Prevention of donor-derived disease among pediatric solid organ transplant recipients requires judicious risk-benefit assessment. Comprehensive guidelines outline specific donor risk factors and post-transplant monitoring strategies to prevent and mitigate transmission of HIV, hepatitis B, and hepatitis C. However, elimination of unanticipated donor-derived infections remains challenging. The objectives of this review are to (1) define risk of anticipated vs. unanticipated disease transmission events in pediatric solid organ transplant recipients; (2) discuss donor presentations that confer greater risk of unanticipated disease transmission; (3) develop a matrix for consideration of donor acceptance; and (4) discuss limitations and future directions for donor screening. Although solid organ transplant confers inherent risk of infection transmission, the risk of significant disease transmission events may be mitigated by a comprehensive approach including donor assessment, consideration of recipient need, post-transplant monitoring, and early intervention. Balamuthia mandrillaris granulomatous amebic encephalitis from a single, four-year-old organ donor who had signs and symptoms of meningoencephalitis and who was incorrectly presumed to have died following influenza A-associated acute disseminated encephalomyelitis  reported two kidney transplant recipients who acquired Solid organ transplantation (SOT) remains the definitive therapy for children with organ failure. Donor-derived infections, while rare, are an inherent risk of solid organ transplantation and may result in significant morbidity and mortality , 3. It iDonor-derived infections can be categorized into two groups: “expected” and “unexpected.” Expected transmission events occur when a known infection is identified in a potential donor, with the recognized potential for transmission to one or more recipients. The most common infections in this category are viral pathogens such as cytomegalovirus (CMV), Epstein-Barr virus (EBV), and hepatitis B and C. Bacterial, fungal, and parasitic transmissions can also occur as the result of infection or colonization of the donor organ, contamination during organ recovery, or transmission through the bloodstream during the transplantation process . PreventUnexpected disease transmission events occur when pathogens are not detected in an organ donor prior to organ recovery or are transmitted to SOT recipients despite routine screening and preventative measures. Unexpected disease transmission events are reported to occur in fewer than 0.2% of SOT recipients but can result in significant consequences for the recipient , 6, 7. WEarly recognition of donor-derived infection is critical for appropriate management. If a SOT recipient develops signs or symptoms of an unusual infection shortly after transplantation, a donor-derived infection should be considered. Recipients with donor-derived infections typically manifest within the first month post-transplant; however, it is important to note that time to presentation may vary significantly depending on the type of infection that is transmitted, the net state of immunosuppression of the recipient, and the type of organ transplanted .Donor-derived neurotropic viruses may result in central nervous system (CNS) disease in as little as one week following transplant, whereas tuberculosis, parasitic infections, and fungal infections may take several months to manifest. Interestingly, donor-derived hepatitis B in liver transplant recipients is often reported more than a year post-transplant . A case Certain donor presentations may confer a greater risk of disease transmission. Screening donors at potentially increased risk for transmission of infection may require evaluation on an individual basis; published guidelines exist to identify donors with behaviors that increase the risk for unanticipated HIV, hepatitis B, and hepatitis C acquisition . These iCoccidioides may transmit the infectious agent to the recipient  organisms has posed a significant threat to SOT recipients who are exposed to these organisms through transplantation. Transplantation from donors who are colonized or infected with MDR gram-negative organisms has resulted in fatal post-transplant infection in SOT recipients despite antimicrobial treatment , 22. RisDespite laboratory screening of potential donors, transmission of respiratory viral infections from donor to recipient does occur. The risk of donor-derived respiratory viral infection is highest among lung transplant recipients –25. WhilCryptococcus gattii, and B. mandrillaris through organ transplant  causes of non-bacterial meningoencephalitis, such as LCMV and arboviruses. Thus, centers should exercise extreme caution in transplanting organs from donors with meningoencephalitis of unknown etiology, and recipients who develop meningoencephalitis require aggressive evaluation. Donor-derived meningoencephalitis typically manifests within the first few weeks to months after transplantation; therefore if a SOT recipient develops CNS symptoms during the early post-transplant period, the possibility of donor-derived meningoencephalitis should be considered . ThorougMycobacterium tuberculosis (TB) infection (Donor-derived pneumonia most often occurs after lung transplantation but has been transmitted through transplantation of other solid organs as well. Typical symptoms that should raise suspicion for pneumonia include fever, dyspnea, and radiographic evidence of lung infiltrates. However, because transplant recipients are immunosuppressed, they may have atypical clