCV20 or PCV15) in adults aged 19-64 years with certain underlying medical conditions or other risk factors not previously received pneumococcal conjugate vaccine or if previous vaccination history is unknown. E Show 5 more Offer 1 dose of PPSV23 in all adults aged 65. E Show 7 more Post-exposure prophylaxis: As per ESCMID 2016 guidelines, administer antibiotic prophylaxis consisting of ceftriaxone, ciprofloxacin, or rifampicin to household contacts and other close contacts of patients with meningitis due to N. meningitidis. A As per EFNS 2008 guidelines, administer post-exposure prophylaxis with either rifampicin, ciprofloxacin or ceftriaxone to household or close contacts of patients with suspected or proven meningitis due to N. meningitidis or H. influenzae. B https://web.pathway.md/diseases/reclISc8dymrnSrCz 5/7 6/23/23, 1:37 AM Acute bacterial meningitis Pathway 8. Follow-up and surveillance Indications for specialist referral: offer access to specialist neurology services for all survivors of ABM. Follow-up lumbar puncture: repeat CSF analysis in patients who have not responded clinically after 48 hours of appropriate antimicrobial therapy. B Surveillance for hearing loss, audiometry: As per EFNS 2008 guidelines, perform audiometry in patients recovering from bacterial meningitis in whom hearing impairment is suspected. As per EFNS 2008 guidelines, test for hearing loss during admission in children and adults with bacterial meningitis. In the case of hearing loss, refer patients to an ear-nose-throat specialist in a medical centre performing cochlear implants. A 9. Quality improvement Public health reporting: report all cases of suspected meningococcal or H. influenzae type B meningitis to the local public health authorities on an urgent basis. B Likelihood Ratios Pertinent positives The following findings increase the probability of acute bacterial meningitis in adults. -1 Finding LR+ Value Presence of jolt accentuation of headache 2.4 (1.4-4.2) History of nausea 1.3 (1.1-1.6) History of headache 1.1 (1.0-1.3) Pertinent negatives The following findings decrease the probability of acute bacterial meningitis in adults. -1 Finding LR- Value Absence of jolt accentuation of headache 0.05 (0.01-0.35) No history of headache 0.43 (0.19-0.96) No history of nausea 0.64 (0.44-0.92) References 1. Chaudhuri A, Martinez-Martin P, Kennedy PG et al. EFNS guideline on the management of community- acquired bacterial meningitis: report of an EFNS Task Force on acute bacterial meningitis in older children and adults. Eur J Neurol. 2008 Jul;15 7 649 59. Open https://web.pathway.md/diseases/reclISc8dymrnSrCz 6/7 6/23/23, 1:37 AM Acute bacterial meningitis Pathway 2. Tunkel AR, Hartman BJ, Kaplan SL et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004 Nov 1;39 9 1267 84. Open 3. van de Beek D, Cabellos C, Dzupova O et al. ESCMID guideline: diagnosis and treatment of acute bacterial meningitis. Clin Microbiol Infect. 2016 May;22 Suppl 3 S37 62. Open 4. Miwako Kobayashi, Jennifer L Farrar, Ryan Gierke et al. Use of 15 Valent Pneumococcal Conjugate Vaccine and 20 Valent Pneumococcal Conjugate Vaccine Among U.S. Adults: Updated Recommendations of the Advisory Committee on Immunization Practices United States, 2022. MMWR Morb Mortal Wkly Rep. 2022 Jan 28;71 4 109 117. Open 5. Almea Matanock, Grace Lee, Ryan Gierke et al. Use of 13 Valent Pneumococcal Conjugate Vaccine and 23 Valent Pneumococcal Polysaccharide Vaccine Among Adults Aged 65 Years: Updated Recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2019 Nov 22;68 46 1069 1075. Open 6. Lisa R Park, Amanda M Griffin, Douglas P Sladen et al. American Cochlear Implant Alliance Task Force Guidelines for Clinical Assessment and Management of Cochlear Implantation in Children With Single- Sided Deafness. Ear Hear. 2022 Mar/Apr;43 2 255 267. Open 7. Olaf Hoffman, R Joerg Weber. Pathophysiology and treatment of bacterial meningitis. 2009 Nov;2 6 1 7.2009 Nov;2 6 1 7. Open 8. Catherine Liu, Arnold Bayer, Sara E Cosgrove et al. Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus aureus Infections in Adults and Children. Clin Infect Dis. 2011 Feb 1;52 3):e18 55. Open https://web.pathway.md/diseases/reclISc8dymrnSrCz 7/7

Guideline sources The following summarized guidelines for the evaluation and management of acute bacterial prostatitis are prepared by our editorial team based on guidelines from the European Association of Urology (EAU 2022) and the Canadian Urological Association (CUA 2011). 1 2 Guidelines 1. Diagnostic investigations Physical examination: As per EAU 2022 guidelines, do not perform prostatic massage in patients with acute bacterial prostatitis. D As per CUA 2011 guidelines, perform a physical examination (including the abdomen, external genitalia, perineum, and prostate) in patients with suspected acute bacterial prostatitis. Do not perform prostatic massage during DRE. B Urine tests: As per EAU 2022 guidelines: Obtain a midstream urine dipstick to check nitrites and WBCs in patients with clinical suspicion of acute bacterial prostatitis. B https://web.pathway.md/diseases/reczV9TLWSsc4JYIy 1/3 6/23/23, 1:42 AM Acute bacterial prostatitis Pathway Obtain a midstream urine culture in patients with symptoms of acute bacterial prostatitis to guide diagnosis and tailor antibiotic therapy. B As per CUA 2011 guidelines, obtain a urinalysis and urine culture in patients with suspected acute bacterial prostatitis. B Blood tests: As per EAU 2022 guidelines, obtain a CBC and blood culture in patients presenting with acute bacterial prostatitis. B As per CUA 2011 guidelines, do not obtain serum prostate-specific antigen in patients with acute bacterial prostatitis as elevated levels of prostate-specific antigen associated with acute bacterial prostatitis usually leads to confusion and worry. D Transrectal ultrasound: As per EAU 2022 guidelines, obtain transrectal ultrasound in selected cases to rule out the presence of prostatic abscess. B As per CUA 2011 guidelines, consider obtaining transrectal prostatic ultrasound or CT to rule out prostatic abscess/pathology in patients with acute bacterial prostatitis refractory to initial therapy. B Pelvic imaging: consider obtaining pelvic ultrasound or bladder scan in patients with acute bacterial prostatitis with severe obstructive symptoms, poor bladder emptying, or physical examination findings of possible urinary retention. C 2. Medical management General principles: treat acute bacterial prostatitis according to the recommendations for complicated UTIs. C Setting of care: admit patients to hospital in case of fever, prolonged vomiting, severe dehydration, tachycardia, tachypnea, hypotension, and other symptoms related to urosepsis, as well as high-risk patients (diabetes, immunosuppression, older age, or prostatic abscess) and patients with severe voiding disorders. B Antibiotic therapy: Administer IV high-dose aminoglycosides in combination with ampicillin, a broad spectrum penicillin in combination with a -lactamase inhibitor, a third-generation cephalosporin, or a fluoroquinolone in patients with severe symptomatic febrile acute bacterial prostatitis until defeverescence and normalization of associated urosepsis. B . Switch to outpatient oral fluoroquinolones for 2-4 weeks following resolution of severe infection and for less severely ill patients. B Consider administering oral fluoroquinolones for 2-4 weeks in non-severely ill patients. C Management of pain: administer nonsteroidal anti-inflammatory agents for symptom relief including fever. https://web.pathway.md/diseases/reczV9TLWSsc4JYIy 2/3 6/23/23, 1:43 AM Acute bacterial prostatitis Pathway Management of voiding symptoms: consider administering alpha-blockers to reduce the risk of urinary retention and facilitate micturition, particularly in patients with moderately severe obstructive voiding symptoms. 3. Therapeutic procedures Urethral catheterization: Perform urethral catheterization with a trial of voiding or short-term small caliber urethral catheterization in patients with severe obstructive voiding symptoms or urinary retention. B Consider placing a suprapubic tube in patients not tolerating a urethral catheter. C 4. Surgical interventions Drainage of prostatic abscess: perform incision and drainage of the prostatic abscess, preferably via transurethral route. B References 1. J Curtis Nickel. Prostatitis. Can Urol Assoc J. 2011 Oct;5 5 306 15. Open 2. G. Bonkat, R. Bartoletti, F. Bruy re et al. EAU Guidelines on Urological Infections. EAU. 2022. Open 3. Jerneja Vide nik Zorman, Mojca Mati i , Samo Jeverica et al. Diagnosis and treatment of bacterial prostatitis. Acta Dermatovenerol Alp Pannonica Adriat. 2015;24 2 25 9. Open https://web.pathway.md/diseases/reczV9TLWSsc4JYIy 3/3

Guideline sources The following summarized guidelines for the evaluation and management of acute bacterial rhinosinusitis (ABRS) are prepared by our editorial team based on guidelines from the American Academy of Otolaryngology-Head and Neck Surgery Foundation (AAO-HNSF 2015; 2013) and the Infectious Diseases Society of America (IDSA 2012). 1 2 3 4 4 4 5 Definition ABRS, also known as acute sinusitis, is an inflammation of the nasal cavity and paranasal sinuses that lasts up to 4 weeks. 4 Epidemiology ABRS is mostly caused by S. pneumoniae, Haemophilus influenza, and Moraxella catarrhalis. 4 Disease course Nasal and paranasal infection results in ABRS, which causes clinical manifestations of nasal congestion and obstruction, purulent nasal discharge, facial pain or pressure, fever, fatigue, cough, hyposmia, ear pressure, headache, and halitosis. Disease progression may result in orbital and CNS complications. 4 Prognosis and risk of recurrence https://web.pathway.md/diseases/recWH9VnX7b3GYOHL 1/5 6/23/23, 1:37 AM Acute bacterial rhinosinusitis Pathway ABRS with ocular complications is associated with a 3.17% mortality rate. 5 Calculator Clinical criteria for acute bacteri Guidelines 1. Screening and diagnosis Diagnostic criteria: As per AAO-HNSF 2015 guidelines, diagnose ABRS in patients with: symptoms or signs of acute rhinosinusitis that persist for 10 days after the onset of symptoms, without evidence of improvement symptoms or signs of acute rhinosinusitis that worsen after an initial improvement, within 10 days of the onset of symptoms. B As per IDSA 2012 guidelines, diagnose ABRS in patients with: symptoms or signs of acute rhinosinusitis that persist for 10 days, without any evidence of improvement symptoms or signs of acute rhinosinusitis that worsen, after initial improvement of symptoms of a typical viral upper respiratory infection that lasted 5-6 days, with new onset of fever, headache, or increase in nasal discharge severe symptoms or signs of acute rhinosinusitis, with high fever ( 39 C or 102 F) and purulent nasal discharge or facial pain, lasting for at least 3-4 consecutive days at the beginning of illness. B 2. Diagnostic investigations Diagnostic imaging: As per AAO-HNSF 2015 guidelines, avoid obtaining diagnostic imaging in patients who meet clinical criteria for acute rhinosinusitis, unless a complication or alternative diagnosis is suspected. D As per IDSA 2013 guidelines, avoid obtaining diagnostic imaging (such as sinus X-ray, contrast- enhanced CT, MRI, or ultrasound) to distinguish acute bacterial sinusitis from viral upper respiratory infection. D Sinus cultures: as per IDSA 2012 guidelines, avoid obtaining nasopharyngeal cultures in patients with ABRS. D Show 2 more https://web.pathway.md/diseases/recWH9VnX7b3GYOHL 2/5 6/23/23, 1:37 AM Acute bacterial rhinosinusitis Pathway Evaluation of recurrent acute rhinosinusitis: as per AAO-HNSF 2015 guidelines, assess patients with recurrent acute rhinosinusitis for chronic conditions that would modify management, such as asthma, cystic fibrosis, immunodeficiency, and ciliary dyskinesia. B 3. Medical management Symptomatic treatment: As per AAO-HNSF 2015 guidelines, consider using analgesics, topical intranasal steroids, and/or intranasal saline irrigation for symptomatic relief in patients with ABRS. C As per IDSA 2012 guidelines, advise intranasal saline irrigation (with either physiologic or hypertonic saline) as an adjunctive treatment in adult patients with ABRS. B Show 2 more Antibiotic therapy: As per AAO-HNSF 2015 guidelines: Offer either watchful waiting or antibiotic therapy for adults with uncomplicated ABRS. Watchful waiting should be offered only when adequate follow-up can be ensured, such that antibiotic therapy is started if the patient fails to improve within 7 days, or worsens at any time. B Administer amoxicillin (with or without clavulanate) as first-line antibiotic therapy in most adult patients with ABRS, and complete 5-10 days of treatment. B As per IDSA 2012 guidelines, initiate antibiotic therapy in patients in whom a clinical diagnosis of ABRS is established, as defined by IDSA criteria. B Show 2 more 4. Follow-up and surveillance Indications for specialist referral: Obtain specialist consultation with an otolaryngologist, infectious disease specialist, or allergist in the following situations: patients who are seriously ill and immunocompromised patients who continue to deteriorate clinically despite extended courses of antimicrobial therapy patients who have recurrent bouts of acute rhinosinusitis with clearing between episodes. B Management of nonresponse to treatment: As per AAO-HNSF 2015 guidelines, reassess initial management in patients who worsen or fail to improve within 7 days of diagnosis, in order to confirm the diagnosis, exclude other causes of illness, and detect potential complications. B Show 2 more As per IDSA 2012 guidelines: Reassess initial management in patients who worsen despite 48-72 hours of initial antibiotic therapy, or who fail to improve despite 3-5 days of antibiotic therapy. B https://web.pathway.md/diseases/recWH9VnX7b3GYOHL 3/5 6/23/23, 1:37 AM Acute bacterial rhinosinusitis Pathway Evaluate for the presence of factors associated with treatment failure (such as resistant pathogens, structural abnormalities, or a noninfectious etiology) in patients who worsen despite 72 hours of initial antibiotic therapy, or who fail to improve despite 3-5 days of antibiotic therapy. B Likelihood Ratios Pertinent positives The following findings increase the probability of acute bacterial rhinosinusitis in adults. 1 1 Finding LR+ Value Presence of any 4 of 5 clinical findings of acute sinusitis* 6.4 (2.2-19) Presence of halo sign 4.8 Presence of air-fluid levels 4.2 (2.6-6.7) History of maxillary toothache 2.6 maxillary toothache, purulent nasal secretion, poor response to decongestant, abnormal transillumination result, patient report of colored nasal discharge Show 11 more Pertinent negatives The following findings decrease the probability of acute bacterial rhinosinusitis in adults. 1 1 Finding LR- Value Absence of sinus opacification 0.01 Absence of air-fluid levels 0.26 (0.17-0.37) Absence of halo sign 0.3 Negative transillumination test 0.5 Show 10 more References 1. Rosenfeld RM, Piccirillo JF, Chandrasekhar SS et al. Clinical practice guideline (update): adult sinusitis. Otolaryngol Head Neck Surg. 2015 Apr;152 2 Suppl):S1 S39. Open 2. Chow AW, Benninger MS, Brook I et al. IDSA Clinical Practice Guideline for Acute Bacterial Rhinosinusitis in Children and Adults. Clin Infect Dis. 2012 Apr;54 8):e72-e112. Open 3. Wald ER, Applegate KE, Bordley C et al. Clinical practice guideline for the diagnosis and management of acute bacterial sinusitis in children aged 1 to 18 years. Pediatrics. 2013 Jul;132 1):e262 80. Open 4. Anthony W Chow, Michael S Benninger, Itzhak Brook et al. IDSA clinical practice guideline for acute bacterial rhinosinusitis in children and adults. 2012 Apr;54 8):e72-e112.2012 Apr;54 8):e72-e112. Open https://web.pathway.md/diseases/recWH9VnX7b3GYOHL 4/5 6/23/23, 1:37 AM Acute bacterial rhinosinusitis Pathway 5. Patorn Piromchai, Sanguansak Thanaviratananich. Invasive fungal rhinosinusitis versus bacterial rhinosinusitis with orbital complications: a case-control study. 2013 Nov 3;2013 453297.2013 Nov 3;2013 453297. Open 6. American Association of Family Physicians. Choosing Wisely AAFP recommendations. Choosing Wisely. 2012. Open 7. American College of Emergency Physicians. Choosing Wisely ACEP recommendations. Choosing Wisely. 2014. Open 8. American Academy of Allergy, Asthma & Immunology. Choosing Wisely AAAAI recommendations. Choosing Wisely. 2012. Open 9. American Academy of Ophthalmology. Choosing Wisely AAO recommendations. Choosing Wisely. 2013. Open 10. Aaron M Harris, Lauri A Hicks, Amir Qaseem et al. Appropriate Antibiotic Use for Acute Respiratory Tract Infection in Adults: Advice for High-Value Care From the American College of Physicians and the Centers for Disease Control and Prevention. Ann Intern Med. 2016 Mar 15;164 6 425 34. Open 11. Anthony W Chow, Michael S Benninger, Itzhak Brook et al. IDSA clinical practice guideline for acute bacterial rhinosinusitis in children and adults. Clin Infect Dis. 2012 Apr;54 8):e72-e112. Open 12. Roger Zoorob, Mohamad A Sidani, Richard D Fremont et al. Antibiotic use in acute upper respiratory tract infections. Am Fam Physician. 2012 Nov 1;86 9 817 22. Open https://web.pathway.md/diseases/recWH9VnX7b3GYOHL 5/5

Guideline sources The following summarized guidelines for the evaluation and management of acute bronchitis are prepared by our editorial team based on guidelines from the American College of Physicians (ACP 2021), the American College of Chest Physicians (ACCP 2020; 2006), the American Association of Family Physicians (AAFP 2016), the American College of Physicians (ACP/CDC 2016), and the Infectious Diseases Society of America (IDSA 2016). 1 2 3 4 5 6 7 7 7 8 Definition Acute bronchitis is a transient inflammation of the tracheobronchial tree in response to infection without a history of chronic pulmonary disease or evidence of pneumonia or sinusitis. 7 Epidemiology The most common cause of acute bronchitis are viruses (90%) including adenovirus, influenza, measles, respiratory syncytial, parainfluenza, and HSV. Nonvirus (10%) causes include bacteria (Mycoplasma pneumoniae, Bordetella pertussis, and Chlamydia pneumoniae) and inhaled lung irritants. 7 Disease course Inflammation of the tracheobronchial tree results in acute bronchitis, which causes clinical manifestations of cough (dry or productive), chest tightness, burning with or without wheezing, headache, low-grade fever, rhinorrhea, sore throat, malaise, and myalgia. 7 https://web.pathway.md/diseases/recHyEthkR74ppYwt 1/5 6/23/23, 1:37 AM Acute bronchitis Pathway Prognosis and risk of recurrence Acute bronchitis is not associated with an increase in mortality. 8 Pathway Calculator Acute bronchitis Diagnostic criteria for acute bro Diagnosis and management Guidelines 1. Screening and diagnosis Diagnostic criteria: diagnose acute bronchitis in patients with an acute respiratory infection manifested predominantly by cough, with or without sputum production, lasting 3 weeks, if there is no clinical or radiographic evidence of pneumonia, common cold, acute asthma, and COPD exacerbation. E 2. Diagnostic investigations Chest X-ray: As per ACCP 2020 guidelines, avoid obtaining routine CXRs in immunocompetent adult outpatients with cough due to suspected acute bronchitis. As per ACCP 2006 guidelines, avoid obtaining CXRs routinely in patients with acute cough and sputum production meeting all of the following criteria: HR 100 beats/min respiratory rate 24 breaths/min oral body temperature of 38 C normal chest examination. D Laboratory tests: As per ACCP 2020 guidelines, avoid obtaining routine investigation with sputum for microbial culture, respiratory tract samples for viral PCR, CRP, and procalcitonin in immunocompetent adult outpatients with cough due to suspected acute bronchitis. As per ACCP 2006 guidelines, do not obtain sputum analyses, viral cultures, or serologic assays routinely in patients with a presumed diagnosis of acute bronchitis, since the causative pathogen is rarely identified in clinical practice. D Spirometry: avoid obtaining routine spirometry and peak flow measurements in immunocompetent adult outpatients with cough due to suspected acute bronchitis. https://web.pathway.md/diseases/recHyEthkR74ppYwt 2/5 6/23/23, 1:37 AM Acute bronchitis Pathway Further evaluation: consider obtaining reassessment and targeted investigations to help establish the etiology in immunocompetent adult outpatients with persisting or worsening acute bronchitis. 3. Medical management Antibiotic therapy: As per ACP 2021 guidelines, limit antibiotic treatment duration to 5 days when managing patients with acute uncomplicated bronchitis with clinical signs of a bacterial infection (presence of increased sputum purulence in addition to increased dyspnea, and/or increased sputum volume). B Updated evidence: TRAP-LRTI In adults with clinically suspected non-pneumonia lower respiratory tract infection and symptom duration from 24 hours to 28 days, placebo was not noninferior to azithromycin with respect to clinical improvement at day 5. Ephraim L Tsalik et al. Lancet Infect Dis. 2023 Apr. As per ACCP 2020 guidelines: Avoid initiating antibiotics routinely in immunocompetent adult outpatients with cough due to acute bronchitis. Consider initiating antibiotics in patients with worsening acute bronchitis if a complicating bacterial infection is thought likely. As per AAFP 2016 guidelines: Avoid initiating antibiotics routinely in patients with uncomplicated acute bronchitis. D Implement strategies to reduce antibiotic use, such as asking patients to call for or pick up an antibiotic, or to hold an antibiotic prescription for a set amount of time. A As per CDC 2016 guidelines, do not initiate antibiotic therapy in patients with bronchitis unless pneumonia is suspected. D As per ACCP 2006 guidelines, do not initiate antibiotics routinely in patients with a presumed diagnosis of acute bronchitis. D Address the issue of not prescribing antibiotics individually and provide explanations because many patients expect to receive an antibiotic based on previous experiences and public expectations. D Antiviral therapy: avoid initiating antibiotics routinely in immunocompetent adult outpatients with cough due to acute bronchitis. Symptomatic therapy: As per ACCP 2020 guidelines, avoid initiating antitussives, inhaled -agonists, inhaled anticholinergics, ICSs, oral corticosteroids, oral NSAIDs, or other therapies in immunocompetent https://web.pathway.md/diseases/recHyEthkR74ppYwt 3/5 6/23/23, 1:37 AM Acute bronchitis Pathway adult outpatients with cough due to acute bronchitis. As per AAFP 2016 guidelines, consider offering dextromethorphan, guaifenesin, or honey for the management of acute bronchitis symptoms. C Show 2 more As per ACCP 2006 guidelines, do not use -2 agonist bronchodilators routinely to alleviate cough in most patients with acute bronchitis. D Consider offering -2 agonist bronchodilators in selected adult patients with acute bronchitis and wheezing accompanying the cough. D Show 2 more 4. Specific circumstances Patients with Aspergillus bronchitis: Obtain both PCR and galactomannan on respiratory secretions, usually sputum, for the detection of Aspergillus species to confirm the diagnosis of Aspergillus bronchitis in non- transplant patients. B Consider initiating oral itraconazole or voriconazole with therapeutic drug monitoring in non- transplant patients with Aspergillus bronchitis. C References 1. Braman SS. Chronic cough due to acute bronchitis: ACCP evidence-based clinical practice guidelines. Chest. 2006 Jan;129 1 Suppl):95S 103S. Open 2. Rachael A Lee, Robert M Centor, Linda L Humphrey et al. Appropriate Use of Short-Course Antibiotics in Common Infections: Best Practice Advice From the American College of Physicians. Ann Intern Med. 2021 Apr 6. Open 3. Kinkade S, Long NA. Acute Bronchitis. Am Fam Physician. 2016 Oct 1;94 7 560 565. Open 4. Aaron M Harris, Lauri A Hicks, Amir Qaseem et al. Appropriate Antibiotic Use for Acute Respiratory Tract Infection in Adults: Advice for High-Value Care From the American College of Physicians and the Centers for Disease Control and Prevention. Ann Intern Med. 2016 Mar 15;164 6 425 34. Open 5. Maeve P Smith, Mark Lown, Sonal Singh et al. Acute Cough Due to Acute Bronchitis in Immunocompetent Adult Outpatients: CHEST Expert Panel Report. Chest. 2020 May;157 5 1256 1265. Open 6. Patterson TF, Thompson GR rd, Denning DW et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016 Aug 15;63 4):e1-e60. Open 7. James L Whiteside, John W Whiteside. Acute bronchitis: a review of diagnosis and evidence-based management. May-Jun 2002;9 3 105 109.May-Jun 2002;9 3 105 109. Open 8. Peter Wark. Bronchitis (acute). 2015 Jul 17;2015 1508.2015 Jul 17;2015 1508. Open 9. Albert RH. Diagnosis and treatment of acute bronchitis. Am Fam Physician. 2010 Dec 1;82 11 1345 50. Open https://web.pathway.md/diseases/recHyEthkR74ppYwt 4/5 6/23/23, 1:37 AM Acute bronchitis Pathway 10. Infectious Diseases Society of America. Choosing Wisely: Recommendations of the Infectious Diseases Society of America. Choosing Wisely. 2015 Feb. Open 11. American Academy of Pediatrics. Choosing Wisely AAP recommendations. Choosing Wisely. 2018. Open https://web.pathway.md/diseases/recHyEthkR74ppYwt 5/5

Guideline sources The following summarized guidelines for the evaluation and management of acute cholangitis are prepared by our editorial team based on guidelines from the American Society for Gastrointestinal Endoscopy (ASGE 2021; 2015), the American College of Radiology (ACR 2019), the Tokyo Guidelines (TG 2018), and the European Association for the Study of the Liver (EASL 2016). 1 2 3 4 5 Calculator CholeS score for duration of lap Guidelines 1. Diagnostic investigations Clinical evaluation: https://web.pathway.md/diseases/recAlaNWnZiNz808n 1/7 6/23/23, 1:38 AM Acute cholangitis Pathway Elicit medical history and perform physical examination to identify the characteristic symptoms of gallbladder stones, such as episodic attacks of severe pain in the right upper abdominal quadrant or epigastrium for at least 15-30 minutes with radiation to the right back or shoulder and a positive reaction to analgesics. B Evaluate for common bile duct stones in patients with jaundice, acute cholangitis, or acute pancreatitis. A Laboratory tests: Obtain the following tests as part of the initial evaluation of patients with fever, chills, abdominal pain and/or jaundice: WBCs CRP liver biochemical tests. B Obtain liver biochemical tests in patients with suspected common bile duct stones. B Abdominal ultrasound: obtain abdominal ultrasound as the initial investigation in patients with fever, chills, abdominal pain and/or jaundice. B Show 4 more Endoscopic retrograde cholangiopancreatography: As per ASGE 2021 guidelines: Consider performing ERCP over percutaneous transhepatic biliary drainage in patients with cholangitis. C Consider performing ERCP within 48 hours after admission. C As per EASL 2016 guidelines, perform ERCP with sphincterotomy and stone extraction in patients with biliary pancreatitis with suspected coexistent acute cholangitis, with timing depending on the severity of cholangitis but preferably within 24 hours. A Show 2 more As per ASGE 2015 guidelines, perform ERCP in patients with acute biliary pancreatitis with concomitant cholangitis or biliary obstruction. A Show 2 more Magnetic resonance cholangiopancreatography: consider obtaining MRCP in case of strong clinical suspicion of gallbladder stones and negative abdominal ultrasound. C Show 4 more Endoscopic ultrasound: consider obtaining EUS in case of strong clinical suspicion of gallbladder stones and negative abdominal ultrasound. C Show 3 more 2. Medical management Antibiotics: As per TG 2018 guidelines: https://web.pathway.md/diseases/recAlaNWnZiNz808n 2/7 6/23/23, 1:38 AM Acute cholangitis Pathway Administer antibiotics for 4-7 days in patients with acute cholangitis, once the source of infection is controlled. B Administer antibiotics according to the following regimens in patients with cholangitis: Situation Guidance Penicillins - do not use ampicillin + sulbactam if the resistance rate is > 20% Grade 1 Cephalosporins - cefazolin/cefotiam/cefuroxime/ceftriaxone/c efotaxime +/- metronidazole, cefmetazole, cefoxitin, flomoxef, cefoperazone + sulbactam Carbapenems - ertapenem Fluoroquinolones - ciprofloxacin/levofloxacin/pazufloxacin +/- metronidazole, moxifloxacin Penicillins - piperacillin + tazobactam Grade 2 Cephalosporins - ceftriaxone/cefotaxime/cefepime/cefozopra n/ceftazidime with or without metronidazole, cefoperazone + sulbactam Carbapenems - ertapenem Fluoroquinolones - ciprofloxacin/levofloxacin/pazufloxacin +/- metronidazole, moxifloxacin Penicillins - piperacillin + tazobactam Grade 3 Cephalosporins - cefepime/ceftazidime/cefozopran +/- metronidazole Carbapenems - imipenem + cilastatin, meropenem, doripenem, ertapenem Monobactams - aztreonam +/- metronidazole Penicillins - piperacillin + tazobactam Healthcare-associated cholangitis Cephalosporins - cefepime/ceftazidime/cefozopran +/- metronidazole Carbapenems - imipenem/cilastatin, meropenem, doripenem, ertapenem https://web.pathway.md/diseases/recAlaNWnZiNz808n 3/7 6/23/23, 1:38 AM Acute cholangitis Pathway Monobactams - aztreonam +/- metronidazole. B As per EASL 2016 guidelines, administer immediate broad-spectrum antibiotics in patients with cholangitis. B Spasmolytics and opioids: Consider administering spasmolytics (such as butylscopolamine) for the management of symptomatic patients with gallstones. B Consider administering opioids for the management of severe symptoms in patients with gallstones. B Nonsteroidal anti-inflammatory drugs: administer NSAIDs (such as diclofenac or indomethacin) for the management of patients with biliary colic. B 3. Therapeutic procedures Biliary decompression: As per ACR 2019 guidelines, place an endoscopic internal biliary catheter with a removable plastic stent or a percutaneous internal/external biliary catheter as the initial therapeutic procedure in patients with dilated bile ducts and suspected biliary sepsis or acute cholangitis. Decide between procedures depending on the patient's anatomy and availability of resources and institutional preferences. B As per EASL 2016 guidelines, perform biliary decompression for the management of patients with cholangitis. B Show 3 more Endoscopic sphincterotomy: perform endoscopic sphincterotomy and stone extraction for the management of patients with bile duct stones. B . Obtain intraoperative ERCP or laparoscopic bile duct exploration in combination with cholecystectomy as alternatives if adequate expertise is available. B Show 2 more Percutaneous or endoscopic biliary drainage: consider performing percutaneous or balloon endoscopy-assisted treatment of bile duct stones in patients with altered anatomy, such as previous Roux-en-Y anastomosis or bariatric surgery. C Litholysis and lithotripsy: Avoid offering litholysis with bile acids alone or in combination with extracorporeal shock wave as first-line treatment for gallbladder stones. D Consider offering extracorporeal shock wave, electrohydraulic or laser lithotripsy in patients failed standard stone extraction procedures. C 4. Perioperative care https://web.pathway.md/diseases/recAlaNWnZiNz808n 4/7 6/23/23, 1:38 AM Acute cholangitis Pathway Preoperative evaluation: Avoid obtaining routine preoperative tests other than abdominal ultrasound to confirm the presence of gallstones in patients planned to undergo cholecystectomy. D Consider obtaining liver biochemical tests before elective cholecystectomy in individually selected patients. C Intraoperative cholangiography: avoid obtaining routine or selective intraoperative cholangiography during cholecystectomy in patients at low risk of common bile duct stones. D Postoperative evaluation: consider obtaining EUS or MRCP in the diagnostic evaluation of patients with biliary symptoms after cholecystectomy. C 5. Surgical interventions Indications for cholecystectomy (symptomatic stones): perform cholecystectomy as the preferred option for treatment of patients with symptomatic gallbladder stones. B Indications for cholecystectomy (concomitant abdominal surgery): Avoid performing routine cholecystectomy in patients with asymptomatic stones during abdominal surgery for other indications, including bariatric surgery, as well as kidney, lung or pancreas transplantation. D Defer cholecystectomy whenever possible in patients in the early phase after heart or lung transplantation with symptomatic gallbladder stones. B Indications for cholecystectomy (acute biliary pancreatitis): perform cholecystectomy during the index hospital admission in patients with mild acute biliary pancreatitis. A Indications for cholecystectomy (bile duct stones): Perform cholecystectomy combined with bile duct exploration or intraoperative ERCP in patients with bile duct stones failed endoscopic therapy. B Consider preferring primary closure over T-tube drainage in low risk cases, in the event of surgical bile duct exploration. C Choice of surgical approach: perform laparoscopic cholecystectomy as the preferred surgical modality in patients with symptomatic gallbladder stones, including acute calculous cholecystitis A and Child-Pugh A or B liver cirrhosis. B Show 3 more Timing for cholecystectomy: perform cholecystectomy as early as possible in patients with uncomplicated biliary colic. B Show 3 more Intraoperative management of bile duct stones: consider performing bile duct exploration, transcystic stone extraction or endoscopic clearance as alternative treatment options in case of intraoperative detection of bile duct stones. C Intraoperative management of bile duct injuries: consider performing primary surgical repair of intraoperatively recognized bile duct lesions A, B or C, if surgical expertise is available. C https://web.pathway.md/diseases/recAlaNWnZiNz808n 5/7 6/23/23, 1:38 AM Acute cholangitis Pathway Show 3 more 6. Specific circumstances Asymptomatic patients: avoid offering routine treatment in patients with asymptomatic gallbladder stones. D Show 2 more Elderly patients: Perform cholecystectomy as soon as the patient is deemed fit for surgery in the elderly and in patients with high anesthetic risk with gallstone complications (such as acute cholecystitis, gallstone pancreatitis, or obstructive jaundice). B Do not withhold laparoscopic cholecystectomy solely based on the chronological age of the patient. D Pregnant patients: recognize that the use of radiographs is not contraindicated during pregnancy provided care is taken to minimize radiation exposure. B Show 3 more 7. Preventative measures Lifestyle modifications: advise healthy lifestyle and food, regular physical activity and maintenance of an ideal body weight to prevent cholesterol gallbladder stones and symptomatic gallstones. B Ursodeoxycholic acid: avoid offering pharmacological agents for the prevention of gallstones in general population. D Show 2 more Prophylactic cholecystectomy: Consider performing cholecystectomy in patients with hereditary spherocytosis or sickle cell disease with asymptomatic gallstones undergoing splenectomy or other abdominal surgery. C Avoid performing routine prophylactic cholecystectomy during bariatric surgery. D Measures with no evidence for benefit: insufficient evidence to recommend any pharmacological agent for the prevention of recurrent bile duct stones. I Show 2 more References 1. EASL. EASL Clinical Practice Guidelines on the prevention, diagnosis and treatment of gallstones. J Hepatol. 2016 Jul;65 1 146 181. Open 2. Expert Panel on Interventional Radiology:, Alexandra H Fairchild, Eric J Hohenwalter et al. ACR Appropriateness Criteria Radiologic Management of Biliary Obstruction. J Am Coll Radiol. 2019 https://web.pathway.md/diseases/recAlaNWnZiNz808n 6/7 6/23/23, 1:38 AM Acute cholangitis Pathway May;16 5S S196 S213. Open 3. James L Buxbaum, Carlos Buitrago, Alice Lee et al. ASGE guideline on the management of cholangitis. Gastrointest Endosc. 2021 Aug;94 2 207 221.e14. Open 4. Harumi Gomi, Joseph S Solomkin, David Schlossberg et al. Tokyo Guidelines 2018 antimicrobial therapy for acute cholangitis and cholecystitis. J Hepatobiliary Pancreat Sci. 2018 Jan;25 1 3 16. Open 5. ASGE Standards of Practice Committee, Krishnavel V Chathadi, Vinay Chandrasekhara et al. The role of ERCP in benign diseases of the biliary tract. Gastrointest Endosc. 2015 Apr;81 4 795 803. Open 6. Manes G, Paspatis G, Aabakken L et al. Endoscopic management of common bile duct stones: European Society of Gastrointestinal Endoscopy ESGE guideline. Endoscopy. 2019 May;51 5 472 491. Open 7. Society of American Gastrointestinal and Endoscopic Surgeons. Choosing Wisely SAGES recommendations. Choosing Wisely. 2019. Open 8. Miura F, Okamoto K, Takada T et al. Tokyo Guidelines 2018 initial management of acute biliary infection and flowchart for acute cholangitis. J Hepatobiliary Pancreat Sci. 2018 Jan;25 1 31 40. Open 9. Tadahiro Takada. Tokyo Guidelines 2018 updated Tokyo Guidelines for the management of acute cholangitis/acute cholecystitis. J Hepatobiliary Pancreat Sci. 2018 Jan;25 1 1 2. Open 10. Shuntaro Mukai, Takao Itoi, Todd H Baron et al. Indications and techniques of biliary drainage for acute cholangitis in updated Tokyo Guidelines 2018. J Hepatobiliary Pancreat Sci. 2017 Oct;24 10 537 549. Open 11. Susumu Tazuma, Michiaki Unno, Yoshinori Igarashi et al. Evidence-based clinical practice guidelines for cholelithiasis 2016. J Gastroenterol. 2017 Mar;52 3 276 300. Open 12. Expert Panel on Gastrointestinal Imaging:, Christine M Peterson, Michelle M McNamara et al. ACR Appropriateness Criteria Right Upper Quadrant Pain. J Am Coll Radiol. 2019 May;16 5S S235 S243. Open 13. Tram T Tran, Joseph Ahn, Nancy S Reau. ACG Clinical Guideline: Liver Disease and Pregnancy. Am J Gastroenterol. 2016 Feb;111 2 176 94; quiz 196. Open https://web.pathway.md/diseases/recAlaNWnZiNz808n 7/7

Guideline sources The following summarized guidelines for the evaluation and management of acute cholecystitis are prepared by our editorial team based on guidelines from the Danish Surgical Society (DSS 2022), the World Society of Emergency Surgery (WSES 2020), the World Society of Emergency Surgery (WSES/SICG 2019), the Tokyo Guidelines (TG 2018), the European Association for the Study of the Liver (EASL 2016), and the American Society for Gastrointestinal Endoscopy (ASGE 2015). 1 2 3 4 5 6 7 8 9 10 11 11 12 Definition Acute cholecystitis is an inflammation of the gallbladder and is usually caused by obstruction of the cystic duct. 10 Epidemiology Acute cholecystitis is mostly caused by gall stones or by impacted biliary sludge with or without secondary bacterial infection (E. coli, Klebsiella, and Streptococcus faecalis). 11 Disease course https://web.pathway.md/diseases/recSrhoDrXV1gdurf 1/9 6/23/23, 1:43 AM Acute cholecystitis Pathway The inflammatory process due to obstruction of cystic duct results in acute cholecystitis, which causes clinical manifestations of persistent pain and tenderness in the RUQ, and mild jaundice. Disease progression may lead to gangrenous cholecystitis, gallbladder perforation, cholecystoenteric fistulas, gallstone ileus, and acalculous cholecystitis. 11 Prognosis and risk of recurrence In the US, the overall mortality associated with untreated complications of acute cholecystitis is approximately 20%. 12 Guidelines 1. Screening and diagnosis Clinical presentation: As per TG 2018 guidelines, recognize that severe (grade III) acute cholecystitis causes systemic symptoms because of organ damage and affects survival prognosis. B As per EASL 2016 guidelines, suspect acute cholecystitis in patients with fever, severe pain located in the right upper abdominal quadrant lasting for several hours, and right upper abdominal tenderness on palpation. B Diagnostic criteria: use the TG18/TG13 criteria for the diagnosis of acute cholecystitis. B 2. Classification and risk stratification Severity grading and prognosis: As per WSES 2020 guidelines, insufficient evidence to suggest the use of any prognostic model in patients with acute calculous cholecystitis. I As per TG 2018 guidelines, use the TG18/TG13 severity grading for the assessment of severity of acute cholecystitis and for predicting prognosis: Situation Guidance No organ dysfunction and mild inflammatory changes in the gallbladder Grade I Leukocytosis > 18, 000/mm Grade II RUQ palpable tender mass Duration of complaints > 72 hours Marked local inflammation (gangrenous cholecystitis, pericholecystic abscess, hepatic abscess, biliary peritonitis, emphysematous cholecystitis) https://web.pathway.md/diseases/recSrhoDrXV1gdurf 2/9 6/23/23, 1:43 AM Acute cholecystitis Pathway Grade III Cardiovascular dysfunction (hypotension requiring treatment with dopamine 5 g/kg/min, or any dose of norepinephrine) Neurological dysfunction (decreased level of consciousness) Respiratory dysfunction (PaO /FiO ratio < 300) Renal dysfunction (oliguria or creatinine > 2.0 mg/dL) Hepatic dysfunction (INR) > 1.5 Hematological dysfunction (thrombocytopenia < 100, 000/mm ). B Risk stratification of choledocholithiasis: Consider stratifying the risk of choledocholithiasis according to the proposed classification modified from the ASGE and SAGES guidelines. C Use the classification scheme recommended for the general population to assess the risk of choledocholithiasis in elderly patients with acute cholecystitis. B Risk stratification of elderly patients: Evaluate the risk for elderly patients with acute calculous cholecystitis by including: mortality rate for conservative and surgical therapeutic options rate of gallstone-related disease relapse and the time to relapse age-related life expectancy frailty evaluation by the use of frailty scores estimation of specific risks (patient/type of surgery) by the use of surgical clinical scores. B 3. Diagnostic investigations General principles: Consider using a combination of detailed history, complete clinical examination, laboratory tests, and imaging for the diagnosis of acute calculous cholecystitis, although recognize that the best combination is not known. C Do not rely on a single clinical or laboratory finding to confirm or exclude acute cholecystitis. D Abdominal ultrasound: As per WSES 2020 guidelines: Obtain abdominal ultrasound as the initial imaging in patients with suspected acute calculous cholecystitis, due to its cost-effectiveness, wide availability, reduced invasiveness and good accuracy for gallstones disease. A https://web.pathway.md/diseases/recSrhoDrXV1gdurf 3/9 6/23/23, 1:43 AM Acute cholecystitis Pathway Consider visualizing stones in the common bile duct on abdominal ultrasound as a predictor of choledocholithiasis in patients with acute calculous cholecystitis. C As per TG 2018 guidelines: Obtain abdominal ultrasound as the first-choice imaging for the morphological diagnosis of acute cholecystitis, due to its low invasiveness, widespread availability, ease of use, and cost- effectiveness. B Avoid obtaining color or power Doppler ultrasound for the diagnosis of acute cholecystitis. Recognize that the evaluation of blood flow by Doppler ultrasound is strongly affected by factors such as device performance and the patient's body type which makes quantification difficult. D Further imaging, general population: As per WSES 2020 guidelines, consider obtaining further imaging for the diagnosis of acute calculous cholecystitis in selected patients, depending on local expertise and availability, recognizing that: hepatobiliary iminodiacetic acid scan has the highest sensitivity and specificity for the diagnosis of acute calculous cholecystitis diagnostic accuracy of CT is poor MRI has the same accuracy as abdominal ultrasound. B As per TG 2018 guidelines: Consider obtaining the following investigations to reduce the risk of bile duct injury in patients with acute cholecystitis: preoperative MRCP intraoperative fluorescence cholangiography intraoperative ultrasound. C Insufficient evidence to support the use of intraoperative cholangiography to reduce the risk of bile duct injury in patients with acute cholecystitis. I As per TG 2018 guidelines, obtain MRI/MRCP for the diagnosis of acute cholecystitis if abdominal ultrasound does not provide a definitive diagnosis. B Show 2 more As per EASL 2016 guidelines, consider obtaining abdominal CT in patients with a strong clinical suspicion of acute cholecystitis. C Further imaging (elderly patients): Recognize that: evidence on the diagnostic accuracy of CT are scarce and remain elusive diagnostic accuracy of MRI might be comparable to that of abdominal ultrasound in elderly patients, but no sufficient data are provided to support this hypothesis hepatobiliary iminodiacetic acid scan has the highest sensitivity and specificity for acute cholecystitis than other imaging modalities although its scarce availability, long time of execution and exposure to ionizing radiations limit its use. B Laboratory tests: https://web.pathway.md/diseases/recSrhoDrXV1gdurf 4/9 6/23/23, 1:43 AM Acute cholecystitis Pathway Obtain ALT, AST, GGT, bilirubin, and ALP to assess the risk of choledocholithiasis in all patients with acute calculous cholecystitis. B Insufficient evidence to support the use of procalcitonin for the diagnosis or severity grading in patients with acute cholecystitis. I Do not obtain routine blood cultures in patients with mild (grade I) community-acquired acute cholecystitis. D Evaluation for choledocholithiasis: Obtain the following tests to assess the risk of choledocholithiasis in patients with acute calculous cholecystitis: ALT, AST, GGT bilirubin, ALP abdominal ultrasound. B Show 4 more 4. Medical management Indications for non-operative management: Consider offering nonoperative management with antibiotics and observation in patients with acute calculous cholecystitis refusing or not suitable for surgery. C Consider offering alternative treatment options (such as gallstone dissolution or extracorporeal shock wave lithotripsy) in patients with acute calculous cholecystitis who have failed nonoperative management and are still refusing or not suitable for surgery. C Antibiotic therapy, general population: As per WSES 2020 guidelines: Administer antibiotics in patients with complicated acute calculous cholecystitis, based on the presumed pathogens and risk factors for major resistance patterns. A Adapt the targeted antibiotic regimen to the results of microbiological analysis, ensuring adequate antimicrobial coverage in patients at high risk for antimicrobial resistance or with complicated acute calculous cholecystitis. B As per TG 2018 guidelines, administer antimicrobial therapy in patients with mild-to-moderate (grade I-II) acute cholecystitis only before and at the time of surgery. B Show 3 more As per EASL 2016 guidelines, do not administer antibiotics in patients with mild acute cholecystitis without cholangitis, bacteremia/sepsis, abscess or perforation. D Antibiotic therapy (elderly patients): Administer broad-spectrum antibiotics in elderly patients with complicated acute cholecystitis. Guide the empiric antibiotic therapy by most frequently isolated bacteria taking into consideration antibiotic resistance and the clinical condition of the patient. B Consider using the results of microbiological analysis in designing targeted therapeutic strategies for individual patients with healthcare infections to customize antibiotic treatments and https://web.pathway.md/diseases/recSrhoDrXV1gdurf 5/9 6/23/23, 1:43 AM Acute cholecystitis Pathway ensure adequate antimicrobial coverage. B 5. Perioperative care Preoperative antibiotics: avoid administering routine antibiotic prophylaxis before elective laparoscopic cholecystectomy. D Postoperative antibiotics: do not administer routine postoperative antibiotics in patients with uncomplicated acute calculous cholecystitis if the focus of infection is controlled by cholecystectomy. D 6. Surgical interventions Cholecystectomy, indications: As per DSS 2022 guidelines, consider performing acute laparoscopic cholecystectomy in favor of gallbladder drainage in high-risk patients with acute cholecystitis. C As per WSES 2020 guidelines, perform laparoscopic cholecystectomy as first-line treatment in patients with acute calculous cholecystitis. A Show 2 more As per SICG/WSES 2019 guidelines, perform cholecystectomy as the preferred treatment of acute cholecystitis in elderly patients. B Show 3 more Cholecystectomy, timing: As per DSS 2022 guidelines, consider performing acute rather than delayed laparoscopic cholecystectomy in patients with acute cholecystitis. B As per WSES 2020 guidelines, perform immediate laparoscopic cholecystectomy as first-line treatment in high-risk patients with acute calculous cholecystitis, recognizing that laparoscopic cholecystectomy is superior to percutaneous transhepatic gallbladder drainage in this group of patients. A Show 3 more As per SICG/WSES 2019 guidelines, perform early laparoscopic cholecystectomy in elderly patients as soon as possible, within 10 days of onset of symptoms, recognizing that earlier surgery is associated with shorter hospital stay and fewer complications. B Cholecystectomy, surgical approach: As per WSES 2020 guidelines: Perform laparoscopic or open subtotal cholecystectomy in patients with acute calculous cholecystitis if anatomic identification is difficult or the risk of iatrogenic injuries is high. B Convert from laparoscopic to open cholecystectomy in patients with acute calculous cholecystitis and any of the following: severe local inflammation https://web.pathway.md/diseases/recSrhoDrXV1gdurf 6/9 6/23/23, 1:43 AM Acute cholecystitis Pathway adhesions bleeding from the Calot's triangle suspected bile injury. B As per SICG/WSES 2019 guidelines, consider performing laparoscopic or open subtotal cholecystectomy in elderly patients with advanced inflammation, gangrenous gallbladder, and "difficult gallbladder" where anatomy is difficult to be recognized and main bile duct injuries are highly probable. C Show 2 more As per TG 2018 guidelines, view intraoperative findings as appropriate indicators of surgical difficulty in laparoscopic cholecystectomy for acute cholecystitis. B Show 4 more Cholecystectomy (intraoperative bile and tissue cultures): consider obtaining bile and tissue cultures if perforation, emphysematous changes, or necrosis of gallbladder are noted during cholecystectomy. C Cholecystectomy (management of postoperative leaks): perform ERCP as first-line therapy for postoperative biliary leaks. A Gallbladder drainage, indications: As per DSS 2022 guidelines, consider performing percutaneous transhepatic gallbladder drainage as an interval procedure until delayed laparoscopic cholecystectomy in patients with acute cholecystitis and temporary contraindications to surgery. C As per WSES 2020 guidelines, perform gallbladder drainage in patients with acute calculous cholecystitis not suitable for surgery with an intention to control sepsis. B As per SICG/WSES 2019 guidelines: Consider performing percutaneous cholecystostomy for the treatment of elderly patients (> 65 years old) with acute calculous cholecystitis and American Society of Anesthesiologist III/IV, performance status 3 to 4, or septic shock, deemed unfit for surgery. C Consider performing percutaneous cholecystostomy as a bridge to cholecystectomy if medical therapy failed in acutely ill (high-risk) elderly patients deemed unfit for surgery, in order to convert them into a moderate risk patient, more suitable for surgery. C Gallbladder drainage, surgical technique: As per WSES 2020 guidelines, consider performing endoscopic transpapillary gallbladder drainage or endoscopic US-guided transmural gallbladder drainage as alternative options to percutaneous transhepatic gallbladder drainage in patients with acute calculous cholecystitis not suitable for surgery, if performed in high-volume centers by skilled endoscopists. B Show 2 more As per SICG/WSES 2019 guidelines, prefer percutaneous transhepatic approach for percutaneous cholecystostomy in elderly patients with acute cholecystitis. B As per TG 2018 guidelines, perform percutaneous transhepatic gallbladder drainage as standard drainage method in surgically high-risk patients with acute cholecystitis. B https://web.pathway.md/diseases/recSrhoDrXV1gdurf 7/9 6/23/23, 1:43 AM Acute cholecystitis Pathway Show 2 more Gallbladder drainage, timing for removal: As per WSES 2020 guidelines, remove metal stents within 4 weeks, if US-guided transmural gallbladder drainage was performed using metal stents, to avoid food impaction and subsequent high risk of acute calculous cholecystitis recurrence. B As per SICG/WSES 2019 guidelines, remove percutaneous cholecystostomy catheter 4-6 weeks after placement in elderly patients, if a cholangiography performed 2-3 weeks after percutaneous cholecystostomy demonstrated biliary tree patency. B Management of choledocholithiasis: remove common bile duct stones preoperatively, intraoperatively, or postoperatively, depending on local expertise and availability. A Likelihood Ratios Pertinent positives The following findings increase the probability of acute cholecystitis in adults. -1 Finding LR+ Value Presence of clinical impression of acute cholecystitis 25-30 Presence of findings of acute cholecystitis 2.7 (1.7-4.1) Presence of RUQ tenderness 1.6 (1.0-2.5) Pertinent negatives The following findings decrease the probability of acute cholecystitis in adults. -1 Finding LR- Value Absence of findings of acute cholecystitis 0.13 (0.04-0.39) Absence of Murphy's sign 0.5 (0.2-1.0) References 1. Harumi Gomi, Joseph S Solomkin, David Schlossberg et al. Tokyo Guidelines 2018 antimicrobial therapy for acute cholangitis and cholecystitis. J Hepatobiliary Pancreat Sci. 2018 Jan;25 1 3 16. Open 2. Pisano M, Ceresoli M, Cimbanassi S et al. 2017 WSES and SICG guidelines on acute calculous cholecystitis in elderly population. World J Emerg Surg. 2019 Mar 4;14 10. Open 3. ASGE Standards of Practice Committee, Krishnavel V Chathadi, Vinay Chandrasekhara et al. The role of ERCP in benign diseases of the biliary tract. Gastrointest Endosc. 2015 Apr;81 4 795 803. Open 4. Michele Pisano, Niccol Allievi, Kurinchi Gurusamy et al. 2020 World Society of Emergency Surgery updated guidelines for the diagnosis and treatment of acute calculus cholecystitis. World J Emerg Surg. 2020; 15 61. Open https://web.pathway.md/diseases/recSrhoDrXV1gdurf 8/9 6/23/23, 1:43 AM Acute cholecystitis Pathway 5. Yasuhisa Mori, Takao Itoi, Todd H Baron et al. Tokyo Guidelines 2018 management strategies for gallbladder drainage in patients with acute cholecystitis (with videos). J Hepatobiliary Pancreat Sci. 2018 Jan;25 1 87 95. Open 6. EASL. EASL Clinical Practice Guidelines on the prevention, diagnosis and treatment of gallstones. J Hepatol. 2016 Jul;65 1 146 181. Open 7. Masamichi Yokoe, Jiro Hata, Tadahiro Takada et al. Tokyo Guidelines 2018 diagnostic criteria and severity grading of acute cholecystitis (with videos). J Hepatobiliary Pancreat Sci. 2018 Jan;25 1 41 54. Open 8. Go Wakabayashi, Yukio Iwashita, Taizo Hibi et al. Tokyo Guidelines 2018 surgical management of acute cholecystitis: safe steps in laparoscopic cholecystectomy for acute cholecystitis (with videos). J Hepatobiliary Pancreat Sci. 2018 Jan;25 1 73 86. Open 9. Daniel M nsted Shabanzadeh, Dorthe Wiinholdt Christensen, Caroline Ewertsen et al. National clinical practice guidelines for the treatment of symptomatic gallstone disease: 2021 recommendations from the Danish Surgical Society. Scand J Surg. 2022 Aug 24;14574969221111027. Open 10. Lawrence M Knab, Anne-Marie Boller, David M Mahvi. Cholecystitis. 2014 Apr;94 2 455 70.2014 Apr;94 2 455 70. Open 11. Adrian A Indar, Ian J Beckingham. Acute cholecystitis. 2002 Sep 21;325 7365 639 43.2002 Sep 21;325 7365 639 43. Open 12. Valerie Halpin. Acute cholecystitis. 2014 Aug 20;2014 0411.2014 Aug 20;2014 0411. Open 13. Ansaloni L, Pisano M, Coccolini F et al. 2016 WSES guidelines on acute calculous cholecystitis. World J Emerg Surg. 2016 Jun 14;11 25. Open 14. Pisano M, Ceresoli M, Cimbanassi S et al. 2017 WSES and SICG guidelines on acute calcolous cholecystitis in elderly population. World J Emerg Surg. 2019 Mar 4;14 10. Open 15. Society of American Gastrointestinal and Endoscopic Surgeons. Choosing Wisely SAGES recommendations. Choosing Wisely. 2019. Open 16. Robert L Trowbridge, Nicole K Rutkowski, Kaveh G Shojania. Does this patient have acute cholecystitis?. JAMA. 2003 Jan 1;289 1 80 6. Open 17. Masamichi Yokoe, Jiro Hata, Tadahiro Takada et al. Tokyo Guidelines 2018 diagnostic criteria and severity grading of acute cholecystitis (with videos). J Hepatobiliary Pancreat Sci. 2018 Jan;25 1 41 54. Open 18. Kohji Okamoto, Kenji Suzuki, Tadahiro Takada et al. Tokyo Guidelines 2018 flowchart for the management of acute cholecystitis. J Hepatobiliary Pancreat Sci. 2018 Jan;25 1 55 72. Open 19. Expert Panel on Gastrointestinal Imaging:, Christine M Peterson, Michelle M McNamara et al. ACR Appropriateness Criteria Right Upper Quadrant Pain. J Am Coll Radiol. 2019 May;16 5S S235 S243. Open 20. Susumu Tazuma, Michiaki Unno, Yoshinori Igarashi et al. Evidence-based clinical practice guidelines for cholelithiasis 2016. J Gastroenterol. 2017 Mar;52 3 276 300. Open 21. Italian Association for the Study of the Liver AISF , Italian Association for the Study of the Liver AISF. AISF position paper on liver disease and pregnancy. Dig Liver Dis. 2016 Feb;48 2 120 37. Open https://web.pathway.md/diseases/recSrhoDrXV1gdurf 9/9

Guideline sources The following summarized guidelines for the evaluation and management of acute colonic pseudo- obstruction (ACPO) are prepared by our editorial team based on guidelines from the American Society for Gastrointestinal Endoscopy (ASGE 2020), the European Society of Gastrointestinal Endoscopy (ESGE 2020), and the American Society of Colon and Rectal Surgeons (ASCRS 2016). 1 2 3 Guidelines 1. Diagnostic investigations Initial assessment: Elicit a focused history, perform physical examination, and obtain the following tests in the initial evaluation of patients with suspected colonic volvulus: CBC serum electrolytes renal function tests diagnostic imaging. B 2. Medical management Conservative management: https://web.pathway.md/diseases/rect8YLQsr95UKtcB 1/3 6/23/23, 1:43 AM Acute colonic pseudo-obstruction Pathway Co se at e a age e t: As per ASGE 2020 guidelines, initiate conservative therapy as the preferred initial management, including identifying and correcting potentially contributing metabolic, infectious, and pharmacologic factors, in patients with uncomplicated ACPO (absence of ischemia, peritonitis, cecal diameter < 12 cm, and/or significant abdominal pain). E As per ASCRS 2016 guidelines, initiate supportive treatment in patients with ACPO and focus on the elimination or correction of conditions that predispose to ACPO or prolong its course. B Neostigmine: As per ASGE 2020 guidelines, initiate pharmacologic therapy with neostigmine (2 mg over 3-5 minutes) with appropriate cardiovascular monitoring in patients with ACPO not being candidates for conservative therapy, failed conservative therapy (up to 72 hours), or at risk for perforation and having no contraindication to its use. E Show 2 more As per ASCRS 2016 guidelines, initiate pharmacologic therapy with neostigmine in patients with ACPO not responding to supportive therapy. B 3. Therapeutic procedures Endoscopic decompression: As per ASGE 2020 guidelines, consider performing colonic decompression with decompression tube placement as an alternative in patients with ACPO not being candidates for conservative therapy or failed conservative therapy (up to 72 hours) and having no contraindication to endoscopy. E As per ESGE 2020 guidelines, consider performing endoscopic decompression of the colon in patients with ACPO not improving with conservative treatment. B Show 5 more As per ASCRS 2016 guidelines, consider performing endoscopic decompression of the colon in patients with ACPO if neostigmine therapy is contraindicated or ineffective. B Percutaneous colostomy creation: consider performing percutaneous endoscopic colostomy/cecostomy creation in patients with ACPO refractory to pharmacologic and endoscopic treatment, especially in patients not amenable to surgical intervention because of increased perioperative risk. B 4. Surgical interventions Indications for surgery: As per ASGE 2020 guidelines, perform surgery in patients with ACPO with overt perforation or signs of peritonitis. E As per ASCRS 2016 guidelines, perform surgery in patients with ACPO complicated by colon ischemia or perforation or ACPO refractory to pharmacologic and endoscopic therapies. B https://web.pathway.md/diseases/rect8YLQsr95UKtcB 2/3 6/23/23, 1:43 AM Acute colonic pseudo-obstruction Pathway References 1. Mariam Naveed, Laith H Jamil, Larissa L Fujii-Lau et al. American Society for Gastrointestinal Endoscopy guideline on the role of endoscopy in the management of acute colonic pseudo-obstruction and colonic volvulus. Gastrointest Endosc. 2020 Feb;91 2 228 235. Open 2. Vogel JD, Feingold DL, Stewart DB et al. Clinical Practice Guidelines for Colon Volvulus and Acute Colonic Pseudo-Obstruction. Dis Colon Rectum. 2016 Jul;59 7 589 600. Open 3. Bas L A M Weusten, Maximilien Barret, Albert J Bredenoord et al. Endoscopic management of gastrointestinal motility disorders - part 2 European Society of Gastrointestinal Endoscopy ESGE Guideline. Endoscopy. 2020 Jul;52 7 600 614. Open https://web.pathway.md/diseases/rect8YLQsr95UKtcB 3/3

Guideline sources The following summarized guidelines for the evaluation and management of acute compartment syndrome (ACS) are prepared by our editorial team based on guidelines from the Association of Anaesthetists of Great Britain and Ireland (AAGBI 2021), the American Academy of Orthopaedic Surgeons (AAOS 2020), the British Orthopaedic Association (BOA 2014), and the Acute Limb Compartment Syndrome Working Group (ALCS-WG 2010). 1 2 3 4 Guidelines 1. Diagnostic investigations Indications for assessment: As per AAGBI 2021 guidelines: Identify patients at risk of ACS on admission to the hospital or at the time of surgery. C Obtain post-injury and postoperative ward observations and surveillance to identify signs and symptoms of ACS. Use objective scoring charts for ACS identification. C As per BOA 2014 guidelines: https://web.pathway.md/diseases/recbxgvTobKs8b9qM 1/4 6/23/23, 1:44 AM Acute compartment syndrome Pathway s pe O 0 gu de es Assess for ACS as part of the routine evaluation of patients presenting with significant limb injuries, after surgery for limb injuries, and after any prolonged surgical procedure resulting in hypoperfusion of a limb. C Obtain routine nursing limb observations at hourly intervals for early signs of ACS in patients documented to be at risk of ACS. C Clinical examination: As per AAOS 2020 guidelines, obtain serial clinical examination to assist in diagnosing ACS. B As per BOA 2014 guidelines, obtain clinical assessment in patients with limb injuries, including: pain out of proportion to the associated injury pain on passive movement of the muscles of the involved compartments limb perfusion, including capillary refill and distal pulses neurological examination. C Show 3 more Serum biomarkers: consider measuring troponin levels to assist in diagnosing ACS in patients with traumatic lower extremity injury. C Show 2 more Urine biomarkers: Consider obtaining urine myoglobin testing to assist in diagnosing ACS in patients with traumatic lower extremity injury. C Do not use the presence of myoglobinuria to assist in diagnosing ACS in patients with electrical injury. D Other diagnostic modalities: do not obtain other diagnostic modalities (such as EMG or infrared spectroscopy) to guide decision-making for fasciotomy in patients with ACS. D 2. Diagnostic procedures Intracompartmental pressure measurement: As per AAOS 2020 guidelines, consider obtaining intracompartmental pressure monitoring to assist in diagnosing ACS. C Show 3 more As per BOA 2014 guidelines, obtain intracompartmental pressure measurement in situations where the clinical signs are not completely convincing. C 3. Medical management Blood pressure control: maintain normal BP in patients with symptoms or clinical signs of acute decompression syndrome. C https://web.pathway.md/diseases/recbxgvTobKs8b9qM 2/4 6/23/23, 1:44 AM Acute compartment syndrome Pathway 4. Nonpharmacologic interventions Removal of circumferential bandages: remove circumferential dressings and elevate the limb to heart level in all patients with symptoms or clinical signs of compartment syndrome. C 5. Therapeutic procedures Fracture stabilization: Perform operative fixation (external or internal) for initial stabilization of long bone fractures with concomitant ACS requiring fasciotomy. C Perform fracture stabilization using a technique (external fixation/casting) not violating the compartment in patients with evidence of irreversible intracompartmental (neuromuscular/vascular) damage. C Neuraxial anesthesia: As per AAGBI 2021 guidelines: Avoid administering neuraxial or peripheral regional anesthesia resulting in dense blocks of long duration significantly exceeding the duration of surgery. D Recognize that single-shot or continuous peripheral nerve blocks using lower concentrations of local anesthetic drugs without adjuncts do not delay ACS diagnosis, provided post-injury and postoperative surveillance is appropriate and effective. C As per AAOS 2020 guidelines, avoid administering neuraxial anesthesia as it may complicate ACS. Obtain frequent clinical assessment and/or pressure monitoring if neuraxial anesthesia is administered. D As per BOA 2014 guidelines, avoid administering regional anesthesia in high-risk patients as it can mask the symptoms of ACS. D 6. Surgical interventions Indications for fasciotomy: As per AAOS 2020 guidelines, do not perform fasciotomy in adult patients with evidence of irreversible intracompartmental (neuromuscular/vascular) damage. D As per BOA 2014 guidelines, perform urgent surgical decompression in patients with symptoms of ACS persisting 30 minutes after removing circumferential dressings and elevation of the limb. C Show 3 more Fasciotomy technique: As per AAOS 2020 guidelines, recognize that fasciotomy technique (one- versus two-incision, placement of incisions) is less important than achieving complete decompression of the compartments of the affected extremity. C https://web.pathway.md/diseases/recbxgvTobKs8b9qM 3/4 6/23/23, 1:44 AM Acute compartment syndrome Pathway As per BOA 2014 guidelines, perform a 2-incision 4-compartment decompression for lower leg fasciotomies. C Show 2 more Wound care: as per AAOS 2020 guidelines, consider offering negative pressure wound therapy to reduce the time to wound closure and the need for skin grafting in patients with fasciotomy wounds. C 7. Follow-up and surveillance Surgical re-exploration: perform re-exploration at approximately 48 hours, or earlier if clinically indicated, in all patients. C 8. Quality improvement Hospital requirements: As per AAGBI 2021 guidelines, ensure the availability of equipment for intracompartmental pressure measurement on wards caring for patients at risk of ACS. Ensure that the personnel is trained in its use and there are standard operating procedures available and implemented addressing the performance of such measurements and the urgent steps to be taken if measurements are abnormal. C As per BOA 2014 guidelines: Implement a clear, written management policy for patients with diagnostic uncertainty and for patients with risk factors where clinical assessment is not possible (such as reduced level of consciousness). C Ensure that hospitals treating patients with significant injuries have the capability to conduct intracompartmental pressure monitoring. C References 1. Col Patrick M Osborn, Andrew H Schmidt. Management of Acute Compartment Syndrome. J Am Acad Orthop Surg. 2020 Feb 1;28 3):e108-e114. Open 2. No authors listed. Diagnosis and Management of Compartment Syndrome of the Limbs. BOAST. 2014 Jul. Open 3. Christopher J Wall, Joan Lynch, Ian A Harris et al. Clinical practice guidelines for the management of acute limb compartment syndrome following trauma. ANZ J Surg. 2010 Mar;80 3 151 6. Open 4. M H Nathanson, W Harrop-Griffiths, D J Aldington et al. Regional analgesia for lower leg trauma and the risk of acute compartment syndrome: Guideline from the Association of Anaesthetists. Anaesthesia. 2021 Nov;76 11 1518 1525. Open https://web.pathway.md/diseases/recbxgvTobKs8b9qM 4/4

Guideline sources The following summarized guidelines for the evaluation and management of acute cystitis are prepared by our editorial team based on guidelines from the European Association of Urology (EAU 2022), the Infectious Diseases Society of America (IDSA 2022; 2016), the American College of Physicians (ACP 2021), the German Society of Urology (GUS 2018), the Spanish Society of Clinical Microbiology and Infectious Diseases (SEIMC 2017), the American Urological Association (AUA 2017), the Infectious Diseases Society of America (IDSA/ESCMID 2011), and the American Association of Family Physicians (AAFP 2011). 1 2 3 4 5 6 7 7 7 7 8 9 10 Definition Acute uncomplicated cystitis is a lower UTI occurring in the absence of anatomic or functional abnormalities of the urinary tract or any other complicating factors. 10 Epidemiology Acute uncomplicated cystitis is mostly caused by bacteria, including E. coli (86%), S. saprophyticus (4%), Klebsiella species (3%), Proteus species (3%), Enterobacter species (1.4%), Citrobacter species (0.8%), and Enterococcus species (0.5%). 7 Disease course https://web.pathway.md/diseases/recrCqxg7Xppqpnel 1/6 6/23/23, 1:38 AM Acute cystitis Pathway Disease course Bacterial infection of the lower urinary tract results in acute uncomplicated cystitis, which causes classic symptoms of dysuria, frequent voiding of small volumes, and urinary urgency. Occasional hematuria and suprapubic discomfort may be present. 7 Prognosis and risk of recurrence Acute uncomplicated cystitis is not associated with an increase in mortality. 7 Calculator Pediatric Emergency Care Appli Guidelines 1. Screening and diagnosis Etiology: Recognize that the most common cause of uncomplicated UTIs is E. coli, followed by S. saprophyticus, K. pneumoniae, and P. mirabilis. Recognize that other pathogens are rare. A Recognize that Enterococci are most commonly found in mixed infections, therefore, their pathogenicity is uncertain in uncomplicated UTIs. B Diagnostic criteria: As per EAU 2022 guidelines, diagnose uncomplicated cystitis in females with no other risk factors for complicated UTIs based on a focused history of LUTS (dysuria, frequency, and urgency) and the absence of vaginal discharge. A As per GUS 2018 guidelines: Suspect uncomplicated cystitis with high probability in female patients with typical symptoms (pain on micturition, pollakiuria, urgency), no vaginal symptoms (itching, altered discharge), no fever and flank pain, and in the absence of risk factors for complicated UTIs. B View colony counts of 10 CFU/mL of a typical uropathogen as clinically significant for acute uncomplicated cystitis in female patients with typical symptoms. B As per SEIMC 2017 guidelines, define a culture of 10 CFU/mL of a uropathogen as significant for cystitis in symptomatic female patients, A and a culture of 10 CFU/mL in male patients. B Differential diagnosis: Evaluate for other diagnoses, such as gynecological infections (chlamydia or trichomonas infection) at an early stage in patients with nonspecific symptoms, or inconsistent urine examination, including negative urine culture. B https://web.pathway.md/diseases/recrCqxg7Xppqpnel 2/6 6/23/23, 1:38 AM Acute cystitis Pathway Consider evaluating for other diagnoses in patients presenting with vaginal complaints, B such as vaginal itching or vaginal discharge. B 2. Classification and risk stratification Severity assessment: use the Acute Cystitis Symptom Score to assess the severity of symptoms, the course of the disease over time, and the effect of therapy. B 3. Diagnostic investigations History and physical examination: obtain a symptom-related medical examination with clinical examination in the first presentation of acute UTI or if the patient is unknown to the physician. B Urine dipstick: As per EAU 2022 guidelines, obtain urine dipstick testing for the diagnosis of acute uncomplicated cystitis. B As per GUS 2018 guidelines: Consider obtaining a urine dipstick for nitrite/WBCs to rule out UTI with sufficient certainty in patients with a low pretest probability. C Recognize that the presence of RBCs, WBCs, and nitrites independently increases the likelihood of the presence of a UTI, and the combination of the positive findings further increases the likelihood of the diagnosis. B Urine culture: As per EAU 2022 guidelines, obtain urine culture in the following situations: suspected acute pyelonephritis symptoms not resolving or recurring within 4 weeks after completion of treatment females presenting with atypical symptoms pregnant patients. A As per GUS 2018 guidelines, do not obtain urine culture in female patients with uncomplicated, non-recurrent or -refractory cystitis with clear clinical symptoms. D Show 2 more As per SEIMC 2017 guidelines, obtain a pre-treatment urine culture if the diagnosis is not clear from the history and physical examination, the episode represents an early symptomatic recurrence, there is reason to suspect antimicrobial resistance, or the patient's therapeutic options are limited due to medication intolerance. B Show 2 more Urethrocystoscopy: Perform urethrocystoscopy in patients with persistent hematuria or persistent detection of pathogens other than E. coli. B https://web.pathway.md/diseases/recrCqxg7Xppqpnel 3/6 6/23/23, 1:38 AM Acute cystitis Pathway Do not perform routine cystoscopy in female patients without recurrent UTIs and without relevant comorbidities. D Diagnostic imaging: obtain further imaging in patients with persistent hematuria or persistent detection of pathogens other than E. coli. B 4. Medical management Antibiotic therapy, first-line therapy: As per EAU 2022 guidelines, initiate fosfomycin trometamol, pivmecillinam, or nitrofurantoin as first-line therapy in female patients with uncomplicated cystitis. A As per ACP 2021 guidelines, initiate a short course of antibiotics with either nitrofurantoin for 5 days, TMP-sulfamethoxazole for 3 days, or fosfomycin as a single dose in female patients with uncomplicated bacterial cystitis. B As per SEIMC 2017 guidelines: Initiate fosfomycin trometamol (3 g in a single dose) or nitrofurantoin (for 5-7 days) as first-line therapy in female patients with uncomplicated cystitis, due to minimal resistance and propensity for collateral damage. A Complete a longer course of antibiotic therapy (at least 7 days) in male patients and in female patients with symptoms > 7 days, recent UTI, diabetes, renal insufficiency, immunosuppression, or with a vaginal diaphragm. B As per AAFP 2011 guidelines, initiate nitrofurantoin macrocrystals (100 mg BID for 5 days), TMP-sulfamethoxazole (160/800 mg BID for 3 days in regions where the uropathogen resistance is < 20%), or fosfomycin (a single 3-g dose) as first-line therapy in patients with acute uncomplicated cystitis. B As per ESCMID/IDSA 2011 guidelines, initiate any of the following regimens as first-line therapy in female patients with uncomplicated cystitis: nitrofurantoin monohydrate/macrocrystals 100 mg BID for 5 days, due to minimal resistance and propensity for collateral damage and efficacy compared to 3 days of TMP- sulfamethoxazole TMP-sulfamethoxazole 160/800 mg BID for 3 days, if local resistance rates of uropathogens causing acute uncomplicated cystitis are < 20% or if the infecting strain is known to be susceptible fosfomycin trometamol 3 g in a single dose, due to minimal resistance and propensity for collateral damage, recognizing that it appears to have inferior efficacy compared with standard short-course regimens pivmecillinam (in regions where it is available) 400 mg BID for 3-7 days, due to minimal resistance and propensity for collateral damage, recognizing that it may have inferior efficacy compared with other available therapies. A Antibiotic therapy, second-line therapy: https://web.pathway.md/diseases/recrCqxg7Xppqpnel 4/6 6/23/23, 1:38 AM Acute cystitis Pathway As per EAU 2022 guidelines, do not use aminopenicillins or fluoroquinolones for the treatment of uncomplicated cystitis. D As per AUA 2017 guidelines, do not use fluoroquinolones for the treatment of female patients with uncomplicated cystitis if other oral antibiotic treatment options exist. D As per SEIMC 2017 guidelines, consider reserving fluoroquinolones as alternative antimicrobials because of their high propensity for collateral damage C despite their high efficacy in 3-day regimens. B Show 2 more As per ESCMID/IDSA 2011 guidelines, reserve fluoroquinolones, ofloxacin, ciprofloxacin, and levofloxacin as alternative options for acute cystitis because of the propensity for collateral damage. B Show 2 more 5. Specific circumstances Patients with antimicrobial-resistant UTI: consider initiating ceftriaxone as a treatment option in patients with uncomplicated cystitis caused by organisms at moderate-to-high risk of clinically significant AmpC production (E. cloacae, K. aerogenes, and C. freundii) when susceptibility is demonstrated. E Show 8 more Landmark trials: ALLIUM In adult patients with a clinical diagnosis of complicated UTI or acute pyelonephritis caused by Gram-negative urinary pathogens, cefepime/enmetazobactam was superior to piperacillin/tazobactam with respect to overall treatment success at day 14. Keith S Kaye et al. JAMA. 2022 Oct 4. Patients with Candida UTI: initiate oral fluconazole 200 mg (3 mg/kg) daily for 2 in patients with symptomatic Candida cystitis caused by fluconazole-susceptible organisms. B Show 5 more 6. Preventative measures Periprocedural antibiotic prophylaxis: do not use antibiotic prophylaxis to reduce the rate of symptomatic urinary infection following urodynamics, cystoscopy, or extracorporeal shockwave lithotripsy. D Show 4 more https://web.pathway.md/diseases/recrCqxg7Xppqpnel 5/6 6/23/23, 1:38 AM Acute cystitis Pathway 7. Follow-up and surveillance Post-treatment surveillance: do not obtain routine post-treatment cultures in asymptomatic female patients following treatment for cystitis. D References 1. G. Bonkat, R. Bartoletti, F. Bruy re et al. EAU Guidelines on Urological Infections. EAU. 2022. Open 2. Kranz J, Schmidt S, Lebert C et al. The 2017 Update of the German Clinical Guideline on Epidemiology, Diagnostics, Therapy, Prevention, and Management of Uncomplicated Urinary Tract Infections in Adult Patients: Part 1. Urol Int. 2018;100 3 263 270. Open 3. Gupta K, Hooton TM, Naber KG et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 2011 Mar 1;52 5):e103 20. Open 4. de Cueto M, Aliaga L, Al s JI et al. Executive summary of the diagnosis and treatment of urinary tract infection: Guidelines of the Spanish Society of Clinical Microbiology and Infectious Diseases SEIMC . Enferm Infecc Microbiol Clin. 2017 May;35 5 314 320. Open 5. Pappas PG, Kauffman CA, Andes DR et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016 Feb 15;62 4):e1 50. Open 6. Rachael A Lee, Robert M Centor, Linda L Humphrey et al. Appropriate Use of Short-Course Antibiotics in Common Infections: Best Practice Advice From the American College of Physicians. Ann Intern Med. 2021 Apr 6. Open 7. Richard Colgan, Mozella Williams. Diagnosis and treatment of acute uncomplicated cystitis. Am Fam Physician. 2011 Oct 1;84 7 771 6. Open 8. Pranita D. Tamma, Samuel L. Aitken, Robert A. Bonomo et al. Infectious Diseases Society of America Guidance on the Treatment of Extended-Spectrum -lactamase Producing Enterobacterales ESBL E , Carbapenem-Resistant Enterobacterales CRE , and Pseudomonas aeruginosa with Difficult-to-Treat Resistance DTR P. aeruginosa). IDSA. 2022 Mar 7. Open 9. American Urological Association. Choosing Wisely AUA recommendations. Choosing Wisely. 2017. Open 10. No authors listed. Recurrent uncomplicated cystitis in women: allowing patients to self-initiate antibiotic therapy. 2014 Feb;23 146 47 9.2014 Feb;23 146 47 9. Open https://web.pathway.md/diseases/recrCqxg7Xppqpnel 6/6

Guideline sources The following summarized guidelines for the evaluation and management of acute diarrhea are prepared by our editorial team based on guidelines from the Infectious Diseases Society of America (IDSA 2017) and the American College of Gastroenterology (ACG 2016). 1 2 3 3 4 5 6 Definition Acute diarrhea is a clinical syndrome that is defined as the passage of 3 or more unformed stools per day for less than 2 weeks. 3 Epidemiology Frequent causes include viruses (norovirus, rotavirus), bacteria (Campylobacter, C. difficile, Salmonella, E. coli, Shigella), parasites (Giardia, Cryptosporidium), side-effects of medications (antibiotics, colchicine), abdominal surgeries, gastroenterologic diseases (ulcerative colitis, Crohn's disease, diverticulitis, appendicitis), and endocrine diseases (hyperthyroidism, carcinoid tumors). 4 Pathophysiology https://web.pathway.md/diseases/rec0RaPLxgg1546ED 1/7 6/23/23, 1:44 AM Acute diarrhea Pathway In the United States, the incidence of acute diarrhea is approximately 60,000 cases per 100,000 person-years. 3 Disease course Untreated, severe diarrhea may lead to dehydration, renal failure, and shock. 5 Prognosis and risk of recurrence In developing countries, it is a common cause of death, especially in children. 6 Guidelines 1. Diagnostic investigations Clinical history: Obtain a detailed clinical and exposure history in patients presenting with acute diarrhea. B Evaluate for postinfectious and extraintestinal manifestations of enteric infections in patients with acute diarrhea. B Physical examination: assess patients with acute diarrhea for dehydration, which increases the risk of life-threatening illness and death, especially in young and elderly patients. A Complete blood count: consider obtaining a peripheral WBC count and differential in patients with acute diarrhea. C Blood cultures: obtain blood cultures in patients of any age with signs of septicemia or when enteric fever is suspected, patients with systemic manifestations of infection, patients who are immunocompromised, patients with certain high-risk conditions such as hemolytic anemia, infants < 3 months of age, and patients who traveled to or have had contact with travelers from enteric fever-endemic areas with a febrile illness of unknown etiology. B Clostridioides difficile testing: consider testing for C. difficile infection in patients with persistent diarrhea without an etiology and recognized risk factors. C Show 2 more Indications for diagnostic testing: As per IDSA 2017 guidelines, obtain stool testing for Salmonella, Shigella, Campylobacter, Yersinia, C. difficile, and Shiga toxin-producing E. coli in patients with diarrhea accompanied by fever, bloody or mucoid stools, severe abdominal cramping or tenderness, or signs of sepsis. B Show 3 more Updated evidence: GastroPOC In adult patients hospitalized with suspected gastroenteritis, molecular point-of-care testing was superior to routine clinical care with respect to duration of single-occupancy room isolation. https://web.pathway.md/diseases/rec0RaPLxgg1546ED 2/7 6/23/23, 1:44 AM Acute diarrhea Pathway Nathan J Brendish et al. Lancet Infect Dis. 2023 Apr 25. As per ACG 2016 guidelines: Obtain stool testing in patients with acute diarrhea who are at high risk of spreading disease to others, and during known or suspected outbreaks. B Consider obtaining stool testing, if available, in patients with dysentery, moderate-severe disease, and symptoms lasting > 7 days, in order to clarify the etiology of the patient's illness and enable specific directed therapy. B Culture-independent stool testing: As per IDSA 2017 guidelines, perform culture-independent, including panel-based multiplex molecular diagnostics from stool and blood specimens, and, when indicated, culture-dependent diagnostic testing, when there is a clinical suspicion of enteric fever or diarrhea with bacteremia. B Show 5 more As per ACG 2016 guidelines, consider culture-independent methods of diagnosis, if available, as an adjunct to traditional methods to identify infectious causes of acute diarrhea. B Diagnostic imaging: Consider obtaining diagnostic imaging to detect aortitis, mycotic aneurysms, or extravascular foci of infection in patients with S. enterica or Yersinia infections and: sustained fever or bacteremia despite adequate antimicrobial therapy underlying atherosclerosis recent-onset chest, back, or abdominal pain. C Fecal leukocytes: avoid using fecal leukocyte examination to establish the cause of acute infectious diarrhea. D Fecal lactoferrin: avoid using fecal lactoferrin to establish the cause of acute infectious diarrhea. D Fecal calprotectin: insufficient evidence to make a recommendation on the value of fecal calprotectin measurements in people with acute infectious diarrhea. C Antibiotic sensitivity testing: avoid obtaining routine antibiotic sensitivity testing for individuals with acute diarrheal infection. D 2. Diagnostic procedures Upper GI endoscopy: consider obtaining a duodenal aspirate in patients in whom there is a suspected diagnosis of Giardia, Strongyloides, Cystoisospora, or microsporidia infection. C Lower GI endoscopy: Consider performing colonoscopy or a proctoscopic examination: in patients with persistent, unexplained diarrhea who have AIDS in patients with certain underlying medical conditions in patients with acute diarrhea with clinical colitis or proctitis https://web.pathway.md/diseases/rec0RaPLxgg1546ED 3/7 6/23/23, 1:44 AM Acute diarrhea Pathway in patients with persistent diarrhea who engage in anal intercourse. B 3. Medical management General principles: avoid empiric anti-microbial therapy for acute diarrheal infection, except in cases of travellers' diarrhea, where the likelihood of bacterial pathogens is high enough to justify the potential side effects of antibiotics. D Show 2 more Treatment of dehydration: As per IDSA 2017 guidelines, administer reduced osmolarity oral rehydration solution as the first-line therapy for mild-to-moderate dehydration in pediatric and adult patients with acute diarrhea from any cause, and in patients with mild-to-moderate dehydration associated with vomiting or severe diarrhea. B Show 5 more As per ACG 2016 guidelines, provide balanced oral electrolyte rehydration for most patients with acute diarrhea who can keep up with fluid and salt consumption PO. B Symptomatic therapy: As per IDSA 2017 guidelines, consider providing symptomatic treatment with antimotility, antinausea, or antiemetic agents once the patient is adequately hydrated, but avoid using them as a substitute for fluid and electrolyte therapy. C Show 3 more As per ACG 2016 guidelines, consider bismuth subsalicylates to control rates of passage of stool and help travellers function better during bouts of mild-to-moderate diarrheal illness. B Empiric antibiotic therapy (bloody diarrhea): Avoid empiric antimicrobial therapy for bloody diarrhea while waiting for results of investigations in immunocompetent pediatric and adult patients D , except in the following situations: infants < 3 months of age with suspicion of a bacterial etiology ill immunocompetent patients with fever documented in a medical setting, abdominal pain, bloody diarrhea, and bacillary dysentery, as evidenced by frequent scant bloody stools, fever, abdominal cramps, and tenesmus, presumptively due to Shigella patients who have recently travelled internationally with body temperatures 38.5 C and/or signs of sepsis D Show 4 more Empiric antibiotic therapy (watery diarrhea): avoid empiric antimicrobial therapy in most patients with acute watery diarrhea and without recent international travel. D Show 2 more Choice of antibiotic agent: treat patients with clinical features of sepsis who are suspected of having enteric fever empirically with broad-spectrum antimicrobial therapy after blood, stool, and urine culture collection. B Show 5 more https://web.pathway.md/diseases/rec0RaPLxgg1546ED 4/7 6/23/23, 1:44 AM Acute diarrhea Pathway 4. Nonpharmacologic interventions Probiotics: As per IDSA 2017 guidelines, consider offering probiotic preparations to reduce the symptom severity and duration in immunocompetent adult and pediatric patients with infectious or antimicrobial-associated diarrhea. C As per ACG 2016 guidelines, avoid the use of probiotics or prebiotics for the treatment of acute diarrhea in adults, except in cases of postantibiotic-associated illness. D 5. Specific circumstances Patients with traveler's diarrhea: avoid obtaining diagnostic testing in most patients with uncomplicated traveler's diarrhea, unless treatment is indicated. D Show 2 more Patients with STEC infection: Obtain a peripheral blood smear to assess for the presence of RBC fragments when HUS is suspected. A Monitor Hgb and platelet counts, electrolytes, and BUN and creatinine in patients with E. coli O157 or another Shiga toxin-producing E. coli infection (especially Shiga toxin-producing E. coli that produce Shiga toxin 2 or are associated with bloody diarrhea), in order to detect hematologic and renal function abnormalities that are early manifestations of HUS and precede renal injury. A Immunocompromised patients: Develop a broad differential diagnosis in immunocompromised patients with diarrhea, especially those with moderate and severe primary or secondary immune deficiencies, and obtain evaluation of stool specimens by culture, viral studies, and examination for parasites. B Perform additional testing for other organisms including, but not limited to, Cryptosporidium, Cyclospora, Cystoisospora, microsporidia, Mycobacterium avium complex, and CMV, in patients with acquired immune deficiency syndrome and persistent diarrhea. B Patients with asymptomatic infection: consider treating all asymptomatic patients with S. enterica subspecies enterica serovar Typhi in their stool, in order to reduce potential for transmission. C Show 2 more 6. Patient education Food safety practices: counsel patients on appropriate food safety practices to avoid cross- contamination of other foods or cooking surfaces and utensils during grocery shopping, food preparation, and storage; advise patients to ensure that foods containing meats and eggs are cooked and maintained at proper temperatures. B https://web.pathway.md/diseases/rec0RaPLxgg1546ED 5/7 6/23/23, 1:44 AM Acute diarrhea Pathway Pretravel counseling: counsel patients who are planning to travel regarding high-risk food/beverage avoidance to prevent traveler's diarrhea. B 7. Preventative measures Hand hygiene: As per IDSA 2017 guidelines, counsel patients to perform hand hygiene after using the bathroom, changing diapers, before and after preparing food, before eating, after handling garbage or soiled laundry items, and after touching animals or their feces or environments, especially in public settings such as petting zoos. B Show 2 more As per ACG 2016 guidelines, recognize that frequent and effective hand washing and alcohol- based hand sanitizers is of limited value in preventing most forms of traveler's diarrhea, but may be useful where low-dose pathogens are responsible for the illness (such as during a cruise ship outbreak of norovirus infection, institutional outbreak, or in endemic diarrhea prevention). B Rotavirus immunization: provide rotavirus immunization to all infants without a known contraindication. A Typhoid immunization: Provide typhoid immunization, as an adjunct to hand hygiene and the avoidance of high-risk foods and beverages, in the following clinical scenarios: patients who are planning travel to areas with moderate to high risk for exposure to S. enterica subspecies enterica serovar Typhi patients with intimate exposure to a documented S. enterica subspecies enterica serovar Typhi chronic carrier microbiologists and other laboratory personnel routinely exposed to cultures of S. enterica subspecies enterica serovar Typhi. A Cholera immunization: provide cholera immunization (live attenuated vaccine) to patients 18-64 years of age who travel to cholera-affected areas, unless contraindicated. A Antibiotic prophylaxis: consider short-term antibiotic prophylaxis in selected situations for patients at high-risk of bacterial diarrheal illness. B Bismuth subsalicylates: consider bismuth subsalicylates for the prevention of diarrhea in travelers who do not have any contraindications to use and can adhere to the frequent dosing requirements. B 8. Follow-up and surveillance Public health reporting: report all diseases listed in the table of National Notifiable Diseases Surveillance System at the national level, including those that cause diarrhea, to the appropriate state, territorial, or local health department with submission of isolates of certain pathogens such as Salmonella, Shiga toxin-producing E. coli, Shigella, and Listeria, to ensure implementation of control and prevention practices. A https://web.pathway.md/diseases/rec0RaPLxgg1546ED 6/7 6/23/23, 1:44 AM Acute diarrhea Pathway Show 2 more Follow-up testing: avoid obtaining follow-up testing in most patients following resolution of diarrhea. D Show 2 more Management of nonresponse to treatment: As per IDSA 2017 guidelines, consider performing a clinical and laboratory reevaluation, also taking into account noninfectious conditions including lactose intolerance, in patients who do not respond to an initial course of therapy. C Show 2 more As per ACG 2016 guidelines, avoid obtaining serological testing or endoscopy in individuals with persistent diarrheal symptoms for < 30 days. D References 1. Riddle MS, DuPont HL, Connor BA. ACG Clinical Guideline: Diagnosis, Treatment, and Prevention of Acute Diarrheal Infections in Adults. Am J Gastroenterol. 2016 May;111 5 602 22. Open 2. Shane AL, Mody RK, Crump JA et al. 2017 Infectious Diseases Society of America Clinical Practice Guidelines for the Diagnosis and Management of Infectious Diarrhea. Clin Infect Dis. 2017 Nov 29;65 12):e45-e80. Open 3. DuPont HL. Acute infectious diarrhea in immunocompetent adults. N Engl J Med. 2014 Apr 17;370 16 1532 40. Open 4. Wendy Barr, Andrew Smith. Acute diarrhea. Am Fam Physician. 2014 Feb 1;89 3 180 9. Open 5. Surawicz CM. Mechanisms of diarrhea. Curr Gastroenterol Rep. 2010 Aug;12 4 236 41. Open 6. Gottlieb T, Heather CS. Diarrhoea in adults (acute). BMJ Clin Evid. 2011 Feb 15;2011. pii: 0901. Open 7. Riddle MS, Connor BA, Beeching NJ et al. Guidelines for the prevention and treatment of travelers' diarrhea: a graded expert panel report. J Travel Med. 2017 Apr 1;24(suppl_1 S57 S74. Open 8. American Society for Clinical Pathology. Choosing Wisely ASCP recommendations. Choosing Wisely. 2019. Open 9. Infectious Diseases Society of America. Choosing Wisely IDSA recommendations. Choosing Wisely. 2015. Open 10. Gregory Juckett, Rupal Trivedi. Evaluation of chronic diarrhea. Am Fam Physician. 2011 Nov 15;84 10 1119 26. Open 11. J Aranda-Michel, R A Giannella. Acute diarrhea: a practical review. Am J Med. 1999 Jun;106 6 670 6. Open 12. Yasmine Gaber. Diarrhoea and the COVID 19 pandemic. Arab J Gastroenterol. 2020 Sep;21 3 146 150. Open 13. ASGE Standards of Practice Committee, Bo Shen, Khalid Khan et al. The role of endoscopy in the management of patients with diarrhea. Gastrointest Endosc. 2010 May;71 6 887 92. Open https://web.pathway.md/diseases/rec0RaPLxgg1546ED 7/7

Guideline sources The following summarized guidelines for the evaluation and management of acute diverticulitis are prepared by our editorial team based on guidelines from the American College of Radiology (ACR 2023; 2022), the Academy of Emergency Medicine and Care (AcEMC/SIFIPAC/SICUT/WSES/ACOI/SICG 2022), the German Society of General and Visceral Surgery (DGAV/DGVS 2022), the American College of Physicians (ACP 2022), the European Society of Coloproctology (ESCP 2020), the World Society of Emergency Surgery (WSES 2020), the American Society of Colon and Rectal Surgeons (ASCRS 2020; 2014), the Japanese Gastroenterological Association (JGA 2019), and the American Gastroenterological Association (AGA 2015). 1 2 3 4 5 6 7 8 9 10 11 12 13 13 14 15 Definition https://web.pathway.md/diseases/rec3Z5lhIppiQuZrO 1/13 6/23/23, 1:44 AM Acute diverticulitis Pathway Acute diverticulitis is a disease resulting from acute inflammation and/or micro-perforation of colonic diverticula. 12 Epidemiology The putative etiology of acute diverticulitis include alterations in colonic structure, colonic motility, microbiome, genetics, immune system, in addition to connective tissue disorders and environmental factors (obesity, smoking, non-steroidal anti-inflammatory drugs). 14 Pathophysiology The incidence of acute diverticulitis has increased in the past several decades and is estimated at 188 cases per 100,000 person-years in the United States. 13 Disease course Alterations in gut motility, intraluminal pressure, and the accumulation of inspissated fecal particles in diverticula leads to erosion of the diverticular wall, causing inflammation that can progress to perforation and diffuse peritonitis. The sequelae of diverticula covered by mesentery may cause phlegmons or abscesses, as well as fistulas. 15 Prognosis and risk of recurrence Acute diverticulitis has a recurrence rate of 13-23% in patients with uncomplicated disease, and around 40% in patients with complicated disease. 13 Guidelines 1. Screening and diagnosis Differential diagnosis: Include diverticulitis in the differential diagnosis of acute abdominal pain, even in younger patients (< 40 years of age). B Include diverticulitis in the differential diagnosis of acute abdominal pain, even if the localization of pain is right-sided or suprapubic. E 2. Diagnostic investigations Initial evaluation: As per DGVS 2022 guidelines, elicit medical history B and perform a physical examination in patients with suspected diverticulosis. B Show 3 more As per WSES 2020 guidelines: https://web.pathway.md/diseases/rec3Z5lhIppiQuZrO 2/13 6/23/23, 1:44 AM Acute diverticulitis Pathway Consider obtaining a complete assessment including clinical history, signs, laboratory inflammation markers, and radiological findings in patients with suspected acute left-sided colonic diverticulitis. C Do not rely solely on clinical examination for the diagnosis of patients with suspected acute left-sided colonic diverticulitis. D As per JGA 2019 guidelines, examine for complications such as abscess, perforation, and peritonitis at the initial assessment for colonic diverticulitis. B As per ASCRS 2014 guidelines, elicit problem-specific history, perform a physical examination, and obtain appropriate laboratory studies in the initial evaluation of patients with suspected acute diverticulitis. B Diagnostic imaging: As per ACR 2023 guidelines, obtain CT of the abdomen and pelvis with IV contrast for the initial imaging of LLQ pain, including suspected diverticulitis or complications of complications. B As per ACP 2022 guidelines, consider obtaining abdominal CT if there is diagnostic uncertainty in patients with suspected acute left-sided colonic diverticulitis. C As per ACR 2022 guidelines, obtain CT of the abdomen and pelvis with IV contrast for the initial imaging of RLQ pain. B As per DGVS 2022 guidelines, obtain cross-sectional imaging (ultrasound or CT) to confirm the diagnosis of diverticulitis. A Show 2 more As per ESCP 2020 guidelines, obtain imaging to confirm the diagnosis of acute diverticulitis if there is no proceeding diagnostic information. B Show 3 more As per WSES 2020 guidelines, consider obtaining an ultrasound (by an expert operator) in the initial evaluation of patients with suspected acute left-sided colonic diverticulitis. C Show 2 more As per JGA 2019 guidelines, obtain diagnostic imaging (CT scan of the abdomen and pelvis or abdominal ultrasound) in patients with suspected acute diverticulitis, in addition to physical examination and laboratory testing. B As per ASCRS 2014 guidelines: Obtain CT of the abdomen and pelvis as the most appropriate initial imaging modality for the assessment of patients with suspected acute diverticulitis. B Consider ultrasound and MRI as useful alternatives for the initial evaluation of patients with suspected acute diverticulitis when CT is not available or is contraindicated. B Poppy seed test: obtain a poppy seed test in patients with suspected sigmovesical fistula, if the fistula has not already been described morphologically (ultrasound, CT, MRI, colonoscopy). B 3. Diagnostic procedures https://web.pathway.md/diseases/rec3Z5lhIppiQuZrO 3/13 6/23/23, 1:44 AM Acute diverticulitis Pathway Colonoscopy: consider performing a colonoscopy (probably with a slightly increased risk of perforation) in certain situations (such as an uncharacteristic clinical picture or disease course) in patients with acute diverticulitis, provided covert perforation and abscesses have been ruled out. C Show 4 more 4. Medical management Setting of care: As per ACP 2022 guidelines, manage most patients with acute uncomplicated left-sided colonic diverticulitis in an outpatient setting. B As per ESCP 2020 guidelines, consider managing patients with uncomplicated diverticulitis in an outpatient setting in the absence of sepsis, significant comorbidity, immunosuppression and with an adequate social network tolerating oral intake. C As per WSES 2020 guidelines, consider managing patients with uncomplicated acute left-sided colonic diverticulitis and no comorbidities in an outpatient setting. Consider reevaluation within 7 days. Reevaluate earlier if the clinical condition deteriorates. C Indications for non-operative management: As per ESC 2020 guidelines, consider observing immunocompetent hemodynamically stable patients with diverticulitis even if there are radiological signs of extraluminal air. C As per WSES 2020 guidelines: View immunocompromised patients with acute left-sided colonic diverticulitis as patients at high risk for failure of standard, nonoperative treatment. B Consider a nonoperative treatment in selected patients with CT findings of distant free gas without diffuse intra-abdominal fluid, only if a close follow-up can be performed. C Antibiotic therapy: As per ACP 2022 guidelines, manage selected patients with acute uncomplicated left-sided colonic diverticulitis initially without antibiotics. B As per ASCRS 2020 guidelines: Treat selected patients with uncomplicated diverticulitis without antibiotics. A Consider antibiotic therapy for nonoperative treatment of patients with diverticulitis. B As per ESCP 2020 guidelines, do not routinely offer antibiotic therapy in patients with acute uncomplicated diverticulitis. Show 2 more As per WSES 2020 guidelines, do not offer antibiotic therapy for immunocompetent patients with uncomplicated diverticulitis without signs of systemic inflammation. D Show 5 more As per JGA 2019 guidelines, consider antibiotic therapy in patients with acute diverticulitis, acknowledging that antibiotics have been reported to be unnecessary for colonic diverticulitis https://web.pathway.md/diseases/rec3Z5lhIppiQuZrO 4/13 6/23/23, 1:44 AM Acute diverticulitis Pathway without abscess or perforation. C Show 2 more As per AGA 2015 guidelines, consider the use of antibiotics selectively, rather than routinely, in patients with acute uncomplicated diverticulitis. C As per ASCRS 2014 guidelines, administer oral or IV antibiotics and implement dietary modification in most patients with diverticulitis who are managed nonoperatively. B Nonsteroidal anti-inflammatory drugs: consider advising patients with a history of diverticulitis to avoid the use of nonsteroidal anti-inflammatoy drugs other than aspirin, if possible. C 5. Inpatient care Bowel rest: advise dietary restriction and bowel rest in patients with acute diverticulitis who display an inflammatory response without abscess formation or bowel perforation. B 6. Nonpharmacologic interventions Dietary modifications: As per ASCRS 2020 guidelines, advise reduced meat intake to potentially reduce the risk of diverticulitis. B As per ESCP 2020 guidelines: Insufficient evidence to support dietary restrictions in patients with acute diverticulitis. Prefer an unrestricted diet when tolerated. I Insufficient evidence to support a high-fiber diet for the sole purpose of prevention of recurrent episodes or persistent symptoms in patients with acute diverticulitis, although it may be recommendable for general health purposes. I As per AGA 2015 guidelines, consider a fiber-rich diet or fiber supplementation in patients with a history of acute diverticulitis. C Smoking cessation: advise smoking cessation to potentially reduce the risk of diverticulitis. B Physical activity: As per ASCRS 2020 guidelines, advise physical activity to potentially reduce the risk of diverticulitis. B As per AGA 2015 guidelines, consider advising patients with diverticular disease to undertake vigorous physical activity. C Weight loss: advise weight loss to potentially reduce the risk of diverticulitis. B Bed rest: insufficient evidence to recommend bed rest in patients with acute diverticulitis. Avoid bed rest since imposed physical inactivity may impair the patient's general condition. I 7. Therapeutic procedures https://web.pathway.md/diseases/rec3Z5lhIppiQuZrO 5/13 6/23/23, 1:44 AM Acute diverticulitis Pathway Percutaneous drainage of diverticular abscesses: As per ASCRS 2020 guidelines, perform image-guided percutaneous drainage in stable patients with abscesses > 3 cm in size. B As per ESCP 2020 guidelines, consider performing percutaneous drainage of abscesses in patients with an abscess > 3 cm, although the role of this procedure in acute diverticulitis is not completely clear. Reserve emergency surgery as last resort for patients failing other non- surgical treatments. C As per WSES 2020 guidelines, consider percutaneous drainage combined with antibiotic therapy in patients with large abscesses. C As per ASCRS 2014 guidelines, perform image-guided percutaneous drainage in stable patients with large diverticular abscesses. B Laparoscopic lavage and drainage: As per ASCRS 2020 guidelines: Do not perform laparoscopic lavage in patients with feculent peritonitis. Perform colectomy in this situation. D Prefer colectomy over laparoscopic lavage in patients with purulent peritonitis, as laparoscopic lavage is associated with higher rates of secondary intervention in comparison with colectomy. A As per ESCP 2020 guidelines, consider performing laparoscopic lavage in selected patients with Hinchey III peritonitis. Alternatively, perform a resection. C As per WSES 2020 guidelines, consider laparoscopic peritoneal lavage and drainage only in very selected patients with generalized peritonitis, but not as first-line therapy in patients with peritonitis from acute colonic diverticulitis. B 8. Perioperative care Postoperative antibiotic therapy: consider a 4-day postoperative antibiotic therapy in patients with complicated acute left-sided colonic diverticulitis if source control has been adequate. C 9. Surgical interventions Emergency colectomy: As per DGVS 2022 guidelines, consider performing surgical exploration, possibly with colectomy (dissection at the terminal ileum and in the upper third of the rectum), in the threatening situation of severe active bleeding that cannot be either endoscopically or angiographically located. E As per ASCRS 2020 guidelines, perform urgent sigmoid colectomy in patients with diffuse peritonitis or when nonoperative management of acute diverticulitis fails. B Show 3 more https://web.pathway.md/diseases/rec3Z5lhIppiQuZrO 6/13 6/23/23, 1:44 AM Acute diverticulitis Pathway As per ESCP 2020 guidelines, consider performing immediate surgery in hemodynamically unstable or septic patients with diverticulitis. C Show 2 more As per WSES 2020 guidelines, consider performing emergency laparoscopic sigmoidectomy in patients with diffuse peritonitis due to perforated diverticulitis only if technical skills and equipment are available. C As per JGA 2019 guidelines: Perform emergency surgery for colonic diverticulitis in patients presenting with generalized peritonitis. A Perform colectomy when antibiotic therapy and drainage are ineffective in patients with complicated diverticulitis. B As per ASCRS 2014 guidelines, perform urgent sigmoid colectomy in patients with diffuse peritonitis, or if nonoperative management of acute diverticulitis fails. B Elective colectomy: As per DGVS 2022 guidelines, consider performing elective partial colectomy during the remission interval in patients with recurrent, hemodynamically effective diverticular hemorrhage and a need for lifelong anticoagulation. E As per ASCRS 2020 guidelines, perform elective colectomy in patients with diverticulitis complicated by fistula, obstruction, or stricture. B Show 6 more As per ESCP 2020 guidelines, avoid performing elective surgery to prevent complicated disease, irrespective of the number of previous attacks. D Show 5 more As per WSES 2020 guidelines: Consider evaluating patient-related factors and not number of previous episodes of diverticulitis in planning elective sigmoid resection. C Consider planning an elective sigmoid resection after an episode of acute left-sided colonic diverticulitis treated conservatively in high-risk patients, such as immunocompromised patients. C As per JGA 2019 guidelines, consider performing elective colectomy in selected patients with recurrent colonic diverticulitis without abscess or perforation, such as in immunocompromised patients. C As per AGA 2015 guidelines, avoid performing routine elective prophylactic colonic resection in patients with an initial episode of acute uncomplicated diverticulitis. D As per ASCRS 2014 guidelines, individualize the decision to recommend elective sigmoid colectomy after recovery from uncomplicated acute diverticulitis. B Technical considerations for surgery: As per DGVS 2022 guidelines, consider performing segmental resection if diverticular bleeding is recurrent or not to stop but clearly localizable. E https://web.pathway.md/diseases/rec3Z5lhIppiQuZrO 7/13 6/23/23, 1:44 AM Acute diverticulitis Pathway As per ESCP 2020 guidelines, decide on surgical approach in patients with fecal peritonitis based on the experience of the surgeon. Insufficient evidence to support laparoscopic over open surgery. Perform resection as the treatment of choice. B Show 7 more As per WSES 2020 guidelines, perform Hartmann's procedure for the management of diffuse peritonitis in critically ill patients and in selected patients with multiple comorbidities. B Show 2 more As per ASCRS 2014 guidelines, resect the entire sigmoid colon with margins of healthy colon and rectum in patients in whom an elective surgical approach is undertaken. B Show 5 more 10. Specific circumstances Patients with complicated diverticulitis (general indications): Consider antibiotic therapy and bowel rest in patients with complicated colonic diverticulitis, localized peritonitis, and an abscess 3 cm. Consider ultrasound- or CT-guided drainage in patients with an abscess 5 cm. Individualize treatment based on clinical status, feasibility of drainage, and resource availability in patients with an abscess 3-5 cm. C Perform colectomy when antibiotic therapy and drainage are ineffective. B Patients with complicated diverticulitis, abscess and localized peritonitis: As per ASCRS 2020 guidelines: Perform image-guided percutaneous drainage in stable patients with abscesses > 3 cm in size. B Consider elective resection after successful nonoperative treatment of a diverticular abscess. B As per ESCP 2020 guidelines: Consider performing percutaneous drainage of abscesses in patients with an abscess > 3 cm, although the role of this procedure in acute diverticulitis is not completely clear. Reserve emergency surgery as last resort for patients failing other non-surgical treatments. C Consider performing laparoscopic or open resection of the diseased bowel with or without anastomosis in patients with persistent abscesses. C As per WSES 2020 guidelines, consider an initial trial of nonoperative treatment with antibiotics alone in patients with a small (< 4-5 cm) diverticular abscess. C Show 2 more As per JGA 2019 guidelines, consider antibiotic therapy and bowel rest as first-line therapy in patients with complicated colonic diverticulitis with abscess and localized peritonitis when the abscess measures 3 cm. However, consider instituting ultrasound or CT-guided drainage, antibiotic therapy, and bowel rest if it measures 5 cm. For abscesses measuring 3-5 cm, consider individualized treatment based on disease state and feasibility of drainage depending on the availability of human and facility sources. C https://web.pathway.md/diseases/rec3Z5lhIppiQuZrO 8/13 6/23/23, 1:44 AM Acute diverticulitis Pathway Show 2 more Patients with complicated diverticulitis, fistula: As per ESCP 2020 guidelines, consider performing laparoscopic or open resection of the diseased bowel with or without anastomosis in patients with fistulas. C As per JGA 2019 guidelines, perform colectomy for complicated colonic diverticulitis with fistulization between the colon and other organs due to diverticula. B Patients with complicated diverticulitis (stricture): perform colectomy in patients with complicated colonic diverticulitis with stricture that develops after remission of colonic diverticulitis. B Elderly patients (diagnosis): avoid basing the diagnosis of acute left colonic diverticulitis in elderly patients solely on patient clinical signs, symptoms and laboratory tests. D Elderly patients (diagnostic imaging): consider obtaining appropriate imaging for suspected diverticulitis in elderly patients presenting with abdominal guarding or pain in the lower left abdomen on physical examination, regardless of the value of WBCs and of CRP. C Show 2 more Elderly patients (indications for non-operative management): Avoid offering nonoperative management as a viable option in elderly patients with acute left colonic diverticulitis and CT findings of distant intraperitoneal free air and no free fluid (WSES stage 2b). D Do not offer nonoperative management as a viable option in elderly patients with acute left colonic diverticulitis and diffuse peritonitis (WSES stage 3-4). D Elderly patients (antibiotic therapy): avoid administering antibiotic therapy in immunocompetent elderly patients with uncomplicated left colonic diverticulitis (WSES stage 0) without sepsis-related organ failures. D Show 5 more Elderly patients (percutaneous drainage of diverticular abscesses): Consider performing percutaneous drainage in addition to antibiotic therapy in elderly patients with acute left colonic diverticulitis and an abscess > 4 cm (WSES stage 2a), when skills and facilities are available. C Obtain cultures from percutaneous drainage to guide the antibiotic therapy. B Elderly patients (laparoscopic lavage and drainage): avoid performing laparoscopic lavage as the preferred surgical approach in elderly patients with acute left colonic diverticulitis and acute peritonitis because of the higher risk of failure to control the source of sepsis. D Elderly patients (emergency colectomy): perform prompt and effective source control surgery in elderly patients with acute left colonic diverticulitis and diffuse peritonitis (WSES stage 3-4). B Show 3 more Elderly patients (elective colectomy): avoid performing elective sigmoid resection after a conservatively treated episode of acute left colonic diverticulitis in asymptomatic elderly patients without stenosis, fistulae or recurrent diverticular bleeding. D https://web.pathway.md/diseases/rec3Z5lhIppiQuZrO 9/13 6/23/23, 1:44 AM Acute diverticulitis Pathway Show 3 more Elderly patients (follow-up): Consider planning early colonic evaluation in elderly patients after an episode of acute left colonic diverticulitis. C Obtain further diagnostic investigation in elderly patients with complicated diverticulitis with ongoing signs of peritonitis or systemic illness (ongoing infection) beyond 5-7 days of antibiotic treatment. B 11. Preventative measures Aminosalicylates: As per ASCRS 2020 guidelines, do not offer mesalamine for reducing the risk of diverticulitis recurrence, but consider for reducing chronic symptoms. D As per ESCP 2020 guidelines, do not offer mesalazine for the prevention of recurrent diverticulitis or persistent complaints after an episode of acute diverticulitis. D As per AGA 2015 guidelines, avoid the use of mesalamine after acute uncomplicated diverticulitis. D Rifaximin: As per ASCRS 2020 guidelines, do not offer rifaximin for reducing the risk of diverticulitis recurrence, but consider for reducing chronic symptoms. D As per ESCP 2020 guidelines, do not offer rifaximin for the prevention of recurrent diverticulitis or persistent complaints after an episode of acute diverticulitis. D As per AGA 2015 guidelines, consider avoiding the use of rifaximin after acute uncomplicated diverticulitis. D Probiotics: As per ASCRS 2020 guidelines, do not offer probiotics for reducing the risk of diverticulitis recurrence, but consider for reducing chronic symptoms. D As per ESCP 2020 guidelines, do not offer probiotics for the prevention of recurrent diverticulitis or persistent complaints after an episode of acute diverticulitis. D As per AGA 2015 guidelines, consider avoiding the use of probiotics after acute uncomplicated diverticulitis. D Secondary prevention: insufficient evidence to recommend any interventions for secondary prevention. I 12. Follow-up and surveillance Follow-up: As per ESCP 2020 guidelines, avoid obtaining endoscopic follow-up in patients with symptom- free recovery after a single episode of CT-verified uncomplicated diverticulitis. Follow-up all https://web.pathway.md/diseases/rec3Z5lhIppiQuZrO 10/13 6/23/23, 1:44 AM Acute diverticulitis Pathway other patients treated without resection for acute diverticulitis with an examination of the colon at least 6 weeks after the acute episode, if not done within the last 3 years. D As per WSES 2020 guidelines: Consider planning an early colonic evaluation (4-6 weeks) in patients with diverticular abscesses treated nonoperatively. C Do not perform routine colonic evaluation in patients with CT-proven uncomplicated diverticulitis treated nonoperatively. D As per JGA 2019 guidelines, perform colonoscopy at least once to eliminate the possibility of lesions other than colonic diverticulosis as the possible cause of disease, although the association between colonic diverticulitis and colorectal cancer is currently unknown. B As per AGA 2015 guidelines, consider performing a follow-up colonoscopy after resolution of acute diverticulitis, in appropriate candidates, to exclude the misdiagnosis of a colonic neoplasm if a high-quality examination of the colon has not been recently performed. C As per ASCRS 2014 guidelines, perform a follow-up colonoscopy after resolution of acute diverticulitis to confirm the diagnosis if this is the first episode, or recent colonoscopy has not been performed. B Management of recurrent diverticulitis: consider conservative treatment when recurrent colonic diverticulitis is not accompanied by abscess. When abscess is present, however, treat as a first episode of diverticulitis. C Likelihood Ratios Pertinent positives The following findings increase the probability of acute diverticulitis in adults. 15 Finding LR+ Value Presence of findings of diverticulitis* 94 Presence of LLQ tenderness 10.4 History of LLQ pain 3.3 Increased serum CRP 2.2 diverticulae, bowel wall thickening, pericolic fat stranding Show 1 more Pertinent negatives The following findings decrease the probability of acute diverticulitis in adults. 15 https://web.pathway.md/diseases/rec3Z5lhIppiQuZrO 11/13 6/23/23, 1:44 AM Acute diverticulitis Pathway LR- * diverticulae, bowel wall thickening, pericolic fat stranding 0.1 Finding Value Absence of findings of diverticulitis* Show 1 more serum CRP not increased 0.3 No history of LLQ pain References Absence of LLQ tenderness 0.5 0.7 1. Paola Fugazzola, Marco Ceresoli, Federico Coccolini et al. The WSES/SICG/ACOI/SICUT/AcEMC/SIFIPAC guidelines for diagnosis and treatment of acute left colonic diverticulitis in the elderly. World J Emerg Surg. 2022 Jan 21;17 1 5. Open 2. J K Schultz, N Azhar, G A Binda et al. European Society of Coloproctology: guidelines for the management of diverticular disease of the colon. Colorectal Dis. 2020 Sep;22 Suppl 2 5 28. Open 3. Massimo Sartelli, Dieter G Weber, Yoram Kluger et al. 2020 update of the WSES guidelines for the management of acute colonic diverticulitis in the emergency setting. World J Emerg Surg. 2020 May 7;15 1 32. Open 4. Stollman N, Smalley W, Hirano I. American Gastroenterological Association Institute Guideline on the Management of Acute Diverticulitis. Gastroenterology. 2015 Dec;149 7 1944 9. Open 5. Nagata N, Ishii N, Manabe N et al. Guidelines for Colonic Diverticular Bleeding and Colonic Diverticulitis: Japan Gastroenterological Association. Digestion. 2019;99 Suppl 1 1 26. Open 6. Jason Hall, Karin Hardiman, Sang Lee et al. The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Treatment of Left-Sided Colonic Diverticulitis. Dis Colon Rectum. 2020 Jun;63 6 728 747. Open 7. Wolfgang Kruis, Christoph-Thomas Germer, Stephan B hm et al. German guideline diverticular disease/diverticulitis Part I Methods, pathogenesis, epidemiology, clinical characteristics (definitions), natural course, diagnosis and classification. United European Gastroenterol J. 2022 Nov 21. Open 8. Feingold D, Steele SR, Lee S et al. Practice parameters for the treatment of sigmoid diverticulitis. Dis Colon Rectum. 2014 Mar;57 3 284 94. Open 9. Amir Qaseem, Itziar Etxeandia-Ikobaltzeta, Jennifer S Lin et al. Diagnosis and Management of Acute Left-Sided Colonic Diverticulitis: A Clinical Guideline From the American College of Physicians. Ann Intern Med. 2022 Jan 18. Online ahead of print. Open 10. Stefanie Weinstein, MDa, David H. Kim et al. ACR Appropriateness Criteria Left Lower Quadrant Pain. ACR. 2023. Open 11. Expert Panel on Gastrointestinal Imaging, Avinash R Kambadakone, Cynthia S Santillan et al. ACR Appropriateness Criteria Right Lower Quadrant Pain: 2022 Update. J Am Coll Radiol. 2022 Nov;19 11S S445 S461. Open 12. Feuerstein JD, Falchuk KR. Diverticulosis and Diverticulitis. Mayo Clin Proc. 2016 Aug;91 8 1094 104. Open 13. Adil E Bharucha, Gopanandan Parthasarathy, Ivo Ditah et al. Temporal Trends in the Incidence and Natural History of Diverticulitis: A Population-Based Study. Am J Gastroenterol. 2015 Nov;110 11 1589 96. Open 14. Schieffer KM, Kline BP, Yochum GS et al. Pathophysiology of diverticular disease. Expert Rev Gastroenterol Hepatol. 2018 Jul;12 7 683 692. Open https://web.pathway.md/diseases/rec3Z5lhIppiQuZrO 12/13 6/23/23, 1:44 AM Acute diverticulitis Pathway 15. Young-Fadok TM. Diverticulitis. N Engl J Med. 2018 Oct 25;379 17 1635 1642. Open 16. Thad Wilkins, Katherine Embry, Ruth George. Diagnosis and Management of Acute Diverticulitis. Am Fam Physician. 2013 May 1;87 9 612 20. Open 17. Sophia M Swanson, Lisa L Strate. Acute Colonic Diverticulitis. Ann Intern Med. 2018 May 1;168 9 ITC65 ITC80. Open 18. Lisa L Strate, Arden M Morris. Epidemiology, Pathophysiology, and Treatment of Diverticulitis. Gastroenterology. 2019 Apr;156 5 1282 1298.e1. Open 19. Catherine D. Linzay, Sudha Pandit. Acute Diverticulitis. In: StatPearls Internet]. Treasure Island FL StatPearls Publishing; 2020 Jan. 2020 Nov 20. Open 20. Laura Mora-L pez, Neus Ruiz-Edo, Oscar Estrada-Ferrer et al. Efficacy and Safety of Nonantibiotic Outpatient Treatment in Mild Acute Diverticulitis DINAMO-study): A Multicentre, Randomised, Open-label, Noninferiority Trial. Ann Surg. 2021 Nov 1;274 5):e435-e442. Open https://web.pathway.md/diseases/rec3Z5lhIppiQuZrO 13/13

Guideline sources The following summarized guidelines for the evaluation and management of acute epididymitis are prepared by our editorial team based on guidelines from the European Association of Urology (EAU 2022), the Center for Disease Control (CDC 2021), the International Union Against Sexually Transmitted Infections (IUSTI 2017), and the American Association of Family Physicians (AAFP 2016). 1 2 3 4 4 4 5 5 Definition Acute epididymitis is the acute inflammation of the epididymis characterized by pain and scrotal swelling present for < 6 weeks. 4 Epidemiology Acute epididymitis is caused by a bacterial ascent (UTIs or STIs), viral genesis (adenovirus, enterovirus), fungi (C. albicans, Histoplasma capsulatum), parasites (Trichomonas vaginalis, Schistosoma species, Filariasis), drug-induced (amiodaron), rheumatic (Beh et's disease, vasculitis, Henoch-Sch nlein purpura), obstruction (vasectomy), genital trauma, and sterile reflux. 5 Disease course https://web.pathway.md/diseases/reczx4WxHw93aZE2V 1/5 6/23/23, 1:38 AM Acute epididymitis Pathway Disease course The inflammation of the epididymis results in acute epididymis, which causes clinical manifestations of gradual unilateral scrotal pain and epididymal swelling with concurrent symptoms of fever, hematuria, dysuria, and urinary frequency. Disease progression may lead to abscess formation or Fournier gangrene, infertility, and chronic pain. 4 Prognosis and risk of recurrence Acute epididymis is not associated with an increase in mortality. 5 Guidelines 1. Screening and diagnosis Clinical presentation: Recognize that: acute epididymitis is characterized by pain, swelling, and inflammation of the epididymis lasting < 6 weeks sometimes a testicle is also involved, a condition referred to as epididymo-orchitis acute epididymitis can be caused by STIs (such as Chlamydia trachomatis, Neisseria gonorrhoeae, or Mycoplasma genitalium) or enteric organisms (such as E. coli) acute epididymitis caused by STIs is usually accompanied by urethritis, which is frequently asymptomatic acute epididymitis caused by sexually transmitted enteric organisms might also occur in males who are the insertive partner during anal sex nonsexually transmitted acute epididymitis caused by genitourinary pathogens typically occurs with bacteriuria secondary to bladder outlet obstruction (such as benign prostatic hyperplasia) nonsexually transmitted acute epididymitis in older males is also associated with prostate biopsy, urinary tract instrumentation or surgery, systemic disease, or immunosuppression. E Recognize that: chronic epididymitis is characterized by a 6-week history of symptoms of discomfort or pain in the scrotum, testicle, or epididymis chronic infectious epididymitis is most frequently observed with conditions associated with a granulomatous reaction, with Mycobacterium tuberculosis as the most common granulomatous disease affecting the epididymis, especially in patients with a known history of or recent exposure to tuberculosis the differential diagnosis of chronic noninfectious epididymitis, sometimes termed orchialgia or epididymalgia, is broad (including trauma, cancer, autoimmune conditions, or idiopathic conditions). E Differential diagnosis: Suspect spermatic cord (testicular) torsion in patients with a sudden onset of symptoms associated with epididymitis, especially in adolescents and patients without evidence of https://web.pathway.md/diseases/reczx4WxHw93aZE2V 2/5 6/23/23, 1:38 AM Acute epididymitis Pathway inflammation or infection. E Refer patients with severe unilateral pain with sudden onset and test results not supporting a diagnosis of urethritis or UTI, or if the diagnosis of acute epididymitis is questionable, immediately to a urologist for evaluation for testicular torsion. E 2. Diagnostic investigations Urine tests: As per EAU 2022 guidelines, obtain a midstream urine and a first-voided urine sample for pathogen identification by culture and NAAT. A As per CDC 2021 guidelines, obtain any of the following point-of-care tests in all patients with suspected acute epididymitis: gram, methylene blue, or gentian violet stain of urethral secretions to demonstrate 2 WBCs/oil immersion field (preferred for evaluating urethritis to document both urethral inflammation and presence or absence of gonococcal infection; establish gonococcal infection by documenting the presence of WBC-containing intracellular Gram-negative or purple diplococci on urethral Gram, methylene blue, or gentian violet stain, respectively) leukocyte esterase test on first-void urine microscopic examination of sediment from a spun first-void urine to demonstrate 10 WBCs/hpf. E Show 2 more Scrotal ultrasound: obtain scrotal ultrasound in patients with suspected testicular torsion and in patients with scrotal pain failed to receive an accurate diagnosis by history, physical examination, and objective laboratory findings. E Screening for other sexually transmitted infections: screen for human immunodeficiency virus and syphilis in all patients with acute epididymitis. E 3. Medical management Setting of care: Treat the majority of patients with acute epididymitis on an outpatient basis. E Refer patients to a specialist and consider admitting to the hospital in case of severe pain or fever indicating other diagnoses (such as torsion, testicular infarction, abscess, or necrotizing fasciitis) or when patients are unable to comply with an antimicrobial treatment. E Antibiotic therapy: As per EAU 2022 guidelines, initiate a single antibiotic or a combination of two antibiotics active against Chlamydia trachomatis and Enterobacterales as initial treatment in young sexually active patients. Consider initiating antibiotics only against Enterobacterales in older patients without sexual risk factors. A Show 2 more https://web.pathway.md/diseases/reczx4WxHw93aZE2V 3/5 6/23/23, 1:38 AM Acute epididymitis Pathway As per CDC 2021 guidelines, initiate presumptive therapy in all sexually active patients at the time of the visit before all laboratory test results are available, to prevent complications and transmission of sexually transmitted. Decide on the choice of regimen based on the risks for chlamydial and gonococcal infections or enteric organisms. E Show 4 more As per IUSTI 2017 guidelines, initiate combination therapy with the following medications as first-line therapy in patients with sexually transmitted epididymo-orchitis: ceftriaxone intramuscularly 500 mg once doxycycline PO 100 mg BID for 10-14 days. B Show 5 more As per AAFP 2016 guidelines, administer intramuscularly ceftriaxone with oral doxycycline if acute epididymitis is thought to be caused by Neisseria gonorrhoeae or Chlamydia trachomatis. B Show 2 more Management of sexual partners: Instruct patients with acute sexually transmitted epididymitis confirmed or suspected to be caused by Neisseria gonorrhoeae or Chlamydia trachomatis to refer all sex partners during the previous 60 days before symptom onset (or the most recent sex partner if the last sexual intercourse was > 60 days before the onset of symptoms or diagnosis) for evaluation, testing, and presumptive treatment. E Instruct partners to abstain from sexual intercourse until they and their sex partners are treated and symptoms have resolved. E 4. Nonpharmacologic interventions Supportive measures: offer bed rest, scrotal elevation, and NSAIDs as an adjunct to antibiotic therapy until fever and local inflammation have subsided. E 5. Patient education General counseling: Counsel patients with acute epididymitis confirmed or suspected to be caused by Neisseria gonorrhoeae or Chlamydia trachomatis to abstain from sexual intercourse until they and their partners have been treated and symptoms have resolved. E Instruct patients to return to their healthcare providers if their symptoms do not improve < 72 hours after treatment. E 6. Follow-up and surveillance Follow-up: https://web.pathway.md/diseases/reczx4WxHw93aZE2V 4/5 6/23/23, 1:38 AM Acute epididymitis Pathway Reevaluate the diagnosis and therapy if signs and symptoms of epididymitis do not subside in < 3 days. E Evaluate for alternative diagnoses (including tumor, abscess, infarction, testicular cancer, tuberculosis, and fungal epididymitis) in patients experiencing swelling and tenderness persisting after completion of antimicrobial therapy. E 7. Quality improvement Reporting: follow national policies on reporting and tracing/treatment of contacts for STIs. A References 1. Emma J Street, Edwin D Justice, Zsolt Kopa et al. The 2016 European guideline on the management of epididymo-orchitis. Int J STD AIDS. 2017 Jul;28 8 744 749. Open 2. Kimberly A Workowski, Laura H Bachmann, Philip A Chan et al. Sexually Transmitted Infections Treatment Guidelines, 2021. MMWR Recomm Rep. 2021 Jul 23;70 4 1 187. Open 3. G. Bonkat, R. Bartoletti, F. Bruy re et al. EAU Guidelines on Urological Infections. EAU. 2022. Open 4. McConaghy JR, Panchal B. Epididymitis: An Overview. Am Fam Physician. 2016 Nov 1;94 9 723 726. Open 5. Vera Michel, Adrian Pilatz, Mark P Hedger et al. Epididymitis: revelations at the convergence of clinical and basic sciences. Sep-Oct 2015;17 5 756 63.Sep-Oct 2015;17 5 756 63. Open 6. Suneeta Soni, Paddy Horner, Michael Rayment et al. British Association for Sexual Health and HIV national guideline for the management of infection with Mycoplasma genitalium 2018 . BASHH. 2018. Open https://web.pathway.md/diseases/reczx4WxHw93aZE2V 5/5

Guideline sources The following summarized guidelines for the evaluation and management of acute fatty liver of pregnancy (AFLP) are prepared by our editorial team based on guidelines from the Chinese Society of Obstetrics Gynecology (CSOG 2021), the American Association for the Study of Liver Diseases (AASLD 2021), the American College of Gastroenterology (ACG 2016), and the Italian Association for the Study of the Liver (AISF 2016). 1 2 3 4 Guidelines 1. Screening and diagnosis Indications for screening: Obtain prenatal screening for AFLP in outpatients at 35-37 weeks of gestation. B Obtain routine blood tests, liver function, and coagulation function as first-line screening indicators. Obtain testing immediately in pregnant patients with gastrointestinal symptoms, such as nausea and vomiting, and suspected AFLP. B https://web.pathway.md/diseases/recKyH4P0mQaY6BKV 1/4 6/23/23, 1:44 AM Acute fatty liver of pregnancy Pathway Obtain retesting within 24 hours to identify AFLP as soon as possible in patients with suspected AFLP based on initial screening. B Diagnosis: As per AASLD 2021 guidelines, diagnose AFLP based on clinical and laboratory parameters, and rarely liver biopsy. E As per CSOG 2021 guidelines: Use the Swansea criteria for diagnosing AFLP. B Diagnose AFLP mainly based on clinical manifestations; liver biopsy is unnecessary. B 2. Classification and risk stratification Prognosis: Assess postoperative prothrombin activity, TBIL, platelet count, and serum creatinine as prognostic indicators. B Evaluate patients by a multidisciplinary team if the abovementioned indicators continue to be abnormal after delivery or the patient is not recovering by 1 week after delivery, and offer liver transplantation if the patient is suitable. B 3. Diagnostic investigations Abdominal imaging: obtain abdominal imaging to rule out hepatic hemorrhage, infarction, or rupture in patients with AFLP. Transfer patients with hepatic rupture or ALF promptly to a transplant center for evaluation. E Genetic testing: as per ACG 2016 guidelines, obtain molecular testing for long-chain 3- hydroxyacyl-CoA dehydrogenase in all patients with AFLP and their children. B 4. Medical management Supportive therapy: administer prompt supportive therapy in an intensive care setting to stabilize patients with AFLP. B 5. Inpatient care Serial laboratory assessment: obtain routine monitoring blood tests including glucose, liver function, kidney function, and coagulation function during the treatment period. B 6. Therapeutic procedures Liver support system: offer artificial liver treatment in patients with severe AFLP. B https://web.pathway.md/diseases/recKyH4P0mQaY6BKV 2/4 6/23/23, 1:44 AM Acute fatty liver of pregnancy Pathway 7. Perioperative care Preoperative risk assessment: use levels of prothrombin activity/INR, TBIL, platelet count, lactic acid, serum creatinine, and disease duration as indicators for preoperative risk assessment. B Show 3 more 8. Follow-up and surveillance Delivery: As per AASLD 2021 guidelines, perform expeditious delivery in patients with suspected AFLP after maternal stabilization. E As per CSOG 2021 guidelines, perform complete vaginal delivery, if vaginal delivery is inevitable, as soon as possible while improving coagulation function and preventing postpartum hemorrhage. B Show 3 more As per ACG 2016 guidelines, perform prompt delivery in patients with AFLP. B As per AISF 2016 guidelines: Ensure not exceeding one week interval from onset of AFLP to delivery. B Perform C-section when vaginal delivery cannot be achieved quickly in AFLP. B Newborn monitoring: As per AASLD 2021 guidelines, screen all newborns of mothers with AFLP at birth for long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency or other fatty acid oxidation defects. Refer affected families to genetic counseling. E As per ACG 2016 guidelines, obtain careful monitoring for manifestations of deficiency of long- chain 3-hydroxyacyl-CoA dehydrogenase including hypoketotic hypoglycemia and fatty liver in children born to mothers with AFLP. B References 1. Li, Ping, Chen et al. CSOG MFM Committee Guideline: Clinical Management Guidelines for Acute Fatty Liver of Pregnancy in China 2021 . Maternal-Fetal Medicine. 2021 Oct;3 4 238 245. Open 2. Monika Sarkar, Carla W Brady, Jaquelyn Fleckenstein et al. Reproductive Health and Liver Disease: Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2021 Jan;73 1 318 365. Open 3. Tram T Tran, Joseph Ahn, Nancy S Reau. ACG Clinical Guideline: Liver Disease and Pregnancy. Am J Gastroenterol. 2016 Feb;111 2 176 94; quiz 196. Open 4. Italian Association for the Study of the Liver AISF , Italian Association for the Study of the Liver AISF. AISF position paper on liver disease and pregnancy. Dig Liver Dis. 2016 Feb;48 2 120 37. Open https://web.pathway.md/diseases/recKyH4P0mQaY6BKV 3/4 6/23/23, 1:44 AM Acute fatty liver of pregnancy Pathway 5. C L Ch'ng, M Morgan, I Hainsworth et al. Prospective study of liver dysfunction in pregnancy in Southwest Wales. Gut. 2002 Dec;51 6 876 80. Open https://web.pathway.md/diseases/recKyH4P0mQaY6BKV 4/4

Guideline sources The following summarized guidelines for the evaluation and management of acute hepatic porphyrias are prepared by our editorial team based on guidelines from the American Gastroenterological Association (AGA 2023). 1 Guidelines 1. Screening and diagnosis Indications for screening: consider screening for acute hepatic porphyrias in 15-50 years old female patients with unexplained, recurrent severe abdominal pain without a clear etiology after an initial workup. C 2. Diagnostic investigations Laboratory testing: obtain biochemical testing of D-ALA, porphobilinogen, and creatinine on a random urine sample for the initial diagnosis of acute hepatic porphyrias. B https://web.pathway.md/diseases/receyA41NfbuurNBL 1/3 6/23/23, 1:45 AM Acute hepatic porphyrias Pathway Genetic testing: obtain genetic testing to confirm the diagnosis of acute hepatic porphyrias in patients with positive biochemical testing. B 3. Medical management Intravenous hemin: administer IV hemin, given daily, preferably into a high-flow central vein, in patients with acute attacks of acute hepatic porphyrias severe enough to require hospital admission. B Supportive care: control pain, administer antiemetics, manage systemic arterial hypertension, tachycardia, hyponatremia, and hypomagnesemia, if present, in addition to IV hemin in patients with acute attacks of acute hepatic porphyrias. B 4. Surgical interventions Liver transplantation: reserve liver transplantation for patients with acute hepatic porphyrias with intractable symptoms and significantly decreased quality of life refractory to pharmacotherapy. B 5. Patient education General counseling: Advise avoiding identifiable triggers precipitating acute attacks, such as alcohol and porphyrinogenic medications. B Counsel patients about chronic and long-term complications of acute hepatic porphyrias, including neuropathy, CKD, hypertension, and HCC, and the need for long-term monitoring. B 6. Preventative measures Prophylactic hemin therapy: consider administering prophylactic heme therapy or givosiran, given in an outpatient setting, in patients with recurrent attacks ( 4 per year). C 7. Follow-up and surveillance Monitoring for liver disease: obtain annual monitoring for liver disease in patients with acute hepatic porphyrias. B Monitoring for chronic kidney disease: obtain annual surveillance for CKD with serum creatinine and estimated GFR in patients with acute hepatic porphyrias receiving treatment. B Surveillance for hepatocellular carcinoma: obtain surveillance for HCC with liver ultrasound every 6 months, starting at the age of 50 years, in patients with acute hepatic porphyrias, regardless of the severity of symptoms. B https://web.pathway.md/diseases/receyA41NfbuurNBL 2/3 6/23/23, 1:45 AM Acute hepatic porphyrias Pathway References 1. Bruce Wang, Herbert L Bonkovsky, Joseph K Lim et al. AGA Clinical Practice Update on Diagnosis and Management of Acute Hepatic Porphyrias: Expert Review. Gastroenterology. 2023 Jan 13;S0016 5085 22 01356 7. Open https://web.pathway.md/diseases/receyA41NfbuurNBL 3/3

Guideline sources The following summarized guidelines for the evaluation and management of acute interstitial nephritis (AIN) are prepared by our editorial team based on guidelines from the American Association of Family Physicians (AAFP 2003). 1 1 2 2 2 Definition AIN is an acute disease characterized by the presence of inflammatory infiltrates and edema within the interstitium that is associated with a decline in renal function. 2 Epidemiology AIN is mostly caused by drugs (> 75%) such as NSAIDs, allopurinol, acyclovir, furosemide, famotidine, omeprazole, phenytoin; infections (5-10%) such as viruses (HIV, CMV, EBV), Mycobacterium tuberculosis, Mycoplasma, Rickettsia, Toxoplasma, Leptospira, Schistosoma; idiopathic (5-10%) such as tubulointerstitial nephritis and uveitis syndrome; and associated with systemic diseases (10-15%) such as sarcoidosis, Sjogren's syndrome and SLE. 2 Disease course The delayed hypersensitivity immune reactions to foreign antigens result in AIN, which leads to the clinical features of AKI, acute renal failure requiring dialysis, arthralgias, fever, skin rash, and gross hematuria. 2 Prognosis and risk of recurrence https://web.pathway.md/diseases/rec52jA9P3m9WGEa5 1/3 6/23/23, 1:45 AM Acute interstitial nephritis Pathway Prognosis and risk of recurrence AIN is not associated with an increase in mortality. 1 Guidelines 1. Diagnostic investigations Laboratory investigations: basic laboratory investigations (urinalysis and microscopy, serum chemistry profile, CBC, LFTs) may provide evidence suggestive of AIN and help guide conservative management or empiric treatment with steroids. Unfortunately, none of these tests have sufficient predictive value to be diagnostically reliable. Renal ultrasound: renal ultrasound may demonstrate kidneys that are normal to enlarged in size, with increased cortical echogenicity, but there are no ultrasonographic findings that will reliably confirm or exclude AIN versus other causes of acute renal failure. 2. Diagnostic procedures Kidney biopsy: Consider implementing a trial of supportive management in patients in whom the diagnosis seems likely, for whom a probable precipitating drug can be easily withdrawn, or who improve readily after withdrawal of a potentially offending drug. Consider obtaining a renal biopsy in patients who do not improve following withdrawal of the likely precipitating medications, who have no contraindications to renal biopsy, and who are being considered for steroid therapy. 3. Medical management Withdrawal of offending agents: discontinue any potential precipitating medications in patients with AIN. Supportive care measures: Provide standard supportive care interventions in patients with AIN, such as: fluid and electrolyte management avoiding volume depletion or overload symptomatic relief for fever and rash avoiding use of nephrotoxic drugs avoiding use of drugs that impair renal blood flow adjusting drug dosages for existing level of renal function. Immunosuppressive therapy: insufficient evidence to make a recommendation regarding the use of corticosteroids in treatment of AIN. If steroid therapy is started, a reasonable dosage is prednisone, 1 mg per kg per day PO (or equivalent intravenous dose) for two to three weeks, https://web.pathway.md/diseases/rec52jA9P3m9WGEa5 2/3 6/23/23, 1:45 AM Acute interstitial nephritis Pathway followed by a gradually tapering dose over three to four weeks. In patients who do not respond to corticosteroids within two to three weeks, treatment with cyclophosphamide can be considered. Likelihood Ratios Pertinent positives The following findings increase the probability of acute interstitial nephritis in adults. -1 Finding LR+ Value Increased urine eosinophils 3.72 Pertinent negatives The following findings decrease the probability of acute interstitial nephritis in adults. -1 Finding LR- Value urine eosinophils not increased 0.41 References 1. Charles M Kodner, Archana Kudrimoti. Diagnosis and management of acute interstitial nephritis. Am Fam Physician. 2003 Jun 15;67 12 2527 34. Open 2. Manuel Praga, Ester Gonzalez. Acute interstitial nephritis. 2010 Jun;77 11 956 61.2010 Jun;77 11 956 61. Open https://web.pathway.md/diseases/rec52jA9P3m9WGEa5 3/3

Guideline sources The following summarized guidelines for the evaluation and management of acute ischemic stroke (AIS) are prepared by our editorial team based on guidelines from the European Stroke Organisation (ESO 2023; 2022; 2017; 2016; 2015), the American Diabetes Association (ADA 2023), the U.S. Preventive Services Task Force (USPSTF 2022), the American Heart Association (AHA/ASA 2021; 2019; 2018; 2014), the European Stroke Organisation (ESO/ESSD 2021), the United States Department of Defense (DoD/VA 2019), the European Thyroid Association (ETA 2018), the American College of Emergency Physicians (ACEP 2015), and the American Heart Association (AHA 2011). 1 2 3 4 5 6 7 8 9 10 12 14 15 16 17 18 19 20 21 21 22 23 Definition https://web.pathway.md/diseases/recwd1RIpW03JSM4H 1/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway AIS is a rapid onset of cerebral function disturbance lasting more than 24 hours or leading to death that is caused by occlusion of blood vessels limiting blood supply to the brain. 21 Epidemiology AIS is caused due to cardioembolism (AF, VHD), arteroembolism (atherosclerotic disease in the extracranial cervical carotid or vertebral artery), lacunar (microatheroma with plaque rupture and microembolism), and embolic stroke of undetermined source (ESUS). Less common causes include arterial dissection, vasculitis, vasospasm, and hypercoagulable states. 22 Disease course The blockage of blood vessels limiting blood supply to a part of brain results in AIS, which causes clinical manifestations of sudden facial droop, arm weakness, slurred speech, dizziness, and visual disturbance. Disease progression may lead to cerebral infarction, paralysis, coma and death. 21 Prognosis and risk of recurrence All-cause mortality associated with AIS is 3-fold compared with the age-matched cohort. 23 Calculator Calculator Calculator ABCD score for stroke Alberta stroke program early CT ATRIA stro Guidelines 1. Screening and diagnosis Screening for intracranial atherosclerotic disease: insufficient evidence to recommend routine screening for asymptomatic intracranial atherosclerotic disease in adult stroke-free individuals. I 2. Classification and risk stratification Severity assessment: assess patients with AIS using a stroke severity rating scale, preferably the NIHSS. B 3. Diagnostic investigations General principles: obtain diagnostic evaluation for gaining insights into the etiology and planning optimal strategies for preventing recurrent stroke, completed or underway within 48 hours of the onset of stroke symptoms, in patients with ischemic stroke or TIA. B https://web.pathway.md/diseases/recwd1RIpW03JSM4H 2/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway Brain CT/MRI, for acute evaluation: As per ASA/AHA 2021 guidelines, obtain brain CT or MRI to confirm the diagnosis of symptomatic ischemic cerebral vascular disease in patients with suspected stroke or TIA. B Show 3 more As per ASA/AHA 2019 guidelines, obtain emergency brain imaging on arrival to a hospital before initiating any specific treatment for AIS in all patients with suspected acute stroke. A Show 2 more Brain CT/MRI (for secondary prevention): insufficient evidence to recommend obtaining routine brain MRI to guide treatment selection for the prevention of recurrent stroke. I Show 2 more CT/MR angiography, for acute evaluation: As per ASA/AHA 2021 guidelines: Obtain CT angiography or MRA (or carotid ultrasound) to screen for carotid stenosis in patients with symptomatic anterior circulation cerebral infarction or TIA eligible for revascularization. B Consider obtaining MRA or CT angiography of the intracranial large arteries and extracranial vertebrobasilar arterial system to identify atherosclerotic disease, dissection, Moyamoya disease, or other etiologically relevant vasculopathies in patients with ischemic stroke or TIA. C As per ASA/AHA 2019 guidelines, obtain noninvasive vessel imaging of the intracranial arteries in the initial imaging evaluation of patients otherwise meeting criteria for mechanical thrombectomy. A Show 6 more CT/MR angiography (for secondary prevention): consider obtaining intracranial vessel imaging in some patients with AIS to provide additional information to guide the selection of appropriate secondary stroke prevention treatments. C Show 2 more Carotid and vertebral artery imaging: As per AHA 2021 guidelines, obtain noninvasive cervical carotid imaging with carotid ultrasound, CT angiography, or MRA to screen for carotid stenosis in patients with symptomatic anterior circulation cerebral infarction or TIA eligible for revascularization. B As per AHA 2019 guidelines: Consider obtaining imaging of the extracranial carotid and vertebral arteries in addition to the intracranial circulation to provide useful information on patient eligibility and endovascular procedural planning in patients being potential candidates for mechanical thrombectomy. C Obtain noninvasive imaging of the cervical carotid arteries routinely within 24 hours of admission in patients with nondisabling (mRS score 0-2) AIS in the carotid territory eligible for carotid endarterectomy or stenting. B Cardiac imaging: https://web.pathway.md/diseases/recwd1RIpW03JSM4H 3/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway As per AHA 2021 guidelines, consider obtaining echocardiography with or without contrast to evaluate for possible cardiac sources of or transcardiac pathways for cerebral embolism in patients with cryptogenic stroke. C Show 2 more As per AHA 2019 guidelines, consider obtaining echocardiography in some patients with AIS to provide additional information to guide the selection of appropriate secondary stroke prevention. C Show 2 more Laboratory tests: As per AHA 2021 guidelines: Consider obtaining blood tests including the following in patients with a confirmed diagnosis of symptomatic ischemic cerebrovascular disease to gain insight into risk factors for stroke and to inform therapeutic goals: CBC PT, PTT blood glucose hgb A1c creatinine fasting or nonfasting lipid profile. B Consider obtaining tests for the following as clinically indicated to identify contributors to or relevant risk factors for stroke in patients with cryptogenic stroke: markers of systemic inflammation inherited or acquired hypercoagulable state inherited diseases associated with stroke bloodstream or cerebral spinal fluid infections infections causing CNS vasculitis (such as human immunodeficiency virus and syphilis) drug use (such as cocaine and amphetamines). C As per AHA 2019 guidelines: Assess blood glucose levels before administering IV alteplase since hypoglycemia and hyperglycemia may mimic acute stroke presentations. B Obtain baseline troponin assessment in patients presenting with AIS without delaying initiation of IV alteplase or mechanical thrombectomy. B Electrocardiogram: As per AHA 2021 guidelines, obtain an ECG to screen for AF and atrial flutter and to assess for other concomitant cardiac conditions in patients with suspected stroke or TIA. B As per AHA 2019 guidelines, obtain baseline ECG in patients presenting with AIS without delaying initiation of IV alteplase. B Cardiac monitoring: obtain cardiac monitoring to screen for AF and other potentially serious cardiac arrhythmias requiring emergency cardiac interventions. Obtain cardiac monitoring for at https://web.pathway.md/diseases/recwd1RIpW03JSM4H 4/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway least the first 24 hours. B Show 2 more Chest radiography: insufficient evidence to support the use of CXRs in the hyperacute stroke setting in the absence of evidence of acute pulmonary, cardiac, or pulmonary vascular disease. Avoid unnecessarily delaying the administration of IV alteplase to obtain CXRs. I Screening for thrombophilic states: insufficient evidence to recommend screening for thrombophilic states in patients with ischemic stroke. I Show 2 more Screening for dyslipidemia: consider assessing the plasma lipid profile (fasting or nonfasting) for estimating atherosclerotic CVD risk and documenting baseline LDL-C in 20 years old adult patients not on lipid-lowering therapy. B Screening for diabetes mellitus: As per AHA 2021 guidelines, consider obtaining Hgb A1c to screen for prediabetes/diabetes in patients with ischemic stroke or TIA. C As per AHA 2019 guidelines, consider obtaining screening for diabetes mellitus with testing of fasting plasma glucose, Hgb A1c, or an oral glucose tolerance test in all patients after AIS. Guide the choice of test and timing by clinical judgment and recognition that acute illness may temporarily perturb measures of plasma glucose. Recognize that Hgb A1c may be more accurate than other screening tests in the immediate post-event period. C Screening for obstructive sleep apnea: As per AHA 2021 guidelines: Consider obtaining evaluation for obstructive sleep apnea in patients with ischemic stroke or TIA. C Consider offering positive airway pressure (such as CPAP) to relieve sleep apnea and improve BP, sleepiness, and other apnea-related outcomes in patients with ischemic stroke or TIA and obstructive sleep apnea. C As per AHA 2019 guidelines, do not obtain routine screening for obstructive sleep apnea in patients with recent ischemic stroke. D Screening for central hypothyroidism: evaluate for central hypothyroidism in all patients with stroke, particularly in the presence of hypothyroid manifestations. B 4. Respiratory support Airway support: provide airway support and ventilatory assistance for the treatment of patients with acute stroke having decreased consciousness or having bulbar dysfunction causing compromise of the airway. B Supplemental oxygen: administer supplemental oxygen to maintain oxygen saturation > 94%. B Show 2 more https://web.pathway.md/diseases/recwd1RIpW03JSM4H 5/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway Hyperbaric oxygen therapy: do not use hyperbaric oxygen therapy in patients with AIS except when caused by air embolization. D 5. Medical management Prehospital care: as per AHA 2019 guidelines, ensure the use of a stroke assessment tool by first aid providers including emergency medical services dispatch personnel. B Show 4 more Intravenous alteplase, timing: As per ASA/AHA 2019 guidelines, initiate treatment as quickly as possible in patients eligible for IV alteplase because the benefit of therapy is time-dependent. A Show 9 more As per ACEP 2015 guidelines, administer IV alteplase with a goal to improve functional outcomes in selected patients with AIS within 3 hours after symptom onset at institutions where systems are in place to safely administer the medication. Take the increased risk of symptomatic intracerebral hemorrhage into consideration when deciding whether to administer IV alteplase in patients with AIS. B Show 2 more Intravenous alteplase (pre-administration evaluation): Assess blood glucose levels before administering IV alteplase since hypoglycemia and hyperglycemia may mimic acute stroke presentations. B . Do not administer IV alteplase for nonvascular conditions. B Obtain baseline ECG B and troponin assessment not delaying initiation of IV alteplase in patients presenting with AIS. B Landmark trials: NINDS In patients with ischemic stroke, tPA was superior to placebo with respect to death at 90 days. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995 Dec 14. Intravenous alteplase (concomitant thrombectomy): Administer IV alteplase in patients eligible for IV alteplase even if mechanical thrombectomy is being considered. A Do not obtain observation after IV alteplase for the assessment of clinical response in patients under consideration for mechanical thrombectomy. D Intravenous alteplase, bleeding risk: As per ASA/AHA 2019 guidelines, avoid delaying urgent IV alteplase administration while waiting for hematologic or coagulation testing if there is no reason to suspect an abnormal test, https://web.pathway.md/diseases/recwd1RIpW03JSM4H 6/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway given the extremely low risk of unsuspected abnormal platelet counts or coagulation studies in a population. D Show 6 more As per ASA/AHA 2018 guidelines, do not administer IV alteplase in patients with AIS with platelets < 100, 000/mm , INR > 1.7, activated PTT > 40 sec, or PT > 15. D Show 9 more Intravenous alteplase (complications): Discuss the potential risks of IV alteplase administration during eligibility deliberation and weigh the risks against the anticipated benefits during decision-making. B Be prepared to treat potential emergent adverse effects including bleeding complications and angioedema causing partial airway obstruction in patients undergoing fibrinolytic therapy. B Intravenous alteplase (post-administration care): Maintain BP at < 180/105 mmHg for at least the first 24 hours after IV alteplase administration. B Insufficient evidence regarding the risk of antithrombotic therapy (other than IV aspirin) within the first 24 hours after treatment with IV alteplase (with or without mechanical thrombectomy). Consider initiating antithrombotic therapy in the presence of concomitant conditions for which such treatment given in the absence of IV alteplase is known to provide a substantial benefit or withholding such treatment is known to cause substantial risk. I Intravenous tenecteplase: As per ESO 2023 guidelines, consider administering tenecteplase 0.25 mg/kg as an alternative to alteplase 0.9 mg/kg in patients with AIS of < 4.5 hours duration eligible for IV thrombolysis. B Consider preferring tenecteplase 0.25 mg/kg over alteplase 0.9 mg/kg in these patients in light of safety and efficacy data and because tenecteplase can be administered with a single bolus rather than a 1-hour infusion. E Do not use tenecteplase at a dose of 0.40 mg/kg. B Show 4 more As per AHA 2019 guidelines, consider administering tenecteplase (single IV bolus of 0.25 mg/kg, maximum 25 mg) over IV alteplase in patients eligible for mechanical thrombectomy and not having contraindications to IV fibrinolysis. C Show 2 more Antiplatelet therapy: As per ESO 2022 guidelines: Consider initiating dual antiplatelet therapy in preference to single antiplatelet therapy in patients with ischemic stroke or TIA related to intracranial stenosis due to intracranial atherosclerotic disease. C Insufficient evidence to recommend an additional infusion of glycoprotein IIb/IIIa inhibitors after initial mechanical thrombectomy in patients with AIS due to an intracranial atherosclerotic disease-related intracranial arterial occlusion. I As per AHA 2021 guidelines, initiate antiplatelet therapy over oral anticoagulation to reduce the risk of recurrent ischemic stroke and other cardiovascular events while minimizing the risk of https://web.pathway.md/diseases/recwd1RIpW03JSM4H 7/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway bleeding in patients with non-cardioembolic ischemic stroke or TIA. A Show 5 more As per AHA 2019 guidelines, initiate aspirin in patients with AIS within 24-48 hours after onset. Consider delaying aspirin initiation until 24 hours later in patients treated with IV alteplase, but consider initiating in the presence of concomitant conditions for which such treatment given in the absence of IV alteplase is known to provide a substantial benefit or withholding such treatment is known to cause substantial risk. A Show 8 more Updated evidence: RESCUE BT In patients with stroke and proximal intracranial large vessel occlusion presenting < 24 hours of time last known well, tirofiban was not superior to placebo with respect to disability level, mRS score, at day 90. RESCUE BT Trial Investigators et al. JAMA. 2022 Aug 9. Anticoagulant therapy: As per ESO 2022 guidelines, do not use oral anticoagulation over aspirin, unless there is another formal indication for it, in patients with ischemic stroke or TIA due to high-grade stenosis related to intracranial atherosclerotic disease. D As per AHA 2019 guidelines, insufficient evidence to recommend urgent anticoagulation in patients with severe stenosis of an internal carotid artery ipsilateral to an ischemic stroke. I Show 6 more Updated evidence: ARAIS In adult patients with acute ischemic stroke who were assigned within 4.5 hours of symptom onset, argatroban plus alteplase was not superior to alteplase alone with respect to excellent functional outcome at day 90. Hui-Sheng Chen et al. JAMA. 2023 Feb 9. Management of blood pressure: As per ESO 2022 guidelines, insufficient evidence to recommend permissive or induced hypertension over conventional BP management (target normotension) during the acute phase in patients with AIS or TIA related to high-grade intracranial atherosclerosis causing severe hemodynamic compromise. I As per AHA 2021 guidelines, consider initiating thiazide diuretics, ACEIs, or ARBs to lower BP and reduce recurrent stroke risk in patients with hypertension experiencing a stroke or TIA. B Show 3 more https://web.pathway.md/diseases/recwd1RIpW03JSM4H 8/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway As per AHA 2019 guidelines, correct hypotension and hypovolemia to maintain systemic perfusion levels necessary to support organ function. B Show 9 more Management of glucose levels: As per AHA 2019 guidelines: Treat hypoglycemia (blood glucose < 60 mg/dL) in patients with AIS. B Consider treating hyperglycemia to achieve blood glucose levels of 140-180 mg/dL and obtaining close monitoring to prevent hypoglycemia in patients with AIS since persistent in- hospital hyperglycemia during the first 24 hours after AIS is associated with worse outcomes. C As per ESO 2017 guidelines, avoid administering IV insulin routinely to achieve tight glycemic control in order to improve functional outcome, survival, or infarct growth in patients with AIS. D Management of temperature: As per ESO 2019 guidelines, identify and treat sources of hyperthermia (temperature > 38 C), and administer antipyretic medications to lower temperature in hyperthermic patients with stroke. B Show 2 more As per AHA 2015 guidelines, insufficient evidence to recommend treating hyperthermia in order to improve functional outcome and/or survival in patients with AIS and hyperthermia. I Show 2 more Management of cerebral edema (general principles): Recognize that patients with large territorial cerebral and cerebellar infarctions are at high risk for developing brain swelling and herniation. Discuss care options and possible outcomes quickly with patients (if possible) and family or next of kin. Ensure that medical professionals and caregivers ascertain and include patient-centered preferences in shared decision-making, especially during prognosis formation and when considering interventions or limitations in care. B Underake measures to lessen the risk of swelling and obtain close monitoring for signs of neurological worsening during the first days after stroke. Consider transferring patients at risk for malignant brain swelling early to an institution with appropriate neurosurgical expertise. B Management of cerebral edema (medical management): consider administering osmotic therapy in patients with clinical deterioration from cerebral edema associated with cerebral infarction. C Show 3 more Management of cerebral edema (surgical management, supratentorial infarction): Consider performing decompressive craniectomy in patients with supratentorial infarction and decreased level of consciousness attributed to brain swelling. B Consider performing decompressive craniectomy with dural expansion in patients, either aged 60 years B or > 60 years, deteriorating neurologically within 48 hours from brain swelling associated with unilateral middle cerebral artery infarction despite medical therapy. C https://web.pathway.md/diseases/recwd1RIpW03JSM4H 9/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway Management of cerebral edema (surgical management, cerebellar infarction): perform ventriculostomy for the treatment of obstructive hydrocephalus after cerebellar infarction. Consider performing concomitant or subsequent decompressive craniectomy based on factors such as the size of the infarction, neurological condition, degree of brainstem compression, and effectiveness of medical management. B Show 2 more Management of seizures: As per AHA 2019 guidelines: Manage recurrent seizures after stroke similarly to seizures occurring with other acute neurological conditions, with the choice of antiseizure drugs based on specific patient characteristics. B Do not administer prophylactic antiseizure drugs. D As per ESO 2017 guidelines, avoid administering primary or secondary antiepileptic drug prophylaxis to prevent acute symptomatic seizures after stroke. D Show 5 more Management of dyslipidemia: As per ESO 2022 guidelines, consider ensuring aggressive vascular risk factor control, including lipid management and lifestyle changes (increased physical activity), in order to improve outcomes in patients with ischemic stroke or TIA related to intracranial atherosclerotic disease. C As per AHA 2021 guidelines, initiate atorvastatin 80 mg/day to reduce the risk of stroke recurrence in patients with ischemic stroke with no known coronary heart disease, no major cardiac sources of embolism, and LDL cholesterol > 100 mg/dL. A Show 5 more As per AHA 2019 guidelines, consider continuing statin therapy during the acute period in patients already taking statins at the time of onset of ischemic stroke. C Show 15 more Therapies with no evidence for benefit: Do not use the following therapies for the treatment of patients with AIS: hemodilution by volume expansion high-dose albumin vasodilatory agents, such as pentoxifylline. D Avoid using devices for mechanical augmentation of cerebral blood flow in patients with AIS. D Palliative care: consider referring patients and families with stroke to palliative care resources as appropriate. C 6. Inpatient care Thromboprophylaxis, intermittent pneumatic compression: https://web.pathway.md/diseases/recwd1RIpW03JSM4H 10/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway As per ASA/AHA 2019 guidelines, offer intermittent pneumatic compression, if not contraindicated, in addition to routine care (aspirin and hydration) to reduce the risk of deep vein thrombosis in immobile patients with stroke. B As per ESO 2016 guidelines: Offer intermittent pneumatic compression (thigh-length, sequential) in immobile patients with AIS. B Do not use intermittent pneumatic compression in patients with open wounds on the legs. Be cautious when using in patients with existing deep vein thrombosis, HF, severe peripheral vascular disease, or confusion where attempts to mobilize when unsupervised could lead to falls and injury. D Thromboprophylaxis, anticoagulation: As per ASA/AHA 2019 guidelines: Insufficient evidence to support the use of prophylactic-dose SC heparin (UFH or LMWH) in patients with AIS. I Insufficient evidence to recommend prophylactic-dose LMWH in preference to prophylactic- dose UFH when prophylactic anticoagulation is used. I As per ESO 2016 guidelines: Consider administering prophylactic anticoagulation with UFH (5,000 U BID or TID) or LMWH or heparinoids in immobile patients with AIS if the benefits of reducing the risk of VTE is high enough to offset the increased risks of intracranial and extracranial bleeding associated with their use. C Consider administering LMWH or heparinoids over UFH for prophylactic anticoagulation because of their greater reduction in risk of deep vein thrombosis, the greater convenience, reduced staff costs, and patient comfort associated single daily dose versus multiple daily injections, while weighing these advantages against the higher risk of extracranial bleeding, higher drug costs, and risks in elderly patients with poor renal function. C Thromboprophylaxis, compression stockings: As per ASA/AHA 2019 guidelines, do not use elastic compression stockings in patients with AIS. D As per ESO 2016 guidelines, do not use graduated compression stockings in patients with AIS. D Antibiotic prophylaxis: avoid using routine prophylactic antibiotics in patients with ischemic stroke. D Pressure ulcer prophylaxis: obtain regular skin assessments with objective scales of risk (such as the Braden scale) during hospitalization and inpatient rehabilitation. B Show 2 more Nutritional support: start enteral diet within 7 days of admission after an acute stroke. B Show 2 more https://web.pathway.md/diseases/recwd1RIpW03JSM4H 11/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway Indwelling bladder catheters: do not place indwelling bladder catheters routinely because of the associated risk of catheter-associated UTIs. D 7. Nonpharmacologic interventions Dietary modifications: Consider advising to follow a Mediterranean-type diet, typically with an emphasis on monounsaturated fat, plant-based foods, and fish consumption, with either high extra virgin olive oil or nut supplementation, in preference to a low-fat diet, to reduce the risk of recurrent stroke in patients with stroke and TIA. C Consider advising to reduce the sodium intake by at least 1 g/day sodium (2.5 g/day salt) to reduce the risk of CVD events, including stroke, in patients with stroke or TIA and hypertension. C Physical activity: advise practicing at least moderate-intensity aerobic activity for a minimum of 10 minutes 4 times weekly or vigorous-intensity aerobic activity for a minimum of 20 minutes twice weekly to lower the risk of recurrent stroke and the composite cardiovascular endpoint of recurrent stroke, myocardial infarction, or vascular death in patients with stroke or TIA capable of physical activity. B Show 3 more Weight loss: calculate BMI at the time of the event and annually thereafter to screen for and to classify obesity in patients with ischemic stroke or atherosclerotic CVD. B Show 2 more Smoking cessation: As per AHA 2021 guidelines, offer counseling with or without pharmacotherapy (nicotine replacement, bupropion, or varenicline) to assist in quitting smoking in smoker patients with stroke or TIA. A Show 2 more As per AHA 2019 guidelines, provide in-hospital high-intensity behavioral interventions to promote smoking cessation in smoker patients with AIS. Offer nicotine replacement therapy in patients receiving in-hospital high-intensity behavioral interventions. A Show 3 more Alcohol consumption: advise eliminating or reducing consumption of alcohol to reduce stroke risk in patients with ischemic stroke or TIA consuming excess alcohol (> 2 alcoholic drinks a day for males or > 1 alcoholic drink a day for females). B Substance use cessation: Provide counseling and advise stopping using stimulants in patients with stroke or TIA using stimulants (such as amphetamines, amphetamine derivatives, cocaine, or khat) and patients with infective endocarditis in the context of IV drug use. B Offer specialized services to help manage dependency in patients with stroke or TIA having a substance use disorder (drugs or alcohol). B https://web.pathway.md/diseases/recwd1RIpW03JSM4H 12/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway Head positioning: insufficient evidence to recommend flat-head positioning early after hospitalization for stroke. I 8. Therapeutic procedures Indications for thrombectomy (0-6 hours from onset): Perform mechanical thrombectomy with a stent retriever in patients meeting all the following criteria: age 18 years pre-stroke mRS score of 0-1 causative occlusion of the internal carotid artery or middle cerebral artery segment 1 (M1) NIHSS score of 6 alberta Stroke Program Early CT Score of 6 treatment can be initiated (groin puncture) within 6 hours of symptom onset. A Show 4 more Indications for thrombectomy (6-24 hours from onset): Perform mechanical thrombectomy in selected patients with AIS with large vessel occlusion in the anterior circulation within 6-16 hours of last known normal meeting other DAWN or DEFUSE 3 eligibility criteria. A Consider performing mechanical thrombectomy in selected patients with AIS with large vessel occlusion in the anterior circulation within 16-24 hours of last known normal meeting other DAWN eligibility criteria. C Technical considerations for thrombectomy: strive to achieve a mTICI grade 2b/3 angiographic result as the technical goal of thrombectomy to maximize the probability of a good functional clinical outcome. Attempt achieving reperfusion to mTICI grade 2b/3 as early as possible within the therapeutic window to ensure benefit. A Proceed to evaluation and treatment as rapidly as possible in the 6-24-hour thombectomy window to ensure access to treatment for the greatest proportion of patients. B Show 5 more Intracranial angioplasty/stenting: As per ESO 2022 guidelines: Do not perform angioplasty and/or stenting, in addition to best medical treatment, as first-line treatment in patients with ischemic stroke or TIA related to high-grade stenosis due to intracranial atherosclerotic disease. D Insufficient evidence to recommend angioplasty and/or stenting after initial mechanical thrombectomy in patients with AIS due to an intracranial atherosclerotic disease-related intracranial arterial occlusion. I As per AHA 2021 guidelines, insufficient evidence to recommend angioplasty alone or stent placement to prevent ischemic stroke in the territory of the stenotic artery in patients with severe stenosis (70-99%) of a major intracranial artery and actively progressing symptoms or recurrent https://web.pathway.md/diseases/recwd1RIpW03JSM4H 13/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway TIA or stroke after institution of aspirin and clopidogrel therapy, achievement of systolic BP < 140 mmHg, and high-intensity statin therapy (so-called medical failures). I Show 2 more Carotid artery revascularization: As per AHA 2021 guidelines, perform carotid endarterectomy to reduce the risk of future stroke in patients with non-disabling ischemic stroke or TIA within the past 6 months and ipsilateral severe (70-99%) carotid artery stenosis, provided the perioperative morbidity and mortality risk is < 6%. A Show 9 more As per AHA 2019 guidelines, insufficient evidence to recommend emergent or urgent carotid endarterectomy/carotid angioplasty and stenting when clinical indicators or brain imaging suggests a small infarct core with large territory at risk (such as penumbra), compromised by inadequate flow from critical carotid stenosis or occlusion, or in the case of acute neurological deficit after carotid endarterectomy with suspected acute thrombosis of the surgical site. I Show 2 more Vertebral artery revascularization: insufficient evidence to recommend stenting I or open surgical procedures including vertebral endarterectomy in patients with ischemic stroke or TIA and extracranial vertebral artery stenosis having symptoms despite optimal medical treatment. I Ischemic preconditioning: considering performing ischemic preconditioning as an adjuvant to best medical treatment in patients with ischemic stroke or TIA related to high-grade stenosis due to intracranial atherosclerotic disease. Consider enrolling patients in a dedicated RCT whenever possible. C Intra-arterial thrombolysis: perform mechanical thrombectomy with stent retrievers over intra- arterial fibrinolysis as first-line therapy. B Show 2 more Laser therapy: do not perform transcranial near-infrared laser therapy for the treatment of AIS. D Ultrasound-enhanced systemic thrombolysis: do not use sonothrombolysis as adjuvant therapy with IV fibrinolysis. D 9. Surgical interventions Decompressive craniectomy (supratentorial infarction): Consider performing decompressive craniectomy in patients with supratentorial infarction and decreased level of consciousness attributed to brain swelling. B Consider performing decompressive craniectomy with dural expansion in patients, either aged 60 years B or > 60 years, deteriorating neurologically within 48 hours from brain swelling associated with unilateral middle cerebral artery infarction despite medical therapy. C Decompressive craniectomy (cerebellar infarction): perform ventriculostomy for the treatment of obstructive hydrocephalus after cerebellar infarction. Consider performing concomitant or subsequent decompressive craniectomy based on factors such as the size of the infarction, https://web.pathway.md/diseases/recwd1RIpW03JSM4H 14/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway neurological condition, degree of brainstem compression, and effectiveness of medical management. B Show 2 more Extracranial-intracranial bypass surgery: Do not perform extracranial-intracranial bypass surgery in patients with stroke or TIA attributable to 50-99% stenosis or occlusion of a major intracranial artery. D Do not perform extracranial-intracranial bypass surgery in patients with a recent (within 120 days) TIA or ischemic stroke ipsilateral to atherosclerotic stenosis or occlusion of the middle cerebral or carotid artery. D 10. Specific circumstances Female patients (lifestyle modifications): Advise a healthy lifestyle consisting of the following for primary stroke prevention in patients with cardiovascular risk factors: regular physical activity moderate alcohol consumption (< 1 drink/day for nonpregnant females) abstention from cigarette smoking diet rich in fruits, vegetables, grains, nuts, and olive oil, and low in saturated fat (such as the DASH diet). B Advise lifestyle interventions focusing on diet and exercise for primary stroke prevention in individuals at high risk for stroke. B Female patients (use of oral contraceptives): recognize that oral contraceptives may be harmful in patients with additional risk factors (such as cigarette smoking, history of thromboembolic events). B Show 3 more Female patients, use of postmenopausal hormone therapy: As per ESO 2022 guidelines, avoid using HRT to reduce the risk of ischemic stroke or mortality from acute stroke in postmenopausal females. D As per ASA/AHA 2014 guidelines: Do not use hormone therapy (conjugated equine estrogen with or without medroxyprogesterone) for primary or secondary prevention of stroke in postmenopausal females. D Do not use selective estrogen receptor modulators, such as raloxifene, tamoxifen, or tibolone, for primary prevention of stroke. D Female patients (secondary prevention): screen female patients with asymptomatic carotid stenosis for other treatable risk factors for stroke and institute appropriate lifestyle changes and medical therapies. B Show 8 more https://web.pathway.md/diseases/recwd1RIpW03JSM4H 15/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway Female patients (patients with migraine with aura): Consider offering treatment to reduce migraine frequency because there is an association between higher migraine frequency and stroke risk, although evidence is lacking that this treatment reduces the risk of first stroke. C Consider advising smoking cessation in patients with migraine with aura because of the increased stroke risk. C Female patients (patients with atrial fibrillation): use risk stratification tools in AF accounting for age- and sex-specific differences in the incidence of stroke. A Show 4 more Female patients (patients with CVT, nonpregnant): obtain a CBC, chemistry panel, PT, and activated PTT in patients with suspected cerebral venous thrombosis. B Show 4 more Female patients (patients with CVT, pregnant): continue LMWH in full anticoagulant doses throughout pregnancy, and LMWH or vitamin K antagonist with a target INR of 2.0-3.0 for 6 weeks postpartum (for a total minimum duration of therapy of 6 months) in patients with cerebral venous thrombosis during pregnancy. B Show 3 more Female patients (stroke during menstruation): Insufficient evidence to recommend IV thrombolysis in female patients with ischemic stroke during menstruation. Consider administering IV alteplase after appropriate assessment of the benefit/risk profile on an individual basis in female patients with AIS during menstruation, otherwise meeting eligibility criteria. E Pregnant patients, IV alteplase: As per ESO 2022 guidelines: Insufficient evidence to recommend IV thrombolysis in pregnant patients with AIS. I Consider administering IV alteplase after appropriate assessment of the benefit/risk profile on an individual basis in pregnant patients with acute disabling ischemic stroke, otherwise meeting eligibility criteria. E As per ASA/AHA 2018 guidelines: Consider administering IV alteplase in pregnant patients with AIS when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding. C Insufficient evidence regarding the safety and efficacy of IV alteplase in the early postpartum period (such as < 14 days after delivery). I Pregnant patients (mechanical thrombectomy): Insufficient evidence to recommend mechanical thrombectomy in pregnant patients with AIS. I Consider performing mechanical thrombectomy after appropriate assessment of the benefit/risk profile on an individual basis in pregnant patients with AIS and large vessel occlusion, otherwise https://web.pathway.md/diseases/recwd1RIpW03JSM4H 16/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway meeting eligibility criteria. Consider preferring mechanical thrombectomy alone, if available, over IV thrombolysis or bridging therapy (IV thrombolysis with mechanical thrombectomy) in pregnant patients with AIS related to large vessel occlusion. E Pregnant patients (anticoagulation therapy): Consider the following options for pregnant women with ischemic stroke or TIA and high-risk thromboembolic conditions such as hypercoagulable state or mechanical heart valves: adjusted dose UFH throughout pregnancy, for example, a subcutaneous dose every 12 hours with monitoring of activated PTT; adjusted-dose LMWH with monitoring of anti-factor Xa throughout pregnancy; or UFH or LMWH until week 13, followed by warfarin until the middle of the third trimester and reinstatement of UFH or LMWH until delivery. C Consider pregnant women with stroke or TIA for treatment with UFH or LMWH throughout the first trimester, followed by low-dose aspirin for the remainder of the pregnancy in the absence of a high-risk thromboembolic condition. C Pregnant patients (prevention of preeclampsia): initiate low-dose aspirin from the 12th week of gestation until delivery in pregnant patients with chronic primary or secondary hypertension or previous pregnancy-related hypertension. A Show 6 more Pregnant patients (lipid-lowering therapy): Advise using a reliable form of contraception in sexually active females of childbearing age treated with statin therapy. B Advise stopping statins 1-2 months before attempting pregnancy in females of childbearing age with hypercholesterolemia, or as soon as the pregnancy is discovered. B Postpartum patients: insufficient evidence to recommend IV thrombolysis in postpartum patients with AIS. I Show 3 more

Intra-arterial thrombolysis: perform mechanical thrombectomy with stent retrievers over intra- arterial fibrinolysis as first-line therapy. B Show 2 more Laser therapy: do not perform transcranial near-infrared laser therapy for the treatment of AIS. D Ultrasound-enhanced systemic thrombolysis: do not use sonothrombolysis as adjuvant therapy with IV fibrinolysis. D 9. Surgical interventions Decompressive craniectomy (supratentorial infarction): Consider performing decompressive craniectomy in patients with supratentorial infarction and decreased level of consciousness attributed to brain swelling. B Consider performing decompressive craniectomy with dural expansion in patients, either aged 60 years B or > 60 years, deteriorating neurologically within 48 hours from brain swelling associated with unilateral middle cerebral artery infarction despite medical therapy. C Decompressive craniectomy (cerebellar infarction): perform ventriculostomy for the treatment of obstructive hydrocephalus after cerebellar infarction. Consider performing concomitant or subsequent decompressive craniectomy based on factors such as the size of the infarction, https://web.pathway.md/diseases/recwd1RIpW03JSM4H 14/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway neurological condition, degree of brainstem compression, and effectiveness of medical management. B Show 2 more Extracranial-intracranial bypass surgery: Do not perform extracranial-intracranial bypass surgery in patients with stroke or TIA attributable to 50-99% stenosis or occlusion of a major intracranial artery. D Do not perform extracranial-intracranial bypass surgery in patients with a recent (within 120 days) TIA or ischemic stroke ipsilateral to atherosclerotic stenosis or occlusion of the middle cerebral or carotid artery. D 10. Specific circumstances Female patients (lifestyle modifications): Advise a healthy lifestyle consisting of the following for primary stroke prevention in patients with cardiovascular risk factors: regular physical activity moderate alcohol consumption (< 1 drink/day for nonpregnant females) abstention from cigarette smoking diet rich in fruits, vegetables, grains, nuts, and olive oil, and low in saturated fat (such as the DASH diet). B Advise lifestyle interventions focusing on diet and exercise for primary stroke prevention in individuals at high risk for stroke. B Female patients (use of oral contraceptives): recognize that oral contraceptives may be harmful in patients with additional risk factors (such as cigarette smoking, history of thromboembolic events). B Show 3 more Female patients, use of postmenopausal hormone therapy: As per ESO 2022 guidelines, avoid using HRT to reduce the risk of ischemic stroke or mortality from acute stroke in postmenopausal females. D As per ASA/AHA 2014 guidelines: Do not use hormone therapy (conjugated equine estrogen with or without medroxyprogesterone) for primary or secondary prevention of stroke in postmenopausal females. D Do not use selective estrogen receptor modulators, such as raloxifene, tamoxifen, or tibolone, for primary prevention of stroke. D Female patients (secondary prevention): screen female patients with asymptomatic carotid stenosis for other treatable risk factors for stroke and institute appropriate lifestyle changes and medical therapies. B Show 8 more https://web.pathway.md/diseases/recwd1RIpW03JSM4H 15/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway Female patients (patients with migraine with aura): Consider offering treatment to reduce migraine frequency because there is an association between higher migraine frequency and stroke risk, although evidence is lacking that this treatment reduces the risk of first stroke. C Consider advising smoking cessation in patients with migraine with aura because of the increased stroke risk. C Female patients (patients with atrial fibrillation): use risk stratification tools in AF accounting for age- and sex-specific differences in the incidence of stroke. A Show 4 more Female patients (patients with CVT, nonpregnant): obtain a CBC, chemistry panel, PT, and activated PTT in patients with suspected cerebral venous thrombosis. B Show 4 more Female patients (patients with CVT, pregnant): continue LMWH in full anticoagulant doses throughout pregnancy, and LMWH or vitamin K antagonist with a target INR of 2.0-3.0 for 6 weeks postpartum (for a total minimum duration of therapy of 6 months) in patients with cerebral venous thrombosis during pregnancy. B Show 3 more Female patients (stroke during menstruation): Insufficient evidence to recommend IV thrombolysis in female patients with ischemic stroke during menstruation. Consider administering IV alteplase after appropriate assessment of the benefit/risk profile on an individual basis in female patients with AIS during menstruation, otherwise meeting eligibility criteria. E Pregnant patients, IV alteplase: As per ESO 2022 guidelines: Insufficient evidence to recommend IV thrombolysis in pregnant patients with AIS. I Consider administering IV alteplase after appropriate assessment of the benefit/risk profile on an individual basis in pregnant patients with acute disabling ischemic stroke, otherwise meeting eligibility criteria. E As per ASA/AHA 2018 guidelines: Consider administering IV alteplase in pregnant patients with AIS when the anticipated benefits of treating moderate or severe stroke outweigh the anticipated increased risks of uterine bleeding. C Insufficient evidence regarding the safety and efficacy of IV alteplase in the early postpartum period (such as < 14 days after delivery). I Pregnant patients (mechanical thrombectomy): Insufficient evidence to recommend mechanical thrombectomy in pregnant patients with AIS. I Consider performing mechanical thrombectomy after appropriate assessment of the benefit/risk profile on an individual basis in pregnant patients with AIS and large vessel occlusion, otherwise https://web.pathway.md/diseases/recwd1RIpW03JSM4H 16/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway meeting eligibility criteria. Consider preferring mechanical thrombectomy alone, if available, over IV thrombolysis or bridging therapy (IV thrombolysis with mechanical thrombectomy) in pregnant patients with AIS related to large vessel occlusion. E Pregnant patients (anticoagulation therapy): Consider the following options for pregnant women with ischemic stroke or TIA and high-risk thromboembolic conditions such as hypercoagulable state or mechanical heart valves: adjusted dose UFH throughout pregnancy, for example, a subcutaneous dose every 12 hours with monitoring of activated PTT; adjusted-dose LMWH with monitoring of anti-factor Xa throughout pregnancy; or UFH or LMWH until week 13, followed by warfarin until the middle of the third trimester and reinstatement of UFH or LMWH until delivery. C Consider pregnant women with stroke or TIA for treatment with UFH or LMWH throughout the first trimester, followed by low-dose aspirin for the remainder of the pregnancy in the absence of a high-risk thromboembolic condition. C Pregnant patients (prevention of preeclampsia): initiate low-dose aspirin from the 12th week of gestation until delivery in pregnant patients with chronic primary or secondary hypertension or previous pregnancy-related hypertension. A Show 6 more Pregnant patients (lipid-lowering therapy): Advise using a reliable form of contraception in sexually active females of childbearing age treated with statin therapy. B Advise stopping statins 1-2 months before attempting pregnancy in females of childbearing age with hypercholesterolemia, or as soon as the pregnancy is discovered. B Postpartum patients: insufficient evidence to recommend IV thrombolysis in postpartum patients with AIS. I Show 3 more Patients with diabetes mellitus: As per ADA 2023 guidelines, consider offering pioglitazone to lower the risk of stroke or myocardial infarction in patients with a history of stroke and evidence of insulin resistance and prediabetes, balancing the benefits with the increased risk of weight gain, edema, and fracture. B Consider offering lower doses to mitigate the risk of adverse effects. C As per AHA 2021 guidelines, " consider advising lifestyle optimization (healthy diet, regular physical activity, and smoking cessation) to prevent the progression of prediabetes to diabetes in patients with ischemic stroke or TIA and prediabetes. B Show 6 more Patients with renal disease: administer IV alteplase in patients with end-stage renal disease on hemodialysis and normal activated PTT. B Patients with rercent traumatic injury: do not administer IV alteplase in patients with AIS with recent severe head trauma (within 3 months). D Show 2 more https://web.pathway.md/diseases/recwd1RIpW03JSM4H 17/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway Patients with a history of recent surgery: Avoid administering IV alteplase in patients with AIS and a history of intracranial/spinal surgery within the prior 3 months. D Consider administering IV alteplase in carefully selected patients presenting with AIS undergone major surgery in the preceding 14 days, but weigh the potential increased risk of surgical-site hemorrhage against the anticipated benefits of reduced stroke-related neurological deficits. C Patients with a history of recent ischemic stroke: avoid administering IV alteplase in patients presenting with AIS with a prior ischemic stroke within 3 months. D Patients with hyperdense MCA sign: consider administering IV alteplase in patients with a hyperdense middle cerebral artery sign. C Patients with severe hypoattenuation lesions: insufficient evidence to recommend a threshold of hypoattenuation severity or extent affecting treatment response to alteplase. Do not administer IV alteplase in patients with extensive regions of clear hypoattenuation on CT. Recognize that these patients have a poor prognosis despite IV alteplase, and severe hypoattenuation defined as obvious hypodensity represents irreversible injury. I Patients with embolic stroke of undetermined source: do not use direct OACs D or ticagrelor to reduce the risk of secondary stroke in patients with embolic stroke of undetermined source. D Patients with hemorrhagic transformation: consider initiating or continuing antiplatelet or anticoagulation therapy depending on the specific clinical scenario and underlying indication in patients with AIS and hemorrhagic transformation. C Patients with procedural stroke: consider administering IV alteplase for the treatment of AIS complications of cardiac or cerebral angiographic procedures, depending on the usual eligibility criteria. B Patients with drug-associated ischemic stroke: recognize that illicit drug use may be a contributing factor to incident stroke. Consider administering IV alteplase in instances of illicit drug use-associated AIS in patients with no other exclusions. B Patients with cerebral venous sinus thrombosis: Consider anticoagulation for patients with acute cerebral venous sinus thrombosis. C Consider anticoagulation for at least 3 months, followed by antiplatelet therapy in the absence of trial data to define the optimal duration of anticoagulation for acute cerebral venous sinus thrombosis. C Patients with neurological deficits: consider administering IV alteplase in patients with stroke with severe neurological deficits and a high likelihood of morbidity and mortality, to outweigh the anticipated risk of intracerebral hemorrhage secondary to thrombolysis, because of the increased risk of intracerebral hemorrhage in this group of patients. C Patients with disability or impairement: consider administering IV alteplase in patients with preexisting disability (Modified Rankin Score 2), taking into account relevant factors including quality of life, social support, place of residence, need for a caregiver, patients and family preferences, and goals of care. C https://web.pathway.md/diseases/recwd1RIpW03JSM4H 18/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway Show 2 more Patients with inherited thrombophilias: Consider initiating antiplatelet therapy to reduce the risk of recurrent stroke or TIA in patients with ischemic stroke or TIA of unknown source despite thorough diagnostic evaluation, no other thrombotic history, and having any of the following: prothrombin 20210A mutation activated protein C resistance elevated factor VIII levels protein C deficiency protein S deficiency antithrombin III deficiency. C Patients with antiphospholipid syndrome: initiate antiplatelet therapy alone to reduce the risk of recurrent stroke in patients with ischemic stroke or TIA having an isolated antiphospholipid antibody but not fulfilling the criteria for antiphospholipid syndrome. B Show 3 more Patients with hyperhomocysteinemia: Do not initiate folate, vitamin B6, or vitamin B12 supplementation for the prevention of subsequent stroke in patients with ischemic stroke or TIA and hyperhomocysteinemia. D Offer a low-methionine, cysteine-enhanced diet and initiate vitamin B6, vitamin B12, and folate supplementation to reduce plasma homocysteine to population normal levels and thereby reduce the risk of recurrent ischemic stroke in patients with ischemic stroke or TIA and cystathionine -synthase deficiency. B Patients with malignancy: As per AHA 2021 guidelines, consider initiating anticoagulation with direct OACs in preference to warfarin for the prevention of stroke in patients with ischemic stroke or TIA in the setting of AF and cancer. C As per AHA 2018 guidelines, insufficient evidence regarding the safety and efficacy of IV alteplase in patients with current malignancy. I Patients with sickle cell disease (management): consider administering IV alteplase in adult patients with known sickle cell disease presenting with an AIS. C Patients with sickle cell disease (secondary prevention): Administer chronic blood transfusions to reduce Hgb S to < 30% of total Hgb for the prevention of recurrent ischemic stroke in patients with sickle cell disease and prior ischemic stroke or TIA. B Consider initiating hydroxyurea for the prevention of recurrent ischemic stroke in patients with sickle cell disease with prior ischemic stroke or TIA, if transfusion therapy is not available or practical. C Patients with autoimmune vasculitis: initiate immediate oral high-dose corticosteroids to reduce recurrent stroke risk in patients with ischemic stroke or TIA and symptoms attributed to giant cell arteritis. B https://web.pathway.md/diseases/recwd1RIpW03JSM4H 19/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway Show 3 more Patients with infectious vasculitis: Treat the underlying infectious etiology (such as VZV, cerebral vasculitis, neurosyphilis, or bacterial meningitis) to reduce the risk of stroke in patients with ischemic stroke or TIA and infectious vasculitis. B Consider initiating daily aspirin plus combined ART to reduce the risk of recurrent stroke in patients with ischemic stroke or TIA in the context of human immunodeficiency virus vasculopathy. C Patients with Fabry disease: insufficient evidence regarding the role of agalsidase alfa or agalsidase beta in preventing recurrent stroke or TIA in patients with ischemic stroke or TIA and Anderson-Fabry disease. I Patients with carotid artery stenosis: initiate intensive medical therapy with antiplatelet therapy, lipid-lowering therapy, and antihypertensive therapy to reduce the risk of stroke in patients with TIA or stroke and carotid artery stenosis. A Show 11 more Patients with vertebral artery stenosis: Initiate intensive medical therapy (antiplatelet therapy, lipid-lowering, BP control) to reduce stroke risk in patients with recently symptomatic extracranial vertebral artery stenosis. A Insufficient evidence to recommend stenting I or open surgical procedures, including vertebral endarterectomy and vertebral artery transposition, in patients with ischemic stroke or TIA and extracranial vertebral artery stenosis having symptoms despite optimal medical treatment. I Patients with carotid or vertebral artery dissection: As per AHA 2021 guidelines, initiate antithrombotic therapy for at least 3 months to prevent recurrent stroke or TIA in patients with ischemic stroke or TIA after an extracranial carotid or vertebral arterial dissection. B Show 2 more As per AHA 2019 guidelines: Consider initiating either antiplatelet or anticoagulant therapy for 3-6 months in patients with AIS and extracranial carotid or vertebral arterial dissection. C Insufficient evidence to recommend extracranial endovascular therapy (stenting) in patients with AIS and extracranial carotid or extracranial vertebral arterial dissection experiencing definite recurrent cerebral ischemic events despite medical therapy. I Patients with aortic arch atherosclerosis: Initiate intensive lipid management with an LDL-C target of < 70 mg/dL to prevent recurrent stroke in patients with stroke or TIA and evidence of an aortic arch atheroma. B Initiate antiplatelet therapy to prevent recurrent stroke in patients with stroke or TIA and evidence of an aortic arch atheroma. B Patients with aortic arch dissection: do not administer IV alteplase in patients with AIS known or suspected to be associated with aortic arch dissection. D https://web.pathway.md/diseases/recwd1RIpW03JSM4H 20/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway Patients with intracranial aneurysms: consider administering IV alteplase in patients presenting with AIS known to harbor a small or moderate-sized, unruptured, and unsecured intracranial aneurysm. C Show 2 more Patients with intracranial neoplasms: Consider administering IV alteplase in patients with AIS harboring an extra-axial intracranial neoplasm. C Avoid administering IV alteplase in patients with AIS harboring an intra-axial intracranial neoplasm. D Patients with Moyamoya disease: Consider initiating antiplatelet therapy, typically aspirin monotherapy, for the prevention of ischemic stroke or TIA in patients with Moyamoya disease and a history of ischemic stroke or TIA. C Consider performing surgical revascularization with direct or indirect extracranial-intracranial bypass for the prevention of ischemic stroke or TIA in patients with Moyamoya disease and a history of ischemic stroke or TIA. C Patients with small vessel disease: insufficient evidence to support the use of cilostazol for secondary prevention of stroke in patients with ischemic stroke related to small vessel disease. I Patients with carotid web: Initiate antiplatelet therapy to prevent recurrent ischemic stroke or TIA in patients with carotid web in the distribution of ischemic stroke and TIA without other attributable causes of stroke. B Consider performing carotid stenting or carotid endarterectomy to prevent recurrent ischemic stroke in patients with carotid web in the distribution of ischemic stroke refractory to medical management with no other attributable cause of stroke despite comprehensive workup. C Patients with fibromuscular dysplasia: initiate antiplatelet therapy, control BP control, and offer lifestyle modifications for the prevention of future ischemic events in patients with a history of ischemic stroke or TIA and FMD without other attributable causes. B Show 2 more Patients with vertebrobasilar dolichoectasia: consider initiating antiplatelet or anticoagulant therapy for the prevention of recurrent ischemic events in patients with a history of ischemic stroke or TIA and vertebrobasilar dolichoectasia without other attributable causes. C Patients with atrial fibrillation, anticoagulation therapy: As per ASA/AHA 2021 guidelines, initiate oral anticoagulation, such as apixaban, dabigatran, edoxaban, rivaroxaban, or warfarin, to reduce the risk of recurrent stroke in patients with stroke or TIA and nonvalvular AF. A Initiate oral anticoagulation to reduce the risk of recurrent stroke regardless of the pattern of AF, i.e. paroxysmal, persistent, or permanent. B Show 7 more As per ASA/AHA 2019 guidelines: Consider initiating oral anticoagulation between 4-14 days after the onset of neurological symptoms in most patients with AIS and AF. C https://web.pathway.md/diseases/recwd1RIpW03JSM4H 21/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway Insufficient evidence to support adding antiplatelet therapy to OACs for purposes of reducing the risk of ischemic cardiovascular and cerebrovascular events in patients with a history of ischemic stroke, AF, and coronary artery disease. Consider initiating dual antiplatelet/oral anticoagulation in patients with unstable angina and coronary artery stenting. I Patients with atrial fibrillation (LAA closure): consider performing percutaneous closure of the LA appendage with the Watchman device to reduce the risk of recurrent stroke and bleeding in patients with stroke or TIA in the setting of nonvalvular AF having contraindications for lifelong anticoagulation but able to tolerate at least 45 days. C Patients with patent foramen ovale: decide between patent foramen ovale closure and medical management jointly with the patient, a cardiologist, and a neurologist taking into account the probability of a causal role for the patent foramen ovale in patients with a non-lacunar ischemic stroke of undetermined cause and a patent foramen ovale. B Show 3 more Patients with valvular heart disease (antithrombotic therapy): initiate warfarin to reduce the risk of recurrent stroke or TIA in patients with ischemic stroke or TIA and valvular AF (moderate-to- severe mitral stenosis or any mechanical heart valve). B Show 4 more Patients with valvular heart disease (valvular surgery): consider performing early surgery (during initial hospitalization before completion of a full therapeutic course of antibiotics) to reduce the risk of recurrent embolisms, if there is no evidence of ICH or extensive neurological damage, in patients with ischemic stroke or TIA and infective endocarditis presenting with recurrent emboli and persistent vegetations despite appropriate antibiotic therapy. C Show 4 more Patients with myocardial infarction: Consider administering IV alteplase at the dose appropriate for cerebral ischemia, followed by percutaneous coronary angioplasty and stenting if indicated, in patients presenting with concurrent AIS and acute myocardial infarction. C Consider administering IV alteplase in patients presenting with AIS and a history of recent myocardial infarction in the past 3 months, if the recent myocardial infarction was non-STEMI or STEMI involving the right, inferior, C or left anterior myocardium. C Patients with intracardiac thrombi: As per AHA 2021 guidelines, consider obtaining advanced cardiac imaging (such as contrast- enhanced echocardiography or cardiac MRI) to assess for the presence of LV thrombus in patients with stroke or TIA in the setting of acute myocardial infarction. C Show 3 more As per AHA 2018 guidelines: Consider administering IV alteplase in patients with a known LA or ventricular thrombus major AIS likely to produce severe disability. C Insufficient evidence to recommend IV alteplase administration in patients with a known LA or ventricular thrombus presenting with moderate AIS likely to produce mild disability. I https://web.pathway.md/diseases/recwd1RIpW03JSM4H 22/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway Patients with congenital heart disease: Initiate anticoagulation with warfarin to reduce the risk of recurrent stroke or TIA in patients with ischemic stroke or TIA and Fontan palliation. B Consider initiating anticoagulation with warfarin to reduce the risk of recurrent stroke or TIA in patients with cyanotic congenital heart disease and other complex lesions and ischemic stroke or TIA of presumed cardioembolic origin. C Patients with cardiomyopathy: initiate anticoagulation with warfarin for at least 3 months to reduce the risk of recurrent stroke or TIA in patients with ischemic stroke or TIA and LA or LA appendage thrombus in the setting of ischemic, non-ischemic, or restrictive cardiomyopathy and LV dysfunction. B Show 4 more Patients with cardiac tumors: As per AHA 2021 guidelines, consider performing tumor resection to reduce the risk of recurrent stroke in patients with stroke or TIA with a left-sided cardiac tumor. C As per AHA 2018 guidelines: Consider administering IV alteplase in patients with cardiac myxoma and major AIS likely to produce severe disability. C Consider administering IV alteplase in patients with papillary fibroelastoma presenting with major AIS likely to produce severe disability. C Patients with infective endocarditis: do not administer IV alteplase in patients with AIS and symptoms consistent with infective endocarditis because of the increased risk of ICH. D Patients with acute pericarditis: Consider administering IV alteplase in patients with acute pericarditis and major AIS likely to produce severe disability. C Insufficient evidence to recommend administering IV alteplase in patients presenting with acute pericarditis and moderate AIS likely to produce mild disability. I 11. Preventative measures Primary prevention (statin therapy): initiate statins for primary prevention of CVDs in 40-75 years old adults with 1 CVD risk factors (dyslipidemia, diabetes, hypertension, or smoking) and an estimated 10-year CVD risk 10%. B Show 2 more Primary prevention (antiplatelet therapy): insufficient to support the use of antiplatelet therapy to reduce the risk of major adverse cardiovascular events including ischemic stroke in patients with asymptomatic intracranial atherosclerosis. Secondary prevention (antiplatelet therapy): initiate aspirin 325 mg/day over warfarin to reduce the risk of recurrent ischemic stroke and vascular death in patients with stroke or TIA caused by 50-99% stenosis of a major intracranial artery. B https://web.pathway.md/diseases/recwd1RIpW03JSM4H 23/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway Show 4 more Secondary prevention (health system-based interventions): implement voluntary hospital- based or outpatient-focused quality monitoring and improvement programs to improve short-term and long-term adherence to nationally accepted, evidence-based guidelines for secondary stroke prevention in patients with ischemic stroke or TIA. B Show 2 more Secondary prevention (behavioral changes): offer behavior change interventions targeting stroke literacy, lifestyle factors, and medication adherence to reduce cardiovascular events in patients with ischemic stroke or TIA. B Show 5 more 12. Follow-up and surveillance Rehabilitation, approach and timing: As per ASA/AHA 2019 guidelines, provide early rehabilitation in patients hospitalized for stroke in environments with organized, interprofessional stroke care. A Show 3 more As per DoD/VA 2019 guidelines, provide a team-based approach in an organized inpatient unit encompassing comprehensive rehabilitation in order to improve the likelihood of discharge to home after acute stroke. A Show 3 more Rehabilitation, motor therapy: As per ASA/AHA 2019 guidelines, insufficient evidence to support the use of fluoxetine or other SSRIs to enhance motor recovery. I Updated evidence: EFFECTS In adult patients with a clinical diagnosis of ischemic or intracerebral hemorrhage in the previous 2-15 days, fluoxetine was not superior to placebo with respect to physical function as measured by the stroke impact scale score. EFFECTS Trial Collaboration. Lancet Neurol. 2020 Aug. As per DoD/VA 2019 guidelines, offer task-specific practice ("task-oriented practice" or "repetitive task practice") for improving upper- and lower-extremity motor function, gait, posture, and activities of daily living. A Show 17 more Rehabilitation, evaluation for dysphagia: As per ESSD/ESO 2021 guidelines, obtain a formal dysphagia screening test (either water- swallow tests or multiple-consistency tests) as soon as possible after admission to prevent post- stroke pneumonia and decrease the risk of early mortality in all patients with acute stroke. B https://web.pathway.md/diseases/recwd1RIpW03JSM4H 24/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway Show 2 more As per ASA/AHA 2019 guidelines, obtain dysphagia screening before the patient begins eating, drinking, or receiving oral medications to identify patients at increased risk for aspiration. B Consider obtaining dysphagia screening by speech-language pathologists or other trained healthcare providers. B Show 2 more Rehabilitation, dysphagia therapy, nutritional support: As per ESSD/ESO 2021 guidelines, do not administer any food or liquid items, including oral medications, until a dysphagia screening is obtained and swallowing is deemed safe. D Show 2 more As per DoD/VA 2019 guidelines, consider placing a gastrostomy tube to maintain optimal nutrition in patients with dysphagia in the post-acute phase of stroke requiring tube feeding. C Rehabilitation, dysphagia therapy, exercises: As per ESSD/ESO 2021 guidelines, consider offering behavioral swallowing exercises to rehabilitate swallowing function in patients with post-stroke dysphagia. Avoid limiting behavioral interventions to one specific maneuver or training but tailor the treatment to the specific swallowing impairment of the individual patient with post-stroke dysphagia based on a careful assessment of dysphagia. C As per DoD/VA 2019 guidelines, consider offering Shaker exercise or chin tuck against resistance exercises in addition to conventional dysphagia therapy. C Show 2 more Rehabilitation, dysphagia therapy, oral hygiene: As per ESSD/ESO 2021 guidelines, consider implementing oral health care interventions to reduce the risk of pneumonia in patients with stroke. C As per ASA/AHA 2019 guidelines, consider implementing oral hygiene protocols to reduce the risk of pneumonia after stroke. C Rehabilitation (dysphagia therapy, pharmacotherapy): offer pharmacological treatment of post- stroke dysphagia within clinical trial settings. B Show 3 more Rehabilitation, dysphagia therapy, electrical stimulation: As per ESSD/ESO 2021 guidelines, offer neurostimulation techniques in patients with post- stroke dysphagia within clinical trial settings. B Show 2 more As per DoD/VA 2019 guidelines, insufficient evidence to recommend for or against neuromuscular electrical stimulation or pharyngeal electrical stimulation for the treatment of dysphagia. I Rehabilitation (dysphagia therapy, acupuncture): consider offering acupuncture for the rehabilitation of swallowing function in patients with post-stroke dysphagia. C https://web.pathway.md/diseases/recwd1RIpW03JSM4H 25/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway Rehabilitation (cognitive, speech, and sensory therapy): insufficient evidence to recommend for or against the use of any specific cognitive rehabilitation methodology or pharmacotherapy to improve cognitive outcomes. I Show 4 more Rehabilitation, depression and anxiety: As per ASA/AHA 2019 guidelines: Use a structured depression inventory to routinely screen for post-stroke depression. B Initiate antidepressants in the absence of contraindications and closely monitor to verify effectiveness in patients with post-stroke depression. B As per DoD/VA 2019 guidelines, insufficient evidence for or against the universal use of SSRIs or SNRIs for the prevention of post-stroke depression. I Show 6 more Rehabilitation (return to work): Insufficient evidence to recommend for or against any specific assessments or interventions regarding return to work. I Insufficient evidence to recommend for or against using any specific assessments or interventions to facilitate a return to driving. I 13. Quality improvement EMS services: Develop regional systems of stroke care consisting of healthcare facilities providing initial emergency care, including administration of IV alteplase, and centers capable of performing endovascular stroke treatment with comprehensive periprocedural care to which rapid transport can be arranged when appropriate. A Develop triage paradigms and protocols to ensure that patients with a known or suspected stroke are rapidly identified and assessed by use of a validated and standardized tool for stroke screening by emergency medical services leaders, in coordination with local, regional, and state agencies and in consultation with medical authorities and local experts. B Stroke centers/units: certify stroke centers by an independent external body. B Show 6 more Organization of care: develop, adopt, and adhere to care protocols reflecting current care guidelines as established by national and international professional organizations in all hospitals caring for stroke patients within a stroke system of care. B Show 4 more Telemedicine: implement teleradiology systems (approved by the US FDA) for timely review of brain imaging in patients with suspected acute stroke in sites without in-house imaging interpretation expertise. Recognize that teleradiology systems (approved by the US FDA) implemented within a telestroke network are effective in supporting rapid imaging interpretation in time for IV alteplase administration decision making. A https://web.pathway.md/diseases/recwd1RIpW03JSM4H 26/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway Show 5 more Outcome measures: organize a multidisciplinary quality improvement committee in healthcare institutions to review and monitor stroke care quality benchmarks, indicators, evidence-based practices, and outcomes. Consider forming a clinical process improvement team and using a stroke care registry for such quality of care assurances. Consider using a data repository to identify the gaps or disparities in quality stroke care. Consider initiating specific interventions once the gaps have been identified to address these gaps or disparities. B Show 2 more Public health measures: design and implement public education programs focused on stroke systems and the need to seek emergency care in a rapid manner. B Health equity: assess and address social determinants of health (literacy level, language proficiency, medication affordability, food insecurity, housing, and transportation barriers) when managing stroke risk factors to reduce healthcare disparities. B Show 3 more References 1. William J Powers, Alejandro A Rabinstein, Teri Ackerson 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 Dec;50 12):e344-e418. Open 2. Dawn O Kleindorfer, Amytis Towfighi, Seemant Chaturvedi 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 Jul;52 7):e364-e467. Open 3. George Ntaios, Tomasz Dziedzic, Patrik Michel et al. European Stroke Organisation ESO guidelines for the management of temperature in patients with acute ischemic stroke. Int J Stroke. 2015 Aug;10 6 941 9. Open 4. Blanca Fuentes, George Ntaios, Jukka Putaala et al. European Stroke Organisation ESO guidelines on glycaemia management in acute stroke. Eur Stroke J. 2018 Mar;3 1 5 21. Open 5. Rainer Dziewas, Emilia Michou, Michaela Trapl-Grundschober et al. European Stroke Organisation and European Society for Swallowing Disorders guideline for the diagnosis and treatment of post-stroke dysphagia. Eur Stroke J. 2021 Sep;6 3 LXXXIX CXV. Open 6. Furie KL, Kasner SE, Adams RJ et al. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the american heart association/american stroke association. Stroke. 2011 Jan;42 1 227 76. Open 7. Marios Psychogios, Alex Brehm, Elena L pez-Cancio et al. European Stroke Organisation guidelines on treatment of patients with intracranial atherosclerotic disease. Eur Stroke J. 2022 Sep;7 3 III IV. Open 8. 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 Mar;49 3):e46-e110. Open https://web.pathway.md/diseases/recwd1RIpW03JSM4H 27/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway 9. 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 May;45 5 1545 88. Open 10. Christine Kremer, Zuzana Gdovinova, Yannick Bejot et al. European Stroke Organisation guidelines on stroke in women: Management of menopause, pregnancy and postpartum. Eur Stroke J. 2022 Jun;7 2 I XIX. Open 11. A Kobayashi, A Czlonkowska, G A Ford et al. European Academy of Neurology and European Stroke Organization consensus statement and practical guidance for pre-hospital management of stroke. Eur J Neurol. 2018 Mar;25 3 425 433. Open 12. Sonia Alamowitch, Guillaume Turc, Lina Palaiodimou et al. European Stroke Organisation ESO expedited recommendation on tenecteplase for acute ischaemic stroke. Eur Stroke J. 2023 Mar;8 1 8 54. Open 13. Stephanie Debette, Mikael Mazighi, Philippe Bijlenga et al. ESO guideline for the management of extracranial and intracranial artery dissection. Eur Stroke J. 2021 Sep;6 3 XXXIX LXXXVIII. Open 14. Martin Dennis, Valeria Caso, L Jaap Kappelle et al. European Stroke Organisation ESO guidelines for prophylaxis for venous thromboembolism in immobile patients with acute ischaemic stroke. Eur Stroke J. 2016 Mar;1 1 6 19. Open 15. Brown MD, Burton JH, Nazarian DJ et al. Clinical Policy: Use of Intravenous Tissue Plasminogen Activator for the Management of Acute Ischemic Stroke in the Emergency Department. Ann Emerg Med. 2015 Sep;66 3 322 333.e31. Open 16. James Sall, Blessen C Eapen, Johanna Elizabeth Tran et al. The Management of Stroke Rehabilitation: A Synopsis of the 2019 U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guideline. Ann Intern Med. 2019 Dec 17;171 12 916 924. Open 17. Martin Holtkamp, Ettore Beghi, Felix Benninger et al. European Stroke Organisation guidelines for the management of post-stroke seizures and epilepsy. Eur Stroke J. 2017 Jun;2 2 103 115. Open 18. Persani L, Brabant G, Dattani M et al. 2018 European Thyroid Association ETA Guidelines on the Diagnosis and Management of Central Hypothyroidism. Eur Thyroid J. 2018 Oct;7 5 225 237. Open 19. US Preventive Services Task Force, Carol M Mangione, Michael J Barry et al. Statin Use for the Primary Prevention of Cardiovascular Disease in Adults: US Preventive Services Task Force Recommendation Statement. JAMA. 2022 Aug 23;328 8 746 753. Open 20. Steven E. Kahn, Cheryl A.M. Anderson, John B. Buse et al. Standards of Care in Diabetes 2023. Diabetes Care. 2023 Jan;46 Supplement_1 S1 S291. Open 21. Chandril Chugh. Acute Ischemic Stroke: Management Approach. 2019 Jun;23 Suppl 2 S140 S146.2019 Jun;23 Suppl 2 S140 S146. Open 22. Tapuwa D Musuka, Stephen B Wilton, Mouhieddin Traboulsi et al. Diagnosis and management of acute ischemic stroke: speed is critical. 2015 Sep 8;187 12 887 93.2015 Sep 8;187 12 887 93. Open 23. Angela M Carter, Andrew J Catto, Michael W Mansfield et al. Predictive variables for mortality after acute ischemic stroke. 2007 Jun;38 6 1873 80.2007 Jun;38 6 1873 80. Open

13. Quality improvement EMS services: Develop regional systems of stroke care consisting of healthcare facilities providing initial emergency care, including administration of IV alteplase, and centers capable of performing endovascular stroke treatment with comprehensive periprocedural care to which rapid transport can be arranged when appropriate. A Develop triage paradigms and protocols to ensure that patients with a known or suspected stroke are rapidly identified and assessed by use of a validated and standardized tool for stroke screening by emergency medical services leaders, in coordination with local, regional, and state agencies and in consultation with medical authorities and local experts. B Stroke centers/units: certify stroke centers by an independent external body. B Show 6 more Organization of care: develop, adopt, and adhere to care protocols reflecting current care guidelines as established by national and international professional organizations in all hospitals caring for stroke patients within a stroke system of care. B Show 4 more Telemedicine: implement teleradiology systems (approved by the US FDA) for timely review of brain imaging in patients with suspected acute stroke in sites without in-house imaging interpretation expertise. Recognize that teleradiology systems (approved by the US FDA) implemented within a telestroke network are effective in supporting rapid imaging interpretation in time for IV alteplase administration decision making. A https://web.pathway.md/diseases/recwd1RIpW03JSM4H 26/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway Show 5 more Outcome measures: organize a multidisciplinary quality improvement committee in healthcare institutions to review and monitor stroke care quality benchmarks, indicators, evidence-based practices, and outcomes. Consider forming a clinical process improvement team and using a stroke care registry for such quality of care assurances. Consider using a data repository to identify the gaps or disparities in quality stroke care. Consider initiating specific interventions once the gaps have been identified to address these gaps or disparities. B Show 2 more Public health measures: design and implement public education programs focused on stroke systems and the need to seek emergency care in a rapid manner. B Health equity: assess and address social determinants of health (literacy level, language proficiency, medication affordability, food insecurity, housing, and transportation barriers) when managing stroke risk factors to reduce healthcare disparities. B Show 3 more References 1. William J Powers, Alejandro A Rabinstein, Teri Ackerson 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 Dec;50 12):e344-e418. Open 2. Dawn O Kleindorfer, Amytis Towfighi, Seemant Chaturvedi 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 Jul;52 7):e364-e467. Open 3. George Ntaios, Tomasz Dziedzic, Patrik Michel et al. European Stroke Organisation ESO guidelines for the management of temperature in patients with acute ischemic stroke. Int J Stroke. 2015 Aug;10 6 941 9. Open 4. Blanca Fuentes, George Ntaios, Jukka Putaala et al. European Stroke Organisation ESO guidelines on glycaemia management in acute stroke. Eur Stroke J. 2018 Mar;3 1 5 21. Open 5. Rainer Dziewas, Emilia Michou, Michaela Trapl-Grundschober et al. European Stroke Organisation and European Society for Swallowing Disorders guideline for the diagnosis and treatment of post-stroke dysphagia. Eur Stroke J. 2021 Sep;6 3 LXXXIX CXV. Open 6. Furie KL, Kasner SE, Adams RJ et al. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the american heart association/american stroke association. Stroke. 2011 Jan;42 1 227 76. Open 7. Marios Psychogios, Alex Brehm, Elena L pez-Cancio et al. European Stroke Organisation guidelines on treatment of patients with intracranial atherosclerotic disease. Eur Stroke J. 2022 Sep;7 3 III IV. Open 8. 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 Mar;49 3):e46-e110. Open https://web.pathway.md/diseases/recwd1RIpW03JSM4H 27/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway 9. 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 May;45 5 1545 88. Open 10. Christine Kremer, Zuzana Gdovinova, Yannick Bejot et al. European Stroke Organisation guidelines on stroke in women: Management of menopause, pregnancy and postpartum. Eur Stroke J. 2022 Jun;7 2 I XIX. Open 11. A Kobayashi, A Czlonkowska, G A Ford et al. European Academy of Neurology and European Stroke Organization consensus statement and practical guidance for pre-hospital management of stroke. Eur J Neurol. 2018 Mar;25 3 425 433. Open 12. Sonia Alamowitch, Guillaume Turc, Lina Palaiodimou et al. European Stroke Organisation ESO expedited recommendation on tenecteplase for acute ischaemic stroke. Eur Stroke J. 2023 Mar;8 1 8 54. Open 13. Stephanie Debette, Mikael Mazighi, Philippe Bijlenga et al. ESO guideline for the management of extracranial and intracranial artery dissection. Eur Stroke J. 2021 Sep;6 3 XXXIX LXXXVIII. Open 14. Martin Dennis, Valeria Caso, L Jaap Kappelle et al. European Stroke Organisation ESO guidelines for prophylaxis for venous thromboembolism in immobile patients with acute ischaemic stroke. Eur Stroke J. 2016 Mar;1 1 6 19. Open 15. Brown MD, Burton JH, Nazarian DJ et al. Clinical Policy: Use of Intravenous Tissue Plasminogen Activator for the Management of Acute Ischemic Stroke in the Emergency Department. Ann Emerg Med. 2015 Sep;66 3 322 333.e31. Open 16. James Sall, Blessen C Eapen, Johanna Elizabeth Tran et al. The Management of Stroke Rehabilitation: A Synopsis of the 2019 U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guideline. Ann Intern Med. 2019 Dec 17;171 12 916 924. Open 17. Martin Holtkamp, Ettore Beghi, Felix Benninger et al. European Stroke Organisation guidelines for the management of post-stroke seizures and epilepsy. Eur Stroke J. 2017 Jun;2 2 103 115. Open 18. Persani L, Brabant G, Dattani M et al. 2018 European Thyroid Association ETA Guidelines on the Diagnosis and Management of Central Hypothyroidism. Eur Thyroid J. 2018 Oct;7 5 225 237. Open 19. US Preventive Services Task Force, Carol M Mangione, Michael J Barry et al. Statin Use for the Primary Prevention of Cardiovascular Disease in Adults: US Preventive Services Task Force Recommendation Statement. JAMA. 2022 Aug 23;328 8 746 753. Open 20. Steven E. Kahn, Cheryl A.M. Anderson, John B. Buse et al. Standards of Care in Diabetes 2023. Diabetes Care. 2023 Jan;46 Supplement_1 S1 S291. Open 21. Chandril Chugh. Acute Ischemic Stroke: Management Approach. 2019 Jun;23 Suppl 2 S140 S146.2019 Jun;23 Suppl 2 S140 S146. Open 22. Tapuwa D Musuka, Stephen B Wilton, Mouhieddin Traboulsi et al. Diagnosis and management of acute ischemic stroke: speed is critical. 2015 Sep 8;187 12 887 93.2015 Sep 8;187 12 887 93. Open 23. Angela M Carter, Andrew J Catto, Michael W Mansfield et al. Predictive variables for mortality after acute ischemic stroke. 2007 Jun;38 6 1873 80.2007 Jun;38 6 1873 80. Open 24. Eric J ttler, Andreas Unterberg, Johannes Woitzik et al. Hemicraniectomy in Older Patients with Extensive Middle-Cerebral-Artery Stroke. N Engl J Med. 2014 Mar 20;370 12 1091 100. Open https://web.pathway.md/diseases/recwd1RIpW03JSM4H 28/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway 25. Gronseth GS, Mess SR. Practice advisory: Etanercept for poststroke disability: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2016 Jun 7;86 23 2208 11. Open 26. Sacks D, Black CM, Cognard C et al. Multisociety consensus quality improvement guidelines for intraarterial catheter-directed treatment of acute ischemic stroke, from the American Society of Neuroradiology, Canadian Interventional Radiology Association, Cardiovascular and Interventional Radiological Society of Europe, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, European Society of Minimally Invasive Neurological Therapy, and Society of Vascular and Interventional Neurology. J Vasc Interv Radiol. 2013 Feb;24 2 151 63. Open 27. Schellinger PD, Bryan RN, Caplan LR et al. Evidence-based guideline: The role of diffusion and perfusion MRI for the diagnosis of acute ischemic stroke: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2010 Jul 13;75 2 177 85. Open 28. Jauch EC, Saver JL, Adams HP Jr et al. 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. 2013 Mar;44 3 870 947. Open 29. Culebras A, Mess SR, Chaturvedi S et al. Summary of evidence-based guideline update: prevention of stroke in nonvalvular atrial fibrillation: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2014 Feb 25;82 8 716 24. Open 30. American Association of Neurological Surgeons. Choosing Wisely AANS recommendations. Choosing Wisely. 2014. Open 31. Turc G, Bhogal P, Fischer U et al. European Stroke Organisation ESO European Society for Minimally Invasive Neurological Therapy ESMINT Guidelines on Mechanical Thrombectomy in Acute Ischemic Stroke. J Neurointerv Surg. 2019 Feb 26. pii: neurintsurg-2018 014569. Open 32. Pengfei Yang, Yongwei Zhang, Lei Zhang et al. Endovascular Thrombectomy with or without Intravenous Alteplase in Acute Stroke. N Engl J Med. 2020 May 21;382 21 1981 1993. Open 33. Bruce C V Campbell, Peter J Mitchell, Leonid Churilov et al. Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke. N Engl J Med. 2018 Apr 26;378 17 1573 1582. Open 34. Gregory W Albers, Michael P Marks, Stephanie Kemp et al. Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging. N Engl J Med. 2018 Feb 22;378 8 708 718. Open 35. Craig S Anderson, Thompson Robinson, Richard I Lindley et al. Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke. N Engl J Med. 2016 Jun 16;374 24 2313 23. Open 36. Arthur Wang, Noorie Pednekar, Rachel Lehrer et al. DRAGON score predicts functional outcomes in acute ischemic stroke patients receiving both intravenous tissue plasminogen activator and endovascular therapy. Surg Neurol Int. 2017 Jul 18;8 149. Open 37. Jennifer E. Fugate, DO and Alejandro A. Rabinstein, MD. Absolute and Relative Contraindications to IV rt-PA for Acute Ischemic Stroke. Neurohospitalist. 2015 Jul; 5 3 110 121. Open 38. Arturo Ren , M nica Mill n, Luis San Rom n 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 Mar 1;327 9 826 835. Open https://web.pathway.md/diseases/recwd1RIpW03JSM4H 29/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway 39. Shinichi Yoshimura, Nobuyuki Sakai, Hiroshi Yamagami et al. Endovascular Therapy for Acute Stroke with a Large Ischemic Region. N Engl J Med. 2022 Apr 7;386 14 1303 1313. Open 40. Bruce C V Campbell, Peter J Mitchell, Timothy J Kleinig et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med. 2015 Mar 12;372 11 1009 18. Open 41. RESCUE BT Trial Investigators, Zhongming Qiu, Fengli Li et al. Effect of Intravenous Tirofiban vs Placebo Before Endovascular Thrombectomy on Functional Outcomes in Large Vessel Occlusion Stroke: The RESCUE BT Randomized Clinical Trial. JAMA. 2022 Aug 9;328 6 543 553. Open 42. P Lyden, T Brott, B Tilley et al. Improved reliability of the NIH Stroke Scale using video training. NINDS TPA Stroke Study Group. Stroke. 1994 Nov;25 11 2220 6. Open 43. Pengfei Yang, Lili Song, Yongwei Zhang 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 Nov 5;400 10363 1585 1596. Open 44. Hui-Sheng Chen, Yu Cui, Zhong-He Zhou et al. Effect of Argatroban Plus Intravenous Alteplase vs Intravenous Alteplase Alone on Neurologic Function in Patients With Acute Ischemic Stroke: The ARAIS Randomized Clinical Trial. JAMA. 2023 Feb 9;e230550. Open 45. Mikael Mazighi, Sebastien Richard, Bertrand Lapergue 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 Apr;20 4 265 274. Open 46. N Attal, G Cruccu, R Baron et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol. 2010 Sep;17 9 1113-e88. Open 47. Xiaochuan Huo, Gaoting Ma, Xu Tong et al. Trial of Endovascular Therapy for Acute Ischemic Stroke with Large Infarct. N Engl J Med. 2023 Apr 6;388 14 1272 1283. Open 48. Russell Chabanne, Thomas Geeraerts, Marc Begard et al. Outcomes After Endovascular Therapy With Procedural Sedation vs General Anesthesia in Patients With Acute Ischemic Stroke: The AMETIS Randomized Clinical Trial. JAMA Neurol. 2023 Apr 3;e230413. Open 49. Silke Walter, Heinrich J Audebert, Aristeidis H Katsanos et al. European Stroke Organisation ESO guidelines on mobile stroke units for prehospital stroke management. Eur Stroke J. 2022 Mar;7 1 XXVII LIX. Open 50. Guillaume Turc, Georgios Tsivgoulis, Heinrich J Audebert et al. European Stroke Organisation European Society for Minimally Invasive Neurological Therapy expedited recommendation on indication for intravenous thrombolysis before mechanical thrombectomy in patients with acute ischaemic stroke and anterior circulation large vessel occlusion. Eur Stroke J. 2022 Mar;7 1 I XXVI. Open 51. Catharina Jm Klijn, Maurizio Paciaroni, Eivind Berge et al. Antithrombotic treatment for secondary prevention of stroke and other thromboembolic events in patients with stroke or transient ischemic attack and non-valvular atrial fibrillation: A European Stroke Organisation guideline. Eur Stroke J. 2019 Sep;4 3 198 223. Open 52. Jesse Dawson, ine Merwick, Alastair Webb 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 Jun;6 2 CLXXXVII CXCI. Open 53. Else Charlotte Sandset, Craig S Anderson, Philip M Bath et al. European Stroke Organisation ESO guidelines on blood pressure management in acute ischaemic stroke and intracerebral haemorrhage. Eur https://web.pathway.md/diseases/recwd1RIpW03JSM4H 30/31 6/23/23, 1:57 AM Acute ischemic stroke Pathway Stroke J. 2021 Jun;6 2 XLVIII LXXXIX. Open 54. Eivind Berge, William Whiteley, Heinrich Audebert et al. European Stroke Organisation ESO guidelines on intravenous thrombolysis for acute ischaemic stroke. Eur Stroke J. 2021 Mar;6 1 I LXII. Open 55. Nadinda A M van der Ende, Bob Roozenbeek, Lucas E M Smagge et al. Safety and Efficacy of Dual Thrombolytic Therapy With Mutant Prourokinase and Small Bolus Alteplase for Ischemic Stroke. JAMA Neurol. 2023 May 22;e231262. Online ahead of print. Open 56. Steven J Warach, Anna Ranta, Joosup Kim et al. Symptomatic Intracranial Hemorrhage With Tenecteplase vs Alteplase in Patients With Acute Ischemic Stroke: The Comparative Effectiveness of Routine Tenecteplase vs Alteplase in Acute Ischemic Stroke CERTAIN Collaboration. JAMA Neurol. 2023 May 30;e231449. Open https://web.pathway.md/diseases/recwd1RIpW03JSM4H 31/31

Guideline sources The following summarized guidelines for the evaluation and management of acute kidney injury (AKD) are prepared by our editorial team based on guidelines from the American College of Radiology (ACR 2023; 2021), the American Society for Extracorporeal Technology (AmSECT/STS/SCA 2022), the Canadian Association of Radiologists (CAR 2022), the European Society of Cardiology (ESC 2021), the National Institutes of Health (NIH 2021), the Acute Disease Quality Initiative (ADQI 2020; 2017), the United Kingdom Kidney Association (UKKA 2019), the Japanese Society of Blood Purification in Critical Care (JSBPCC/JSPN/JSDT/JSICM/JSN 2018), the European Society for Vascular Surgery (ESVS 2017), the Kidney Disease: Improving Global Outcomes Foundation (KDIGO 2012), the European Renal Best Practice Foundation (ERBP 2012), the European Society of Intensive Care Medicine (ESICM 2010), and the American Society for Parenteral and Enteral Nutrition (ASPEN 2010). 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 17 18 18 19 20 21 Definition https://web.pathway.md/diseases/recRY6zuQyeq4bFgI 1/19 6/23/23, 1:57 AM Acute kidney injury Pathway AKD is a sudden decrease in kidney function resulting from structural or functional injury that is characterized by decreased GFR, increased serum creatinine, and oliguria. 18 Epidemiology AKD has multiple possible causes, including renal hypoperfusion, intrinsic renal dysfunction (glomerulonephritis, vasculitis, tubular necrosis, interstitial nephritis), or obstruction to the emptying of the kidneys (post-renal AKD). 20 Pathophysiology The incidence of AKD in the United States is estimated at 179-317 cases per 100,000 person-years. 19 Disease course Hypoperfusion of the kidneys with resultant ischemic injury represents the most important group of etiologies, mediating AKD through cellular injury caused by a mismatch between oxygen and nutrient delivery to the nephrons. 18 Prognosis and risk of recurrence Approximately 40% of patients with AKD do not recover renal function by hospital discharge. In this group of patients, AKD is associated with 1-year age-adjusted mortality of approximately 60%, compared to approximately 10% in patients who recovered renal function within 7 days. 21 Calculator Calculator Calculator AKIN classification for acute kid Diagnostic criteria for acute kidn Licurse sc Guidelines 1. Screening and diagnosis Diagnostic criteria: As per ERBP 2012 guidelines, diagnose and stage the severity of AKI as follows (meeting any of the criteria): Situation Guidance Serum creatinine increase 1.5-1.9 times baseline Stage 1 https://web.pathway.md/diseases/recRY6zuQyeq4bFgI 2/19 6/23/23, 1:57 AM Acute kidney injury Pathway Serum creatinine increase > 0.3 mg/dL (26.5 mcmol/L) Urinary output < 0.5 mL/kg/hour during a 6 hour block Serum creatinine increase 2.0-2.9 times baseline Stage 2 Urinary output < 0.5 mL/kg/hour during two 6 hour block Serum creatinine increase > 3 times baseline Stage 3 Serum creatinine increase > 4.0 mg/dL (353 mcmol/L) Initiation of RRT Urinary output < 0.3 mL/kg/hour during > 24 hours Anuria for > 12 hours. As per KDIGO 2012 guidelines, diagnose AKI in patients meeting any of the following criteria: increase in serum creatinine by 0.3 mg/dL (26.5 mcmol/L) within 48 hours increase in serum creatinine to 1.5 times baseline, known or presumed to have occurred within the prior 7 days urine volume of 0.5 mL/kg/hour for 6 hours. Definitions: As per ADQI 2017 guidelines, define persistent AKI as an AKI (by serum creatinine or urine output criteria) lasting > 48 hours from onset. B Show 4 more As per ERBP 2012 guidelines, use a uniform definition of AKI based on urinary output and on changes in serum creatinine level. B Differential diagnosis: suspect RPGN when a patient with no obvious cause of progressive or non-resolving AKI has urine dipstick results showing hematuria and proteinuria, without UTI or trauma due to catheterization. B 2. Classification and risk stratification Risk assessment: As per ADQI 2020 guidelines, avoid using biomarkers of acute damage before a kidney injury for the assessment of AKI risk. D Show 6 more https://web.pathway.md/diseases/recRY6zuQyeq4bFgI 3/19 6/23/23, 1:57 AM Acute kidney injury Pathway As per UKKA 2019 guidelines, identify patients at risk of AKI by the most appropriate risk factor profile for that population or, where no specific risk factor profile exists, through clinical judgment and recognition of generic risk factors for AKI. B As per JSN 2018 guidelines, consider involving the urine output whenever possible for AKI staging for better reflection of the survival outcomes and the renal outcomes. C Show 4 more As per ERBP 2012 guidelines, stratify patients for risk of AKI according to their susceptibilities, especially preexisting proteinuria and CKD, and exposures to nephrotoxic medication or interventions. B 3. Diagnostic investigations Baseline renal function testing: As per JSN 2018 guidelines, assess the baseline renal function using multiple methods whenever possible. B As per ERBP 2012 guidelines: Use the first documented serum creatinine value of the episode as 'baseline' rather than historical creatinine values or a calculated value based on a presumed GFR of 75 mL/min. B Consider using 'shift-based' calculation of the urinary output criteria, especially in patients without a bladder catheter. C Use the ideal weight rather than the true weight in calculating the diuresis in mL/min/kg. As per KDIGO 2012 guidelines, test patients at increased risk for AKI with serum creatinine measurements and urine output to detect AKI. Urinalysis: obtain urine dipstick testing for blood, protein, leukocytes, nitrites, and glucose in all patients as soon as AKI is suspected or detected unless already obtained. Document the results and take appropriate measures if abnormal. B Renal ultrasound: As per ACR 2021 guidelines, obtain renal ultrasound as initial imaging of unspecified AKI to detect hydronephrosis and evaluate renal size and morphology. B As per UKKA 2019 guidelines, obtain a renal tract ultrasound in all patients with AKI within 24 hours (unless a clear cause of AKI is apparent or AKI is improving) or within 6 hours if pyonephrosis is suspected or there is a high index of suspicion for urinary tract obstruction. B Novel biomarkers: As per ADQI 2020 guidelines, consider obtaining a combination of damage and functional biomarkers along with clinical information to improve the diagnostic accuracy of AKI, recognize the different pathophysiological processes, discriminate AKI etiology, and assess AKI severity. C As per JSN 2018 guidelines: https://web.pathway.md/diseases/recRY6zuQyeq4bFgI 4/19 6/23/23, 1:57 AM Acute kidney injury Pathway Consider obtaining urinary neutrophil gelatinase-associated lipocalin and liver-type fatty acid- binding protein for early diagnosis of AKI. C Consider obtaining urinary neutrophil gelatinase-associated lipocalin for the differentiation of pre-renal AKI from renal AKI. C Evaluation for etiology: As per UKKA 2019 guidelines: Elicit appropriate history and perform a physical examination to help determine the cause of the episode of acute injury. B Determine and document the cause or presumed causes of AKI wherever possible. B As per JSN 2018 guidelines: Obtain evaluation to determine the cause of AKI and eliminate the reversible factors. B Assess the potential presence of CKD and other comorbidities. B As per ADQI 2017 guidelines, evaluate patients with AKI for the underlying etiology. Consider obtaining a nephrology consultation if the etiology is not clear or subspecialty care is required. B As per ERBP 2012 guidelines, determine the cause of AKI whenever possible. Assess the presence of hypovolemia, post-renal causes, low cardiac output, use of nephrotoxic agents, acute glomerulonephritis, and renal microangiopathy as underlying contributors to AKI. As per KDIGO 2012 guidelines, evaluate all patients with AKI promptly to determine the cause, with special attention to reversible causes. Show 2 more 4. Medical management General principles: As per UKKA 2019 guidelines, obtain relevant assessment in patients at risk of AKI exposed to a significant renal insult, to ensure that exposure is limited and further insults are avoided or minimized. B Show 3 more As per ADQI 2017 guidelines, guide selection of drugs, dosing, and monitoring in patients with acute kidney disease by the functional phase, trajectory, and stage of acute kidney disease with the aim to personalize clinical decision-making. Individualize the decision to discontinue, introduce and/or reintroduce medications in patients with acute kidney disease. B Show 2 more Fluid resuscitation: consider administering isotonic crystalloids rather than colloids for expansion of intravascular volume in patients with AKI in the absence of hemorrhagic shock. C Vasopressors: administer vasopressors in conjunction with uids in patients with vasomotor shock with, or at risk for, AKI. B https://web.pathway.md/diseases/recRY6zuQyeq4bFgI 5/19 6/23/23, 1:57 AM Acute kidney injury Pathway Management of hyperglycemia: consider administering insulin therapy targeting plasma glucose 6.1-8.3 mmol/L (110-149 mg/dL) in critically ill patients. C Therapies with no evidence for benefit: As per JSN 2018 guidelines: Avoid using loop diuretics for the treatment of AKI except to correct fluid overload. D Do not use low-dose dopamine for the treatment of AKI. D As per KDIGO 2012 guidelines, do not use low-dose dopamine D or recombinant human IGF- 1 for the treatment of AKI. D Show 2 more 5. Inpatient care Renal function monitoring, patients at risk for AKI: As per UKKA 2019 guidelines, obtain close monitoring for AKI in adult inpatients deemed at high risk of AKI, particularly if there has been a new exposure. Monitor urine output and measure serum creatinine daily until at least 48 hours after the period of increased risk has elapsed. B Show 2 more As per ERBP 2012 guidelines, obtain serial measurements of serum creatinine and urine output at frequencies and duration based on the patient's risk and clinical course, to detect AKI at an early stage in patients at increased risk for AKI. Renal function monitoring, patients with AKI: As per UKKA 2019 guidelines, obtain urea and electrolytes monitoring in adult hospital inpatients with newly diagnosed AKI, at a minimum frequency of once daily (unless more frequent testing is indicated, such for hyperkalemia management) until renal function has returned to baseline or has stabilized, and then regularly, thereafter, in order to detect progressive or recurrent AKI in a timely fashion. B Show 2 more As per ADQI 2017 guidelines: Obtain timed urine CrCl assessment to estimate the renal function in patients with persistent AKI in a stable condition. B Recognize that equations to estimate GFR are not accurate for the assessment of renal function in patients with persistent AKI in the setting of CKD. B As per KDIGO 2012 guidelines: Monitor patients with AKI with measurements of serum creatinine and urine output to stage the severity. Individualize the frequency and duration of monitoring based on patient risk and clinical course. Hemodynamic monitoring: https://web.pathway.md/diseases/recRY6zuQyeq4bFgI 6/19 6/23/23, 1:57 AM Acute kidney injury Pathway As per UKKA 2019 guidelines, assess the physiological status of the patient promptly after identification of AKI or recognition of high risk for it. A Show 3 more As per ADQI 2017 guidelines, obtain additional monitoring in patients with persistent AKI to reevaluate hemodynamic and volume status, adequacy of kidney perfusion, and to identify complications of AKI, such as fluid overload, acidosis, and hyperkalemia, as these could indicate a need for RRT. B As per KDIGO 2012 guidelines, consider providing protocol-based management of hemodynamic and oxygenation parameters to prevent the development or worsening of AKI in high-risk patients in the perioperative setting or in patients with septic shock. C 6. Nonpharmacologic interventions Nutritional support: As per UKKA 2019 guidelines, refer patients with AKI receiving RRT to a dietitian for individual assessment. B As per JSN 2018 guidelines, consider tailoring nutritional support (calories, protein) in patients with AKI to the severity and the underlying disease. C Show 2 more As per KDIGO 2012 guidelines, consider aiming for a total energy intake of 20-30 kcal/kg/day in patients with any stage of AKI. C Show 3 more As per ASPEN 2010 guidelines, obtain formal nutritional assessment, including evaluation of inflammation, and develop a nutrition care plan in patients with renal disease. B Show 5 more 7. Therapeutic procedures Renal replacement therapy, indications: As per UKKA 2019 guidelines, consider initiating acute RRT in patients with progressive or severe AKI unless a decision has been made not to escalate therapy. B Show 4 more Updated evidence: STARRT-AKI In critically ill patients with severe AKI, an accelerated strategy was not superior to a standard strategy with respect to death from any cause at 90 days. STARRT-AKI Investigators et al. N Engl J Med. 2020 Jul 16. https://web.pathway.md/diseases/recRY6zuQyeq4bFgI 7/19 6/23/23, 1:57 AM Acute kidney injury Pathway As per JSPN/JSBPCC/JSDT/JSICM/JSN 2018 guidelines: Decide on the timing of initiation of blood purification based on the clinical symptoms and disease conditions. B Consider using improvements in clinical condition and urine output to determine the timing of discontinuation of blood purification. C Landmark trials: IDEAL-ICU In patients with early-stage septic shock who had severe AKI at the failure stage of the risk, injury, failure, loss, and end-stage kidney disease classification system but without life- threatening complications related to AKI, an early strategy was not superior to a delayed strategy with respect to death at 90 days. Saber D Barbar et al. N Engl J Med. 2018 Oct 11. As per KDIGO 2012 guidelines, initiate RRT emergently when life-threatening changes in uid, electrolyte, and acid-base balance are present. Show 2 more Landmark trials: ATN In critically ill patients with AKI and failure of at least one nonrenal organ or sepsis, intensive RRT was not superior to less-intensive RRT with respect to death at 60 days. VA/NIH Acute Renal Failure Trial Network et al. N Engl J Med. 2008 Jul 3. Renal replacement therapy, choice of modality: As per UKKA 2019 guidelines, decide on the choice of modality based on the condition of the patient as a whole, the severity of the underlying disease, the degree of fluid overload and its impact on other organs, rather than on isolated creatinine or urea values. B Show 2 more As per JSPN/JSBPCC/JSDT/JSICM/JSN 2018 guidelines, consider performing blood purification either continuously or intermittently in hemodynamically stable patients. C Prefer continuous blood purification in hemodynamically unstable patients. C Landmark trials: Atan In patients in the ICU with AKI who were vasopressor-dependent, continuous venovenous hemofiltration-high cutoff was not superior to continuous venovenous hemofiltration-standard with respect to a norepinephrine-free time over 7 days. Rafidah Atan et al. Crit Care Med. 2018 Oct. https://web.pathway.md/diseases/recRY6zuQyeq4bFgI 8/19 6/23/23, 1:57 AM Acute kidney injury Pathway As per KDIGO 2012 guidelines: Use continuous and intermittent replacement therapy as complementary therapies in patients with AKI. Consider using continuous RRT rather than standard intermittent RRT in hemodynamically unstable patients, in patients with acute brain injury or other causes of increased ICP or generalized brain edema. C Renal replacement therapy, dosing: As per UKKA 2019 guidelines, prescribe and adjust the dose of acute extracorporeal RRT at each session (for intermittent hemodialysis or hybrid therapies such as sustained low-efficiency dialysis) and daily (for continuous RRT) taking into account the patient's current and predicted metabolic and fluid needs and any measured shortfalls in delivered dose. A Show 4 more As per KDIGO 2012 guidelines, ensure that the dose of RRT to be delivered is before starting each session. Show 4 more Renal replacement therapy, insertion of dialysis catheter: As per UKKA 2019 guidelines, use venovenous access for acute RRT. A Show 4 more As per KDIGO 2012 guidelines, consider using an uncuffed non-tunneled dialysis catheter over a tunneled catheter for RRT in patients with AKI. C Show 5 more Renal replacement therapy, periprocedural anticoagulation: As per UKKA 2019 guidelines, tailor anticoagulation for RRT to the patient's characteristics and the chosen modality of RRT. B Show 3 more As per JSPN/JSBPCC/JSDT/JSICM/JSN 2018 guidelines: Consider administering nafamostat mesylate in patients with a high risk of bleeding. C Consider performing blood purification without the use of anticoagulants in patients with active bleeding. C As per KDIGO 2012 guidelines, individualize the decision to administer anticoagulation for RRT based on the assessment of the patient's potential risks and bene ts from anticoagulation. Show 7 more Renal replacement therapy, technical considerations: As per UKKA 2019 guidelines, ensure that fluids used for continuous or intermittent hemodialysis, hemofiltration, or hemodiafiltration in patients with AKI meet the microbial standards for fluids used for chronic hemodialysis. A As per KDIGO 2012 guidelines, consider using bicarbonate rather than lactate as a buffer in dialysate and replacement uid, C including in patients with liver failure and/or lactic acidemia. https://web.pathway.md/diseases/recRY6zuQyeq4bFgI 9/19 6/23/23, 1:57 AM Acute kidney injury Pathway C Use bicarbonate rather than lactate as a buffer in dialysate and replacement uid in patients with circulatory shock. C Show 2 more Renal replacement therapy (evaluation of fistula malfunction): consider obtaining fluoroscopy fistulography or duplex ultrasound of the hemodialysis access in patients with suspected dysfunction of the upper or lower extremity hemodialysis access (arteriovenous fistula or graft), suggested by an abnormal clinical indicator or hemodynamic indicator (reduction in dialysis vascular access blood flow rate or kinetics). C Show 5 more Renal replacement therapy (management of fistula malfunction): guide interventional radiologic therapy by imaging. B Show 6 more 8. Specific circumstances Pediatric patients (diagnosis and evaluation): consider using the KDIGO diagnostic criteria for AKI to predict the survival outcomes in pediatric patients 3 months of age. C Show 3 more Pediatric patients (renal replacement therapy): Discuss the indications for RRT taking into account the patient's current status and survival prognosis. Explain the advantages and disadvantages of different treatment modalities to the patient's family, and consult with them about suitable therapeutic strategies. B Consider using an appropriate modality tailored to the patient's constitution and disease condition in pediatric patients with AKI requiring blood purification. C Pediatric patients (monitoring): obtain close monitoring for AKI in pediatric inpatients deemed at high risk of AKI, particularly if there has been a new exposure. Monitor urine output and measure serum creatinine regularly (reflecting the potential burden of venipuncture) until at least 48 hours after the period of increased risk has elapsed. B Show 3 more Patients with COVID-19-associated AKI (evaluation): stratify patients for risk of AKI based on their comorbidities and demographics. B Show 4 more Patients with COVID-19-associated AKI (general principles of management): follow published evidence-based guidelines on AKI for risk- and stage-based prevention and management of COVID-19-associated AKI. Show 2 more Patients with COVID-19-associated AKI (hemodynamic support): individualize fluid and hemodynamic management based on a dynamic assessment of cardiovascular status in critically ill patients with COVID-19. B Show 2 more https://web.pathway.md/diseases/recRY6zuQyeq4bFgI 10/19 6/23/23, 1:57 AM Acute kidney injury Pathway Patients with COVID-19-associated AKI, renal replacement therapy: As per NIH 2021 guidelines: Use continuous RRT, if available, in critically ill patients with AKI developing indications for RRT. B Use prolonged intermittent RRT rather than intermittent hemodialysis if continuous RRT is not available or not possible due to limited resources. B As per ADQI 2020 guidelines, decide on the timing of RRT initiation, vascular access site, and modality of acute RRT based on patient needs, local expertise, and the availability of personnel and equipment. Show 7 more 9. Preventative measures Prevention of AKI in the ICU (fluid therapy): initiate controlled fluid resuscitation in true or suspected volume depletion. B Show 2 more Prevention of AKI in the ICU (vasopressors and inotropes): maintain mean arterial pressure 60-65 mmHg B attempting to individualize the target pressure where possible, especially if knowledge of the premorbid BP is available. Show 2 more Prevention of AKI in the ICU (vasodilators): consider administering vasodilators for renal protection when volume status is corrected and the patient is closely hemodynamically monitored with particular regard to the development of hypotension. C Show 2 more Prevention of AKI in the ICU (nutritional support): provide adequate nutritional support, preferably via the enteral route, in all patients at risk of AKI. B Prevention of AKI in the ICU (other measures): do not implement tight glycemic control routinely in the general ICU. population. D Consider implementing 'normal-for-age' glycemic control with IV insulin therapy to prevent AKI in surgical ICU patients. D Show 4 more Prevention of contrast-induced nephropathy, risk assessment: As per CAR 2022 guidelines, use a simple screening questionnaire to detect stable outpatients without a current (3-6 months depending on institutional preference) estimated GFR on file and without a provided history of CKD on the requisition to identify patients with AKI or severe CKD. E Show 4 more As per ERBP 2012 guidelines, obtain a baseline serum creatinine before an intervention encompassing a risk for contrast-induced nephropathy. As per KDIGO 2012 guidelines, assess the risk for contrast-induced AKI and, in particular, screen for preexisting impairment of kidney function in all patients being considered for a https://web.pathway.md/diseases/recRY6zuQyeq4bFgI 11/19 6/23/23, 1:57 AM Acute kidney injury Pathway procedure requiring intravascular administration of iodinated contrast medium. Prevention of contrast-induced nephropathy, restriction of contrast medium use: As per CAR 2022 guidelines, assess the overall risk of worsening AKI with contrast versus the benefit of improved diagnostic capability and therapeutic intervention for the use of IV or intra- arterial contrast in the setting of preexisting AKI. E Show 6 more As per ESC 2021 guidelines, use low- or iso-osmolar contrast media (at the lowest possible volume) for invasive strategies in patients with CKD presenting with myocardial infarction. A As per ERBP 2012 guidelines: Balance the risk for contrast-induced nephropathy against the benefit of administering contrast. Consider obtaining alternative imaging modalities not requiring contrast administration in patients at increased risk for contrast-induced nephropathy, if those carry the same diagnostic accuracy. As per KDIGO 2012 guidelines: Consider obtaining alternative imaging methods in patients at increased risk for contrast- induced AKI. Administer the lowest possible dose of contrast medium in patients at risk for contrast-induced AKI. Administer either iso-osmolar or low-osmolar iodinated contrast media, rather than high- osmolar iodinated contrast media, in patients at increased risk of contrast-induced AKI. B Prevention of contrast-induced nephropathy (discontinuation of medications): do not discontinue metformin before contrast administration and/or re-test kidney function afterward in patients with an estimated GFR > 30 mL/min/1.73 m . D Show 2 more Prevention of contrast-induced nephropathy, IV and oral fluids: As per CAR 2022 guidelines, do not initiate oral or IV hydration in patients with an estimated GFR > 30 mL/min/1.73 m receiving IV or intra-arterial iodinated contrast media. D Show 2 more As per ESC 2021 guidelines, consider offering pre- and post-hydration with isotonic saline if the expected contrast volume is > 100 mL in invasive strategies in patients with CKD and myocardial infarction. C Consider using tailored hydration regimens as an alternative to the pre- and post-hydration regimen. C As per ESVS 2017 guidelines, consider administering isotonic sodium chloride or sodium bicarbonate solutions for volume expansion before contrast administration in patients at increased risk of contrast-induced nephropathy. C As per ERBP 2012 guidelines: Administer either isotonic sodium chloride or sodium bicarbonate solutions for volume expansion in patients at increased risk for contrast-induced nephropathy. B Consider using the oral route for hydration if adequate intake of fluid and salt is assured. C https://web.pathway.md/diseases/recRY6zuQyeq4bFgI 12/19 6/23/23, 1:57 AM Acute kidney injury Pathway As per KDIGO 2012 guidelines: Administer IV isotonic sodium chloride or sodium bicarbonate solution for volume expansion in patients at increased risk for contrast-induced AKI. B Do not use oral uids alone in patients at increased risk of contrast-induced AKI. D As per ESICM 2010 guidelines, administer isotonic crystalloids for prophylactic volume expansion in patients at risk of contrast-induced nephropathy. B Consider administering isotonic sodium bicarbonate solution, especially for emergency procedures. B Prevention of contrast-induced nephropathy, N-acetylcysteine: As per CAR 2022 guidelines, do not use N-acetylcysteine for the prophylaxis of contrast- associated AKI. D As per ERBP 2012 guidelines, consider administering oral N-acetylcysteine only in patients receiving appropriate fluid and salt loading. C Do not use oral N-acetylcysteine as the only method for the prevention of contrast-induced nephropathy. C As per KDIGO 2012 guidelines, consider offering oral N-acetylcysteine together with IV isotonic crystalloids in patients at increased risk of contrast-induced AKI. C As per ESICM 2010 guidelines, avoid using N-acetylcysteine as prophylaxis against contrast- induced nephropathy in critically ill patients. D Updated evidence: ACT In patients undergoing an intravascular angiographic procedure with at least 1 risk factor for contrast-induced AKI (age > 70 years, renal failure, diabetes mellitus, HF, or hypotension), acetylcysteine was not superior to placebo with respect to a contrast-induced AKI. ACT Investigators. Circulation. 2011 Sep 13. Prevention of contrast-induced nephropathy, other agents: As per CAR 2022 guidelines, do not use other pharmacological agents, such as statins, theophylline, prostaglandin E1, nicorandil, ascorbic acid, allopurinol, alpha-tocopherol, fenoldopam, natriuretic peptides, or trimetazidine, for the prevention of contrast-induced AKI. D As per ERBP 2012 guidelines: Avoid using theophylline for the prevention of contrast-induced nephropathy. D Do not use fenoldopam for the prevention of contrast-induced nephropathy. D As per KDIGO 2012 guidelines: Avoid using theophylline for the prevention of contrast-induced AKI. D Do not use fenoldopam for the prevention of contrast-induced AKI. D As per ESICM 2010 guidelines: Do not use fenoldopam for prophylaxis of contrast-induced nephropathy. D https://web.pathway.md/diseases/recRY6zuQyeq4bFgI 13/19 6/23/23, 1:57 AM Acute kidney injury Pathway Consider administering theophylline to minimize the risk of contrast-induced nephropathy, especially in acute interventions when hydration is not feasible. C Prevention of contrast-induced nephropathy, renal replacement therapy: As per CAR 2022 guidelines, do not use any form of post-iodinated contrast media administration RRT, either dialysis or continuous RRT, to reduce the risk of contrast-associated AKI. D As per ERBP 2012 guidelines, do not use prophylactic intermittent hemodialysis or hemofiltration for the sole purpose of preventing contrast-induced nephropathy. D As per KDIGO 2012 guidelines, avoid using prophylactic intermittent hemodialysis or hemo ltration for contrast-media removal in patients at increased risk for contrast-induced AKI. D As per ESICM 2010 guidelines, consider performing periprocedural continuous venovenous hemofiltration in an ICU environment to limit contrast-induced nephropathy after coronary interventions in high-risk patients with advanced chronic renal insufficiency. C Prevention of contrast-induced nephropathy, serial creatinine assessment: As per CAR 2022 guidelines: Obtain a follow-up serum creatinine measurement 48-72 hours after intra-arterial iodinated contrast media administration in all patients with an estimated GFR 30 mL/min/1.73m . Do not obtain routine serum creatinine measurement in the remainder of patients as the risk of AKI is extremely low. Instruct any at-risk patient to seek medical attention and kidney function testing if they develop increased shortness of breath, peripheral edema, or note a marked decline in urine output in the days following the imaging test. E As per ERBP 2012 guidelines, consider obtaining a repeat serum creatinine 12-72 hours after contrast media administration in high-risk patients. C Prevention of postoperative AKI: Avoid performing off-pump CABG surgery solely for the purpose of reducing perioperative AKI or the need for RRT. D Do not use oral or IV N-acetylcysteine for the prevention of postoperative AKI. D Prevention of rhabdomyolysis-induced AKI: administer IV fluids promptly for volume expansion, if not already volume overloaded, in order to achieve a high urinary flow rate and protect against AKI in adult and pediatric patients with rhabdomyolysis. B Prevention of amphotericin B-induced nephrotoxicity: Consider preferring lipid formulations of amphotericin B over conventional formulations of amphotericin B. C Prefer azoles and/or echinocandins over conventional amphotericin B, if equal therapeutic ef cacy can be assumed, in the treatment of systemic mycoses or parasitic infections. B Prevention of aminoglycoside-induced nephrotoxicity: avoid using aminoglycosides for the treatment of infections unless no suitable, less nephrotoxic, alternatives are available. D https://web.pathway.md/diseases/recRY6zuQyeq4bFgI 14/19 6/23/23, 1:57 AM Acute kidney injury Pathway Show 3 more Prevention of cardiac surgery-associated AKI (prevention, pharmacologic strategies): consider administering prophylactic human atrial natriuretic peptide via continuous infusion of 0.02 g/kg/min, started before surgery and continuing for 12 hours into the postoperative period, to prevent cardiac surgery-associated AKI and dialysis in adult patients undergoing cardiac surgery. C Show 3 more Prevention of cardiac surgery-associated AKI (prevention, cardiopulmonary bypass strategies): avoid administering hyperthermic perfusion (> 37 C) to reduce the risk of cardiac surgery-associated AKI in adult patients undergoing cardiac surgery with cardiopulmonary bypass. D Show 2 more Prevention of cardiac surgery-associated AKI (prevention, minimally invasive extracorporeal circulation): consider using minimally invasive extracorporeal circulation techniques to minimize the risk of cardiac surgery-associated AKI in adult patients undergoing cardiac surgery with cardiopulmonary bypass. C Measures with no evidence for benefit: As per JSN 2018 guidelines: Do not use loop diuretics D or low-dose dopamine for the prevention of AKI. D Insufficient evidence to support the use of low-dose atrial natriuretic peptide for the prevention of AKI. I Do not use diuretics, D low-dose dopamine, D or recombinant human IGF-1 for the prevention of AKI. D Show 2 more Landmark trials: Low-dose dopamine in patients with early renal dysfunction In critically ill patients at risk of renal failure, low-dose dopamine was not superior to placebo with respect to peak serum creatinine concentration. Bellomo R et al. Lancet. 2000 Dec 23-30. 10. Follow-up and surveillance Discharge from hospital: include a record in the discharge summary regarding AKI detected whilst in hospital, its maximum stage, etiology, the need for renal support (temporary/ongoing), and discharge renal function, if dialysis-independent. B Show 2 more Follow-up: As per UKKA 2019 guidelines: https://web.pathway.md/diseases/recRY6zuQyeq4bFgI 15/19 6/23/23, 1:57 AM Acute kidney injury Pathway Obtain serum creatinine and potassium measurement 1-2 weeks after restarting potential culprit drugs after an episode of AKI and after any subsequent dose titration. B Arrange a formal post-discharge nephrology visit as follows: Situation Guidance Residual CKD stage G4 at hospital discharge Within 90 days Within 30 days Residual CKD stage G5 (non-dialysis- requiring) at hospital discharge Within 30 days. B Ongoing dialysis requirements at the time of hospital discharge As per JSN 2018 guidelines, consider confirming the patient's condition approximately 3 months later and obtaining long-term follow-up in accordance with their condition. C As per ERBP 2012 guidelines, assess patients 2 months after AKI to evaluate the completeness of resolution, and to detect new-onset CKD or worsening of preexisting CKD. B As per KDIGO 2012 guidelines, evaluate patients 3 months after AKI for resolution, new onset, or worsening of preexisting CKD. References 1. Arif Khwaja. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract. 2012;120 4):c179 84. Open 2. Michael Joannidis, Wilfred Druml, Lui G Forni et al. Prevention of acute kidney injury and protection of renal function in the intensive care unit. Expert opinion of the Working Group for Nephrology, ESICM. Intensive Care Med. 2010 Mar;36 3 392 411. Open 3. Suren Kanagasundaram, Caroline Ashley, Sheetal Bhojani et al. Clinical Practice Guideline Acute Kidney Injury. UKKA. 2019 Aug. Open 4. Ad-hoc working group of ERBP, Danilo Fliser, Maurice Laville et al. A European Renal Best Practice ERBP position statement on the Kidney Disease Improving Global Outcomes KDIGO clinical practice guidelines on acute kidney injury: part 1 definitions, conservative management and contrast-induced nephropathy. Nephrol Dial Transplant. 2012 Dec;27 12 4263 72. Open 5. Jeremiah R Brown, Robert A Baker, Linda Shore-Lesserson et al. The Society of Thoracic Surgeons/Society of Cardiovascular Anesthesiologists/American Society for Extracorporeal Technology Clinical Practice Guidelines for the Prevention of Adult Cardiac Surgery-Associated Acute Kidney Injury. Anesth Analg. 2023 Jan 1;136 1 176 184. Open 6. D. Blair Macdonald, MD, FRCPC et al. Canadian Association of Radiologists Guidance on Contrast Associated Acute Kidney Injury. CAR. 2022 May. Open 7. Kent Doi, Osamu Nishida, Takashi Shigematsu et al. The Japanese clinical practice guideline for acute kidney injury 2016. Clin Exp Nephrol. 2018 Oct;22 5 985 1045. Open https://web.pathway.md/diseases/recRY6zuQyeq4bFgI 16/19 6/23/23, 1:57 AM Acute kidney injury Pathway 8. Jean-Philippe Collet, Holger Thiele, Emanuele Barbato et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J. 2021 Apr 7;42 14 1289 1367. Open 9. National Institutes of Health. Coronavirus Disease 2019 COVID 19 Treatment Guidelines. National Institutes of Health. 2021 Oct. Open 10. Mitra K Nadim, Lui G Forni, Ravindra L Mehta et al. COVID 19-associated acute kidney injury: consensus report of the 25th Acute Disease Quality Initiative ADQI Workgroup. Nat Rev Nephrol. 2020 Dec;16 12 747 764. Open 11. Lakhmir S Chawla, Rinaldo Bellomo, Azra Bihorac et al. Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative ADQI 16 Workgroup. Nat Rev Nephrol. 2017 Apr;13 4 241 257. Open 12. Marlies Ostermann, Alexander Zarbock, Stuart Goldstein et al. Recommendations on Acute Kidney Injury Biomarkers From the Acute Disease Quality Initiative Consensus Conference: A Consensus Statement. JAMA Netw Open. 2020 Oct 1;3 10):e2019209. Open 13. Mikhail C.S.S. Higgins, MD, MPHa et al. ACR Appropriateness Criteria Dialysis Fistula Malfunction. ACR. 2023. Open 14. Expert Panel on Urologic Imaging, Jade J Wong-You-Cheong, Paul Nikolaidis et al. ACR Appropriateness Criteria Renal Failure. J Am Coll Radiol. 2021 May;18 5S S174 S188. Open 15. Rex O Brown, Charlene Compher, American Society for Parenteral and Enteral Nutrition Board of Directors. A.S.P.E.N. clinical guidelines: nutrition support in adult acute and chronic renal failure. JPEN J Parenter Enteral Nutr. 2010 Jul-Aug;34 4 366 77. Open 16. Steven L Flamm, Florence Wong, Joseph Ahn et al. AGA Clinical Practice Update on the Evaluation and Management of Acute Kidney Injury in Patients With Cirrhosis: Expert Review. Clin Gastroenterol Hepatol. 2022 Dec;20 12 2707 2716. Open 17. V Riambau, D B ckler, J Brunkwall et al. Editor's Choice Management of Descending Thoracic Aorta Diseases: Clinical Practice Guidelines of the European Society for Vascular Surgery ESVS . Eur J Vasc Endovasc Surg. 2017 Jan;53 1 4 52. Open 18. Makris K, Spanou L. Acute Kidney Injury: Definition, Pathophysiology and Clinical Phenotypes. Clin Biochem Rev. 2016 May;37 2 85 98. Open 19. Kashani K, Shao M, Li G et al. No increase in the incidence of acute kidney injury in a population-based annual temporal trends epidemiology study. Kidney Int. 2017 Sep;92 3 721 728. Open 20. Bouchard J, Mehta RL. Acute Kidney Injury in Western Countries. Kidney Dis Basel). 2016 Oct;2 3 103 110. Open 21. Hoste EAJ, Kellum JA, Selby NM et al. Global epidemiology and outcomes of acute kidney injury. Nat Rev Nephrol. 2018 Oct;14 10 607 625. Open 22. STARRT AKI Investigators. STandard versus Accelerated initiation of Renal Replacement Therapy in Acute Kidney Injury: Study Protocol for a Multi-National, Multi-Center, Randomized Controlled Trial. Can J Kidney Health Dis. 2019 Jun 10;6 2054358119852937. Open 23. STARRT AKI Investigators, Canadian Critical Care Trials Group, Australian and New Zealand Intensive Care Society Clinical Trials Group et al. Timing of Initiation of Renal-Replacement Therapy in Acute Kidney https://web.pathway.md/diseases/recRY6zuQyeq4bFgI 17/19 6/23/23, 1:57 AM Acute kidney injury Pathway Injury. N Engl J Med. 2020 Jul 16;383 3 240 251. Open

Show 3 more Prevention of cardiac surgery-associated AKI (prevention, cardiopulmonary bypass strategies): avoid administering hyperthermic perfusion (> 37 C) to reduce the risk of cardiac surgery-associated AKI in adult patients undergoing cardiac surgery with cardiopulmonary bypass. D Show 2 more Prevention of cardiac surgery-associated AKI (prevention, minimally invasive extracorporeal circulation): consider using minimally invasive extracorporeal circulation techniques to minimize the risk of cardiac surgery-associated AKI in adult patients undergoing cardiac surgery with cardiopulmonary bypass. C Measures with no evidence for benefit: As per JSN 2018 guidelines: Do not use loop diuretics D or low-dose dopamine for the prevention of AKI. D Insufficient evidence to support the use of low-dose atrial natriuretic peptide for the prevention of AKI. I Do not use diuretics, D low-dose dopamine, D or recombinant human IGF-1 for the prevention of AKI. D Show 2 more Landmark trials: Low-dose dopamine in patients with early renal dysfunction In critically ill patients at risk of renal failure, low-dose dopamine was not superior to placebo with respect to peak serum creatinine concentration. Bellomo R et al. Lancet. 2000 Dec 23-30. 10. Follow-up and surveillance Discharge from hospital: include a record in the discharge summary regarding AKI detected whilst in hospital, its maximum stage, etiology, the need for renal support (temporary/ongoing), and discharge renal function, if dialysis-independent. B Show 2 more Follow-up: As per UKKA 2019 guidelines: https://web.pathway.md/diseases/recRY6zuQyeq4bFgI 15/19 6/23/23, 1:57 AM Acute kidney injury Pathway Obtain serum creatinine and potassium measurement 1-2 weeks after restarting potential culprit drugs after an episode of AKI and after any subsequent dose titration. B Arrange a formal post-discharge nephrology visit as follows: Situation Guidance Residual CKD stage G4 at hospital discharge Within 90 days Within 30 days Residual CKD stage G5 (non-dialysis- requiring) at hospital discharge Within 30 days. B Ongoing dialysis requirements at the time of hospital discharge As per JSN 2018 guidelines, consider confirming the patient's condition approximately 3 months later and obtaining long-term follow-up in accordance with their condition. C As per ERBP 2012 guidelines, assess patients 2 months after AKI to evaluate the completeness of resolution, and to detect new-onset CKD or worsening of preexisting CKD. B As per KDIGO 2012 guidelines, evaluate patients 3 months after AKI for resolution, new onset, or worsening of preexisting CKD. References 1. Arif Khwaja. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract. 2012;120 4):c179 84. Open 2. Michael Joannidis, Wilfred Druml, Lui G Forni et al. Prevention of acute kidney injury and protection of renal function in the intensive care unit. Expert opinion of the Working Group for Nephrology, ESICM. Intensive Care Med. 2010 Mar;36 3 392 411. Open 3. Suren Kanagasundaram, Caroline Ashley, Sheetal Bhojani et al. Clinical Practice Guideline Acute Kidney Injury. UKKA. 2019 Aug. Open 4. Ad-hoc working group of ERBP, Danilo Fliser, Maurice Laville et al. A European Renal Best Practice ERBP position statement on the Kidney Disease Improving Global Outcomes KDIGO clinical practice guidelines on acute kidney injury: part 1 definitions, conservative management and contrast-induced nephropathy. Nephrol Dial Transplant. 2012 Dec;27 12 4263 72. Open 5. Jeremiah R Brown, Robert A Baker, Linda Shore-Lesserson et al. The Society of Thoracic Surgeons/Society of Cardiovascular Anesthesiologists/American Society for Extracorporeal Technology Clinical Practice Guidelines for the Prevention of Adult Cardiac Surgery-Associated Acute Kidney Injury. Anesth Analg. 2023 Jan 1;136 1 176 184. Open 6. D. Blair Macdonald, MD, FRCPC et al. Canadian Association of Radiologists Guidance on Contrast Associated Acute Kidney Injury. CAR. 2022 May. Open 7. Kent Doi, Osamu Nishida, Takashi Shigematsu et al. The Japanese clinical practice guideline for acute kidney injury 2016. Clin Exp Nephrol. 2018 Oct;22 5 985 1045. Open https://web.pathway.md/diseases/recRY6zuQyeq4bFgI 16/19 6/23/23, 1:57 AM Acute kidney injury Pathway 8. Jean-Philippe Collet, Holger Thiele, Emanuele Barbato et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J. 2021 Apr 7;42 14 1289 1367. Open 9. National Institutes of Health. Coronavirus Disease 2019 COVID 19 Treatment Guidelines. National Institutes of Health. 2021 Oct. Open 10. Mitra K Nadim, Lui G Forni, Ravindra L Mehta et al. COVID 19-associated acute kidney injury: consensus report of the 25th Acute Disease Quality Initiative ADQI Workgroup. Nat Rev Nephrol. 2020 Dec;16 12 747 764. Open 11. Lakhmir S Chawla, Rinaldo Bellomo, Azra Bihorac et al. Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative ADQI 16 Workgroup. Nat Rev Nephrol. 2017 Apr;13 4 241 257. Open 12. Marlies Ostermann, Alexander Zarbock, Stuart Goldstein et al. Recommendations on Acute Kidney Injury Biomarkers From the Acute Disease Quality Initiative Consensus Conference: A Consensus Statement. JAMA Netw Open. 2020 Oct 1;3 10):e2019209. Open 13. Mikhail C.S.S. Higgins, MD, MPHa et al. ACR Appropriateness Criteria Dialysis Fistula Malfunction. ACR. 2023. Open 14. Expert Panel on Urologic Imaging, Jade J Wong-You-Cheong, Paul Nikolaidis et al. ACR Appropriateness Criteria Renal Failure. J Am Coll Radiol. 2021 May;18 5S S174 S188. Open 15. Rex O Brown, Charlene Compher, American Society for Parenteral and Enteral Nutrition Board of Directors. A.S.P.E.N. clinical guidelines: nutrition support in adult acute and chronic renal failure. JPEN J Parenter Enteral Nutr. 2010 Jul-Aug;34 4 366 77. Open 16. Steven L Flamm, Florence Wong, Joseph Ahn et al. AGA Clinical Practice Update on the Evaluation and Management of Acute Kidney Injury in Patients With Cirrhosis: Expert Review. Clin Gastroenterol Hepatol. 2022 Dec;20 12 2707 2716. Open 17. V Riambau, D B ckler, J Brunkwall et al. Editor's Choice Management of Descending Thoracic Aorta Diseases: Clinical Practice Guidelines of the European Society for Vascular Surgery ESVS . Eur J Vasc Endovasc Surg. 2017 Jan;53 1 4 52. Open 18. Makris K, Spanou L. Acute Kidney Injury: Definition, Pathophysiology and Clinical Phenotypes. Clin Biochem Rev. 2016 May;37 2 85 98. Open 19. Kashani K, Shao M, Li G et al. No increase in the incidence of acute kidney injury in a population-based annual temporal trends epidemiology study. Kidney Int. 2017 Sep;92 3 721 728. Open 20. Bouchard J, Mehta RL. Acute Kidney Injury in Western Countries. Kidney Dis Basel). 2016 Oct;2 3 103 110. Open 21. Hoste EAJ, Kellum JA, Selby NM et al. Global epidemiology and outcomes of acute kidney injury. Nat Rev Nephrol. 2018 Oct;14 10 607 625. Open 22. STARRT AKI Investigators. STandard versus Accelerated initiation of Renal Replacement Therapy in Acute Kidney Injury: Study Protocol for a Multi-National, Multi-Center, Randomized Controlled Trial. Can J Kidney Health Dis. 2019 Jun 10;6 2054358119852937. Open 23. STARRT AKI Investigators, Canadian Critical Care Trials Group, Australian and New Zealand Intensive Care Society Clinical Trials Group et al. Timing of Initiation of Renal-Replacement Therapy in Acute Kidney https://web.pathway.md/diseases/recRY6zuQyeq4bFgI 17/19 6/23/23, 1:57 AM Acute kidney injury Pathway Injury. N Engl J Med. 2020 Jul 16;383 3 240 251. Open 24. Saber D Barbar, Rapha l Clere-Jehl, Abderrahmane Bourredjem et al. Timing of Renal-Replacement Therapy in Patients with Acute Kidney Injury and Sepsis. N Engl J Med. 2018 Oct 11;379 15 1431 1442. Open 25. Rafidah Atan, Leah Peck, John Prowle et al. A Double-Blind Randomized Controlled Trial of High Cutoff Versus Standard Hemofiltration in Critically Ill Patients With Acute Kidney Injury. Crit Care Med. 2018 Oct;46 10):e988-e994. Open 26. Wesley H Self, Matthew W Semler, Jonathan P Wanderer et al. Balanced Crystalloids versus Saline in Noncritically Ill Adults. N Engl J Med. 2018 Mar 1;378 9 819 828. Open 27. Melanie Meersch, Mira K llmar, Christoph Schmidt et al. Long-Term Clinical Outcomes after Early Initiation of RRT in Critically Ill Patients with AKI. J Am Soc Nephrol. 2018 Mar;29 3 1011 1019. Open 28. Sean M Bagshaw, R T Noel Gibney, Peter Kruger et al. The effect of low-dose furosemide in critically ill patients with early acute kidney injury: A pilot randomized blinded controlled trial (the SPARK study). J Crit Care. 2017 Dec;42 138 146. Open 29. Estelle C Nijssen, Roger J Rennenberg, Patty J Nelemans et al. Prophylactic hydration to protect renal function from intravascular iodinated contrast material in patients at high risk of contrast-induced nephropathy AMACING a prospective, randomised, phase 3, controlled, open-label, non-inferiority trial. Lancet. 2017 Apr 1;389 10076 1312 1322. Open 30. RENAL Replacement Therapy Study Investigators, Rinaldo Bellomo, Alan Cass et al. Intensity of continuous renal-replacement therapy in critically ill patients. N Engl J Med. 2009 Oct 22;361 17 1627 38. Open 31. Alexander Zarbock, John A Kellum, Christoph Schmidt et al. Effect of Early vs Delayed Initiation of Renal Replacement Therapy on Mortality in Critically Ill Patients With Acute Kidney Injury: The ELAIN Randomized Clinical Trial. JAMA. 2016 May 24 31;315 20 2190 9. Open 32. St phane Gaudry, David Hajage, Fr derique Schortgen et al. Initiation Strategies for Renal- Replacement Therapy in the Intensive Care Unit. N Engl J Med. 2016 Jul 14;375 2 122 33. Open 33. Paul Young, Michael Bailey, Richard Beasley et al. Effect of a Buffered Crystalloid Solution vs Saline on Acute Kidney Injury Among Patients in the Intensive Care Unit: The SPLIT Randomized Clinical Trial. JAMA. 2015 Oct 27;314 16 1701 10. Open 34. Zhiping Sun, Hong Ye, Xia Shen et al. Continuous venovenous hemofiltration versus extended daily hemofiltration in patients with septic acute kidney injury: a retrospective cohort study. Crit Care. 2014 Apr 9;18 2 R70. Open 35. VA/NIH Acute Renal Failure Trial Network, Paul M Palevsky, Jane Hongyuan Zhang et al. Intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med. 2008 Jul 3;359 1 7 20. Open 36. Jos Ant nio Lopes, Sofia Jorge. The RIFLE and AKIN classifications for acute kidney injury: a critical and comprehensive review. Clin Kidney J. 2013 Feb;6 1 8 14. Open 37. Kathleen D. Liu, MD, PhD et al. Curbing the Use of Ultrasonography in the Diagnosis of Acute Kidney Injury. Arch Intern Med. 2010 Nov 22; 170 21 1907 1908. Open https://web.pathway.md/diseases/recRY6zuQyeq4bFgI 18/19 6/23/23, 1:57 AM Acute kidney injury Pathway 38. Fernando G Zampieri, Fl via R Machado, Rodrigo S Biondi et al. Effect of Intravenous Fluid Treatment With a Balanced Solution vs 0.9% Saline Solution on Mortality in Critically Ill Patients: The BaSICS Randomized Clinical Trial. JAMA. 2021 Aug 10;326 9 1 12. Open 39. Laurent Brochard, Fekri Abroug, Matthew Brenner et al. An Official ATS/ERS/ESICM/SCCM/SRLF Statement: Prevention and Management of Acute Renal Failure in the ICU Patient: an international consensus conference in intensive care medicine. Am J Respir Crit Care Med. 2010 May 15;181 10 1128 55. Open https://web.pathway.md/diseases/recRY6zuQyeq4bFgI 19/19

Guideline sources The following summarized guidelines for the evaluation of acute leukemia are prepared by our editorial team based on guidelines from the American Society of Hematology (ASH/ACP 2017). 1 2 2 3 4 5 Definition Acute leukemia is a malignant disorder that results from the clonal expansion of an abnormal early hematopoietic progenitor cell. 2 Epidemiology The precise cause of acute leukemia is unknown; however, congenital factors, chromosomal abnormalities (in Down's syndrome, Bloom syndrome, Fanconi's anemia), immunodeficiency states (ataxia telangectasia, Wiskott-Aldrich syndrome), chemotherapy, ionizing radiation, myelodysplastic syndrome, and retrovirus HTLV-1 have been implicated as causative factors in acute leukemia. 2 Disease course Abnormal clonal proliferation of hematopoietic stem cells in the bone marrow results in acute leukemia. In children, it mostly presents as acute lymphoblastic leukemia presenting with fever, lethargy, bleeding, musculoskeletal symptoms (in the spine and long bones), hepatosplenomegaly, lymphadenopathy, and CNS involvement. In adults, it mostly presents as acute myelogenous leukemia presenting with fever, fatigue, weight loss, shortness of breath, chest pain, excessive bruising, nosebleeds, heavy menstrual periods in women, and CNS involvement. 3 https://web.pathway.md/diseases/rec0gYACAyJ8cog7m 1/4 6/23/23, 1:57 AM Acute leukemia Pathway Prognosis and risk of recurrence Age-adjusted mortality rates for acute myeloid leukemia is 1.81/100,000 (95% CI 1.30-2.26). The 5- year survival for adults with acute lymphoblastic leukemia in developed countries is between 30% to 45%. 4 5 Calculator Calculator Eastern Cooperative Oncology G Karnofsky performance status s Guidelines 1. Classification and risk stratification Classification and terminology: Ensure that all tests performed for classification, management, predicting prognosis, and disease monitoring are entered into the patient's medical records. A Use the current WHO terminology for the final diagnosis and classification of acute leukemia. A 2. Diagnostic investigations Clinical history: provide relevant clinical data with pathological specimens, or ensure that such data is readily accessible by the pathologist. A Physical examination: document relevant physical examination and imaging findings or ensure that those results are readily accessible by the pathologist. B Complete blood count: obtain a complete blood cell count, leukocyte differential, and formal review of a peripheral blood smear by a pathologist. A Coagulation studies: obtain rapid detection of PML-RARA in patients with suspected acute promyelocytic leukemia, and obtain appropriate coagulation tests to evaluate for DIC. A Genetic studies: ensure that the following testing is obtained for pediatric patients with suspected or confirmed B-cell acute lymphoblastic leukemia: t(12;21)(p13.2;q22.1); ETV6-RUNX1, t(9;22) (q34.1;q11.2); BCRABL1, KMT2A (MLL) translocation, iAMP21, and trisomy 4 and 10. A 3. Diagnostic procedures Tissue biopsy: refer patients who present with extramedullary disease without bone marrow or blood involvement to a pathologist, who should evaluate a tissue biopsy and process it for https://web.pathway.md/diseases/rec0gYACAyJ8cog7m 2/4 6/23/23, 1:57 AM Acute leukemia Pathway morphologic, immunophenotypic, cytogenetic, and molecular genetic studies, as recommended for the bone marrow. A Bone marrow aspirate: obtain a fresh bone marrow aspirate for all patients with suspected of acute leukemia, a portion of which should be used to make bone marrow aspirate smears for morphologic evaluation. A Lumbar puncture: obtain a CSF sample for patients with acute lymphoblastic leukemia receiving intrathecal therapy. Ensure that a cell count is performed and that examination/enumeration of blasts on a cytocentrifuge preparation is performed and is reviewed by the pathologist. A Additional studies: obtain sufficient samples and perform conventional cytogenetic analysis such as karyotype, appropriate molecular genetic and/or FISH testing, and flow cytometric immunophenotyping, in addition to morphologic assessment. A Cytochemical studies: consider obtaining cytochemical studies in patients with suspected or confirmed acute leukemia to assist in the diagnosis and classification of acute myeloid leukemia. E Molecular studies: Use any of the following for molecular or genetic studies in which the use of such material has been validated: cryopreserved cells or nucleic acid formalin fixed, nondecalcified paraffin-embedded tissue unstained marrow aspirate or peripheral blood smears obtained and prepared from peripheral blood, bone marrow aspirate or other involved tissues. B Mutational analysis: obtain mutational analysis for NPM1, CEBPA, and RUNX1 in patients other than those with confirmed core-binding factor-acute myelocytic leukemia, acute promyelocytic leukemia, or acute myeloid leukemia with myelodysplasia-related cytogenetic abnormalities. A References 1. Arber DA, Borowitz MJ, Cessna M et al. Initial Diagnostic Workup of Acute Leukemia: Guideline From the College of American Pathologists and the American Society of Hematology. Arch Pathol Lab Med. 2017 Oct;141 10 1342 1393. Open 2. K Stewart, A Keating. Acute leukemia: diagnosis, management, and potential for cure. 1988 Nov;34 2463 7.1988 Nov;34 2463 7. Open 3. Amanda S Davis, Anthony J Viera, Monica D Mead. Leukemia: an overview for primary care. 2014 May 1;89 9 731 8.2014 May 1;89 9 731 8. Open 4. Maksimovic N, Zaric M, Gazibara T et al. Incidence and Mortality Patterns of Acute Myeloid Leukemia in Belgrade, Serbia 1999 2013 . Medicina Kaunas). 2018 Mar 20;54 1 . pii: E5. Open 5. Jose Carlos Jaime-Perez, Raul Alberto Jimenez-Castillo, Jose Luis Herrera-Garza et al. Survival Rates of Adults With Acute Lymphoblastic Leukemia in a Low-Income Population: A Decade of Experience at a Single Institution in Mexico. 2017 Jan;17 1 60 68.2017 Jan;17 1 60 68. Open https://web.pathway.md/diseases/rec0gYACAyJ8cog7m 3/4 6/23/23, 1:57 AM Acute leukemia Pathway 6. Tzu-Fei Wang, Robert S Makar, Darko Antic et al. Management of hemostatic complications in acute leukemia: Guidance from the SSC of the ISTH. J Thromb Haemost. 2020 Dec;18 12 3174 3183. Open 7. Val rie de Haas, Nofisat Ismaila, Anjali Advani et al. Initial Diagnostic Work-Up of Acute Leukemia: ASCO Clinical Practice Guideline Endorsement of the College of American Pathologists and American Society of Hematology Guideline. J Clin Oncol. 2019 Jan 20;37 3 239 253. Open https://web.pathway.md/diseases/rec0gYACAyJ8cog7m 4/4

Guideline sources The following summarized guidelines for the evaluation and management of acute limb ischemia are prepared by our editorial team based on guidelines from the Society for Vascular Surgery (SVS 2022), the European Society for Vascular Surgery (ESVS 2020), the American Heart Association (AHA/ACC 2017; 2006), and the American College of Chest Physicians (ACCP 2012). 1 2 3 4 5 Guidelines 1. Classification and risk stratification Severity assessment: Use the Rutherford classification for clinical evaluation of patients presenting with acute limb ischemia: https://web.pathway.md/diseases/recFMC5Qu0dpvOiCu 1/7 6/23/23, 1:58 AM Acute limb ischemia Pathway Situation Guidance Asymptomatic Grade 0, Category 0 Mild claudication Grade I, Category 1 Moderate claudication Grade I, Category 2 Severe claudication Grade I, Category 3 Ischemic rest pain Grade II, Category 4 Ischemic ulcers (minor tissue loss) Grade III, Category 5 Severe ischemic ulcers or gangrene (major tissue loss). B Grade IV, Category 6 2. Diagnostic investigations Clinical assessment: As per ESVS 2020 guidelines, obtain urgent clinical assessment, performed by a vascular specialist responsible for planning further investigation and management, in patients presenting with a possible diagnosis of acute limb ischemia. B As per AHA 2017 guidelines: Obtain a rapid, non-imaging assessment of limb viability and potential for salvage in patients with suspected acute limb ischemia. B Ensure that patients with acute limb ischemia are evaluated emergently by a clinician with sufficient experience to assess limb viability and implement appropriate therapy. B Diagnostic imaging: obtain diagnostic imaging to guide treatment in patients presenting with acute limb ischemia, provided it does not delay treatment, or if the need for primary amputation is obvious. B Show 2 more Laboratory testing: do not use results of myoglobin and CK on admission to decide between revascularization and primary amputation in patients presenting with acute limb ischemia. D Evaluation for underlying causes: Elicit a comprehensive history to determine the cause of thrombosis and/or embolization in patients with acute limb ischemia. B Consider evaluating patients with a history of acute limb ischemia for a cardiovascular cause of thromboembolism. C 3. Respiratory support https://web.pathway.md/diseases/recFMC5Qu0dpvOiCu 2/7 6/23/23, 1:58 AM Acute limb ischemia Pathway Supplemental oxygen: administer supplemental oxygen in patients with acute limb ischemia awaiting revascularization. B 4. Medical management Setting of care: Transfer patients diagnosed with acute limb ischemia in a non-vascular center to a vascular center offering the full range of open and endovascular interventions with an urgency depending on the severity of the ischemia. B Ensure that patients with acute limb ischemia have access to treatment in a hybrid theater or operating theater with C-arm equipment and by a clinical team able to offer a full range of open or endovascular interventions during a single procedure. B Anticoagulant therapy: As per ESVS 2020 guidelines: Initiate heparin in patients with acute limb ischemia awaiting revascularization. B Do not continue heparin administration in patients with acute limb ischemia undergoing thrombolysis. D As per AHA 2017 guidelines, initiate systemic anticoagulation with heparin in patients with acute limb ischemia unless contraindicated. B As per ACCP 2012 guidelines, consider administering immediate systemic anticoagulation with UFH in patients with acute limb ischemia secondary to arterial emboli or thrombosis. C Intravenous thrombolysis: do not use IV thrombolysis in patients with acute limb ischemia. D Pain management: provide adequate analgesia in patients with acute limb ischemia awaiting revascularization. B Rehydration: administer IV rehydration in patients with acute limb ischemia awaiting revascularization. B 5. Therapeutic procedures Catheter-directed thrombolysis, indications: As per ESVS 2020 guidelines, do not perform catheter-directed thrombolysis in patients with acute onset, non-limb-threatening claudication (Rutherford grade I). D Show 2 more As per ACC/AHA 2017 guidelines, perform catheter-based thrombolysis in patients with acute limb ischemia and a salvageable limb. A Catheter-directed thrombolysis, imaging guidance: As per ESVS 2020 guidelines, use ultrasound guidance for arterial access in patients undergoing endovascular therapy. A https://web.pathway.md/diseases/recFMC5Qu0dpvOiCu 3/7 6/23/23, 1:58 AM Acute limb ischemia Pathway As per ACC/AHA 2017 guidelines, insufficient evidence regarding the usefulness of ultrasound- accelerated catheter-based thrombolysis in patients with acute limb ischemia and a salvageable limb. I Catheter-directed thrombolysis (intraprocedural heparin): do not administer heparin during catheter-directed thrombolysis. D Catheter-directed thrombolysis, fibrinolytic agents: As per ESVS 2020 guidelines, administer rtPA or urokinase for thrombolysis. A As per ACCP 2012 guidelines, consider administering rtPA or urokinase over streptokinase in patients undergoing intra-arterial thrombolysis. C Catheter-directed thrombolysis (fibrinogen monitoring): do not obtain routine monitoring of plasma fibrinogen in patients undergoing thrombolytic therapy for acute limb ischemia. D Catheter-directed thrombolysis (monitoring for complications): monitor vital signs, the condition of the limb and for access site complications in patients undergoing thrombolytic treatment. B Show 2 more Mechanical thrombectomy: As per ESVS 2020 guidelines, consider performing aspiration and mechanical thrombectomy in patients with acute limb ischemia. C As per AHA 2017 guidelines, consider performing percutaneous mechanical thrombectomy as an adjunct to thrombolysis in patients with acute limb ischemia and a salvageable limb. C 6. Perioperative care Perioperative prostacyclin analogs: consider administering prostacyclin analogs during and after open surgical revascularization of patients with acute limb ischemia. C Intraoperative completion imaging: obtain completion angiography in patients undergoing open or endovascular surgery for acute limb ischemia. B 7. Surgical interventions Surgical thromboembolectomy, indications: As per ACC/AHA 2017 guidelines: Determine the revascularization strategy in patients with acute limb ischemia depending on the local resources and patient factors (such as etiology and degree of ischemia). B Consider performing surgical thromboembolectomy in patients with acute limb ischemia secondary to embolism and a salvageable limb. C As per ACCP 2012 guidelines, prefer surgery over intra-arterial thrombolysis in patients undergoing reperfusion therapy. B https://web.pathway.md/diseases/recFMC5Qu0dpvOiCu 4/7 6/23/23, 1:58 AM Acute limb ischemia Pathway Surgical thromboembolectomy (anesthesia): consider administering regional or local anesthesia in patients with acute limb ischemia undergoing surgical thromboembolectomy. C Surgical thromboembolectomy (embolectomy catheters): consider using over-the-wire embolectomy catheters under fluoroscopic control for surgical thromboembolectomy. C Surgical thromboembolectomy (infrainguinal bypass): consider using a vein graft in patients requiring an infrainguinal bypass procedure for acute limb ischemia. C Surgical thromboembolectomy (intraoperative local thrombolysis): consider administering intraoperative local thrombolysis in patients with residual thrombus after open surgery. C Hybrid technique: consider performing simultaneous endovascular treatment addressing inflow or outflow stenosis after open revascularization for acute limb ischemia. C Prophylactic fasciotomy: Do not perform routine prophylactic fasciotomy in patients undergone revascularization for acute limb ischemia as it is associated with prolonged hospital stay, local infection, and development of late deep venous insufficiency. D Consider performing prophylactic 4-compartment fasciotomy if ischemia before revascularization has been profound or prolonged. C Amputation: perform surgical amputation as the first procedure of choice in patients with acute limb ischemia and an unsalvageable limb. B 8. Specific circumstances Pediatric patients: initiate heparin as initial conservative management of infants and pediatric patients < 2 years of age with acute limb ischemia. B Show 3 more Patients with malignancy: consider performing active revascularization in selected patients with acute limb ischemia and underlying malignant disease as the immediate postoperative outcome is comparable to patients without malignancy. C Patients with popliteal aneurysm thrombosis: As per SVS 2022 guidelines, decide on the intervention for thrombotic and/or embolic complications of popliteal artery aneurysm depending on the severity of acute limb ischemia at presentation. B Show 3 more As per ESVS 2020 guidelines, consider repairing the popliteal artery aneurysm with a saphenous vein bypass in patients with acute limb ischemia secondary to thrombosis of the popliteal artery aneurysm. C Show 5 more As per ACC 2006 guidelines, consider performing catheter-directed thrombolysis or mechanical thrombectomy (or both) to restore distal runoff and resolve emboli in patients with acute ischemia and popliteal artery aneurysms and absent runoff. C https://web.pathway.md/diseases/recFMC5Qu0dpvOiCu 5/7 6/23/23, 1:58 AM Acute limb ischemia Pathway Patients with acute aortic occlusion: Perform urgent revascularization in patients with acute limb ischemia secondary to acute aortic occlusion. B Ensure close collaboration with anesthesiologists and intensivists to reduce complications of ischemia-reperfusion injury after revascularization for acute limb ischemia secondary to acute aortic occlusion. B Patient with acute graft occlusion: Identify and treat the cause of graft occlusion in patients with acute limb ischemia caused by graft occlusion. B Consider initiating long-term anticoagulation after thrombectomy or endovascular treatment of a prosthetic bypass graft occlusion. C Patients with acute upper limb ischemia: Obtain preoperative imaging in patients with acute ischemia of the upper limb unless embolic occlusion is obvious, the limb is immediately threatened and axillary or proximal brachial pulses are palpable. B Do not offer conservative treatment with anticoagulation alone in patients with acute ischemia of the upper limb if the arm is threatened or if limb function is important to quality of life. D 9. Patient education General counseling: take into account the best interests of the patient before deciding on treatment, obtain informed consent to management if at all possible, and clearly record decisions. B 10. Follow-up and surveillance Post-revascularization monitoring: consider monitoring patients after revascularization, including cardiovascular condition and functional status of the limb. C Show 3 more Post-revascularization anticoagulation: initiate long-term anticoagulation after revascularization of acute limb ischemia caused by an embolus secondary to AF or intracardiac thrombus. B Show 2 more Management of post-reperfusion compartment syndrome: As per ESVS 2020 guidelines, perform emergency 4-compartment fasciotomy for the treatment of post-ischemic compartment syndrome. B Show 2 more As per AHA 2017 guidelines, monitor for and treat compartment syndrome after revascularization. B https://web.pathway.md/diseases/recFMC5Qu0dpvOiCu 6/7 6/23/23, 1:58 AM Acute limb ischemia Pathway 11. Quality improvement Vascular registries: monitor outcomes after treatment of acute limb ischemia in vascular registries using variables developed specifically for this group of patients. B References 1. Martin Bj rck, Jonothan J Earnshaw, Stefan Acosta et al. Editor's Choice European Society for Vascular Surgery ESVS 2020 Clinical Practice Guidelines on the Management of Acute Limb Ischaemia. Eur J Vasc Endovasc Surg. 2020 Feb;59 2 173 218. Open 2. Marie D Gerhard-Herman, Heather L Gornik, Coletta Barrett et al. 2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2017 Mar 21;135 12):e686-e725. Open 3. Pablo Alonso-Coello, Sergi Bellmunt, Catherine McGorrian 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 Feb;141 2 Suppl):e669S-e690S. Open 4. Alan T Hirsch, Ziv J Haskal, Norman R Hertzer et al. ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. Circulation. 2006 Mar 21;113 11):e463 654. Open 5. Alik Farber, Niren Angle, Efthymios Avgerinos et al. The Society for Vascular Surgery clinical practice guidelines on popliteal artery aneurysms. J Vasc Surg. 2022 Jan;75 1S 109S 120S. Open https://web.pathway.md/diseases/recFMC5Qu0dpvOiCu 7/7

Guideline sources The following summarized guidelines for the evaluation and management of acute liver failure are prepared by our editorial team based on guidelines from the Society of Critical Care Medicine (SCCM 2023; 2020), the American Society for Apheresis (ASFA 2019), the European Association for the Study of the Liver (EASL 2017; 2012), and the American Gastroenterological Association (AGA 2017). 1 2 3 4 5 6 7 7 7 8 8 Definition ALF is a disease characterized by an acute impairment of liver function, leading to encephalopathy and coagulopathy. Hyper-acute, acute, and sub-ALF are defined as occurring within 7 days, 7-28 days, and 28 days-6 months of the onset of symptoms, respectively. 7 Epidemiology https://web.pathway.md/diseases/reccyeTojFmEAip8l 1/9 6/23/23, 1:58 AM Acute liver failure Pathway Causes of ALF include acetaminophen poisoning, viral hepatitis (hepatitis A, B, C, D, and E, HSV, Ebstein-Barr virus, CMV), AIH, idiosyncratic toxins (tetracycline, halothane, isoniazid, anabolic steroids, phytopharmaceuticals), Wilson's disease, fatty liver of pregnancy, and Budd-Chiari syndrome. 7 Pathophysiology The annual incidence of ALF is estimated at approximately 0.55-0.62 cases per 100,000 person- years. 8 Disease course In patients with ALF, apoptosis and necrosis of parenchymal hepatocytes impairs normal liver function, resulting in coagulopathy, hepatic encephalopathy, multiple organ failure, and death. 7 Prognosis and risk of recurrence The hospital survival rates of ALF patients treated with liver transplantation and without liver transplantation are 80-86% and 35-48%, respectively. 8 Calculator King's College Criteria for aceta Guidelines 1. Screening and diagnosis Definitions and clinical presentation: recognize that severe acute liver injury is defined as a syndrome characterized by markers of liver damage (elevated serum transaminases) and impaired liver function (jaundice and INR > 1.5) usually preceding clinical encephalopathy. B Show 5 more 2. Classification and risk stratification Prognosis: As per AGA 2017 guidelines, consider using the MELD score, rather than King's College Criteria, as a prognostic scoring system in patients presenting with ALF. C As per EASL 2017 guidelines, obtain prognostic assessment both in the transplant center and at the site of first presentation to allow making decisions in relation to patient transfer to a specialist center at the earliest opportunity. B https://web.pathway.md/diseases/reccyeTojFmEAip8l 2/9 6/23/23, 1:58 AM Acute liver failure Pathway Show 2 more 3. Diagnostic investigations Evaluation for viral hepatitis: As per AGA 2017 guidelines: Consider testing and treating HSV in patients presenting with ALF. C Consider avoiding routine testing for VZV in immunocompetent patients with ALF. D As per EASL 2017 guidelines, screen for viral etiologies and co-factor effects in all patients with ALF. B Evaluation for autoimmune hepatitis: As per AGA 2017 guidelines, consider autoantibody testing in patients presenting with ALF. C As per EASL 2017 guidelines, suspect autoimmune etiology in patients presenting with other autoimmune disorders, elevated globulin fraction and autoantibodies, recognizing that these features, however, may be absent and liver biopsy may be required. B Evaluation for drug-induced liver injury: As per SCCM 2020 guidelines, screen patients with ALF for drug-induced causes of liver failure. Discontinue drugs proven or highly suspected to be the cause of ALF. E As per EASL 2017 guidelines, recognize that DILI, especially acetaminophen toxicity is the most frequent cause of severe acute liver injury and ALF. Obtain a toxicology screen and determine acetaminophen level in every patient at admission, although levels will frequently be negative. Initiate N-acetyl cysteine therapy if the patient already has coagulopathy and increased serum transaminases. B Show 2 more Evaluation for malignancy: exclude malignant infiltration by imaging or liver biopsy in patients with a history of cancer or significant hepatomegaly. B Evaluation for Wilson's disease: As per AGA 2017 guidelines, avoid obtaining routine testing for Wilson's disease in patients presenting with ALF. D As per EASL 2017 guidelines, suspect Wilson's disease in patients with Coombs-negative hemolytic anemia and high bilirubin to ALP ratio. B Evaluation for Budd-Chiari syndrome: suspect Budd-Chiari syndrome in patients presenting with ALF with gross ascites. Confirm the diagnosis based on imaging techniques. B Evaluation for other etiologies: Screen for systemic diseases presenting as ALF. B Assess clinical context to identify less common causes of ALF. B Screening for hepatic encephalopathy: obtain intensive screening at the first sign of hepatic encephalopathy as the clinical appearance of hepatic encephalopathy is crucial for the diagnosis https://web.pathway.md/diseases/reccyeTojFmEAip8l 3/9 6/23/23, 1:58 AM Acute liver failure Pathway of ALF but mental alterations may be initially subtle. B Viscoelastic testing: Consider obtaining viscoelastic testing (thromboelastography/rotational thromboelastography) over measuring INR, platelet, and fibrinogen in critically ill patients with ALF. C Obtain viscoelastic testing (thromboelastography/rotational thromboelastography) over measuring INR, platelet, and fibrinogen in critically ill patients with ALF undergoing procedures. B 4. Diagnostic procedures Liver biopsy: As per AGA 2017 guidelines, consider avoiding the routine use of liver biopsy in patients presenting with ALF. D As per EASL 2017 guidelines, recognizing that indications for liver biopsy in ALF are limited. Perform liver biopsy preferably by a transjugular route, in a center experienced in its use, and with access to a histopathologist with liver experience. Exclude underlying chronic liver disease, malignancies or alcohol-induced liver disease if possible, recognizing that this does not provide prognostic information. B 5. Respiratory support Supplemental oxygen: Provide supportive care with supplemental oxygen in the management of patients with hepatopulmonary syndrome, pending possible liver transplantation. E Consider using high-flow nasal cannula over noninvasive ventilation in hypoxic critically ill patients with ALF. C Mechanical ventilation: As per SCCM 2020 guidelines: Consider using a low tidal volume strategy in patients with ALF and ARDS. C Avoid using high PEEP in patients with ALF and ARDS. D As per EASL 2017 guidelines, administer standard sedation and use lung-protective ventilation techniques in patients with ALF. B Show 2 more 6. Medical management Setting of care: obtain prognostic assessment both in the transplant center and at the site of first presentation to allow making decisions in relation to patient transfer to a specialist center at the earliest opportunity. B Show 3 more https://web.pathway.md/diseases/reccyeTojFmEAip8l 4/9 6/23/23, 1:58 AM Acute liver failure Pathway General principles (goals of care): consider targeting a mean arterial pressure of 65 mmHg in patients with ALF, with concomitant assessment of perfusion. C Show 2 more General principles (precautions): adjust the doses of medications undergoing hepatic metabolism based on the patient's residual hepatic function. Consult a clinical pharmacist when available. E Fluid resuscitation: As per SCCM 2020 guidelines: Do not use hydroxyethyl starch for initial fluid resuscitation of patients with ALF. D Avoid using gelatin solutions for initial fluid resuscitation of patients with ALF. D As per EASL 2017 guidelines: Initiate crystalloid volume resuscitation as most patients are volume depleted at presentation. B Recognize that volume overload is as detrimental as underfilling. B Albumin: consider administering albumin over other fluids for resuscitation of patients with ALF, especially if serum albumin is < 3 mg/dL. C Vasopressors: As per SCCM 2020 guidelines: Administer norepinephrine as first-line vasopressor in patients with ALF remaining hypotensive despite fluid resuscitation, or in patients with profound hypotension and tissue hypoperfusion even if fluid resuscitation is ongoing. B Consider adding low-dose vasopressin to norepinephrine in patients with ALF remaining hypotensive despite fluid resuscitation. C As per EASL 2017 guidelines, administer vasopressive agents guided by appropriate monitoring techniques in patients with persistent hypotension. B Administer norepinephrine as the vasopressor of choice. B Inotropes: consider administering inotropic agents in patients with hypoxic hepatitis. B Corticosteroids: As per SCCM 2020 guidelines, consider administering stress-dose corticosteroids for the management of septic shock in patients with ALF. C As per EASL 2017 guidelines: Initiate hydrocortisone therapy to decrease vasopressor requirements, recognizing that it does not reduce mortality. B Consider initiating early treatment with corticosteroids in patients with suspected autoimmune etiology. B N-acetylcysteine: As per AGA 2017 guidelines, initiate N-acetyl cysteine therapy in patients presenting with acetaminophen-associated ALF. B https://web.pathway.md/diseases/reccyeTojFmEAip8l 5/9 6/23/23, 1:58 AM Acute liver failure Pathway As per EASL 2017 guidelines, initiate N-acetylcysteine in patients with coagulopathy and increased serum transaminases. B Management of metabolic derangements: pay stringent attention to detail and normalization of biochemical abnormalities in patients with ALF. B Show 2 more Management of coagulopathy: do not administer routine FFP and other coagulation factors, limit their administration to specific situations, such as insertion of ICP monitors or active bleeding. D Show 2 more Management of infection: obtain regular periodic surveillance cultures in all patients with ALF. B Show 3 more Management of portopulmonary hypertension: consider treating portopulmonary hypertension with agents approved for pulmonary arterial hypertension in patients with mean pulmonary artery pressure > 35 mmHg. C Management of vascular complications: consider administering LMWH or vitamin K antagonists over offering conservative management in patients with portal venous thrombosis or pulmonary embolus. C Management of hepatic encephalopathy: As per SCCM 2023 guidelines, consider administering hypertonic saline in critically ill patients with ALF at risk of developing intracranial hypertension. C Show 3 more As per AGA 2017 guidelines, consider avoiding the empiric use of treatments to reduce ICP in patients presenting with ALF. D As per EASL 2017 guidelines, evaluate patients with low grade encephalopathy frequently for signs of worsening encephalopathy. B Show 5 more 7. Inpatient care Clinical and laboratory monitoring: As per SCCM 2020 guidelines: Consider placing an arterial catheter for BP monitoring in patients with ALF and shock. C Consider obtaining invasive hemodynamic monitoring to guide therapy in patients with ALF and clinically impaired perfusion. C As per EASL 2017 guidelines: Obtain frequent senior clinical review (BID minimum) and assess physiological parameters, blood results and metabolic status in patients with ALF. B Assess hourly urine output as a marker of renal function, alongside creatinine. B https://web.pathway.md/diseases/reccyeTojFmEAip8l 6/9 6/23/23, 1:58 AM Acute liver failure Pathway 8. Nonpharmacologic interventions Nutrition: As per SCCM 2020 guidelines, avoid using a low protein goal in patients with ALF. Consider targeting protein goals comparable to critically ill patients without liver failure (such as 1.2-2.0 g protein/kg dry or ideal body weight per day). D Show 2 more As per EASL 2017 guidelines, initiate enteral or parenteral nutrition because patients with ALF have increased resting energy expenditure. B Show 4 more 9. Therapeutic procedures Plasmapheresis: As per SCCM 2023 guidelines, consider performing plasma exchange, when available, in critically ill patients with ALF developing hyperammonemia. C As per EASL 2017 guidelines, consider performing plasma exchange to improve transplant-free survival and to modulate immune dysfunction in patients with ALF. B Consider performing plasma exchange in patients treated early who will not ultimately undergo liver transplantation. B Renal replacement therapy: As per SCCM 2020 guidelines, consider performing early RRT in patients with ALF and AKI. C As per EASL 2017 guidelines, recognize that lactate elevation is related to increased production and decreased clearance, and remains a poor prognostic marker. Perform RRT to correct acidosis and metabolic disturbances. B Show 3 more Pleurodesis: place a chest tube with an attempt to pleurodesis for hepatic hydrothorax in patients unfit for TIPS or as a palliative intent. E Extracorporeal liver support: As per SCCM 2023 guidelines, consider initiating extracorporeal liver support or standard medical therapy in critically ill patients with ALF. C As per AGA 2017 guidelines, insufficient evidence to make a conclusive recommendation for or against the use of extracorporeal artificial liver support systems in patients with ALF. These systems should only be used within the context of a clinical trial. As per EASL 2017 guidelines, consider using liver support system techniques (biological or adsorbent) only in the context of RCTs. B 10. Surgical interventions Liver transplantation, indications: https://web.pathway.md/diseases/reccyeTojFmEAip8l 7/9 6/23/23, 1:58 AM Acute liver failure Pathway As per EASL 2017 guidelines, assess patients with ALF for emergency liver transplantation by a multidisciplinary team with appropriate experience in this process. B Show 7 more As per EASL 2012 guidelines, perform liver transplantation in patients with ALF due to Wilson's disease if the revised King's score is 11. B Liver transplantation (management of deceased donor liver transplant): Consider administering systemic corticosteroids for deceased liver graft donors. C Consider employing either using goal-directed fluid management or standard fluid management strategies for the deceased organ donor. C Liver transplantation (peri-transplant management): avoid performing selective bowel decontamination in critically ill liver transplant candidates. D Show 6 more 11. Specific circumstances Pediatric patients: Recognize that in pediatric patients: definition of ALF is not dependent upon the presence of encephalopathy some etiologies are specific, notably metabolic disorders transplantation criteria are different compared to adults. B Pregnant patients: As per AGA 2017 guidelines, consider testing for hepatitis E in pregnant women presenting with ALF. C As per EASL 2017 guidelines, initiate prompt delivery of the baby in patients with HELLP and acute fatty liver of pregnancy, especially in patients with elevated lactate levels and hepatic encephalopathy. Offer screening for putative fatty acid defects. B References 1. Rahul Nanchal, Ram Subramanian, Constantine J Karvellas et al. Guidelines for the Management of Adult Acute and Acute-on-Chronic Liver Failure in the ICU Cardiovascular, Endocrine, Hematologic, Pulmonary and Renal Considerations: Executive Summary. Crit Care Med. 2020 Mar;48 3 415 419. Open 2. Wendon, J, Cordoba J et al. EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure. J Hepatol. 2017 May;66 5 1047 1081. Open 3. Rahul Nanchal, Ram Subramanian, Waleed Alhazzani et al. Guidelines for the Management of Adult Acute and Acute-on-Chronic Liver Failure in the ICU Neurology, Peri-Transplant Medicine, Infectious Disease, and Gastroenterology Considerations. Crit Care Med. 2023 May 1;51 5 657 676. Open 4. Flamm SL, Yang YX, Singh S et al. American Gastroenterological Association Institute Guidelines for the Diagnosis and Management of Acute Liver Failure. Gastroenterology. 2017 Feb;152 3 644 647. Open https://web.pathway.md/diseases/reccyeTojFmEAip8l 8/9 6/23/23, 1:58 AM Acute liver failure Pathway 5. European Association for Study of Liver. EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol. 2012 Mar;56 3 671 85. Open 6. Anand Padmanabhan, Laura Connelly-Smith, Nicole Aqui et al. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue. J Clin Apher. 2019 Jun;34 3 171 354. Open 7. Canbay A, Tacke F, Hadem J et al. Acute liver failure: a life-threatening disease. Dtsch Arztebl Int. 2011 Oct;108 42 714 20. Open 8. Thanapirom K, Treeprasertsuk S, Soonthornworasiri N et al. The incidence, etiologies, outcomes, and predictors of mortality of acute liver failure in Thailand: a population-base study. BMC Gastroenterol. 2019 Jan 28;19 1 18. Open 9. Paul Martin, Andrea DiMartini, Sandy Feng et al. Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Hepatology. 2014 Mar;59 3 1144 65. Open 10. J G O'Grady, G J Alexander, K M Hayllar et al. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989 Aug;97 2 439 45. Open https://web.pathway.md/diseases/reccyeTojFmEAip8l 9/9

Guideline sources The following summarized guidelines for the evaluation and management of acute mesenteric ischemia (AMI) are prepared by our editorial team based on guidelines from the World Society of Emergency Surgery (WSES 2022), the American Association for the Study of Liver Diseases (AASLD 2021), the American College of Gastroenterology (ACG 2020), the European Society of Cardiology (ESC/ESVS 2018), the American College of Radiology (ACR 2018), the European Society for Vascular Surgery (ESVS 2017), the European Society for Trauma and Emergency Surgery (ESTES 2016), and the European Association for the Study of the Liver (EASL 2016). 1 2 3 4 5 6 7 8 https://web.pathway.md/diseases/receyfRKUHyVy6myP 1/10 6/23/23, 1:58 AM Acute mesenteric ischemia Pathway Guidelines 1. Screening and diagnosis Diagnosis: As per WSES 2022 guidelines: Suspect AMI in patients with severe abdominal pain out of proportion to physical examination until disproven. B Suspect non-occlusive mesenteric ischemia in critically ill patients with abdominal pain or distension requiring vasopressor support and evidence of multiorgan dysfunction. B As per ESVS 2017 guidelines, diagnose non-occlusive mesenteric ischemia based on clinical suspicion. B Do not obtain biomarkers to diagnose or rule out the condition in patients with suspected non-occlusive mesenteric ischemia. B As per ESTES 2016 guidelines, suspect the diagnosis of AMI in patients with acute abdominal pain without clear diagnosis, particularly when the pain is disproportionate to the physical examination findings, and in elderly patients with a history of cardiovascular comorbidities. B Show 2 more 2. Classification and risk stratification Classification: Differentiate AMI into the following types based on the clinical scenario and risk factors: mesenteric arterial embolism mesenteric arterial thrombosis non-occlusive mesenteric ischemia mesenteric venous thrombosis. B 3. Diagnostic investigations Diagnostic imaging: As per WSES 2022 guidelines: Obtain CT angiography without delay in any patient with suspected AMI. A Do not obtain plain radiographs for the evaluation of intestinal ischemia. D As per ACR 2018 guidelines, obtain CT angiography as initial imaging in patients with suspected AMI. B As per ESC 2018 guidelines, obtain urgent CT angiography in patients with suspected AMI. B As per ESVS 2017 guidelines: Obtain triphasic CT angiography with 1 mm slices (or thinner) to detect mesenteric arterial occlusion in patients with suspected AMI. B https://web.pathway.md/diseases/receyfRKUHyVy6myP 2/10 6/23/23, 1:58 AM Acute mesenteric ischemia Pathway Consider obtaining CT angiography, accepting the risk of contrast-induced renal failure, in patients with suspected AMI and elevated creatinine values. C As per ESTES 2016 guidelines: Obtain immediate multidetector CT with IV contrast in patients with suspected AMI. Avoid using oral contrast as it significantly delays the investigation. B Do not obtain percutaneous angiography for initial diagnosis of AMI, unless non-occlusive mesenteric ischemia is suspected. D Laboratory tests: As per WSES 2022 guidelines, recognize that there are no sufficiently accurate laboratory parameters to conclusively identify the presence or absence of ischemic or necrotic bowel, although assessments for elevated L-lactate, leukocytosis, and D-dimer may assist. B As per ESC 2018 guidelines, consider obtaining D-dimer in patients with suspected AMI to rule out the diagnosis. C As per ESVS 2017 guidelines: Obtain D-dimer measurement to exclude AMI in patients with acute abdominal pain. B Do not obtain L-lactate measurement to diagnose or rule out acute occlusive mesenteric ischemia. D As per ESTES 2016 guidelines: Do not use serum lactate levels for the diagnosis of AMI, as its normal value does not exclude the diagnosis. D Do not use routine laboratory tests for the diagnosis of AMI, instead they reflect disease progression. D 4. Diagnostic procedures Laparoscopy: insufficient evidence to support routine use of laparoscopy in patients with AMI. I 5. Respiratory support Oxygen therapy: administer immediate supplementary oxygen in patients with AMI. B 6. Medical management General principles: As per WSES 2022 guidelines: Manage patients with AMI in dedicated centers using a focused care bundle and a multidisciplinary team. B Treat the underlying cause and improve mesenteric perfusion in patients with suspected non- occlusive mesenteric ischemia. B https://web.pathway.md/diseases/receyfRKUHyVy6myP 3/10 6/23/23, 1:58 AM Acute mesenteric ischemia Pathway As per ESC 2018 guidelines, obtain strict glycemic control in patients with diabetes mellitus and PAD. B As per ESTES 2016 guidelines, perform revascularization within 12 hours from the onset of symptoms in patients with AMI. B Show 2 more Supportive therapy: As per WSES 2022 guidelines: Initiate immediate fluid resuscitation to enhance visceral perfusion once the diagnosis of AMI is made. Correct electrolyte abnormalities. B Provide postoperative intensive care in patients with AMI for improved intestinal perfusion and prevention of multiple organ failure. B As per ESTES 2016 guidelines, obtain quick assessment of fluid volume status and initiate prompt fluid replacement in patients with AMI, but do not delay the diagnosis and interventions. B Show 5 more Antibiotic therapy: As per WSES 2022 guidelines, administer broad-spectrum antibiotics immediately in patients with AMI. B As per ESVS 2017 guidelines, administer antibiotics in patients requiring bowel resection for intestinal infarction. A As per ESTES 2016 guidelines, administer broad-spectrum antibiotics early in the course in patients with AMI. B Antithrombotic therapy: As per WSES 2022 guidelines: Consider administering a continuous infusion of UFH for the treatment of patients with mesenteric venous thrombosis. B Initiate long-term anticoagulation in patients after revascularization. B As per ESTES 2016 guidelines, initiate systemic anticoagulation as soon as possible in patients with acute mesenteric venous thrombosis. B Show 2 more Antihypertensive therapy: Target controlling BP at < 140/90 mmHg in patients with PAD and hypertension. A Consider offering ACEIs or ARBs as first-line therapy in patients with PAD and hypertension. C Lipid-lowering therapy: Offer statins in all patients with PADs. A Target reducing LDL-C to < 1.8 mmol/L (< 70 mg/dL) or decreasing it by 50% if baseline values are 1.8-3.5 mmol/L (70-135 mg/dL). B Palliative care: https://web.pathway.md/diseases/receyfRKUHyVy6myP 4/10 6/23/23, 1:58 AM Acute mesenteric ischemia Pathway As per WSES 2022 guidelines, obtain a careful assessment of underlying comorbidities and use advanced directives to find the optimal therapeutic strategy (including palliation) in patients with massive gut necrosis. B As per ESTES 2016 guidelines: Offer palliative care in patients with AMI considered unsalvageable. B Consider offering palliative care alone in patients with advanced age, late presentation, peritonitis and signs of organ failure, as they are unlikely to benefit from invasive procedures. C 7. Inpatient care Intra-abdominal pressure monitoring: Obtain intra-abdominal pressure monitoring to prevent non-occlusive mesenteric ischemia in patients with known risk factors for intraabdominal hypertension/abdominal compartment syndrome. B Initiate medical treatment in patients with intraabdominal pressure > 12 mmHg to prevent abdominal compartment syndrome and non-occlusive mesenteric ischemia. B 8. Nonpharmacologic interventions Lifestyle modifications: As per ESC 2018 guidelines, advise smoking cessation B , healthy diet and physical activity in all patients with PADs. B As per ESTES 2016 guidelines, advise making appropriate lifestyle changes to reduce the consequences of vascular disease in all patients with AMI. B 9. Therapeutic procedures Nasogastric decompression: perform nasogastric decompression in patients with AMI. B Endovascular revascularization: As per WSES 2022 guidelines, perform endovascular revascularization, if sufficient expertise is available, as the primary procedure in patients with arterial occlusion. B As per ESC 2018 guidelines: Consider performing endovascular revascularization in patients with acute mesenteric arterial embolism. C Consider performing endovascular revascularization as first-line therapy in patients with acute mesenteric arterial thrombosis. C As per ESVS 2017 guidelines, consider performing endovascular therapy as first-line therapy in patients with acute thrombotic superior mesenteric artery occlusion. C https://web.pathway.md/diseases/receyfRKUHyVy6myP 5/10 6/23/23, 1:58 AM Acute mesenteric ischemia Pathway As per ESTES 2016 guidelines, decide on performing endovascular intervention or open surgery in patients with acute mesenteric arterial embolism based on personal experience and technical capabilities of the surgeon and the available resources, if immediate surgical intervention is not required. B Show 2 more 10. Surgical interventions Indications for open surgery: As per WSES 2022 guidelines, perform prompt laparoscopy/laparotomy in patients with overt peritonitis. B As per ESC 2018 guidelines, consider performing open surgical revascularization in patients with acute mesenteric arterial embolism. C As per ESVS 2017 guidelines: Perform decompression laparotomy to prevent non-occlusive mesenteric ischemia in patients with abdominal compartment syndrome (defined as an intraabdominal pressure > 20 mmHg and newly developed organ dysfunction or failure). B Transfer patients with life-threatening non-occlusive mesenteric ischemia to an operating room with the capacity for open and endovascular surgery where angiography (with stenting in the case of stenosis) and/or intra-arterial administration of vasodilators and/or laparotomy for bowel resection can be performed. B As per ESTES 2016 guidelines, decide on performing open surgery or endovascular intervention in patients with acute mesenteric arterial embolism based on personal experience and technical capabilities of the surgeon and the available resources, if immediate surgical intervention is not required. B Show 3 more Bowel resection: As per WSES 2022 guidelines: Perform prompt resection of infarcted bowel in patients with non-occlusive mesenteric ischemia. B Restore digestive continuity in association with hormonal therapy to optimize absorptive function and achieve nutritional autonomy in patients with short bowel syndrome following extensive bowel resection. B As per ESVS 2017 guidelines: Consider performing open or endovascular revascularization before bowel surgery in patients with acute mesenteric arterial ischemia. C Assess bowel viability during laparotomy based on clinical judgment. B As per ESTES 2016 guidelines, perform excision of non-viable, necrotic bowel without delay in patients with AMI considered salvageable. B Show 5 more https://web.pathway.md/diseases/receyfRKUHyVy6myP 6/10 6/23/23, 1:58 AM Acute mesenteric ischemia Pathway Damage control surgery: As per WSES 2022 guidelines, perform damage control surgery with temporary abdominal closure as an adjunct to allow reassessment of bowel viability in patients requiring intestinal resection and in patients with severe abdominal sepsis. B As per ESTES 2016 guidelines, perform life-saving damage control surgery in patients with AMI and severe sepsis or septic shock. B 11. Specific circumstances Patients with isolated mesenteric artery dissection: consider offering conservative management with antiplatelet therapy and control of hypertension in patients with asymptomatic isolated mesenteric artery dissection. C Show 3 more Patients with mesenteric vein thrombosis, diagnostic imaging: As per ACG 2020 guidelines, obtain contrast-enhanced CT or MRI to assess the extension of thrombus into the mesenteric veins and to exclude tumor thrombus in patients with cirrhosis developing new portal and/or mesenteric vein thrombus. B As per ESVS 2017 guidelines: Obtain CT angiography with arterial and portal phases in patients with suspected mesenteric vein thrombosis. B Rule out the possibility of intestinal infarction until the resolution of pain in patients with mesenteric vein thrombosis. B Patients with mesenteric vein thrombosis, evaluation for etiology: As per ESVS 2017 guidelines, evaluate for abdominal cancer, inflammatory disease, and myeloproliferative neoplasms in patients with mesenteric vein thrombosis. B Show 2 more As per ESTES 2016 guidelines, evaluate for thrombophilia in patients with mesenteric vein thrombosis. B Patients with mesenteric vein thrombosis, anticoagulation therapy, indications: As per WSES 2022 guidelines, consider administering a continuous infusion of UFH for the management of patients with mesenteric venous thrombosis. B As per AASLD 2021 guidelines, consider initiating antithrombotic therapy in patients with cirrhosis with recent occlusive or partially occlusive (> 50% obstruction of the lumen) thrombosis of the main portal vein or mesenteric veins, in order to avoid thrombosis progression possibly hindering future liver transplantation or causing progression of portal hypertension. E As per ESVS 2017 guidelines, administer heparin as first-line therapy in patients with acute mesenteric vein thrombosis without peritonitis. B Patients with mesenteric vein thrombosis, anticoagulation therapy, duration: As per ACG 2020 guidelines: https://web.pathway.md/diseases/receyfRKUHyVy6myP 7/10 6/23/23, 1:58 AM Acute mesenteric ischemia Pathway Consider continuing anticoagulation for at least 6 months in patients with non-cirrhotic mesenteric vein thrombosis without thrombophilia and when the etiology of the thrombosis is reversible. Continue anticoagulation indefinitely in patients with non-cirrhotic mesenteric vein thrombosis with thrombophilia. C Consider continuing anticoagulation for 6 months in patients with cirrhotic mesenteric vein thrombosis. Continue anticoagulation beyond this period in patients with cirrhotic mesenteric vein thrombosis awaiting a liver transplant. C As per ESVS 2017 guidelines: Continue anticoagulation for 3-6 months in patients with mesenteric vein thrombosis with reversible causes (such as trauma, infection, or pancreatitis). B Continue anticoagulation lifelong in patients with mesenteric vein thrombosis with any of the following: proven thrombophilia recurrent venous thrombosis progression or recurrence of thrombosis would have severe clinical consequences. B As per EASL 2016 guidelines, consider continuing anticoagulation lifelong in patients with superior mesenteric venous thrombosis with a past history suggestive of intestinal ischemia or being liver transplant candidates. C As per ESTES 2016 guidelines, continue anticoagulation therapy, when indicated, for a minimum of 6 months in patients with mesenteric vein thrombosis. B Patients with mesenteric vein thrombosis (prevention of variceal bleeding): Initiate nonselective -blockers for the prevention of variceal bleeding in patients with high-risk varices and portal and/or mesenteric venous thrombosis requiring anticoagulation. B Consider performing endoscopic variceal ligation if there are contraindications or intolerance to -blockers. Consider interrupting anticoagulation in the periprocedural period. B 12. Preventative measures Secondary prevention: As per ESVS 2017 guidelines, offer secondary medical prevention including smoking cessation, statin therapy, and antiplatelet or anticoagulation therapy in patients surviving AMI. B As per ESTES 2016 guidelines, initiate life-long anticoagulation, if not contraindicated, in patients with emboli to reduce the risk of recurrence. B 13. Follow-up and surveillance Second-look procedures: As per ESVS 2017 guidelines, consider performing second-look laparotomy and damage control surgery in patients undergoing acute intestinal revascularization. C https://web.pathway.md/diseases/receyfRKUHyVy6myP 8/10 6/23/23, 1:58 AM Acute mesenteric ischemia Pathway As per ESTES 2016 guidelines, reassess ischemic bowel after adequate fluid resuscitation and revascularization. Perform a second-look procedure to assess the viability of the bowel if any doubt remains. B Show 4 more Follow-up imaging: As per WSES 2022 guidelines, obtain surveillance imaging after revascularization. B As per ESVS 2017 guidelines: Consider obtaining completion imaging with angiography or transit time flow measurements in patients undergoing mesenteric revascularization. C Consider obtaining imaging follow-up in patients with AMI and stented mesenteric arteries. C As per ESTES 2016 guidelines, obtain duplex ultrasound or CT angiography for graft surveillance or stent follow-up for early detection and management of stenosis and occlusion in patients with vascular stents or bypass procedures. B 14. Quality improvement Hospital requirements: healthcare centers should set up a multidisciplinary vascular team to make decisions for the management of patients with PADs. B References 1. Miklosh Bala, Fausto Catena, Jeffry Kashuk et al. Acute mesenteric ischemia: updated guidelines of the World Society of Emergency Surgery. WSES. 2022 Oct;. Open 2. Victor Aboyans, Jean-Baptiste Ricco, Marie-Louise E L Bartelink et al. 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery ESVS Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteriesEndorsed by: the European Stroke Organization ESO The Task Force for the Diagnosis and Treatment of Peripheral Arterial Diseases of the European Society of Cardiology ESC and of the European Society for Vascular Surgery ESVS . Eur Heart J. 2018 Mar 1;39 9 763 816. Open 3. M Bj rck, M Koelemay, S Acosta et al. Editor's Choice Management of the Diseases of Mesenteric Arteries and Veins: Clinical Practice Guidelines of the European Society of Vascular Surgery ESVS . Eur J Vasc Endovasc Surg. 2017 Apr;53 4 460 510. Open 4. Tilsed JV, Casamassima A, Kurihara H et al. ESTES guidelines: acute mesenteric ischaemia. Eur J Trauma Emerg Surg. 2016 Apr;42 2 253 70. Open 5. Douglas A Simonetto, Ashwani K Singal, Guadalupe Garcia-Tsao et al. ACG Clinical Guideline: Disorders of the Hepatic and Mesenteric Circulation. Am J Gastroenterol. 2020 Jan;115 1 18 40. Open 6. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Vascular diseases of the liver. J Hepatol. 2016 Jan;64 1 179 202. Open https://web.pathway.md/diseases/receyfRKUHyVy6myP 9/10 6/23/23, 1:58 AM Acute mesenteric ischemia Pathway 7. Patrick G Northup, Juan Carlos Garcia-Pagan, Guadalupe Garcia-Tsao et al. Vascular Liver Disorders, Portal Vein Thrombosis, and Procedural Bleeding in Patients With Liver Disease: 2020 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2021 Jan;73 1 366 413. Open 8. Expert Panels on Vascular Imaging and Gastrointestinal Imaging:, Michael Ginsburg, Piotr Obara et al. ACR Appropriateness Criteria Imaging of Mesenteric Ischemia. J Am Coll Radiol. 2018 Nov;15 11S S332 S340. Open 9. Bala M, Kashuk J, Moore EE et al. Acute mesenteric ischemia: guidelines of the World Society of Emergency Surgery. World J Emerg Surg. 2017 Aug 7;12 38. Open 10. Expert Panel on Interventional Radiology, Alexander Lam, Yoon-Jin Kim et al. ACR Appropriateness Criteria Radiologic Management of Mesenteric Ischemia: 2022 Update. J Am Coll Radiol. 2022 Nov;19 11S S433 S444. Open https://web.pathway.md/diseases/receyfRKUHyVy6myP 10/10

Guideline sources The following summarized guidelines for the evaluation and management of acute myeloid leukemia (AML) are prepared by our editorial team based on guidelines from the American Society of Hematology (ASH 2020), the International Society on Thrombosis and Haemostasis (ISTH 2020), the European Society of Medical Oncology (ESMO 2020), the Congress of Neurological Surgeons (CNS 2018), the Infectious Diseases Society of America (IDSA/ASCO 2018), the American Society of Hematology (ASH/ACP 2017), the British Society for Haematology (BSH 2017), the British Committee for Standards In Haematology (BCSH 2015), and the Infectious Diseases Society of America (IDSA 2011). 1 2 3 4 5 7 9 10 11 12 12 13 13 13 Definition AML is a hematopoietic stem cell malignancy associated with abnormal differentiation and proliferation of myeloid clone cells. 12 Epidemiology AML is caused by malignant transformation of hematopoietic progenitor cells secondary to genetic mutations that can be inherited or occur sporadically. 13 Pathophysiology https://web.pathway.md/diseases/recgmiUKfU5PnO7Ja 1/6 6/23/23, 1:58 AM Acute myeloid leukemia Pathway The age-adjusted incidence of AML in the United States is 4.3 per 100,000 person-years. 13 Disease course The oncogenic transformation of hematopoietic progenitor stem cells leads to the production of malignant clones causing increased myeloid blasts (myeloblasts, monoblasts, megakaryoblasts) in the bone marrow and peripheral blood, multiorgan infiltration by blast cells, bone marrow failure, and death. 12 Prognosis and risk of recurrence The median overall survival of AML is 8.5 months, with 2-year and 5-year overall survival being 32.0% and 24.0%, respectively. 13 Calculator Calculator Calculator CIBMTR score for acute myeloid Eastern Cooperative Oncology G Karnofsky Guidelines 1. Classification and risk stratification Classification: use the current WHO terminology for the final diagnosis and classification of acute leukemia. A 2. Diagnostic procedures Tissue biopsy: perform a fresh bone marrow aspiration in all patients with suspected acute leukemia, and use a portion of aspirate to prepare smears for morphologic evaluation. Evaluate an adequate bone marrow trephine core biopsy, bone marrow trephine touch preparations, and/or marrow clots, in conjunction with the bone marrow aspirates, if performed. A Show 2 more Ancillary testing: obtain sufficient samples and conduct conventional cytogenetic analysis (karyotype), appropriate molecular genetic and/or fluorescent in situ hybridization testing, and flow cytometric immunophenotyping in addition to morphologic assessment (blood and bone marrow). Ensure that the flow cytometry panel is sufficient to distinguish AML (including acute promyelocytic leukemia), T-cell acute lymphoblastic leukemia (including early T-cell precursor leukemias), B-cell precursor acute lymphoblastic leukemia, and acute leukemia of ambiguous lineage in all patients diagnosed with acute leukemia, and to allow subsequent detection of minimal residual disease. Recognize that molecular genetic and/or fluorescent in situ hybridization testing does not replace conventional cytogenetic analysis. A https://web.pathway.md/diseases/recgmiUKfU5PnO7Ja 2/6 6/23/23, 1:58 AM Acute myeloid leukemia Pathway Show 5 more 3. Medical management Induction chemotherapy, patients eligible for standard treatment: As per ASH 2020 guidelines, initiate antileukemic therapy over best supportive care in older adult patients with newly diagnosed AML being candidates for antileukemic therapy. B Show 3 more As per ESMO 2020 guidelines, consider discussing the requirement of cytoreduction in patients with non-acute promyelocytic leukemia AML with a WBC count > 100 10 /L and signs of leukostasis. Offer hydroxycarbamide 50-60 mg/kg/day or if the patient cannot swallow either IV or SC cytarabine or IV daunorubicin for cytoreduction. C Show 10 more Induction chemotherapy (patients ineligible for standard treatment): offer hypomethylating agents azacitidine or decitabine as first-line therapy in newly diagnosed unfit patients with AML. B Show 4 more Consolidation therapy: As per ASH 2020 guidelines: Consider initiating postremission therapy in older adult patients with AML achieved remission after at least a single cycle of intensive antileukemic therapy and not being candidates for allogeneic HSCT. C Consider continuing therapy indefinitely until progression or unacceptable toxicity in older adult patients with AML achieved a response after receiving less-intensive therapy. C As per ESMO 2020 guidelines, initiate consolidation therapy as soon as patients achieve complete remission/complete remission with incomplete hematological recovery after 1 or 2 induction cycles. B Show 11 more Management of relapsed/refractory disease: offer allogeneic hematopoietic cell transplantation in an attempt to provide long-term survival in patients with primary refractory AML. B Show 7 more Management of thrombocytopenia: administer empiric platelet transfusion (one standard adult unit) for a daily platelet count < 10 10 /L in patients with acute leukemia without active bleeding or coagulopathy. Consider using a higher transfusion threshold (such as 20 10 /L) in patients with active bleeding, as determined by clinical factors, including the degree of hemorrhage, site of hemorrhage, and responsiveness to platelet transfusion. B Show 4 more Management of DIC: ensure a high level of vigilance for DIC in patients with acute leukemia. Obtain systemic evaluation for coagulopathy (including platelet counts and routine coagulation https://web.pathway.md/diseases/recgmiUKfU5PnO7Ja 3/6 6/23/23, 1:58 AM Acute myeloid leukemia Pathway parameters, such as PT, activated partial thromboplastin, and fibrinogen) at least daily until normalization and use at least one of the standardized scores to diagnose DIC. B Show 7 more 4. Therapeutic procedures Leukapheresis: Do not perform leukapheresis in patients with non-acute promyelocytic leukemia AML. D Avoid performing leukapheresis for hyperleukocytosis in patients with acute promyelocytic leukemia because it may exacerbate coagulopathy. D Blood transfusion: consider ensuring the availability of RBC transfusions for older adult patients with AML no longer receiving antileukemic therapy (including patients receiving end-of-life care or hospice care). C 5. Specific circumstances Pregnant patients (diagnosis): use the WHO classification for diagnosing AML in pregnant patients as for nonpregnant patients. A Pregnant patients (general principles of management): manage pregnant patients with a multidisciplinary team including hematologists, obstetricians, neonatologists, and anesthesiologists. B Show 3 more Pregnant patients (chemotherapy): balance the risks of fetal chemotherapy exposure against risks of prematurity following elective delivery at 24-32 weeks of gestation. B Show 3 more Pregnant patients (supportive therapy): avoid using quinolones, tetracyclines, and sulphonamides during pregnancy. D Show 2 more Pregnant patients (delivery): consider administering a course of corticosteroids over a 48-hour period during the week before delivery, if delivery is anticipated at 24-35 weeks of gestation. B Show 6 more Patients with acute promyelocytic leukemia (induction and consolidation therapy): initiate immediate treatment with all-trans-retinoic acid in patients with suspected acute promyelocytic leukemia, until confirmatory molecular and/or cytogenetic results are available. B Show 7 more Landmark trials: Lo-Coco 2013 In patients with acute promyelocytic leukemia classified as low-to-intermediate risk, ATRA- arsenic trioxide was superior to ATRA-chemotherapy with respect to a event-free survival at 2 https://web.pathway.md/diseases/recgmiUKfU5PnO7Ja 4/6 6/23/23, 1:58 AM Acute myeloid leukemia Pathway years. Lo-Coco F et al. N Engl J Med. 2013 Jul 11. Patients with clonal eosinophilia: offer standard induction therapy in patients with AML with clonal eosinophilia and no molecular or cytogenetic abnormality suggesting a likely response to a TKI. A Patients with CNS involvement: consider administering comprehensive radiotherapy to the CNS in patients with AML with a history of CNS involvement undergoing allogeneic HSCT. E 6. Preventative measures Antibiotic prophylaxis: administer antibiotic prophylaxis with a fluoroquinolone in most patients with AML/myelodysplastic syndromes being at high risk for febrile neutropenia or profound, protracted neutropenia. B Antifungal prophylaxis: As per ASCO 2018 guidelines, administer antifungal prophylaxis with an oral triazole or parenteral echinocandin in most patients with AML/myelodysplastic syndromes being at high risk for profound, protracted neutropenia. Antifungal prophylaxis is not routinely recommended for patients with solid tumors. B As per IDSA 2011 guidelines, consider administering antifungal prophylaxis with posaconazole against invasive Aspergillus infections in selected patients 13 years of age undergoing intensive chemotherapy for AML, if the risk of invasive aspergillosis without prophylaxis is substantial. B References 1. Pinnix CC, Yahalom J, Specht L et al. Radiation in Central Nervous System Leukemia: Guidelines From the International Lymphoma Radiation Oncology Group. Int J Radiat Oncol Biol Phys. 2018 Sep 1;102 1 53 58. Open 2. Randy A Taplitz, Erin B Kennedy, Eric J Bow et al. Antimicrobial Prophylaxis for Adult Patients With Cancer-Related Immunosuppression: ASCO and IDSA Clinical Practice Guideline Update. J Clin Oncol. 2018 Oct 20;36 30 3043 3054. Open 3. Sahra Ali, Gail L Jones, Dominic J Culligan et al. Guidelines for the diagnosis and management of acute myeloid leukaemia in pregnancy. Br J Haematol. 2015 Aug;170 4 487 95. Open 4. Mikkael A Sekeres, Gordon Guyatt, Gregory Abel et al. American Society of Hematology 2020 guidelines for treating newly diagnosed acute myeloid leukemia in older adults. Blood Adv. 2020 Aug 11;4 15 3528 3549. Open 5. Arber DA, Borowitz MJ, Cessna M et al. Initial Diagnostic Workup of Acute Leukemia: Guideline From the College of American Pathologists and the American Society of Hematology. Arch Pathol Lab Med. 2017 Oct;141 10 1342 1393. Open https://web.pathway.md/diseases/recgmiUKfU5PnO7Ja 5/6 6/23/23, 1:58 AM Acute myeloid leukemia Pathway 6. Amanda S Davis, Anthony J Viera, Monica D Mead. Leukemia: an overview for primary care. 2014 May 1;89 9 731 8.2014 May 1;89 9 731 8. Open 7. Tzu-Fei Wang, Robert S Makar, Darko Antic et al. Management of hemostatic complications in acute leukemia: Guidance from the SSC of the ISTH. J Thromb Haemost. 2020 Dec;18 12 3174 3183. Open 8. J Thachil, A Falanga, M Levi et al. Management of cancer-associated disseminated intravascular coagulation: guidance from the SSC of the ISTH. J Thromb Haemost. 2015 Apr;13 4 671 5. Open 9. M Heuser, Y Ofran, N Boissel et al. Acute myeloid leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020 Jun;31 6 697 712. Open 10. Freifeld AG, Bow EJ, Sepkowitz KA et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011 Feb 15;52 4):e56 93. Open 11. Butt NM, Lambert J, Ali S et al. Guideline for the investigation and management of eosinophilia. Br J Haematol. 2017 Feb;176 4 553 572. Open 12. Short NJ, Rytting ME, Cortes JE. Acute myeloid leukaemia. Lancet. 2018 Aug 18;392 10147 593 606. Open 13. Shallis RM, Wang R, Davidoff A et al. Epidemiology of acute myeloid leukemia: Recent progress and enduring challenges. Blood Rev. 2019 Jul;36 70 87. Open 14. Tallman MS, Wang ES, Altman JK et al. Acute Myeloid Leukemia, Version 3.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2019 Jun 1;17 6 721 749. Open 15. Michel Duval, John P Klein, Wensheng He et al. Hematopoietic stem-cell transplantation for acute leukemia in relapse or primary induction failure. J Clin Oncol. 2010 Aug 10;28 23 3730 8. Open 16. Val rie de Haas, Nofisat Ismaila, Anjali Advani et al. Initial Diagnostic Work-Up of Acute Leukemia: ASCO Clinical Practice Guideline Endorsement of the College of American Pathologists and American Society of Hematology Guideline. J Clin Oncol. 2019 Jan 20;37 3 239 253. Open https://web.pathway.md/diseases/recgmiUKfU5PnO7Ja 6/6

Guideline sources The following summarized guidelines for the evaluation and management of acute otitis externa are prepared by our editorial team based on guidelines from the Infectious Diseases Society of America (IDSA 2016) and the American Academy of Otolaryngology-Head and Neck Surgery Foundation (AAO-HNSF 2014). 1 2 Guidelines 1. Diagnostic investigations Assessment: Distinguish diffuse acute otitis externa from other causes of otalgia, otorrhea, and inflammation of the external ear canal. B Assess the patient with diffuse acute otitis externa for factors that modify management (nonintact tympanic membrane, tympanostomy tube, diabetes, immunocompromised state, prior radiotherapy). B 2. Medical management Systemic antibiotics: do not offer systemic antimicrobials as initial therapy for diffuse, uncomplicated acute otitis externa unless there is extension outside the ear canal or the presence https://web.pathway.md/diseases/recKDAkqHsIVEC2Ux 1/3 6/23/23, 2:01 AM Acute otitis externa Pathway of specific host factors that would indicate a need for systemic therapy. D Topical therapy: prescribe topical preparations for initial therapy of diffuse, uncomplicated acute otitis externa. B Show 2 more Updated evidence: Ototopical ABX and CS in AOE (ciprofloxacin plus fluocinolone vs. ciprofloxacin) In adults and children aged > 6 months with acute otitis externa, ciprofloxacin plus fluocinolone acetonide was not superior to ciprofloxacin alone with respect to clinical and microbiological cure at day 8-10. Laurence Chu et al. JAMA Netw Open. 2022 Jul 1. Pain management: assess patients with acute otitis externa for pain and prescribe analgesics based on the severity of pain. B 3. Specific circumstances Patients with Aspergillus otitis externa: perform mechanical cleansing of the external auditory canal and administer topical antifungals or boric acid in patients with non-invasive Aspergillus otitis externa. B 4. Follow-up and surveillance Follow-up: reassess the patient who fails to respond to the initial therapeutic option within 48 to 72 hours to confirm the diagnosis of diffuse acute otitis externa and to exclude other causes of illness. B References 1. Richard M. Rosenfeld, MD, MPH et al. Clinical Practice Guideline: Acute Otitis Externa. 2014 Feb;150 1 Suppl):S1 S24. Open 2. Patterson TF, Thompson GR rd, Denning DW et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016 Aug 15;63 4):e1-e60. Open 3. Rosenfeld RM, Schwartz SR, Cannon CR et al. Clinical practice guideline: acute otitis externa. Otolaryngol Head Neck Surg. 2014 Feb;150 1 Suppl):S1 S24. Open 4. Laurence Chu, Ana M Acosta, Hessam Aazami et al. Efficacy and Safety of Ciprofloxacin Plus Fluocinolone Acetonide Among Patients With Acute Otitis Externa: A Randomized Clinical Trial. JAMA Netw Open. 2022 Jul 1;5 7):e2221699. Open https://web.pathway.md/diseases/recKDAkqHsIVEC2Ux 2/3 6/23/23, 2:01 AM Acute otitis externa Pathway https://web.pathway.md/diseases/recKDAkqHsIVEC2Ux 3/3

Guideline sources The following summarized guidelines for the evaluation and management of acute otitis media (AOM) are prepared by our editorial team based on guidelines from the American Academy of Otolaryngology-Head and Neck Surgery Foundation (AAO-HNSF 2022), the Italian Society of Pediatrics (ISP 2019), the Danish Society of Otorhinolaryngology, Head and Neck Surgery (DSOHH/DHMA 2016), and the American Academy of Pediatrics (AAP/AAFP 2013). 1 2 3 4 5 6 7 7 8 Definition AOM is defined as an infection of the middle ear space. 6 Epidemiology AOM is mostly caused by bacteria (S. pneumoniae, H. influenzae, Moraxella catarrhalis) followed by viruses. 7 Disease course https://web.pathway.md/diseases/recrzrleSMkm8ym6n 1/6 6/23/23, 2:02 AM Acute otitis media Pathway The inflammatory disease due to middle ear space infection with particular involvement of the tympanic membrane results in AOM, which presents with clinical presentations of earache, otorrhea, headache, fever, general malaise, and hearing impairment. AOM is a self-limiting condition. 8 Prognosis and risk of recurrence AOM is not associated with an increase in mortality. 7 Guidelines 1. Screening and diagnosis Diagnostic criteria: As per ISP 2019 guidelines, view the sole presence of otorrhea, not secondary to external otitis, associated with spontaneous perforation of the tympanic membrane as a certain objective sign of AOM. A As per AAFP 2013 guidelines, diagnose AOM in children who present with moderate-to-severe bulging of the tympanic membrane, or new onset of otorrhea not due to acute otitis externa. B 2. Diagnostic investigations Clinical assessment: As per AAO-HNSF 2022 guidelines, assess whether the pediatric patient with recurrent otitis media with effusion of any duration is at increased risk for speech, language, or learning problems from otitis media because of baseline sensory, physical, cognitive, or behavioral factors. B As per ISP 2019 guidelines, assess for the presence and degree of signs and symptoms (including fever, pain, irritability, otorrhea, tympanic membrane hyperemia, bulging, and mobility) in all patients. B Tympanic membrane assessment: As per ISP 2019 guidelines, examine the tympanic membrane for hyperemia, bulging, and mobility in all patients. B Show 4 more As per DHMA 2016 guidelines, examine the mobility of the tympanic membrane by pneumatic otoscopy or tympanometry when diagnosing AOM. B 3. Medical management Analgesics: As per ISP 2019 guidelines: https://web.pathway.md/diseases/recrzrleSMkm8ym6n 2/6 6/23/23, 2:02 AM Acute otitis media Pathway Prioritize assessment and treatment of otalgia in patients with AOM. Administer adequate doses of ibuprofen or acetaminophen. A Do not use topical analgesic drops or analgesic preparations based on natural extracts due to the lack of available high-quality evidence. D As per AAFP 2013 guidelines, assess for pain as part of the management of AOM, and offer analgesic treatment if present. B Systemic antibiotics, indications, young children: As per ISP 2019 guidelines, initiate antibiotic therapy in < 6 months old patients with AOM and in all pediatric patients with otorrhea, intracranial complications, and/or a history of recurrence. Show 2 more As per DHMA/DSOHH 2016 guidelines, offer close observation without prescribing antibiotics in preschool-aged patients with symptoms of AOM without middle ear effusion. E As per AAP/AAFP 2013 guidelines, initiate antibiotic therapy in 6 months old patients with AOM (bilateral or unilateral) with severe signs or symptoms, including: moderate or severe otalgia duration of otalgia 48 hours temperature > 39 C. B Show 2 more Systemic antibiotics, indications, older children: As per ISP 2019 guidelines, consider offering a watchful waiting approach on a case-by-case basis in > 2 years old patients with mild or severe unilateral AOM or mild bilateral AOM, if follow- up is possible within 48-72 hours. B As per AAP/AAFP 2013 guidelines: Initiate antibiotic therapy, or offer observation with close follow-up based on joint decision- making with the parent/caregiver, in 24 months old patients with AOM without severe signs or symptoms. B Ensure follow-up when observation is used as an initial strategy with the initiation of antibiotic therapy when the patient worsens or fails to improve within 48-72 hours of the onset of symptoms. B Systemic antibiotics, regimens: As per ISP 2019 guidelines, administer amoxicillin at a dose of 80-90 mg/kg/day (divided into 3 doses) in pediatric patients with uncomplicated AOM with mild signs and symptoms in the absence of risk factors for bacterial resistance and with no history of recurrence. A Show 7 more As per AAP/AAFP 2013 guidelines: Adminsiter amoxicillin as first-line therapy in patients with uncomplicated AOM in the absence of penicillin allergy, recent treatment with amoxicillin, and purulent conjunctivitis. B Administer an antibiotic with additional -lactamase coverage in patients meeting any of the following criteria: https://web.pathway.md/diseases/recrzrleSMkm8ym6n 3/6 6/23/23, 2:02 AM Acute otitis media Pathway receipt of amoxicillin in the last 30 days presence of concurrent purulent conjunctivitis history of recurrent AOM unresponsive to amoxicillin. B Topical antibiotics: do not use topical antibiotics (with or without corticosteroids) except in patients with tympanostomy tubes. D Decongestants: avoid using systemic or topical decongestants in patients with AOM. D Corticosteroids: avoid using systemic or topical corticosteroids in patients with AOM. D 4. Nonpharmacologic interventions Nasal irrigation: consider performing nasal lavage to remove nasal secretions as a complementary therapeutic measure. C 5. Therapeutic procedures Cerumen removal: consider removing the cerumen from the external auditory canal, performed by an appropriately trained pediatrician or by an otolaryngologist, with various operational and organizational methods depending on the care setting, the level of the practitioner's expertise, and the instruments available. C 6. Surgical interventions Tympanostomy: As per AAO-HNSF 2022 guidelines, offer bilateral tympanostomy tube insertion in pediatric patients with recurrent AOM with unilateral or bilateral middle ear effusion at the time of assessment for tube candidacy. B Show 2 more As per DHMA 2016 guidelines, consider offering ventilating tube insertion in preschool-aged patients with recurrent AOM, with or without middle ear effusion between AOM episodes. C As per AAFP 2013 guidelines, consider offering tympanostomy tubes for children with recurrent AOM (3 episodes in 6 months, or 4 episodes in 1 year with 1 episode occurring in the preceding 6 months). C Adenoidectomy: As per AAO-HNSF 2022 guidelines, consider performing adenoidectomy as an adjunct to tympanostomy tube insertion in pediatric patients with symptoms directly related to the adenoids (adenoid infection or nasal obstruction) or in 4 years old patients to potentially reduce future incidence of recurrent otitis media or the need for repeat tube insertion. C As per DHMA 2016 guidelines, consider offering adjuvant adenoidectomy after careful consideration in preschool-aged patients scheduled for first time ventilation tube insertion for https://web.pathway.md/diseases/recrzrleSMkm8ym6n 4/6 6/23/23, 2:02 AM Acute otitis media Pathway recurrent AOM. C 7. Patient education Assessment of treatment response: reassess patients in whom symptoms worsen or fail to respond to initial antibiotic treatment within 48-72 hours, and determine whether a change in therapy is needed. B 8. Preventative measures Routine immunizations: Provide influenza immunization on an annual basis to all children, according to established national schedules. B Provide pneumococcal immunization to all children, according to established national schedules. B Breastfeeding: encourage exclusive breastfeeding for at least 6 months to prevent AOM in infants. B Avoidance of smoke exposure: encourage avoidance of tobacco smoke exposure to prevent AOM. B Prophylactic antibiotics: avoid prescribing prophylactic antibiotics to reduce the frequency of episodes of AOM in children with recurrent AOM. D References 1. Richard M Rosenfeld, David E Tunkel, Seth R Schwartz et al. Clinical Practice Guideline: Tympanostomy Tubes in Children Update). Otolaryngol Head Neck Surg. 2022 Feb;166 1_suppl):S1 S55. Open 2. Paola Marchisio, Luisa Galli, Barbara Bortone et al. Updated Guidelines for the Management of Acute Otitis Media in Children by the Italian Society of Pediatrics: Treatment. Pediatr Infect Dis J. 2019 Dec;38 12S Suppl):S10 S21. Open 3. C H Heidemann, J Lous, J Berg et al. Danish guidelines on management of otitis media in preschool children. Int J Pediatr Otorhinolaryngol. 2016 Aug;87 154 63. Open 4. Lieberthal AS, Carroll AE, Chonmaitree T et al. The diagnosis and management of acute otitis media. Pediatrics. 2013 Mar;131 3):e964 99. Open 5. Elena Chiappini, Martina Ciarci , Barbara Bortone et al. Updated Guidelines for the Management of Acute Otitis Media in Children by the Italian Society of Pediatrics: Diagnosis. Pediatr Infect Dis J. 2019 Dec;38 12S Suppl):S3 S9. Open 6. Amina Danishyar, John V. Ashurst. Acute Otitis Media. StatPearls Internet]. Treasure Island FL StatPearls Publishing; 2020 Jan. 2020 Nov 22. Open 7. Graham Worrall. Acute otitis media. 2007 Dec;53 12 2147 8.2007 Dec;53 12 2147 8. Open https://web.pathway.md/diseases/recrzrleSMkm8ym6n 5/6 6/23/23, 2:02 AM Acute otitis media Pathway 8. Jan Peter Thomas, Reinhard Berner, Thomas Zahnert et al. Acute otitis media a structured approach. 2014 Feb 28;111 9 151 9; quiz 160.2014 Feb 28;111 9 151 9; quiz 160. Open 9. American Association of Family Physicians. Choosing Wisely AAFP recommendations. Choosing Wisely. 2013. Open 10. Roger Zoorob, Mohamad A Sidani, Richard D Fremont et al. Antibiotic use in acute upper respiratory tract infections. Am Fam Physician. 2012 Nov 1;86 9 817 22. Open https://web.pathway.md/diseases/recrzrleSMkm8ym6n 6/6

Guideline sources The following summarized guidelines for the evaluation and management of acute pain are prepared by our editorial team based on guidelines from the Center for Disease Control (CDC 2022), the United States Department of Defense (DoD/VA 2022), and the European Society for Emergency Medicine (EUSEM 2020). 1 2 3 4 Calculator Calculator Calculator FLACC Scale for assessment of FLACC R Scale for assessment Pain asses Guidelines 1. Diagnostic investigations Clinical examination: review observed signs of pain alongside patient self-reports, including HR, respiratory rate, facial expressions, or patient expressions of pain (such as groaning). Use these https://web.pathway.md/diseases/recDXw6lDrVx6e4eb 1/5 6/23/23, 2:02 AM Acute pain Pathway observations in conjunction with the patient's own evaluation, as alone those can under- or overestimate pain intensity. B Assessment scales: use a patient self-reporting scale that works within the clinical environment and with the patient's ability. A Show 6 more 2. Medical management General principles: Consider using multimodal analgesia, an approach involving the combination of opioid and non- opioid analgesics acting at different sites within the pain pathway to provide an additive or synergistic effect, to optimize outcomes in the treatment of patients with acute pain, reduce opioid-related side effects and prevent chronic pain. C Administer rapidly acting IV agents in small doses at frequent intervals until pain relief is achieved to allow the determination of the patient's individual requirements before long-acting medications or patient-controlled analgesia are initiated. B Non-opioid analgesics (paracetamol): Recognize that pain management with PO paracetamol in patients with acute blunt minor musculoskeletal extremity trauma, B traumatic or inflammatory pain to the extremities when used in combination with codeine, B acute musculoskeletal pain, B and pain caused by ankle sprain B is at least as effective as with NSAIDs; and IV paracetamol has similar analgesic effects to IV morphine in patients with isolated limb trauma. B Recognize that both PO and IV formulations of paracetamol provide significant pain reduction at 30 minutes when used in the emergency department. B Non-opioid analgesics (nonsteroidal anti-inflammatory drugs): recognize that NSAIDs such as ibuprofen, diclofenac, ketoprofen and naproxen are commonly used in both the pre-hospital and emergency department settings for mild-to-moderate pain, particularly with an inflammatory component, and are most commonly administered PO, IV or topically; they remain the preferred analgesic in renal colic, with observed equivalence to opioid or opioid-paracetamol combined analgesia at 30 minutes B , and effective analgesia in fracture. B Show 3 more Non-opioid analgesics (dipyrone): recognize that dipyrone is used differently across Europe, rare in some and widely used in others. Recognize that its use is limited due to its association with life-threatening blood disorders such as agranulocytosis, which are thought to have a possible association with patient ethnicity, and so its use must be weighed against these risks. Recognize that it can be administered PO, IV or subcutaneous and has demonstrated efficacy in patients with renal colic, acute pain due to pancreatitis B , and primary headache - episodic tension-type headache. A Opioids: As per CDC 2022 guidelines, consider initiating opioid therapy for acute if the benefits are anticipated to outweigh the risks to the patient and only after maximization of nonpharmacologic https://web.pathway.md/diseases/recDXw6lDrVx6e4eb 2/5 6/23/23, 2:02 AM Acute pain Pathway and nonopioid pharmacologic therapies. Discuss the realistic benefits and known risks of opioid therapy with patients before prescribing opioid therapy for acute pain. C Show 4 more As per VA 2022 guidelines: Consider screening for pain catastrophizing and co-occurring behavioral health conditions in patients with acute pain when considering opioid therapy, to identify patients at higher risk for negative outcomes as these conditions are associated with a higher risk of harm. C Do not prescribe long-acting opioids for acute pain. D Ketamine: Recognize that ketamine: is administered IV, intramuscular or intranasal provides analgesia at sub-dissociative doses is as effective as morphine, which may be opioid sparing, and with a faster onset of action a number of studies have been carried out which support its use. B Show 2 more Inhaled analgesics (nitrous oxide): recognize that nitrous oxide has demonstrated significant analgesia of NRS 3 at 15 minutes, B and sustained significant reductions in pain scores at 20 minutes associated with high levels of patient and nurse satisfaction in pre-hospital and emergency department settings. B Inhaled analgesics (methoxyfurane): recognize that methoxyfurane has been suggested to be effective and well-tolerated in patients with trauma and visceral pain, with a rapid onset of analgesia, B but in visceral pain overall analgesia was lower than that seen with fentanyl. Recognize that methoxyfurane has been suggested to be effective for analgesia in the majority of pediatric patients but was less effective than morphine and fentanyl in terms of reducing pain score by 30% overall. B 3. Nonpharmacologic interventions Attentional control: advise attention control methods including distraction techniques, concentration and focus on external stimuli using music, imagery, controlled breathing, breastfeeding for infants and play for adult and pediatric patients B . Recognize that virtual reality is emerging as a potential technique to occupy patients. A Cold and heat therapy: Advise applying cold (cryotherapy) for reducing pain, edema, inflammation, and muscle spasm. B Advise applying heat for relieving pain and increasing blood flow and elasticity of connective tissues. B Acupressure: offer acupressure (applying pressure to specific relaxation points) for reducing pain and anxiety during ambulance transport after minor trauma. A https://web.pathway.md/diseases/recDXw6lDrVx6e4eb 3/5 6/23/23, 2:02 AM Acute pain Pathway 4. Therapeutic procedures Transcutaneous electrical nerve stimulation: recognize that transcutaneous electrical nerve stimulation has demonstrated evidence from postoperative settings that it can significantly reduce analgesic requirements. A 5. Specific circumstances Patients with fractures: recognize that:. Show 7 more 6. Patient education General counseling: be aware that it is important to patients that clinicians recognize their patients' pain, acknowledge it, in doing so validate the patient's situation, and if feasible to empathize with the patient. B 7. Follow-up and surveillance Monitoring of analgesia: reassess patients once analgesia has been provided, to ensure that their pain is being successfully managed, and reassess their pain relief regimen regularly during their stay in the emergency department. B References 1. Sa d Hachimi-Idrissi, Viliam Dobias, Wolf E Hautz et al. Approaching acute pain in emergency settings; European Society for Emergency Medicine EUSEM guidelines-part 2 management and recommendations. Intern Emerg Med. 2020 Oct;15 7 1141 1155. Open 2. Sa d Hachimi-Idrissi, Frank Coffey, Wolf E Hautz et al. Approaching acute pain in emergency settings: European Society for Emergency Medicine EUSEM guidelines-part 1 assessment. Intern Emerg Med. 2020 Oct;15 7 1125 1139. Open 3. Deborah Dowell, Kathleen R Ragan, Christopher M Jones et al. CDC Clinical Practice Guideline for Prescribing Opioids for Pain United States, 2022. MMWR Recomm Rep. 2022 Nov 4;71 3 1 95. Open 4. Department of Defense/Veterans Affairs. VA/DoD CLINICAL PRACTICE GUIDELINE FOR THE USE OF OPIOIDS IN THE MANAGEMENT OF CHRONIC PAIN. VA/DoD. 2022 May. Open 5. Schwenk ES, Viscusi ER, Buvanendran A et al. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Acute Pain Management From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med. 2018 Jul;43 5 456 466. Open https://web.pathway.md/diseases/recDXw6lDrVx6e4eb 4/5 6/23/23, 2:02 AM Acute pain Pathway 6. Kathleen S Romanowski, Joshua Carson, Kate Pape et al. American Burn Association Guidelines on the Management of Acute Pain in the Adult Burn Patient: A Review of the Literature, a Compilation of Expert Opinion, and Next Steps. J Burn Care Res. 2020 Nov 30;41 6 1129 1151. Open 7. Mohamed Habib Grissa, Houda Baccouche, Hamdi Boubaker et al. Acupuncture vs intravenous morphine in the management of acute pain in the ED. Am J Emerg Med. 2016 Nov;34 11 2112 2116. Open 8. S I Merkel, T Voepel-Lewis, J R Shayevitz et al. The FLACC a behavioral scale for scoring postoperative pain in young children. Pediatr Nurs. May-Jun 1997;23 3 293 7. Open 9. Shobha Malviya, Terri Voepel-Lewis, Constance Burke et al. The revised FLACC observational pain tool: improved reliability and validity for pain assessment in children with cognitive impairment. Paediatr Anaesth. 2006 Mar;16 3 258 65. Open https://web.pathway.md/diseases/recDXw6lDrVx6e4eb 5/5

Guideline sources The following summarized guidelines for the evaluation and management of acute pancreatitis are prepared by our editorial team based on guidelines from the American Society for Gastrointestinal Endoscopy (ASGE 2023; 2015), the World Society of Emergency Surgery (WSES 2019), the American Gastroenterological Association (AGA 2018), the Eastern Association for the Surgery of Trauma (EAST 2017), the Canadian Best Practice in General Surgery Group (BPIGS 2016), the American Society for Clinical Pathology (ASCP 2016), the European Association for the Study of the Liver (EASL 2016), and the American College of Gastroenterology (ACG 2013). 1 2 3 4 5 6 8 9 10 11 12 13 14 15 Definition Acute pancreatitis is a disease characterized by acute inflammation of the pancreas. 11 Epidemiology https://web.pathway.md/diseases/recaG49TSo0aGldQK 1/13 6/23/23, 2:02 AM Acute pancreatitis Pathway Acute pancreatitis is most frequently due to gallstones (40%) and alcohol (30%). Other minor causes include ERCP (5-10%), surgical complications (5-10%), drugs (< 5%), hypertriglyceridemia (2-5%), trauma (< 1%), infection (< 1%) and autoimmunity (< 1%). 13 Pathophysiology The incidence of acute pancreatitis ranges from 13 to 45 cases per 100,000 person-years. 12 Disease course In patients with acute pancreatitis, localized tissue damage causes activation of pro-inflammatory cytokines, leading to a systemic inflammatory response that can progress to multiple organ failure and early mortality. The compensatory release of anti-inflammatory mediators plays a role in causing increased susceptibility to septic complications, such as infected pancreatic necrosis, and contributes to late mortality. 14 Prognosis and risk of recurrence Mortality associated with acute pancreatitis is approximately 1-5%, and the recurrence rate is approximately 20%. 15 Calculator Calculator Calculator BISAP score for mortality in pan CT severity index for acute panc Determina Guidelines 1. Screening and diagnosis Diagnostic criteria: As per EASL 2016 guidelines, diagnose acute biliary pancreatitis in patients with upper abdominal pain, altered pancreatic and liver biochemical tests, and gallbladder and/or common bile duct stones. B As per ACG 2013 guidelines, diagnose acute pancreatitis in patients presenting with 2 of the following 3 criteria: abdominal pain consistent with the disease serum amylase and/or lipase > 3 times the ULN characteristic findings on abdominal imaging. B 2. Classification and risk stratification https://web.pathway.md/diseases/recaG49TSo0aGldQK 2/13 6/23/23, 2:02 AM Acute pancreatitis Pathway Risk assessment: As per WSES 2019 guidelines, consider using the new classification systems, the determinant- based and revised Atlanta classifications, for the diagnosis and assessment of severity of acute pancreatitis. B Show 3 more As per BPIGS 2016 guidelines: Calculate APACHE II scores on admission and daily thereafter for the first 72 hours after admission. B Diagnose severe acute pancreatitis in patients meeting any of the following criteria: CRP 14,286 nmol/L (150 mg/dL) at baseline or in the first 72 hours APACHE II score 8 at baseline or in the first 72 hours signs of persistent organ failure for > 48 hours despite adequate IV fluid resuscitation. B As per ACG 2013 guidelines: Categorize patients into higher- and lower-risk categories to assist triage in situations such as admission to an intensive care setting. B Admit patients with organ failure to the ICU or intermediary care setting. B 3. Diagnostic investigations Serum lipase and amylase: As per WSES 2019 guidelines, use 3 times the upper limit as the cut-off value of serum amylase and lipase. As per ASCP 2016 guidelines, obtain serum lipase rather than amylase in patients with suspected acute pancreatitis. B As per BPIGS 2016 guidelines, obtain serum lipase in all patients with suspected acute pancreatitis. B C-reactive protein: As per WSES 2019 guidelines, consider using CRP level 150 mg/L at the third day as a prognostic factor for severe acute pancreatitis. B As per BPIGS 2016 guidelines, obtain CRP at admission and daily for the first 72 hours after admission. B Additional laboratory tests: Recognize that: hematocrit > 44% represents an independent risk factor of pancreatic necrosis B urea > 20 mg/dL represents an independent predictor of mortality B procalcitonin is the most sensitive laboratory test for detection of pancreatic infection, and low serum values are strong negative predictors of infected pancreatic necrosis. B Abdominal imaging, ultrasound: As per WSES 2019 guidelines: https://web.pathway.md/diseases/recaG49TSo0aGldQK 3/13 6/23/23, 2:02 AM Acute pancreatitis Pathway Obtain abdominal ultrasound on admission to determine the possible biliary etiology of acute pancreatitis. B Obtain two ultrasound examinations to rule out biliary etiology in patients with idiopathic pancreatitis to prevent recurrent pancreatitis. B As per BPIGS 2016 guidelines, obtain abdominal ultrasound in all patients at baseline to evaluate the biliary tract and the presence of gallstones and/or a stone in the common bile duct. A As per ACG 2013 guidelines, obtain abdominal ultrasound in all patients with acute pancreatitis. B Abdominal imaging, computed tomography/magnetic resonance imaging: As per WSES 2019 guidelines: Obtain CT to provide good evidence of the presence or absence of pancreatitis, when doubt exists. B Obtain contrast-enhanced CT or MRI in all patients with severe acute pancreatitis. Obtain the first contrast-enhanced CT optimally 72-96 hours after onset of symptoms. B As per BPIGS 2016 guidelines, obtain abdominal CT in patients with: broad differential diagnosis that includes acute pancreatitis suspected local complication. B As per ACG 2013 guidelines, reserve contrast-enhanced CT and MRI of the pancreas for patients with unclear diagnosis or failing to improve clinically within the first 48-72 hours after hospital admission. B Magnetic resonance cholangiopancreatography/endoscopic ultrasound: As per WSES 2019 guidelines: Consider obtaining MRCP and/or EUS to screen for occult common bile duct stones in patients with acute pancreatitis of unknown etiology. B Obtain MRCP and/or EUS, if needed, to prevent recurrent pancreatitis in patients with idiopathic pancreatitis. B As per BPIGS 2016 guidelines, obtain MRCP only in patients with elevation of liver enzymes if the common bile duct is either not visualized adequately or is found to be normal on ultrasound. A As per ACG 2013 guidelines, obtain MRCP or EUS instead of diagnostic ERCP to screen for choledocholithiasis, if highly suspected, in patients with acute pancreatitis in the absence of cholangitis and jaundice. B Evaluation for underlying cause: As per WSES 2019 guidelines, obtain serum triglyceride and calcium levels in patients with acute pancreatitis in the absence of gallstones or significant history of alcohol use. Recognize that serum triglyceride levels > 11.3 mmol/L (1,000 mg/dL) indicate it as the etiology. B As per ACG 2013 guidelines, obtain serum triglycerides in patients with suspected acute pancreatitis in the absence of gallstones and/or significant history of alcohol use. Suspect that https://web.pathway.md/diseases/recaG49TSo0aGldQK 4/13 6/23/23, 2:02 AM Acute pancreatitis Pathway hypertriglyceridemia is the cause of pancreatitis at triglyceride levels > 1,000 mg/dL. B Show 2 more 4. Diagnostic procedures Endoscopic retrograde cholangiopancreatography: As per AGA 2018 guidelines, avoid performing urgent ERCP routinely in patients with acute biliary pancreatitis and no cholangitis. D As per ASGE 2015 guidelines, perform ERCP in patients with acute biliary pancreatitis with concomitant cholangitis or biliary obstruction. A Show 2 more As per ACG 2013 guidelines, limit the use of endoscopic investigations in patients with acute idiopathic pancreatitis because of unclear risks and benefits. B Aspiration of peripancreatic fluid collections: As per WSES 2019 guidelines, consider performing CT guided FNA for Gram stain and culture to confirm an infected severe acute pancreatitis and drive antibiotic therapy, but recognize that it is no longer in routine use. B As per BPIGS 2016 guidelines, observe patients with acute peripancreatic fluid collections in the absence of radiological or clinical suspicion of infection, and avoid image-guided FNA owing to the risk of introducing infection into a sterile collection. B As per ACG 2013 guidelines, explore the possibility of infected necrosis in patients with pancreatic or extrapancreatic necrosis deteriorating or failing to improve after 7-10 days of hospitalization. Obtain initial CT-guided FNA for Gram stain and culture to guide use of appropriate antibiotics. Alternatively, start empirical antibiotics without CT-guided FNA. B 5. Respiratory support Mechanical ventilation: Perform mechanical ventilation if oxygen supply, even with high flow nasal oxygen, or CPAP are ineffective in correcting tachypnea and dyspnea in patients with acute pancreatitis. B Use either noninvasive or invasive techniques for mechanical ventilation. Use invasive ventilation when bronchial secretions clearance start to be ineffective and/or the patient is tiring or predicted to tire. Follow lung-protective strategies when invasive ventilation is needed. B 6. Medical management Setting of care, intensive care unit: As per WSES 2019 guidelines: Admit patients with acute pancreatitis and organ failures to an ICU whenever possible. B https://web.pathway.md/diseases/recaG49TSo0aGldQK 5/13 6/23/23, 2:02 AM Acute pancreatitis Pathway Obtain continuous monitoring of vital signs in high dependency care units if organ dysfunction occurs in patients with acute pancreatitis. Admit patients with persistent organ dysfunction or organ failure despite adequate fluid resuscitation to an ICU. B As per BPIGS 2016 guidelines, evaluate the need for transfer to a monitored unit in patients with severe acute pancreatitis, as evidenced by: APACHE II score > 8 CRP > 150 mg/dL presence of or evolving organ dysfunction need for aggressive, ongoing fluid resuscitation. B Setting of care, tertiary care: As per BPIGS 2016 guidelines, refer high-risk patients (extensive necrotizing pancreatitis, lack of clinical improvement) to institutions that have on-site or access to therapeutic endoscopy, interventional radiology, surgeons and intensivists with expertise in dealing with severe acute pancreatitis. B As per ACG 2013 guidelines, refer patients with idiopathic pancreatitis to centers of expertise. B Supportive care, general principles: As per WSES 2019 guidelines, be cautious not to over-resuscitate patients with early severe acute pancreatitis and consider obtaining regular measurements of intra-abdominal pressure. B Show 2 more As per BPIGS 2016 guidelines, provide supportive care including resuscitation with isotonic IV fluids (Ringer's lactate), pain control, and mobilization as the mainstay of treatment for patients with mild acute pancreatitis. B As per ACG 2013 guidelines, assess hemodynamic status immediately upon presentation and begin resuscitative measures as needed. B Supportive care, fluid therapy: As per WSES 2019 guidelines: Initiate early fluid resuscitation preferably with isotonic crystalloids in patients with severe acute pancreatitis to optimize tissue perfusion targets, without waiting for hemodynamic worsening. B Obtain frequent reassessment of the hemodynamic status to guide fluid administration, since fluid overload has detrimental effects. B Updated evidence: WATERFALL In adult patients who presented to the emergency department with acute pancreatitis, aggressive fluid resuscitation was not superior to moderate fluid resuscitation with respect to the development of moderately severe or severe pancreatitis. https://web.pathway.md/diseases/recaG49TSo0aGldQK 6/13 6/23/23, 2:02 AM Acute pancreatitis Pathway Enrique de-Madaria et al. N Engl J Med. 2022 Sep 15. As per AGA 2018 guidelines: Consider using goal-directed therapy for fluid management in patients with acute pancreatitis. C Consider avoiding the use of hydroxyethyl starch fluids in patients with acute pancreatitis. D As per ACG 2013 guidelines, provide aggressive IV hydration, defined as 250-500 mL/hour of isotonic crystalloid solution, in all patients in the first 12-24 hours, unless cardiovascular and/or renal comorbidities exist. B Show 3 more Supportive care (pain management): insufficient evidence to restrict any pain medication in patients with acute pancreatitis. I Show 3 more Antibiotic therapy: As per AGA 2018 guidelines, consider avoiding the use of prophylactic antibiotics in patients with predicted severe acute pancreatitis and necrotizing pancreatitis. D As per BPIGS 2016 guidelines, avoid using routine prophylactic antibiotics in patients with acute pancreatitis. D Show 3 more As per ACG 2013 guidelines, administer antibiotics for an extrapancreatic infection, such as cholangitis, catheter-acquired infections, bacteremia, UTIs, and pneumonia. A Show 4 more Specific pharmacotherapy: do not use any specific pharmacological therapy except for organ support and nutrition in patients with acute pancreatitis. D Management of pancreatic pseudocysts: As per BPIGS 2016 guidelines: Manage asymptomatic pancreatic pseudocysts nonoperatively. B Perform intervention for pseudocysts that are symptomatic, infected, or increasing in size on serial imaging. B 7. Nonpharmacologic interventions Nutrition support: As per WSES 2019 guidelines, provide enteral nutrition to prevent gut failure and infectious complications in patients with severe acute pancreatitis. A Show 2 more As per AGA 2018 guidelines, start oral feeding within 24 hours as tolerated in patients with acute pancreatitis, rather than keeping the patient NPO. B As per AGA 2018 guidelines: https://web.pathway.md/diseases/recaG49TSo0aGldQK 7/13 6/23/23, 2:02 AM Acute pancreatitis Pathway Provide enteral rather than parenteral nutrition in patients with acute pancreatitis unable to feed PO. B Consider using either nasogastric or nasoenteral route in patients with predicted severe or necrotizing pancreatitis requiring enteral tube feeding. C As per BPIGS 2016 guidelines: Allow a regular diet on admission in patients with mild acute pancreatitis. A Allow patients to self-advance their diet from withholding oral food and liquid to a regular diet as tolerated if they initially are unable to tolerate an oral diet owing to abdominal pain, nausea, vomiting, or ileus. A As per ACG 2013 guidelines, consider starting oral feeds immediately in patients with mild acute pancreatitis if there is no nausea and vomiting, and abdominal pain has resolved. C Show 3 more Brief intervention for alcohol misuse: implement a brief alcohol intervention during admission in patients with acute alcoholic pancreatitis. B 8. Therapeutic procedures Endoscopic retrograde cholangiopancreatography, indications: As per WSES 2019 guidelines, do not perform routine ERCP in patients with acute gallstone pancreatitis. D Show 2 more As per BPIGS 2016 guidelines, perform ERCP within 24-48 hours in patients with acute gallstone pancreatitis associated with bile duct obstruction or cholangitis. B As per ACG 2013 guidelines: Perform ERCP within 24 hours of admission in patients with acute pancreatitis and concurrent acute cholangitis. B Avoid performing ERCP in patients with gallstone pancreatitis in the absence of laboratory or clinical evidence of ongoing biliary obstruction. D Percutaneous/endoscopic drainage: As per WSES 2019 guidelines: Perform percutaneous or endoscopic drainage in patients with clinical deterioration with signs or strong suspicion of infected necrotizing pancreatitis: 4 weeks after the onset of the disease: ongoing organ failure without signs of infected necrosis; ongoing gastric outlet, biliary, or intestinal obstruction due to a large walled off necrotic collection; disconnected duct syndrome; symptomatic or growing pseudocyst 8 weeks after the onset of the disease: ongoing pain and/or discomfort. B Perform percutaneous drainage as first-line treatment (step-up approach) in patients with infected pancreatic necrosis, as it delays the surgical treatment to a more favorable time or even results in complete resolution of infection in 25-60% of patients. A https://web.pathway.md/diseases/recaG49TSo0aGldQK 8/13 6/23/23, 2:02 AM Acute pancreatitis Pathway As per BPIGS 2016 guidelines, consider performing percutaneous transhepatic gallbladder drainage in unstable patients with severe acute gallstone pancreatitis and associated bile duct obstruction or cholangitis, if ERCP is not safely feasible. B Endoscopic retrograde cholangiopancreatography, prevention of post-ERCP pancreatitis: As per ASGE 2023 guidelines, administer periprocedural rectal NSAIDs for the prevention of post-ERCP pancreatitis in unselected and high-risk patients undergoing ERCP. B Show 4 more As per ACG 2013 guidelines, perform pancreatic duct stenting and/or administer postprocedural rectal NSAID suppositories to prevent severe pancreatitis after ERCP in high-risk patients. B 9. Surgical interventions General principles: As per WSES 2019 guidelines, perform surgical intervention as a continuum in a step-up approach after percutaneous/endoscopic procedure with the same indications, or in patients with any of the following: abdominal compartment syndrome acute ongoing bleeding if endovascular approach is unsuccessful bowel ischemia or acute necrotizing cholecystitis during acute pancreatitis bowel fistula extending into a peripancreatic collection. B Show 3 more As per ACG 2013 guidelines, delay surgical, radiologic and/or endoscopic drainage preferably for > 4 weeks in stable patients with infected pancreatic necrosis to allow liquefaction of the contents and the development of a fibrous wall around the necrosis (walled-off necrosis). B Cholecystectomy: As per WSES 2019 guidelines, perform laparoscopic cholecystectomy during the index admission in patients with mild acute gallstone pancreatitis. A Show 2 more As per AGA 2018 guidelines, perform cholecystectomy in patients with acute biliary pancreatitis during the initial admission rather than after discharge. B As per BPIGS 2016 guidelines: Perform cholecystectomy during the index admission in patients with mild acute pancreatitis. B Delay cholecystectomy until clinical resolution in patients with severe acute pancreatitis. B As per ACG 2013 guidelines: Perform cholecystectomy in patients with mild acute pancreatitis prior to discharge, if they have gallstones in the gallbladder. B Defer cholecystectomy in patients with necrotizing biliary acute pancreatitis until active inflammation subsides and fluid collections resolve or stabilize. B https://web.pathway.md/diseases/recaG49TSo0aGldQK 9/13 6/23/23, 2:02 AM Acute pancreatitis Pathway Pancreatic necrosectomy: As per WSES 2019 guidelines: Recognize that minimally invasive surgical strategies, such as transgastric endoscopic necrosectomy or video-assisted retroperitoneal debridement, result in less postoperative new- onset organ failure but require more interventions. B Consider performing single-stage surgical transgastric necrosectomy as an option in selected patients with walled-off necrosis or with disconnected pancreatic duct. C As per EAST 2017 guidelines, delay pancreatic necrosectomy until at least day 12 in adult patients with pancreatic necrosis. B Show 2 more As per ACG 2013 guidelines, perform minimally invasive methods of necrosectomy rather than open necrosectomy in symptomatic patients with infected pancreatic necrosis. B Landmark trials: PANTER In patients with necrotizing pancreatitis and suspected or confirmed infected necrotic tissue, a step-up approach to management of pancreatic necrosis were superior to primary open necrosectomy with respect to death or major complications. van Santvoort HC et al. N Engl J Med. 2010 Apr 22. Open abdomen: consider performing surgical decompression and leaving the abdomen open for the treatment of abdominal compartment syndrome in patients with severe acute pancreatitis unresponsive to conservative management of intra-abdominal hypertension/abdominal compartment syndrome. C Show 7 more 10. Follow-up and surveillance Follow-up imaging: As per WSES 2019 guidelines: Obtain follow-up contrast-enhanced CT after 7-10 days from the initial CT in patients with severe acute pancreatitis (CT severity index 3). B Obtain additional contrast-enhanced CT only if clinical status deteriorates or fails to show continued improvement, or when invasive intervention is considered. B As per BPIGS 2016 guidelines, obtain follow-up abdominal CT as dictated by clinical assessment, rather than at set intervals. B Likelihood Ratios https://web.pathway.md/diseases/recaG49TSo0aGldQK 10/13 6/23/23, 2:02 AM Acute pancreatitis Pathway Pertinent positives The following findings increase the probability of acute pancreatitis in adults. 1 1 1 Finding LR+ Value Increased serum lipase (> 3x ULN) 99 Presence of findings of acute pancreatitis 52 Presence of findings of acute pancreatitis 36 Increased serum ALT (> 150 units/L) 12 Show 2 more Pertinent negatives The following findings decrease the probability of acute pancreatitis in adults. 1 1 1 Finding LR- Value serum lipase not increased ( 3x ULN) 0.01 serum immunoreactive trypsinogen not increased 0.04 serum amylase not increased ( 300 units/mL) 0.06 Absence of findings of acute pancreatitis 0.29 Show 2 more References 1. Tenner S, Baillie J, DeWitt J et al. American College of Gastroenterology guideline: management of acute pancreatitis. Am J Gastroenterol. 2013 Sep;108 9 1400 15; 1416. Open 2. Greenberg JA, Hsu J, Bawazeer M et al. Clinical practice guideline: management of acute pancreatitis. Can J Surg. 2016 Apr;59 2 128 40. Open 3. Lepp niemi A, Tolonen M, Tarasconi A et al. 2019 WSES guidelines for the management of severe acute pancreatitis. World J Emerg Surg. 2019 Jun 13;14 27. Open 4. Crockett SD, Wani S, Gardner TB et al. American Gastroenterological Association Institute Guideline on Initial Management of Acute Pancreatitis. Gastroenterology. 2018 Mar;154 4 1096 1101. Open 5. American Society for Clinical Pathology. Choosing Wisely ASCP recommendations. Choosing Wisely. 2016. Open 6. Mowery NT, Bruns BR, MacNew HG et al. Surgical management of pancreatic necrosis: A practice management guideline from the Eastern Association for the Surgery of Trauma. J Trauma Acute Care Surg. 2017 Aug;83 2 316 327. Open 7. Stephan C Bischoff, Johann Ockenga, Ahad Eshraghian et al. Practical guideline on obesity care in patients with gastrointestinal and liver diseases Joint ESPEN/UEG guideline. Clin Nutr. 2023 Apr 10;42 6 987 1024. Open 8. ASGE Standards of Practice Committee, Krishnavel V Chathadi, Vinay Chandrasekhara et al. The role of ERCP in benign diseases of the biliary tract. Gastrointest Endosc. 2015 Apr;81 4 795 803. Open https://web.pathway.md/diseases/recaG49TSo0aGldQK 11/13 6/23/23, 2:02 AM Acute pancreatitis Pathway 9. James L Buxbaum, Martin Freeman, Stuart K Amateau et al. American Society for Gastrointestinal Endoscopy guideline on post-ERCP pancreatitis prevention strategies: summary and recommendations. Gastrointest Endosc. 2023 Feb;97 2 153 162. Open 10. EASL. EASL Clinical Practice Guidelines on the prevention, diagnosis and treatment of gallstones. J Hepatol. 2016 Jul;65 1 146 181. Open 11. Johnson CD, Besselink MG, Carter R. Acute pancreatitis. BMJ. 2014 Aug 12;349:g4859. Open 12. Yadav D, Lowenfels AB. The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology. 2013 Jun;144 6 1252 61. Open 13. Forsmark CE, Vege SS, Wilcox CM. Acute Pancreatitis. N Engl J Med. 2016 Nov 17;375 20 1972 1981. Open 14. Minkov GA, Halacheva KS, Yovtchev YP et al. Pathophysiological mechanisms of acute pancreatitis define inflammatory markers of clinical prognosis. Pancreas. 2015 Jul;44 5 713 7. Open 15. Krishna SG, Kamboj AK, Hart PA et al. The Changing Epidemiology of Acute Pancreatitis Hospitalizations: A Decade of Trends and the Impact of Chronic Pancreatitis. Pancreas. 2017 Apr;46 4 482 488. Open 16. Olaf J Bakker, Sandra van Brunschot, Hjalmar C van Santvoort et al. Early versus on-demand nasoenteric tube feeding in acute pancreatitis. N Engl J Med. 2014 Nov 20;371 21 1983 93. Open 17. Peter A Banks, Thomas L Bollen, Christos Dervenis et al. Classification of acute pancreatitis 2012 revision of the Atlanta classification and definitions by international consensus. Gut. 2013 Jan;62 1 102 11. Open 18. E Patchen Dellinger, Christopher E Forsmark, Peter Layer et al. Determinant-based classification of acute pancreatitis severity: an international multidisciplinary consultation. Ann Surg. 2012 Dec;256 6 875 80. Open 19. E J Balthazar, D L Robinson, A J Megibow et al. Acute pancreatitis: value of CT in establishing prognosis. Radiology. 1990 Feb;174 2 331 6. Open 20. Maisam Abu-El-Haija, Aliye Uc, Steven L Werlin et al. Nutritional Considerations in Pediatric Pancreatitis: A Position Paper from the NASPGHAN Pancreas Committee and ESPGHAN Cystic Fibrosis/Pancreas Working Group. J Pediatr Gastroenterol Nutr. 2018 Jul;67 1 131 143. Open 21. Marianna Arvanitakis, Jean-Marc Dumonceau, J rg Albert et al. Endoscopic management of acute necrotizing pancreatitis: European Society of Gastrointestinal Endoscopy ESGE evidence-based multidisciplinary guidelines. Endoscopy. 2018 May;50 5 524 546. Open 22. Samir Jaber, Marc Garnier, Karim Asehnoune et al. Guidelines for the management of patients with severe acute pancreatitis, 2021. Anaesth Crit Care Pain Med. 2022 Jun;41 3 101060. Open 23. Enrique de-Madaria, James L Buxbaum, Patrick Maisonneuve et al. Aggressive or Moderate Fluid Resuscitation in Acute Pancreatitis. N Engl J Med. 2022 Sep 15;387 11 989 1000. Open 24. Tram T Tran, Joseph Ahn, Nancy S Reau. ACG Clinical Guideline: Liver Disease and Pregnancy. Am J Gastroenterol. 2016 Feb;111 2 176 94; quiz 196. Open 25. Maisam Abu-El-Haija, Soma Kumar, Jose Antonio Quiros et al. Management of Acute Pancreatitis in the Pediatric Population: A Clinical Report From the North American Society for Pediatric Gastroenterology, https://web.pathway.md/diseases/recaG49TSo0aGldQK 12/13 6/23/23, 2:02 AM Acute pancreatitis Pathway Hepatology and Nutrition Pancreas Committee. J Pediatr Gastroenterol Nutr. 2018 Jan;66 1 159 176. Open 26. Matthieu Jabaudon, Alexandra Genevrier, Samir Jaber et al. Thoracic epidural analgesia in intensive care unit patients with acute pancreatitis: the EPIPAN multicenter randomized controlled trial. Crit Care. 2023 May 31;27 1 213. Open 27. Todd H Baron, Christopher J DiMaio, Andrew Y Wang et al. American Gastroenterological Association Clinical Practice Update: Management of Pancreatic Necrosis. Gastroenterology. 2020 Jan;158 1 67 75.e1. Open https://web.pathway.md/diseases/recaG49TSo0aGldQK 13/13

Guideline sources The following summarized guidelines for the evaluation and management of acute pericarditis are prepared by our editorial team based on guidelines from the European Society of Cardiology (ESC/ESTRO/EHA/IC-OS 2022), the European Society for Microbiology and Infectious Diseases (ESCMID 2022), the Society of Cardiovascular Computed Tomography (SCCT/SCMR/AHA/SAEM/ASE/ACC/ACCP 2021), the Infectious Diseases Society of America (IDSA/ACR/AAN 2021), the Single Hub and Access Point for Pediatric Rheumatology in Europe (SHARE initiative 2019), the American Heart Association (AHA/ASA 2018), the Pan-American League of Associations of Rheumatology (PANLAR 2018), the European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases (ERN ReCONNET 2018), the Brazilian Society of Cardiology (BSC/ASE 2018), the European Society of Cardiology (ESC/EACTS 2015), the Wilderness Medical Society (WMS 2014), and the American Heart Association (AHA/ACC 2013). 1 2 3 4 6 7 9 10 11 12 13 14 15 16 16 17 17 Definition Acute pericarditis is a disease characterized by acute inflammation of the pericardium. 15 E id i l https://web.pathway.md/diseases/recyJEDIlWYQGdBVy 1/8 6/23/23, 2:02 AM Acute pericarditis Pathway Epidemiology Most cases of acute pericarditis are idiopathic (80-90%) and assumed to be due to viral infection. Other important causes include post-cardiac injury syndromes, connective tissue diseases (such as SLE), and cancer. 17 Pathophysiology In the United States, the incidence of acute pericarditis requiring hospitalization is estimated at 26 cases per 100,000 person-years. 16 Disease course Inflammation of the pericardium results in the formation of a pericardial effusion, which may progress to cardiac tamponade and obstructive shock. 17 Prognosis and risk of recurrence Acute pericarditis is associated with 5.7% all-cause mortality at 30 days, and 17.3% all-cause mortality at 1 year. 16 Calculator Calculator Calculator Diagnostic criteria for acute peri NYHA functional classification f Risk strati Guidelines 1. Screening and diagnosis Diagnostic criteria: make a clinical diagnosis of acute pericarditis in patients with 2 out of 4 suggestive clinical criteria (chest pain, pericardial rub, ECG changes, and pericardial effusion). 2. Diagnostic investigations Initial evaluation: assess for independent predictors of an identifiable and specifically treatable cause of pericarditis (such as bacterial, neoplastic, or systemic inflammatory diseases). B Show 3 more Transthoracic echocardiography: Obtain TTE in patients with acute chest pain with suspected pericardial effusion. Consider obtaining TTE to determine the presence of pericardial effusion or restrictive physiology in patients with acute chest pain and suspected myopericarditis. (COR : 1, LOE : C-EO). B https://web.pathway.md/diseases/recyJEDIlWYQGdBVy 2/8 6/23/23, 2:02 AM Acute pericarditis Pathway Obtain TTE to assess for pericardial effusion in intermediate-risk patients with acute chest pain. B Consider obtaining TTE to detect pericardial abnormalities in intermediate-high-risk patients with stable chest pain having Q waves, symptoms or signs suggestive of HF, or a heart murmur with an unclear diagnosis. B Cardiac MRI/CT: As per AHA 2021 guidelines, consider obtaining cardiac MRI with gadolinium contrast to distinguish myopericarditis from other causes, including myocardial infarction and nonobstructive coronary arteries, in patients with acute chest pain and myocardial injury having nonobstructive coronary arteries on anatomic testing. B Show 2 more As per ESC 2015 guidelines, obtain cardiac MRI for the confirmation of myocardial involvement in patients with suspected myopericarditis. B Show 2 more Evaluation for viral pericarditis: Do not obtain routine viral serologies, with the possible exception of human immunodeficiency virus and HCV testing. D Consider obtaining a comprehensive panel of histological, cytological, immunohistological, and molecular investigations in pericardial fluid and peri-/epicardial biopsies, for the definite diagnosis of viral pericarditis. C 3. Diagnostic procedures Coronary angiography: perform coronary angiography (according to clinical presentation and risk factor assessment) to rule out acute coronary syndromes in patients with pericarditis and suspected myocarditis. B Diagnostic pericardiocentesis: consider performing diagnostic pericardiocentesis in all patients with suspected tuberculous pericarditis. C Show 2 more Pericardial biopsy: consider performing percutaneous or surgical pericardial biopsy in selected patients with suspected or tuberculous pericarditis. C 4. Medical management Setting of care: Offer outpatient management in low-risk patients with acute pericarditis. B Admit high-risk patients with acute pericarditis to the hospital. B Admit patients with myocardial involvement to the hospital for diagnosis and monitoring. B Nonsteroidal anti-inflammatory drugs: Administer aspirin or NSAIDs as first-line therapy for acute pericarditis, in conjunction with prophylactic acid-suppressive therapy. A https://web.pathway.md/diseases/recyJEDIlWYQGdBVy 3/8 6/23/23, 2:02 AM Acute pericarditis Pathway Consider administering empirical anti-inflammatory therapies (lowest efficacious doses) to control chest pain. C Colchicine: administer colchicine (0.5 mg 1-2 times daily in patients < 70 kg or intolerant to higher doses) as first-line therapy for acute pericarditis as an adjunct to aspirin/NSAID therapy. A Landmark trials: ICAP In adults with acute pericarditis who were receiving conventional treatment, colchicine was superior to placebo with respect to incessant or recurrent pericarditis. Imazio M et al. N Engl J Med. 2013 Oct 17. Corticosteroids: Consider administering low-dose corticosteroids in patients with acute pericarditis in case of aspirin/NSAID and colchicine failure/contraindication or where there is a specific indication for corticosteroids (such as corticosteroid-responsive autoimmune diseases), if infectious causes have been excluded. C Do not use corticosteroids in patients with viral pericarditis. D Management of recurrent pericarditis: administer aspirin and NSAIDs (at full doses, if tolerated) for the treatment of recurrent pericarditis, continued until complete symptom resolution. A Show 5 more 5. Nonpharmacologic interventions Exercise restriction (simple pericarditis): Consider advising exercise restriction until resolution of symptoms and normalization of CRP, ECG, and echocardiogram in non-athletes with acute pericarditis. C Consider advising exercise restriction for at least 3 months and until resolution of symptoms and normalization of CRP, ECG, and echocardiogram in athletes with acute pericarditis. C Exercise restriction (myopericarditis): advise rest and avoidance of physical activity beyond normal sedentary activities for 6 months in non-athletes and athletes with myopericarditis. B 6. Specific circumstances Pediatric patients: administer NSAIDs at high doses as first-line therapy for acute pericarditis in pediatric patients until complete symptom resolution. B Show 4 more Patients with purulent pericarditis: perform effective pericardial drainage in patients with purulent pericarditis. B Show 3 more https://web.pathway.md/diseases/recyJEDIlWYQGdBVy 4/8 6/23/23, 2:02 AM Acute pericarditis Pathway Patients with uremic pericarditis: consider performing dialysis for the treatment of uremic pericarditis. C Show 4 more Patients with post-cardiac injury syndromes: As per ESC 2015 guidelines, consider administering colchicine after cardiac surgery using weight-adjusted doses (0.5 mg once in patients 70 kg; 0.5 mg BID in patients > 70 kg) and without a loading dose for the prevention of postpericardiotomy syndrome, if there are no contraindications and it is tolerated. Continue preventive administration of colchicine for 1 month. B Show 4 more As per AHA 2013 guidelines, administer aspirin in patients with pericarditis following STEMI. B Show 2 more Patients with radiation pericarditis: As per ESC 2022 guidelines, consider obtaining echocardiography surveillance every 5 years in patients after acute pericarditis developed during radiotherapy to a volume including the heart, as these patients are at higher risk of developing chronic constrictive pericarditis. C As per ESC 2015 guidelines, use radiation therapy methods reducing both the volume and the dose of cardiac irradiation, whenever possible, to reduce the risk of radiation pericarditis. B Patients chemotherapy-induced pericarditis: diagnose and manage acute pericarditis in patients with cancer according to current published guidelines for the diagnosis and management of pericardial diseases. Arrange a multidisciplinary discussion before interrupting cancer therapy. B Show 3 more Patients with neoplastic pericardial disease: obtain cytological analyses of pericardial fluid to confirm the malignant pericardial disease. B Show 5 more Patients with systemic lupus erythematosus: consider administering colchicine plus standard of care (hydroxychloroquine and corticosteroids) in patients with acute SLE-related pericarditis. C Patients with relapsing polychondritis: administer corticosteroids, conventional synthetic DMARDs, conventional immunosuppressive agents (such as methotrexate), or biologics in patients with relapsing polychondritis with pericardial involvement. E Patients with polyarteritis nodosa: consider obtaining an ECG and echocardiography for the identification of pericarditis, valve insufficiency, myocarditis, or coronary artery abnormalities in patients with polyarteritis nodosa. C Patients with Lyme disease: Test for Lyme disease in patients with acute myocarditis/pericarditis of unknown cause in an appropriate epidemiologic setting. B Hospitalize and obtain continuous ECG monitoring in patients with or at risk for severe cardiac complications of Lyme disease, including patients with clinical manifestations of myopericarditis. https://web.pathway.md/diseases/recyJEDIlWYQGdBVy 5/8 6/23/23, 2:02 AM Acute pericarditis Pathway B Patients with Chagas disease: suspect acute Chagas disease in patients with a febrile illness accompanied by myocarditis findings on echocardiography and/or pericardial fluid in endemic countries and in Latin American immigrants with immunosuppressed states living in nonendemic countries. Obtain echocardiography in patients with suspected acute Chagas disease. Recognize that hypotension may be a sign of hemodynamically significant pericardial effusion leading to cardiac tamponade. E Patients with lightning injury: counsel patients with lightning injury at discharge to return if they exhibit new chest pain or dyspnea because delayed or recurring cardiac injuries such as pericarditis or cardiomyopathy are possible. B Patients with long COVID: Consider obtaining a TTE in patients presenting with persistent symptoms suggestive of perimyocardial injury (chest pain, palpitations, signs and symptoms of HF) after COVID-19 inection. Consider repeating TTE at 2-3 months in patients with cardiac abnormalities during acute disease (myocarditis, pericarditis, HF). E Exclude other serious/life-threatening conditions including prior overlooked conditions (such as malignancy) and complications of acute COVID-19 (such as thromboembolic events, myopericarditis, and encephalitis) before diagnosing long COVID in symptomatic patients. Evaluate for other conditions guided by symptoms, signs, and other tests, obtained according to the physician's discretion. E Patients with acute ischemic stroke: Consider administering IV alteplase in patients with acute pericarditis and major acute ischemic stroke likely to produce severe disability. C Insufficient evidence to recommend administering IV alteplase in patients presenting with acute pericarditis and moderate acute ischemic stroke likely to produce mild disability. I 7. Follow-up and surveillance Follow-up: Schedule follow-up 1 week after treatment initiation, to assess response to anti-inflammatory therapy. B Consider obtaining echocardiography every 6-12 months after post-cardiac injury pericarditis, to exclude possible evolution towards constrictive pericarditis. C Likelihood Ratios Pertinent positives The following findings increase the probability of acute pericarditis in adults. -1 Finding LR+ Value https://web.pathway.md/diseases/recyJEDIlWYQGdBVy 6/8 6/23/23, 2:02 AM Acute pericarditis Pathway 78 Increased serum D-dimer Presence of PR depression or diffuse ST elevation 39 History of pleuritic chest pain relieved by sitting up 24 Presence of pericardial friction rub 9.0 Show 2 more Pertinent negatives The following findings decrease the probability of acute pericarditis in adults. -1 Finding LR- Value serum D-dimer not increased 0.22 No history of pleuritic chest pain 0.43 Absence of pericardial thickening 0.47 Absence of PR depression or diffuse ST elevation 0.62 Show 2 more References 1. Adler Y, Charron P, Imazio M et al. 2015 ESC Guidelines for the diagnosis and management of pericardial diseases: The Task Force for the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology ESC Endorsed by: The European Association for Cardio-Thoracic Surgery EACTS . Eur Heart J. 2015 Nov 7;36 42 2921 2964. Open 2. Nienke de Graeff, Noortje Groot, Paul Brogan et al. European consensus-based recommendations for the diagnosis and treatment of rare paediatric vasculitides - the SHARE initiative. Rheumatology Oxford). 2019 Apr 1;58 4 656 671. Open 3. 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 Mar;49 3):e46-e110. Open 4. Alexander R Lyon, Teresa L pez-Fern ndez, Liam S Couch et al. 2022 ESC Guidelines on cardio- oncology developed in collaboration with the European Hematology Association EHA , the European Society for Therapeutic Radiology and Oncology ESTRO and the International Cardio-Oncology Society IC OS . Eur Heart J Cardiovasc Imaging. 2022 Sep 10;23 10):e333-e465. Open 5. No authors listed. Guidelines for treatment of drug-susceptible tuberculosis and patient care. Geneva: World Health Organization; 2017. Open 6. Pons-Estel BA, Bonfa E, Soriano ER et al. First Latin American clinical practice guidelines for the treatment of systemic lupus erythematosus: Latin American Group for the Study of Lupus GLADEL, Grupo Latino Americano de Estudio del Lupus)-Pan-American League of Associations of Rheumatology PANLAR . Ann Rheum Dis. 2018 Jul 25. Open 7. Dana Yelin, Charalampos D Moschopoulos, Ili Margalit et al. ESCMID rapid guidelines for assessment and management of long COVID. Clin Microbiol Infect. 2022 Jul;28 7 955 972. Open 8. Payam Nahid, Susan E Dorman, Narges Alipanah et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: https://web.pathway.md/diseases/recyJEDIlWYQGdBVy 7/8 6/23/23, 2:02 AM Acute pericarditis Pathway Treatment of Drug-Susceptible Tuberculosis. Clin Infect Dis. 2016 Oct 1;63 7):e147-e195. Open 9. Martha Gulati, Phillip D Levy, Debabrata Mukherjee et al. 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2021 Nov 30;144 22):e368-e454. Open 10. Chris Davis, Anna Engeln, Eric L Johnson et al. Wilderness Medical Society practice guidelines for the prevention and treatment of lightning injuries: 2014 update. Wilderness Environ Med. 2014 Dec;25 4 Suppl):S86 95. Open 11. O'Gara PT, Kushner FG, Ascheim DD et al. 2013 ACCF/AHA guideline for the management of ST elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013 Jan 29;61 4):e78 140. Open 12. Simona Rednic, Laura Damian, Rosaria Talarico et al. Relapsing polychondritis: state of the art on clinical practice guidelines. RMD Open. 2018 Oct 18;4 Suppl 1):e000788. Open 13. Paul M Lantos, Jeffrey Rumbaugh, Linda K Bockenstedt et al. Clinical Practice Guidelines by the Infectious Diseases Society of America IDSA , American Academy of Neurology AAN , and American College of Rheumatology ACR 2020 Guidelines for the Prevention, Diagnosis, and Treatment of Lyme Disease. Arthritis Care Res Hoboken). 2021 Jan;73 1 1 9. Open 14. Harry Acquatella, Federico M Asch, Marcia M Barbosa et al. Recommendations for Multimodality Cardiac Imaging in Patients with Chagas Disease: A Report from the American Society of Echocardiography in Collaboration With the InterAmerican Association of Echocardiography ECOSIAC and the Cardiovascular Imaging Department of the Brazilian Society of Cardiology DIC SBC . J Am Soc Echocardiogr. 2018 Jan;31 1 3 25. Open 15. Tonini M, Melo DT, Fernandes F. Acute pericarditis. Rev Assoc Med Bras 1992 . 2015 Mar- Apr;61 2 184 90. Open 16. Mody P, Bikdeli B, Wang Y et al. Trends in acute pericarditis hospitalizations and outcomes among the elderly in the USA, 1999 2012. Eur Heart J Qual Care Clin Outcomes. 2018 Apr 1;4 2 98 105. Open 17. LeWinter MM. Clinical practice. Acute pericarditis. N Engl J Med. 2014 Dec 18;371 25 2410 6. Open 18. Barry J Maron, James E Udelson, Robert O Bonow et al. Eligibility and Disqualification Recommendations for Competitive Athletes With Cardiovascular Abnormalities: Task Force 3 Hypertrophic Cardiomyopathy, Arrhythmogenic Right Ventricular Cardiomyopathy and Other Cardiomyopathies, and Myocarditis: A Scientific Statement From the American Heart Association and American College of Cardiology. Circulation. 2015 Dec 1;132 22):e273 80. Open 19. Massimo Imazio, Alessandro Andreis, Marta Lubian et al. The Torino Pericarditis Score: a new-risk stratification tool to predict complicated pericarditis. Intern Emerg Med. 2021 Oct;16 7 1921 1926. Open https://web.pathway.md/diseases/recyJEDIlWYQGdBVy 8/8

Guideline sources The following summarized guidelines for the evaluation and management of acute promyelocytic leukemia (APL) are prepared by our editorial team based on guidelines from the International Society on Thrombosis and Haemostasis (ISTH 2020; 2015), the European Society of Medical Oncology (ESMO 2020), the European Leukemia Net (ELN 2019), and the American Society of Hematology (ASH/ACP 2017). 1 2 3 4 5 Calculator Calculator Eastern Cooperative Oncology G Karnofsky performance status s Guidelines 1. Diagnostic investigations Mutational analysis: https://web.pathway.md/diseases/recBNBa37E5DPGci3 1/4 6/23/23, 2:03 AM Acute promyelocytic leukemia Pathway As per ELN 2019 guidelines, obtain molecular testing for the detection of PML-RARA fusion (or rare molecular variants) to confirm the diagnosis of APL. B As per ACP 2017 guidelines: Obtain mutational analysis for NPM1, CEBPA, and RUNX1 in patients other than those with confirmed core-binding factor-acute myelocytic leukemia, APL, or acute myeloid leukemia with myelodysplasia-related cytogenetic abnormalities. A Obtain rapid detection of PML-RARA in patients with suspected APL. A Coagulation studies: obtain appropriate coagulation tests to evaluate for DIC in patients with APL. A 2. Diagnostic procedures Immunostaining: consider obtaining immunostaining with anti-promyelocytic leukemia antibodies (in addition to FISH, reverse transcriptase PCR, real-time quantitative PCR, reverse transcription- quenching loop-mediated isothermal amplification) for rapid diagnosis of APL. C 3. Medical management General principles: manage the diagnosis of APL (once suspected) as a medical emergency. B Show 3 more Initial therapy: As per ESMO 2020 guidelines, initiate immediate treatment with all-trans-retinoic acid in patients with suspected APL, until confirmatory molecular and/or cytogenetic results are available. B Show 2 more As per ELN 2019 guidelines, offer all-trans retinoic acid and arsenic trioxide without chemotherapy as induction therapy in patients with a WBC count 10 10 /L. Initiate all-trans retinoic acid and anthracycline-based chemotherapy as a second option when arsenic trioxide is contraindicated or unaffordable. B Show 6 more Consolidation therapy: offer 4 consolidation courses of arsenic trioxide (0.15 mg/kg/day 5 days/week, 4 weeks on 4 weeks off) and 7 courses of all-trans retinoic acid (45 mg/m /day in adults; 25 mg/m /day in children, 2 weeks on 2 weeks off) in patients treated with chemotherapy- free approaches. B Show 4 more Maintenance therapy: Do not offer maintenance therapy in patients treated with chemotherapy- free approaches (WBC count 10 10 9/L). D Show 4 more https://web.pathway.md/diseases/recBNBa37E5DPGci3 2/4 6/23/23, 2:03 AM Acute promyelocytic leukemia Pathway Management of coagulopathy: As per ISTH 2020 guidelines, do not preclude or delay antineoplastic therapy (such as all-trans retinoic acid or arsenic trioxide) based on the presence of DIC in patients with APL. D Show 2 more As per ELN 2019 guidelines, initiate treatment with all-trans retinoic acid immediately when a diagnosis of APL is suspected. B Show 4 more As per ISTH 2015 guidelines, consider administering 1-2 doses of platelets (commonly from 5 donors or equivalent) in patients with APL and DIC at high risk of bleeding (such as surgery or invasive procedures), if the platelet count is < than 30 10 /L. C Management of differentiation syndrome: Administer corticosteroids (IV dexamethasone 10 mg BID) immediately at the earliest clinical suspicion of incipient APL differentiation syndrome. Consider discontinuing corticosteroids and reinitiating arsenic trioxide/all-trans retinoic acid once the syndrome has resolved. B Consider discontinuing differentiation therapy (all-trans retinoic acid or arsenic trioxide) temporarily only in case of severe APL differentiation syndrome. C 4. Therapeutic procedures Leukapheresis: As per ESMO 2020 guidelines, avoid performing leukapheresis for hyperleukocytosis in patients with APL because it may exacerbate coagulopathy. D As per ELN 2019 guidelines, avoid performing leukapheresis in patients with hyperleukocytosis due to the risk of precipitating fatal hemorrhage. D 5. Specific circumstances Pediatric patients: administer all-trans retinoic acid at a dose of 25 mg/m /day in pediatric and adolescent patients. B Pregnant patients: advise against conceiving while exposed to all-trans retinoic acid and arsenic trioxide for consolidation and maintenance therapy in female patients with APL. B Show 6 more Elderly patients: manage elderly patients in good clinical condition treated with chemotherapy- based regimens similarly to younger patients but slightly attenuated in dose intensity. Consider offering chemotherapy-free approaches in patients with non-high-risk APL. B Patients with comorbidities: consider offering arsenic trioxide-based therapy schedules in young and older patients with severe comorbidities unfit for chemotherapy (especially anthracyclines). C https://web.pathway.md/diseases/recBNBa37E5DPGci3 3/4 6/23/23, 2:03 AM Acute promyelocytic leukemia Pathway 6. Preventative measures CNS prophylaxis: consider administering CNS prophylaxis only in patients with hyperleukocytosis. C 7. Follow-up and surveillance Treatment monitoring: interpret an increase of WBC counts > 10 10 /L after treatment initiation with all-trans retinoic acid and/or arsenic trioxide as a sign of all-trans retinoic acid/arsenic trioxide-induced differentiation and do not reclassify the patient as having high-risk disease. B Show 4 more Management of relapsed/refractory disease: As per ESMO 2020 guidelines, offer arsenic trioxide/all-trans-retinoic acid for reinduction and consolidation until the achievement of second molecular remission in patients relapsing after all- trans-retinoic acid and chemotherapy or relapsing > 24 months after the end of arsenic trioxide/all-trans-retinoic acid treatment. B Show 3 more As per ELN 2019 guidelines, initiate preemptive therapy promptly to prevent frank relapse in patients with confirmed molecular relapse (defined as 2 successive PCR-positive assays, with stable or rising promyelocytic leukemia-retinoic acid receptor alpha transcript levels detected in independent samples analyzed in 2 laboratories). B Show 6 more References 1. Tzu-Fei Wang, Robert S Makar, Darko Antic et al. Management of hemostatic complications in acute leukemia: Guidance from the SSC of the ISTH. J Thromb Haemost. 2020 Dec;18 12 3174 3183. Open 2. Miguel A Sanz, Pierre Fenaux, Martin S Tallman et al. Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet. Blood. 2019 Apr 11;133 15 1630 1643. Open 3. Arber DA, Borowitz MJ, Cessna M et al. Initial Diagnostic Workup of Acute Leukemia: Guideline From the College of American Pathologists and the American Society of Hematology. Arch Pathol Lab Med. 2017 Oct;141 10 1342 1393. Open 4. J Thachil, A Falanga, M Levi et al. Management of cancer-associated disseminated intravascular coagulation: guidance from the SSC of the ISTH. J Thromb Haemost. 2015 Apr;13 4 671 5. Open 5. M Heuser, Y Ofran, N Boissel et al. Acute myeloid leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020 Jun;31 6 697 712. Open https://web.pathway.md/diseases/recBNBa37E5DPGci3 4/4

Guideline sources The following summarized guidelines for the evaluation and management of acute pyelonephritis are prepared by our editorial team based on guidelines from the European Association of Urology (EAU 2022), the American College of Physicians (ACP 2021), the Spanish Society of Clinical Microbiology and Infectious Diseases (SEIMC 2017), the Infectious Diseases Society of America (IDSA 2016), and the Infectious Diseases Society of America (IDSA/ESCMID 2011). 1 2 3 4 5 6 6 7 8 8 Definition Acute pyelonephritis is a disease resulting from acute infection of the renal pelvis and kidney. 6 Epidemiology Acute pyelonephritis is caused by uropathogenic bacteria, including E. coli (80%), K. pneumoniae (6.2%), Enterococcus (5.3%), Streptococcus agalactiae (2.8%), P. mirabilis (2%), S. saprophyticus (1.4%), K. oxytoca (0.9%) and P. aeruginosa (0.8%). 8 Pathophysiology In the United States, the estimated incidence of acute pyelonephritis requiring hospitalization is 117 cases per 100,000 person-years among females, and 24 cases per 100,000 person-years among males. 7 Disease course https://web.pathway.md/diseases/recZ2NJmv4LxExl9z 1/5 6/23/23, 2:03 AM Acute pyelonephritis Pathway In patients with acute pyelonephritis, bacterial colonization and toxin production in the renal parenchyma leads to an inflammatory response and immune cell recruitment. Host-bacteria interaction leads to local tissue alterations (coagulation, epithelial breakdown, vascular leakage, and tissue destruction). Progression of infection may be associated with renal abscess, bacteremia, septic shock, and death. 8 Prognosis and risk of recurrence In patients with associated sepsis, mortality approaches 10-20%. 6 Calculator Pediatric Emergency Care Appli Guidelines 1. Screening and diagnosis Diagnostic criteria: diagnose acute pyelonephritis in women with compatible symptoms in whom urine cultures demonstrate 10 CFU/mL of a pathogenic organism. B 2. Diagnostic investigations Urine tests: As per EAU 2022 guidelines: Obtain urinalysis (using the dipstick method), including assessment of WBCs, RBCs, and nitrite, for the diagnosis of acute uncomplicated pyelonephritis. A Obtain urine culture and antimicrobial susceptibility testing in patients with pyelonephritis. A As per IDSA 2011 guidelines, obtain urine culture and susceptibility in patients with suspected pyelonephritis, and tailor initial empirical therapy according to urine culture results. B Blood cultures: consider obtaining blood cultures in patients with pyelonephritis, especially in patients with complicated infections or severe sepsis. C Urodynamic testing: obtain urological studies in patients with complicated acute pyelonephritis. B Show 2 more Urinary tract imaging: obtain urinary tract imaging to exclude urgent urological disorders. A https://web.pathway.md/diseases/recZ2NJmv4LxExl9z 2/5 6/23/23, 2:03 AM Acute pyelonephritis Pathway 3. Medical management Setting of care: consider treating women with uncomplicated acute pyelonephritis and mild-to- moderate symptoms (fever < 39 C, no severe flank pain, no vomiting) as outpatients. B Route of administration: administer parenteral antibiotic treatment as initial therapy for patients requiring hospital admission for acute pyelonephritis. B Empiric antibiotics, community-acquired pyelonephritis: As per EAU 2022 guidelines, administer short-course fluoroquinolones as first-line therapy in patients with uncomplicated pyelonephritis not requiring hospitalization. A Show 2 more As per SEIMC 2017 guidelines, use cefuroxime or a third-generation cephalosporin for the empiric treatment of patients with uncomplicated community-acquired acute pyelonephritis in whom there are no specific risk factors for ESBL-producing Enterobacteriaceae. B Show 2 more Updated evidence: ALLIUM In adult patients with a clinical diagnosis of complicated UTI or acute pyelonephritis caused by Gram-negative urinary pathogens, cefepime/enmetazobactam was superior to piperacillin/tazobactam with respect to overall treatment success at day 14. Keith S Kaye et al. JAMA. 2022 Oct 4. Empiric antibiotics (healthcare-associated pyelonephritis): use an antipseudomonal carbapanem as initial treatment for patients with healthcare-associated acute pyelonephritis. B Show 3 more Definitive therapy: As per SEIMC 2017 guidelines, tailor antibiotic treatment according to antibiotic susceptibility testing, once available, and select the agent with the least ecological impact, such as TMP- sulfamethoxazole, among agents to which the infecting pathogen is susceptible. B As per IDSA 2011 guidelines: Use oral TMP-sulfamethoxazole as definitive therapy for acute pyelonephritis, if the uropathogen is known to be susceptible. A Ensure an initial intravenous dose of a long-acting parenteral antimicrobial is given, such as 1 g of ceftriaxone, in patients in whom definitive therapy with oral -lactams is chosen. B Duration of treatment: As per ACP 2021 guidelines, complete a short-course of antibiotic therapy in male and female patients with uncomplicated pyelonephritis with one of the following regimens based on antibiotic susceptibility: fluoroquinolones for 5-7 days https://web.pathway.md/diseases/recZ2NJmv4LxExl9z 3/5 6/23/23, 2:03 AM Acute pyelonephritis Pathway TMP-sulfamethoxazole for 14 days. B As per SEIMC 2017 guidelines, 5 days in patients treated with aminoglycosides. B Show 3 more Landmark trials: Ciprofloxacin for 7 vs. 14 days in pyelonephritis In non-pregnant women with acute pyelonephritis, treatment with ciprofloxacin for 7 days were noninferior to treatment with ciprofloxacin for 14 days with respect to a short-term clinical cure. Sandberg T et al. Lancet. 2012 Aug 4. 4. Specific circumstances Pregnant patients: Consider managing pregnant women with otherwise uncomplicated acute pyelonephritis and non-severe symptoms in the outpatient setting, if appropriate follow-up can be ensured. B Obtain abdominal ultrasound and ensure results are normal before discharging pregnant women with uncomplicated acute pyelonephritis. B Patients with urosepsis: use the Quick SOFA score to identify patients with potential sepsis. A Show 5 more Patients with complicated pyelonephritis: Administer any of the following regimens as empirical therapy in patients with complicated pyelonephritis with systemic symptoms: amoxicillin and an aminoglycoside second-generation cephalosporin and an aminoglycoside IV third-generation cephalosporin. A Show 3 more Patients with Candida pyelonephritis: initiate oral fluconazole 200-400 mg (3-6 mg/kg) daily for 2 weeks in patients with ascending Candida pyelonephritis caused by fluconazole-susceptible organisms. B Show 5 more References 1. de Cueto M, Aliaga L, Al s JI et al. Executive summary of the diagnosis and treatment of urinary tract infection: Guidelines of the Spanish Society of Clinical Microbiology and Infectious Diseases SEIMC . Enferm Infecc Microbiol Clin. 2017 May;35 5 314 320. Open 2. Gupta K, Hooton TM, Naber KG et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of https://web.pathway.md/diseases/recZ2NJmv4LxExl9z 4/5 6/23/23, 2:03 AM Acute pyelonephritis Pathway America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 2011 Mar 1;52 5):e103 20. Open 3. G. Bonkat, R. Bartoletti, F. Bruy re et al. EAU Guidelines on Urological Infections. EAU. 2022. Open 4. Pappas PG, Kauffman CA, Andes DR et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016 Feb 15;62 4):e1 50. Open 5. Rachael A Lee, Robert M Centor, Linda L Humphrey et al. Appropriate Use of Short-Course Antibiotics in Common Infections: Best Practice Advice From the American College of Physicians. Ann Intern Med. 2021 Apr 6. Open 6. Johnson JR, Russo TA. Acute Pyelonephritis in Adults. N Engl J Med. 2018 Jan 4;378 1 48 59. Open 7. Lee DG, Jeon SH, Lee CH et al. Acute pyelonephritis: clinical characteristics and the role of the surgical treatment. J Korean Med Sci. 2009 Apr;24 2 296 301. Open 8. Choong FX, Antypas H, Richter-Dahlfors A. Integrated Pathophysiology of Pyelonephritis. Microbiol Spectr. 2015 Oct;3 5 . Open 9. Keith S Kaye, Adam Belley, Philip Barth et al. Effect of Cefepime/Enmetazobactam vs Piperacillin/Tazobactam on Clinical Cure and Microbiological Eradication in Patients With Complicated Urinary Tract Infection or Acute Pyelonephritis: A Randomized Clinical Trial. JAMA. 2022 Oct 4;328 13 1304 1314. Open https://web.pathway.md/diseases/recZ2NJmv4LxExl9z 5/5

Guideline sources The following summarized guidelines for the management of acute respiratory distress syndrome are prepared by our editorial team based on guidelines from the British Thoracic Society (BTS 2019), the Surviving Sepsis Campaign (SSC 2017), and the European Society of Intensive Care Medicine (ESICM/SCCM/ATS 2017). 1 2 3 4 5 5 6 6 Definition ARDS is an acute inflammatory disease of the lungs that develops secondary to pulmonary or extrapulmonary damage to the alveolar-capillary membrane, leading to interstitial and alveolar edema. Clinically, ARDS is characterized by acute hypoxemic respiratory failure, decreased lung compliance, and bilateral radiographic infiltrates in the absence of cardiogenic pulmonary edema. 4 Epidemiology An acute injury to the lungs (direct or indirect) is the most common cause of ARDS, with pneumonia, aspiration of gastric contents, and sepsis accounting for > 85% of all cases. 6 Pathophysiology In the United States, the incidence of ARDS is estimated at 64.2-78.9 cases per 100,000 person- years. 5 https://web.pathway.md/diseases/recNTWckOcmQM1veT 1/8 6/23/23, 2:03 AM Acute respiratory distress syndrome Pathway Disease course Classically, an initial exudative phase with interstitial and alveolar edema is followed by a proliferative phase, which may further progress to a fibrotic phase. The latter is associated with collagen deposition, along with interstitial and alveolar fibrosis, causing decreased lung compliance, respiratory dysfunction, multisystem organ failure, and death. 6 Prognosis and risk of recurrence ARDS is associated with an in-hospital mortality of 27%, 32%, and 45% for mild, moderate, and severe disease, respectively. 5 Pathway Calculator Acute respiratory distress syndr Murray lung injury score Management Guidelines 1. Respiratory support Noninvasive ventilation: insufficient evidence to assess the risks and benefits of noninvasive ventilation for patients with sepsis-induced ARDS. Head of the bed elevation: maintain the head of the bed elevated to 30-45 degrees in mechanically ventilated patients with sepsis to limit aspiration risk and the development of ventilator-associated pneumonia. B Tidal volume targets: As per BTS 2019 guidelines, use a lower target tidal volume (6 mL/kg predicted body weight) routinely in patients with ARDS. A Landmark trials: ARDSNet In patients with ARDS and acute lung injury, ventilation with lower tidal volumes were superior to traditional tidal volume with respect to hospital death. Brower RG et al. N Engl J Med. 2000 May 4. As per ATS 2017 guidelines, use limiting tidal volumes (4-8 mL/kg predicted body weight) and inspiratory pressures (plateau pressure < 30 cmH O) in adult patients with ARDS. B As per SSC 2017 guidelines: https://web.pathway.md/diseases/recNTWckOcmQM1veT 2/8 6/23/23, 2:03 AM Acute respiratory distress syndrome Pathway Use a target tidal volume of 6 mL/kg predicted body weight in adult patients with sepsis- induced ARDS. A Consider using low tidal volumes over higher tidal volumes in adult patients with sepsis- induced respiratory failure without ARDS. C Plateau pressure targets: target plateau pressures < 30 cm H O in adult patients with sepsis- induced severe acute respiratoire distress syndrome. B PEEP targets: As per BTS 2019 guidelines, consider using a high PEEP strategy in patients with ARDS and a PaO /FiO ratio < 200 mmHg (< 27 kPa). C As per ATS 2017 guidelines, consider using higher rather than lower levels of PEEP strategy in adult patients with moderate or severe ARDS. C As per SSC 2017 guidelines, consider using a high PEEP strategy in adult patients with sepsis- induced moderate-to-severe ARDS. C Prone positioning: As per BTS 2019 guidelines: Use prone positioning for 12 hours/day in patients with ARDS and a PaO /FiO ratio < 150 mmHg (< 20 kPa). A Avoid the routine use of prone positioning for patients with ARDS. D As per ATS 2017 guidelines, use prone positioning for > 12 hours/day in adult patients with severe ARDS. B As per SSC 2017 guidelines, use prone positioning in adult patients with sepsis-induced ARDS and a PaO /FiO ratio < 150 mmHg (< 20 kPa). B Landmark trials: PROSEVA In patients undergoing mechanical ventilation for severe ARDS, performing prone-positioning sessions were superior to standard supine positioning with respect to death at 28 days. Guerin C et al. N Engl J Med. 2013 Jun 6. Recruitment maneuvers: As per ATS 2017 guidelines, consider using recruitment maneuvers in adult patients with ARDS. C As per SSC 2017 guidelines, consider using recruitment maneuvers in patients with sepsis- induced severe ARDS. C High-frequency oscillatory ventilation: As per BTS 2019 guidelines, do not use high-frequency oscillatory ventilation in patients with ARDS. D https://web.pathway.md/diseases/recNTWckOcmQM1veT 3/8 6/23/23, 2:03 AM Acute respiratory distress syndrome Pathway As per ATS 2017 guidelines, do not use high-frequency oscillatory ventilation routinely in patients with moderate or severe ARDS. D As per SSC 2017 guidelines, do not use high-frequency oscillatory ventilation in adult patients with sepsis-induced ARDS. D Landmark trials: OSCILLATE In adults with new-onset, moderate-to-severe ARDS, high-frequency oscillatory ventilation was inferior to low tidal volume ventilation with respect to a in-hospital death. Ferguson ND et al. N Engl J Med. 2013 Feb 28. 2. Medical management Fluid strategy: use a conservative fluid strategy in patients with established sepsis-induced ARDS who do not have evidence of tissue hypoperfusion. B Landmark trials: FACTT In patients with acute lung injury, conservative fluid use was superior to liberal fluid use with respect to death at 60 days. National Heart et al. N Engl J Med. 2006 Jun 15. Neuromuscular blocking agents: As per BTS 2019 guidelines: Consider administering cisatracurium besylate for 48 hours in patients with ARDS and a PaO /FiO ratio < 150 mmHg (< 20 kPa). C Consider avoiding routine use of neuromuscular blocking agents for the treatment of ARDS. D Landmark trials: PETAL In patients with moderate-to-severe ARDS who were treated with a strategy involving a high PEEP, there was no significant difference in mortality at 90 days between patients who received an early and continuous cisatracurium infusion and those who were treated with a usual-care approach with lighter sedation targets (42.5% vs. 42.8%, p=0.930). While in the hospital, patients in the intervention group were less physically active and had more adverse cardiovascular events than patients in the control group. National Heart et al. N Engl J Med. 2019 May 23. https://web.pathway.md/diseases/recNTWckOcmQM1veT 4/8 6/23/23, 2:03 AM Acute respiratory distress syndrome Pathway As per SSC 2017 guidelines, consider administering neuromuscular blocking agents for 48 hours in adult patients with sepsis-induced ARDS and a PaO /FiO ratio < 150 mmHg (< 20 kPa). C Updated evidence: PETAL In patients with moderate-to-severe ARDS who were treated with a strategy involving a high PEEP, there was no significant difference in mortality at 90 days between patients who received an early and continuous cisatracurium infusion and those who were treated with a usual-care approach with lighter sedation targets (42.5% vs. 42.8%, p=0.930). While in the hospital, patients in the intervention group were less physically active and had more adverse cardiovascular events than patients in the control group. National Heart et al. N Engl J Med. 2019 May 23. Intravenous corticosteroids: insufficient evidence of sufficient quality to assess the risks and benefits of corticosteroids for the treatment of established ARDS. I Inhaled nitric oxide: consider avoiding the use of inhaled nitric oxide in patients with ARDS. D Inhaled bronchodilators: avoid the use of -2 agonists for the treatment of patients with sepsis- induced ARDS without bronchospasm. D 3. Inpatient care Pulmonary artery catheters: avoid the routine use of pulmonary artery catheters in patients with sepsis-induced ARDS. D Landmark trials: Pulmonary artery catheters for acute lung injury In patients with established acute lung injury, pulmonary artery catheter-guided resuscitation was not superior to central venous catheter-guided resuscitation with respect to survival at 60 days. National Heart et al. N Engl J Med. 2006 May 25. 4. Therapeutic procedures Extracorporeal membrane oxygenation: Consider using ECMO with lung-protective mechanical ventilation in selected patients with severe ARDS (defined as a Lung Injury Score of 3 or more, or pH < 7.20 due to uncompensated hypercapnia). C https://web.pathway.md/diseases/recNTWckOcmQM1veT 5/8 6/23/23, 2:03 AM Acute respiratory distress syndrome Pathway Consider avoiding the routine use of ECMO in patients with ARDS . D Extracorporeal carbon dioxide removal: insufficient evidence to assess the risks and benefits of extracorporeal CO removal in patients with ARDS. I 5. Follow-up and surveillance Weaning from mechanical ventilation: Use spontaneous breathing trials in mechanically ventilated patients with sepsis who are ready for weaning. A Use a weaning protocol to assist in weaning patients with sepsis-induced respiratory failure from mechanical ventilation. B References 1. Rhodes A, Evans LE, Alhazzani W et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017 Mar;43 3 304 377. Open 2. Griffiths MJD, McAuley DF, Perkins GD et al. Guidelines on the management of acute respiratory distress syndrome. BMJ Open Respir Res. 2019 May 24;6 1):e000420. Open 3. Eddy Fan, Lorenzo Del Sorbo, Ewan C Goligher et al. An Official American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice Guideline: Mechanical Ventilation in Adult Patients with Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. 2017 May 1;195 9 1253 1263. Open 4. Villar J, Blanco J, Kacmarek RM. Current incidence and outcome of the acute respiratory distress syndrome. Curr Opin Crit Care. 2016 Feb;22 1 1 6. Open 5. Walkey AJ, Summer R, Ho V et al. Acute respiratory distress syndrome: epidemiology and management approaches. Clin Epidemiol. 2012;4 159 69. Open 6. Thompson BT, Chambers RC, Liu KD. Acute Respiratory Distress Syndrome. N Engl J Med. 2017 Aug 10;377 6 562 572. Open 7. Society of Hospital Medicine. Choosing Wisely SHM recommendations. Choosing Wisely. 2013. Open 8. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome ARDS Clinical Trials Network et al. Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. N Engl J Med. 2006 May 25;354 21 2213 24. Open 9. Sweet DG, Carnielli V, Greisen G et al. European Consensus Guidelines on the Management of Respiratory Distress Syndrome 2019 Update. Neonatology. 2019;115 4 432 450. Open 10. Loic Barrot, Pierre Asfar, Frederic Mauny et al. Liberal or Conservative Oxygen Therapy for Acute Respiratory Distress Syndrome. N Engl J Med. 2020 Mar 12;382 11 999 1008. Open 11. Alpha A Fowler rd, Jonathon D Truwit, R Duncan Hite et al. Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory https://web.pathway.md/diseases/recNTWckOcmQM1veT 6/8 6/23/23, 2:03 AM Acute respiratory distress syndrome Pathway Failure: The CITRIS ALI Randomized Clinical Trial. JAMA. 2019 Oct 1;322 13 1261 1270. Open 12. Carol L Hodgson, D James Cooper, Yaseen Arabi et al. Maximal Recruitment Open Lung Ventilation in Acute Respiratory Distress Syndrome PHARLAP . A Phase II, Multicenter Randomized Controlled Clinical Trial. Am J Respir Crit Care Med. 2019 Dec 1;200 11 1363 1372. Open 13. National Heart, Lung, and Blood Institute PETAL Clinical Trials Network et al. Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome. N Engl J Med. 2019 May 23;380 21 1997 2008. Open 14. Jeremy R Beitler, Todd Sarge, Valerie M Banner-Goodspeed et al. Effect of Titrating Positive End- Expiratory Pressure PEEP With an Esophageal Pressure-Guided Strategy vs an Empirical High PEEP Fio2 Strategy on Death and Days Free From Mechanical Ventilation Among Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial. JAMA. 2019 Mar 5;321 9 846 857. Open 15. Alain Combes, David Hajage, Gilles Capellier et al. Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome. N Engl J Med. 2018 May 24;378 21 1965 1975. Open 16. Shannon L Goddard, Gordon D Rubenfeld, Venika Manoharan et al. The Randomized Educational Acute Respiratory Distress Syndrome Diagnosis Study: A Trial to Improve the Radiographic Diagnosis of Acute Respiratory Distress Syndrome. Crit Care Med. 2018 May;46 5 743 748. Open 17. Yongfang Zhou, Xiaodong Jin, Yinxia Lv et al. Early application of airway pressure release ventilation may reduce the duration of mechanical ventilation in acute respiratory distress syndrome. Intensive Care Med. 2017 Nov;43 11 1648 1659. Open 18. Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial ART Investigators, Alexandre Biasi Cavalcanti, rica Aranha Suzumura et al. Effect of Lung Recruitment and Titrated Positive End-Expiratory Pressure PEEP vs Low PEEP on Mortality in Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial. JAMA. 2017 Oct 10;318 14 1335 1345. Open 19. Bhakti K Patel, Krysta S Wolfe, Anne S Pohlman et al. Effect of Noninvasive Ventilation Delivered by Helmet vs Face Mask on the Rate of Endotracheal Intubation in Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial. JAMA. 2016 Jun 14;315 22 2435 41. Open 20. Peter G Jones, Sinan Kamona, Owen Doran et al. Randomized Controlled Trial of Humidified High-Flow Nasal Oxygen for Acute Respiratory Distress in the Emergency Department: The HOT ER Study. Respir Care. 2016 Mar;61 3 291 9. Open 21. Robert M Kacmarek, Jes s Villar, Demet Sulemanji et al. Open Lung Approach for the Acute Respiratory Distress Syndrome: A Pilot, Randomized Controlled Trial. Crit Care Med. 2016 Jan;44 1 32 42. Open 22. Laurent Papazian, Jean-Marie Forel, Arnaud Gacouin et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010 Sep 16;363 12 1107 16. Open 23. Daniel F McAuley, John G Laffey, Cecilia M O'Kane et al. Simvastatin in the acute respiratory distress syndrome. N Engl J Med. 2014 Oct 30;371 18 1695 703. Open 24. G U Meduri, A S Headley, E Golden et al. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial. JAMA. 1998 Jul 8;280 2 159 65. Open 25. Duncan Young, Sarah E Lamb, Sanjoy Shah et al. High-frequency oscillation for acute respiratory distress syndrome. N Engl J Med. 2013 Feb 28;368 9 806 13. Open https://web.pathway.md/diseases/recNTWckOcmQM1veT 7/8 6/23/23, 2:03 AM Acute respiratory distress syndrome Pathway 26. Acute Respiratory Distress Syndrome Network, Roy G Brower, Michael A Matthay et al. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000 May 4;342 18 1301 8. Open 27. G Umberto Meduri, Emmel Golden, Amado X Freire et al. Methylprednisolone infusion in early severe ARDS results of a randomized controlled trial. Chest. 2007 Apr;131 4 954 63. Open 28. L Gattinoni, G Tognoni, A Pesenti et al. Effect of prone positioning on the survival of patients with acute respiratory failure. N Engl J Med. 2001 Aug 23;345 8 568 73. Open 29. Jordi Mancebo, Rafael Fern ndez, Lluis Blanch et al. A multicenter trial of prolonged prone ventilation in severe acute respiratory distress syndrome. Am J Respir Crit Care Med. 2006 Jun 1;173 11 1233 9. Open 30. Andrew James Boyle, Peter Ferris, Ian Bradbury et al. Baseline plasma IL 18 may predict simvastatin treatment response in patients with ARDS a secondary analysis of the HARP 2 randomised clinical trial. Crit Care. 2022 Jun 7;26 1 164. Open 31. Sadatomo Tasaka, Shinichiro Ohshimo, Muneyuki Takeuchi et al. ARDS Clinical Practice Guideline 2021. J Intensive Care. 2022 Jul 8;10 1 32. Open https://web.pathway.md/diseases/recNTWckOcmQM1veT 8/8

Guideline sources The following summarized guidelines for the evaluation and management of acute transfusion reactions are prepared by our editorial team based on guidelines from the British Society for Haematology (BSH 2023). 1 Guidelines 1. Diagnostic investigations Clinical assessment: ask patients to report symptoms developing following the completion of transfusion. B Show 3 more Laboratory tests: obtain standard investigations, including CBC, renal and liver enzymes, in patients with moderate and severe transfusion reactions. B Show 4 more Chest X-ray: obtain a CXR in patients with respiratory symptoms not due to allergy. B 2. Medical management https://web.pathway.md/diseases/recz9twzEpwPyiaDi 1/2 6/23/23, 2:03 AM Acute transfusion reactions Pathway General principles: direct initial treatment of acute transfusion reactions according to symptoms and signs. Do not delay treatment of severe reactions until the results of investigations are available. B Intramuscular epinephrine: administer intramuscularly epinephrine for the treatment of anaphylaxis, including in patients with thrombocytopenia or deranged coagulation. A Antipyretics: consider administering oral acetaminophen (500-1,000 mg in adults) in patients with mild isolated febrile reactions. C Antihistamines: consider slowing the transfusion and administering an antihistamine in patients with mild allergic reactions. C Corticosteroids: do not use corticosteroids routinely for the management of allergic reactions. D 3. Therapeutic procedures Discontinuation of transfusion: discontinue transfusion temporarily but maintain venous access in patients developing new symptoms or signs during transfusion. B Show 2 more 4. Specific circumstances Patients with IgA deficiency: discuss the future management of patients with IgA deficiency diagnosed after acute transfusion reactions with a specialist in transfusion medicine. B Show 2 more 5. Preventative measures Secondary prophylaxis: administer a trial of premedication with oral acetaminophen given 1 hour before the anticipated reaction in patients with recurrent febrile reactions (or NSAIDs in patients with predominant chills or rigors, always accompanied by an individualized assessment of the risks of medication against the severity of reaction). B Show 4 more References 1. Richard Soutar, Wendy McSporran, Tracey Tomlinson et al. Guideline on the investigation and management of acute transfusion reactions. Br J Haematol. 2023 Jun;201 5 832 844. Open https://web.pathway.md/diseases/recz9twzEpwPyiaDi 2/2

Guideline sources The following summarized guidelines for the evaluation and management of acute urticaria are prepared by our editorial team based on guidelines from the Asia Pacific Association of Allergy, Asthma and Clinical Immunology (APAAACI/GA LEN/EDF/EAACI 2022), the Australasian College of Dermatologists (ACD 2021), the American Association of Family Physicians (AAFP 2017), and the American Academy of Allergy, Asthma & Immunology (AAAAI/ACAAI 2014). 1 2 3 4 Guidelines 1. Screening and diagnosis Pathophysiology: Recognize that acute urticaria and angioedema are often but not always related to mast cell and basophil activation from multiple triggers, which include IgE- and non-IgE-mediated mechanisms. B Recognize that acute urticaria and angioedema are more frequently associated with identifiable conditions. B Differential diagnosis: https://web.pathway.md/diseases/recV8S4OclNSBlh2R 1/3 6/23/23, 2:07 AM Acute urticaria Pathway As per AAFP 2017 guidelines, exclude underlying anaphylaxis in patients presenting with acute urticaria. B As per AAAAI 2014 guidelines: Differentiate acute urticaria and angioedema from chronic urticaria and angioedema based on the duration of illness. B Differentiate acute urticaria and angioedema from anaphylaxis. B 2. Classification and risk stratification Classification: classify urticaria based on its duration: acute ( 6 weeks) or chronic (> 6 weeks). A 3. Diagnostic investigations Initial evaluation: As per EAACI 2022 guidelines, do not obtain any routine diagnostic evaluation in patients with acute spontaneous urticaria. D As per ACD 2021 guidelines, do not obtain any routine investigations for underlying causes in patients with acute urticaria. D Show 2 more As per AAFP 2017 guidelines, do not obtain an extensive laboratory workup for urticaria. Consider obtaining additional testing if the presentation suggests underlying causes requiring confirmation. D 4. Diagnostic procedures Skin biopsy: consider performing skin biopsy in rare circumstances to differentiate acute urticaria and angioedema from other inflammatory disorders. C 5. Medical management Antihistamines: As per AAFP 2017 guidelines, administer second-generation H1RAs as first-line symptomatic therapy for urticaria. A Show 2 more As per AAAAI 2014 guidelines, administer antihistamines as first-line therapy in patients with acute urticaria and angioedema. B Corticosteroids: https://web.pathway.md/diseases/recV8S4OclNSBlh2R 2/3 6/23/23, 2:07 AM Acute urticaria Pathway As per AAFP 2017 guidelines, consider administering a short course of systemic corticosteroids to help control severe cases of urticaria. C As per AAAAI 2014 guidelines: Consider administering oral corticosteroids in patients with severe acute urticaria and angioedema. C Consider administering a short course of oral corticosteroids in patients with poor response to antihistamines, while attempting to eliminate suspected triggers and develop an effective treatment plan. C Corticosteroids (ECAAI): consider administering a short course of rescue systemic corticosteroids in patients with an acute exacerbation of chronic urticaria. C Leukotriene antagonists: consider offering leukotriene receptor antagonists to control symptoms of chronic urticaria. C Epinephrine autoinjectors: prescribe epinephrine if the diagnosis of anaphylaxis has not been excluded. B 6. Nonpharmacologic interventions Avoidance of causative agents: elicit a detailed history of common causes of acute urticaria and angioedema, including medications and foods, and instruct on proper elimination if identified. B References 1. Jonathan A Bernstein, David M Lang, David A Khan et al. The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol. 2014 May;133 5 1270 7. Open 2. Paul Schaefer. Acute and Chronic Urticaria: Evaluation and Treatment. Am Fam Physician. 2017 Jun 1;95 11 717 724. Open 3. Torsten Zuberbier, Amir Hamzah Abdul Latiff, Mohamed Abuzakouk et al. The international EAACI/GA LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria. Allergy. 2022 Mar;77 3 734 766. Open 4. Australasian College of Dermatologists. Choosing Wisely ACD recommendations. Choosing Wisely. 2021. Open https://web.pathway.md/diseases/recV8S4OclNSBlh2R 3/3

Guideline sources The following summarized guidelines for the evaluation and management of acute viral rhinosinusitis (AVRS) are prepared by our editorial team based on guidelines from the American College of Physicians (ACP/CDC 2016), the Infectious Diseases Society of America (IDSA 2015), and the American Academy of Otolaryngology-Head and Neck Surgery Foundation (AAO-HNSF 2015). 1 2 3 4 4 5 5 Definition AVRS or the common cold is the sudden onset of two or more symptoms, one of which should be either nasal blockage/obstruction/congestion or nasal discharge for less than 12 weeks caused by a viral etiology. 4 Epidemiology AVRS is mostly caused by RSV (RSV), rhinovirus, parainfluenza, and influenza with rhinovirus. 4 Disease course The inflammation and injury of nasal respiratory epithelium and mucosa by viruses results in AVRS, which causes clinical manifestations of rhinorrhea, nasal blockage, sneezing, watery eyes, nasal and ocular pruritus, chills, and muscle aches. The symptoms usually resolve within 4-10 days of a self-limiting course. 5 Prognosis and risk of recurrence https://web.pathway.md/diseases/recZxjK1hg556UCye 1/3 6/23/23, 2:08 AM Acute viral rhinosinusitis Pathway AVRS is not associated with an increase in mortality. 5 Guidelines 1. Screening and diagnosis Differential diagnosis: distinguish presumed AVRS from acute bacterial rhinosinusitis, and from acute rhinosinusitis caused by noninfectious conditions. B 2. Diagnostic investigations Diagnostic imaging: avoid radiographic imaging for patients who meet diagnostic criteria for AVRS, unless a complication or an alternative diagnosis is suspected. D 3. Medical management Antibiotic therapy: As per ACP 2016 guidelines, reserve antibiotic treatment for acute rhinosinusitis in patients with persistent symptoms for > 10 days, onset of severe symptoms or signs of high fever (> 39 C) and purulent nasal discharge or facial pain lasting 3 consecutive days, or onset of worsening symptoms following a typical viral illness lasted 5 days that was initially improving (double sickening). B As per Choosing Wisely 2015 guidelines, avoid using antibiotics in patients with AVRS as antibiotic treatment is ineffective, inappropriate, and potentially harmful. D Symptomatic treatment: consider advising analgesics, topical intranasal steroids, and/or intranasal saline irrigation for symptomatic relief in patients with AVRS. C References 1. Infectious Diseases Society of America. Choosing Wisely: Recommendations of the Infectious Diseases Society of America. Choosing Wisely. 2015 Feb. Open 2. Rosenfeld RM, Piccirillo JF, Chandrasekhar SS et al. Clinical practice guideline (update): adult sinusitis. Otolaryngol Head Neck Surg. 2015 Apr;152 2 Suppl):S1 S39. Open 3. Aaron M Harris, Lauri A Hicks, Amir Qaseem et al. Appropriate Antibiotic Use for Acute Respiratory Tract Infection in Adults: Advice for High-Value Care From the American College of Physicians and the Centers for Disease Control and Prevention. Ann Intern Med. 2016 Mar 15;164 6 425 34. Open 4. Neil Foden, Christopher Burgess, Kathryn Shepherd et al. A guide to the management of acute rhinosinusitis in primary care: management strategy based on best evidence and recent European guidelines. 2013 Nov;63 616 611 3.2013 Nov;63 616 611 3. Open https://web.pathway.md/diseases/recZxjK1hg556UCye 2/3 6/23/23, 2:08 AM Acute viral rhinosinusitis Pathway 5. Anthony W Chow, Michael S Benninger, Itzhak Brook et al. IDSA clinical practice guideline for acute bacterial rhinosinusitis in children and adults. 2012 Apr;54 8):e72-e112.2012 Apr;54 8):e72-e112. Open 6. Wald ER, Applegate KE, Bordley C et al. Clinical practice guideline for the diagnosis and management of acute bacterial sinusitis in children aged 1 to 18 years. Pediatrics. 2013 Jul;132 1):e262 80. Open 7. American Academy of Pediatrics. Choosing Wisely AAP recommendations. Choosing Wisely. 2018. Open https://web.pathway.md/diseases/recZxjK1hg556UCye 3/3

Guideline sources The following summarized guidelines for the evaluation and management of acute-on-chronic liver failure (ACLF) are prepared by our editorial team based on guidelines from the Society of Critical Care Medicine (SCCM 2023; 2020), the American College of Gastroenterology (ACG 2022), and the European Association for the Study of the Liver (EASL 2018). 1 2 3 4 Guidelines 1. Screening and diagnosis Diagnosis: establish the diagnosis of ACLF in patients with cirrhosis and acute decompensation (defined as the acute development or worsening of ascites, overt encephalopathy, gastrointestinal hemorrhage, nonobstructive jaundice, and/or bacterial infections) when organ failures involving high short-term mortality develop. B Show 2 more https://web.pathway.md/diseases/recv7yYarFkEPlvTk 1/6 6/23/23, 2:08 AM Acute-on-chronic liver failure Pathway 2. Diagnostic investigations Medication review: screen patients with ACLF for drug-induced causes of liver failure. Discontinue drugs proven or highly suspected to be the cause of ACLF. E Viscoelastic testing: As per ACG 2022 guidelines, obtain thromboelastography or rotational thromboelastography rather than INR to more accurately assess transfusion needs in patients with cirrhosis requiring invasive procedures. B As per SCCM 2020 guidelines: Consider obtaining viscoelastic testing (thromboelastography/rotational thromboelastography) over measuring INR, platelet, and fibrinogen in critically ill patients with ACLF. C Obtain viscoelastic testing (thromboelastography/rotational thromboelastography) over measuring INR, platelet, and fibrinogen in critically ill patients with ACLF undergoing procedures. B Coagulation studies: avoid obtaining INR as a means to measure coagulation risk in patients with cirrhosis and ACLF. D 3. Respiratory support Supplemental oxygen: Provide supportive care with supplemental oxygen in the management of patients with hepatopulmonary syndrome, pending possible liver transplantation. E Consider using high-flow nasal cannula over noninvasive ventilation in hypoxic critically ill patients with ACLF. C Mechanical ventilation: Consider using a low tidal volume strategy in patients with ACLF and ARDS. C Avoid using high PEEP in patients with ACLF and ARDS. D 4. Medical management General principles, goals of care: As per ACG 2022 guidelines, consider discussing early goals of care with patients with end- stage liver disease admitted to the hospital and if appropriate, refer to palliative care to improve resource utilization. C As per SCCM 2020 guidelines, consider targeting a mean arterial pressure of 65 mmHg in patients with ACLF, with concomitant assessment of perfusion. C Show 2 more General principles (supportive care): recognize that there is no specific therapy for ACLF aside from antiviral therapy in patients with ACLF due to reactivation of HBV infection. B https://web.pathway.md/diseases/recv7yYarFkEPlvTk 2/6 6/23/23, 2:08 AM Acute-on-chronic liver failure Pathway Show 4 more General principles, precautions: As per ACG 2022 guidelines, avoid using PPIs in patients with cirrhosis unless there is a clear indication because PPIs increase the risk of infection. D As per SCCM 2020 guidelines: Adjust the doses of medications undergoing hepatic metabolism based on the patient's residual hepatic function. Consult a clinical pharmacist when available. E Avoid using eltrombopag before surgery/invasive procedures in patients with ACLF with thrombocytopenia. D Fluid resuscitation: Do not use hydroxyethyl starch for initial fluid resuscitation of patients with ACLF. D Avoid using gelatin solutions for initial fluid resuscitation of patients with ACLF. D Albumin: As per ACG 2022 guidelines, avoid administering daily infusion of albumin to maintain albumin > 3 g/dL to improve mortality, prevent renal dysfunction or infection in hospitalized patients with cirrhosis. D As per SCCM 2020 guidelines, consider administering albumin over other fluids for resuscitation of patients with ACLF, especially if serum albumin is < 3 mg/dL. C Vasopressors: administer vasopressors in critically ill patients with ACLF developing hepatorenal syndrome. B Show 2 more Thromboprophylaxis: As per ACG 2022 guidelines, recognize that there is an increased risk of VTE in patients with cirrhosis as compared to non-cirrhotic populations. B As per SCCM 2020 guidelines, consider administering LMWH over offering pneumatic compression stockings for venous thromboprophylaxis in hospitalized patients with ACLF. C Antibiotic prophylaxis: As per SCCM 2023 guidelines, administer antibiotic prophylaxis in critically ill patients with ACLF and any type of upper gastrointestinal bleeding. B As per ACG 2022 guidelines, consider administering antibiotic prophylaxis for secondary SBP to prevent recurrence in patients with cirrhosis with a history of SBP. C Show 2 more Granulocyte colony-stimulating factor: As per ACG 2022 guidelines, avoid administering G-CSF to improve mortality in patients with cirrhosis and ACLF. D As per EASL 2018 guidelines, do not use G-CSF in patients with ACLF. D Antiviral therapy: initiate nucleoside analogs (tenofovir, entecavir) as early as possible in patients with ACLF due to HBV infection. A https://web.pathway.md/diseases/recv7yYarFkEPlvTk 3/6 6/23/23, 2:08 AM Acute-on-chronic liver failure Pathway Sedation: consider administering short-acting dexmedetomidine for sedation to shorten time to extubation in hospitalized patients with ACLF. C Management of portal hypertension: perform upper gastrointestinal endoscopy within 12 hours of presentation in critically ill patients with ACLF and portal hypertensive bleeding (known or suspected). E Show 4 more Management of portopulmonary hypertension: consider treating portopulmonary hypertension with agents approved for pulmonary arterial hypertension in patients with mean pulmonary artery pressure > 35 mmHg. C Management of vascular complications: consider administering LMWH or vitamin K antagonists over offering conservative management in patients with portal venous thrombosis or pulmonary embolus. C Management of infections: obtain assessment for infection in hospitalized patients with decompensated cirrhosis because infection is associated with the development of ACLF and increased mortality. B Show 2 more Management of spontaneous bacterial peritonitis: administer albumin in critically ill patients with ACLF and SBP. B Show 3 more Management of septic shock: As per SCCM 2023 guidelines, consider initiating appropriate antibiotics as soon as possible after recognition and within 1 hour of shock onset in critically ill patients with ACLF and septic shock. C As per SCCM 2020 guidelines, consider administering stress-dose corticosteroids for the management of septic shock in patients with ACLF. C Management of hepatic encephalopathy: consider administering nonabsorbable disaccharides in critically ill patients with ACLF and overt hepatic encephalopathy. C Show 4 more Management of acute kidney injury: As per ACG 2022 guidelines, avoid obtaining biomarkers to predict the development of renal failure in patients with cirrhosis. D Show 4 more As per SCCM 2020 guidelines, consider performing early RRT in patients with ALF and AKI. C 5. Inpatient care Hemodynamic monitoring: Consider placing an arterial catheter for BP monitoring in patients with ACLF and shock. C https://web.pathway.md/diseases/recv7yYarFkEPlvTk 4/6 6/23/23, 2:08 AM Acute-on-chronic liver failure Pathway Consider obtaining invasive hemodynamic monitoring to guide therapy in patients with ACLF and clinically impaired perfusion. C 6. Nonpharmacologic interventions Nutrition: As per ACG 2022 guidelines, avoid administering routine parenteral nutrition, enteral nutrition or oral supplements to improve mortality in hospitalized patients with cirrhosis. As per SCCM 2020 guidelines, avoid using a low protein goal in patients with ACLF. Consider targeting protein goals comparable to critically ill patients without liver failure (such as 1.2-2.0 g protein/kg dry or ideal body weight per day). D Show 2 more 7. Therapeutic procedures Blood transfusion: avoid administering transfusions in the absence of bleeding or a planned procedure in patients with ACLF and altered coagulation parameters. D Large volume paracentesis: Avoid performing large-volume paracentesis in critically ill patients with ACLF and SBP. D Perform large-volume paracentesis with measurement of intra-abdominal pressure in critically ill patients with ACLF with tense ascites and intra-abdominal hypertension or hemodynamic, renal, or respiratory compromise. E Pleurodesis: place a chest tube with an attempt to pleurodesis for hepatic hydrothorax in patients unfit for TIPS or as a palliative intent. E Extracorporeal liver support: consider initiating extracorporeal liver support or standard medical therapy in critically ill patients with ACLF. C 8. Perioperative care Peri-transplant management: consider administering balanced (or normochloremic) crystalloid solution over normal (hyperchloremic) saline for peri-transplant fluid replacement in liver transplant recipients. C Show 4 more 9. Surgical interventions Liver transplantation: As per ACG 2022 guidelines, avoid listing for liver transplant patients with cirrhosis and ACLF still requiring mechanical ventilation because of adult respiratory distress syndrome or brain- related conditions despite optimal therapy. D https://web.pathway.md/diseases/recv7yYarFkEPlvTk 5/6 6/23/23, 2:08 AM Acute-on-chronic liver failure Pathway As per EASL 2018 guidelines, refer patients with ACLF to liver transplant centers early for immediate evaluation. B 10. Specific circumstances Patients with alcohol-associated hepatitis: Administer prednisolone or prednisone (40 mg/day) PO to improve 28-day mortality in patients with severe alcohol-associated hepatitis (MDF 32; MELD score > 20) in the absence of contraindications. B Avoid using pentoxifylline to improve 28-day mortality in patients with severe alcohol-associated hepatitis (MDF 32; MELD score > 20). D References 1. Jasmohan S Bajaj, Jacqueline G O'Leary, Jennifer C Lai et al. Acute-on-Chronic Liver Failure Clinical Guidelines. Am J Gastroenterol. 2022 Jan 10. Open 2. Rahul Nanchal, Ram Subramanian, Waleed Alhazzani et al. Guidelines for the Management of Adult Acute and Acute-on-Chronic Liver Failure in the ICU Neurology, Peri-Transplant Medicine, Infectious Disease, and Gastroenterology Considerations. Crit Care Med. 2023 May 1;51 5 657 676. Open 3. European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol. 2018 Aug;69 2 406 460. Open 4. Rahul Nanchal, Ram Subramanian, Constantine J Karvellas et al. Guidelines for the Management of Adult Acute and Acute-on-Chronic Liver Failure in the ICU Cardiovascular, Endocrine, Hematologic, Pulmonary and Renal Considerations: Executive Summary. Crit Care Med. 2020 Mar;48 3 415 419. Open https://web.pathway.md/diseases/recv7yYarFkEPlvTk 6/6

Guideline sources The following summarized guidelines for the evaluation and management of adenomyosis are prepared by our editorial team based on guidelines from the Society of Obstetricians and Gynaecologists of Canada (SOGC 2023), the European Society of Human Reproduction and Embryology (ESHRE 2023), and the Royal College of Obstetricians and Gynaecologists (RCOG 2012). 1 2 3 Guidelines 1. Screening and diagnosis Clinical presentation: recognize that adenomyosis is associated with heavy menstrual bleeding, pelvic pain, infertility, miscarriage, and adverse pregnancy outcomes. B Indications for testing: consider obtaining a 2D ultrasound to rule out adenomyosis in all patients with recurrent pregnancy loss. C 2. Diagnostic investigations https://web.pathway.md/diseases/recfeoh8FO42JbZbf 1/3 6/23/23, 2:09 AM Adenomyosis Pathway Diagnostic imaging: As per SOGC 2023 guidelines, obtain a transvaginal ultrasound as first-line imaging of suspected adenomyosis in patients with heavy menstrual bleeding, pelvic pain, infertility, miscarriage, and adverse pregnancy outcomes. A Show 2 more As per RCOG 2012 guidelines, obtain pelvic imaging (transvaginal ultrasound or MRI) for the diagnosis of adenomyosis. B 3. Medical management Hormonal therapy: offer oral contraceptives, levonorgestrel-releasing intrauterine system, and dienogest as first-line therapy for pain and heavy menstrual bleeding in patients with adenomyosis. B Show 2 more 4. Therapeutic procedures Uterine artery embolization: consider offering uterine artery embolization for heavy bleeding and pain associated with adenomyosis in patients completed child-bearing and wishing to preserve their uterus. B Thermal ablation: do not offer minimally invasive thermal ablation procedures (such as high- intensity focused ultrasound, radiofrequency ablation, and percutaneous microwave ablation) for the treatment of symptomatic adenomyosis outside of a research context. D 5. Perioperative care Correction of anemia: correct anemia (Hgb < 120 g/L) before adenomyomectomy given the substantial risk of intraoperative hemorrhage. B 6. Surgical interventions Adenomyomectomy: perform adenomyomectomy as a treatment option in patients with symptomatic adenomyosis. B Show 2 more Total hysterectomy: consider offering total hysterectomy for symptomatic adenomyosis in patients completed child-bearing, after appropriate counseling regarding risks, benefits, and alternative treatments. B 7. Patient education https://web.pathway.md/diseases/recfeoh8FO42JbZbf 2/3 6/23/23, 2:09 AM Adenomyosis Pathway Fertility counseling: counsel patients undergoing fertility treatments that the impact of adenomyosis on pregnancy outcomes is uncertain. B Preoperative counseling: Counsel patients undergoing adenomyomectomy about the uncertain impact of this procedure on fertility and pregnancy, including the increased risk of uterine rupture during pregnancy and the need for pre-labor Cesarean delivery. B Counsel patients with dysmenorrhea undergoing surgical management of adenomyosis to have concurrent excision of any coexisting endometriosis during surgery for more complete relief of their symptoms. B References 1. E Shirin Dason, Madalina Maxim, Ari Sanders et al. Guideline No. 437 Diagnosis and Management of Adenomyosis. J Obstet Gynaecol Can. 2023 Jun;45 6 417 429.e1. Open 2. Royal College of Obstetricians and Gynaecologists. The Initial Management of Chronic Pelvic Pain. RCOG. 2012 May. Open 3. ESHRE Guideline Group on RPL, Ruth Bender Atik, Ole Bjarne Christiansen et al. ESHRE guideline: recurrent pregnancy loss: an update in 2022. Hum Reprod Open. 2023 Mar 2;2023 1):hoad002. Open 4. Xuan Che, Jianzhang Wang, Wenting Sun et al. Effect of Mifepristone vs Placebo for Treatment of Adenomyosis With Pain Symptoms: A Randomized Clinical Trial. JAMA Netw Open. 2023 Jun 1;6 6):e2317860. Open https://web.pathway.md/diseases/recfeoh8FO42JbZbf 3/3

Guideline sources The following summarized guidelines for the evaluation and management of adhesive capsulitis are prepared by our editorial team based on guidelines from the American College of Radiology (ACR 2018) and the American Physical Therapy Association (APTA 2013). 1 2 3 3 3 4 Definition Adhesive capsulitis, also known as frozen shoulder syndrome, is the thickening and contraction of the glenohumeral capsule that is characterized by pain, stiffness, and limited function of the glenohumeral joint. 3 Epidemiology The cause of adhesive capsulitis is unknown; however, it is associated with a shoulder injury or surgery, diabetes, rotator cuff injury, cerebrovascular accident, or CVD. 3 Disease course The thickening and contraction of the shoulder capsule and inflammatory changes in the shoulder joint capsule result in adhesive capsulitis, which causes clinical manifestations of pain, stiffness, decrease in the ROM (with flexion, abduction, external and internal rotation) of the affected shoulder. The disease progresses through three phases, namely, painful, stiffness, and recovery or thawing stage. 3 https://web.pathway.md/diseases/receiIdP1bmsyc8PZ 1/4 6/23/23, 2:09 AM Adhesive capsulitis Pathway Prognosis and risk of recurrence Adhesive capsulitis is not associated with an increase in mortality. 4 Pathway Adhesive capsulitis Diagnosis and management Guidelines 1. Screening and diagnosis Differential diagnosis: consider assessing for alternative diagnoses if the reported activity limitations or impairments of body function and structure are not consistent with the diagnosis/clinical presentation of adhesive capsulitis, or if the patient's symptoms do not respond to treatment. E Clinical presentation: recognize that patients with adhesive capsulitis present with a gradual and progressive onset of pain and loss of active and passive shoulder motion in both elevation and rotation. E Show 2 more 2. Diagnostic investigations Functional assessment tools: Use validated functional outcome measures, such as the Disabilities of the Arm, Shoulder and Hand, the American Shoulder and Elbow Surgeons shoulder scale, or the Shoulder Pain and Disability Index, utilized before and after interventions intended to alleviate the impairments of body function and structure, activity limitations, and participation restrictions associated with adhesive capsulitis. A Use easily reproducible activity limitation and participation restriction measures associated with shoulder pain to assess the changes in the level of shoulder function over the episode of care. E Clinical examination: assess for impairments in the capsuloligamentous complex and musculotendinous structures surrounding the shoulder complex when a patient presents with shoulder pain and mobility deficits. Elicit loss of passive motion in multiple planes, particularly external rotation with the arm at the side and in varying degrees of shoulder abduction, which is a significant finding that can be used to guide treatment planning. B Show 2 more Diagnostic imaging: https://web.pathway.md/diseases/receiIdP1bmsyc8PZ 2/4 6/23/23, 2:09 AM Adhesive capsulitis Pathway Obtain a shoulder X-ray as the initial imaging in patients with atraumatic shoulder pain. B Obtain shoulder MRI when initial radiographs are normal or inconclusive in patents with suspected adhesive capsulitis. B 3. Nonpharmacologic interventions Joint mobilization: consider offering joint mobilization procedures primarily directed to the glenohumeral joint to reduce pain and increase motion and function in patients with adhesive capsulitis. C Stretching exercises: instruct patients with adhesive capsulitis to perform stretching exercises, and guide the intensity of the exercises by the patient's tissue irritability level. B 4. Therapeutic procedures Intra-articular corticosteroid injections: perform intra-articular corticosteroid injections in addition to advising shoulder mobility and stretching exercises to improve short-term pain relief and function. A Translational manipulation: Consider performing translational manipulation under anesthesia directed to the glenohumeral joint in patients with adhesive capsulitis who are not responding to conservative interventions. C Consider translational manipulation under anesthesia directed to the glenohumeral joint in patients with adhesive capsulitis who do not respond to conservative treatment. C Electrotherapy: consider performing shortwave diathermy, ultrasound, or electrical stimulation combined with practicing mobility and stretching exercises to reduce pain and improve shoulder ROM in patients with adhesive capsulitis. C 5. Patient education Patient education: educate patients about the natural course of the disease, promote activity modification to encourage functional, pain-free ROM, and ensure that the intensity of stretching matches to the patient's current level of irritability. B References 1. Martin J Kelley, Michael A Shaffer, John E Kuhn et al. Shoulder pain and mobility deficits: adhesive capsulitis. J Orthop Sports Phys Ther. 2013 May;43 5 A1 31. Open 2. Expert Panel on Musculoskeletal Imaging:, Kirstin M Small, Ronald S Adler et al. ACR Appropriateness Criteria Shoulder Pain-Atraumatic. J Am Coll Radiol. 2018 Nov;15 11S S388 S402. Open https://web.pathway.md/diseases/receiIdP1bmsyc8PZ 3/4 6/23/23, 2:09 AM Adhesive capsulitis Pathway 3. Phil Page, Andre Labbe. Adhesive capsulitis: use the evidence to integrate your interventions. 2010 Dec;5 4 266 73.2010 Dec;5 4 266 73. Open 4. Jason Ramirez. Adhesive Capsulitis: Diagnosis and Management. 2019 Mar 1;99 5 297 300.2019 Mar 1;99 5 297 300. Open 5. Joseph D Lamplot, Olivia Lillegraven, Robert H Brophy. Outcomes From Conservative Treatment of Shoulder Idiopathic Adhesive Capsulitis and Factors Associated With Developing Contralateral Disease. Orthop J Sports Med. 2018 Jul 12;6 7 2325967118785169. Open 6. Hai V Le, Stella J Lee, Ara Nazarian et al. Adhesive capsulitis of the shoulder: review of pathophysiology and current clinical treatments. Shoulder Elbow. 2017 Apr;9 2 75 84. Open 7. Richard Dias, Steven Cutts, Samir Massoud. Frozen shoulder. BMJ. 2005 Dec 17;331 7530 1453 6. Open 8. Anthony Ewald. Adhesive capsulitis: a review. Am Fam Physician. 2011 Feb 15;83 4 417 22. Open 9. Shih-Wei Huang, Jia-Wei Lin, Wei-Te Wang et al. Hyperthyroidism is a risk factor for developing adhesive capsulitis of the shoulder: a nationwide longitudinal population-based study. Sci Rep. 2014 Feb 25;4 4183. Open 10. Robert C Manske, Daniel Prohaska. Diagnosis and management of adhesive capsulitis. Curr Rev Musculoskelet Med. 2008 Dec;1 3 4 180 9. Open 11. John M. St Angelo, Sarah E. Fabiano. Adhesive Capsulitis. In: StatPearls Internet]. Treasure Island FL StatPearls Publishing; 2021 Jan. 2020 Oct 27. Open https://web.pathway.md/diseases/receiIdP1bmsyc8PZ 4/4

Guideline sources The following summarized guidelines for the evaluation and management of adnexal torsion are prepared by our editorial team based on guidelines from the Society of Obstetricians and Gynaecologists of Canada (SOGC 2023; 2017) and the American College of Obstetricians and Gynecologists (ACOG 2019; 2016). 1 2 3 4 Guidelines 1. Screening and diagnosis Diagnosis: suspect adnexal torsion in female patients presenting with acute abdominal pain. B 2. Diagnostic investigations Pelvic ultrasound: Obtain ultrasound with and without color flow Doppler as the imaging modality of choice in patients with suspected adnexal torsion. B Recognize that decreased or absent color Doppler flow, increased total ovarian volume, and abnormal adnexal volume ratios may be suggestive of adnexal torsion. B https://web.pathway.md/diseases/recsH3tslb1gzNbmy 1/2 6/23/23, 2:09 AM Adnexal torsion Pathway 3. Surgical interventions Surgical detorsion and cystectomy, indications: as per SOGC 2017 guidelines, perform surgery as soon as possible, recognizing that prompt diagnosis and referral to a surgeon minimize trauma and ischemia to the ovary when torsion is suspected. B Show 2 more Surgical detorsion and cystectomy, technical considerations: As per SOGC 2023 guidelines: Perform laparoscopy as the preferred approach for ovarian cystectomy. B Use sutures or hemostatic sealants over bipolar cautery for hemostasis during cystectomy. B As per SOGC 2017 guidelines, perform laparoscopy as the preferred surgical approach in patients with adnexal torsion. B Show 3 more 4. Specific circumstances Adolescent patients (evaluation): recognize that the most common clinical symptom of adnexal torsion in adolescent patients is sudden-onset, intermittent, non-radiating abdominal associated with nausea and vomiting. E Show 4 more Adolescent patients (management): consult with a obstetrician-gynecologist treating mainly adult patients to manage adnexal torsion in adolescent patients. Recognize that although surgical steps may be similar to those taken when treating adult patients, there are technical adaptations and specific challenges when performing gynecologic surgery in adolescents. E Show 6 more References 1. Sari Kives, Suzy Gascon, lise Dubuc et al. No. 341 Diagnosis and Management of Adnexal Torsion in Children, Adolescents, and Adults. J Obstet Gynaecol Can. 2017 Feb;39 2 82 90. Open 2. American College of Obstetricians and Gynecologists Committee on Practice Bulletins Gynecology. Practice Bulletin No. 174 Evaluation and Management of Adnexal Masses. Obstet Gynecol. 2016 Nov;128 5):e210-e226. Open 3. Tarek Motan, Roland Antaki, Jinglan Han et al. Guideline No. 435 Minimally Invasive Surgery in Fertility Therapy. J Obstet Gynaecol Can. 2023 Apr;45 4 273 282.e2. Open 4. No authors listed. Adnexal Torsion in Adolescents: ACOG Committee Opinion No, 783. Obstet Gynecol. 2019 Aug;134 2):e56-e63. Open https://web.pathway.md/diseases/recsH3tslb1gzNbmy 2/2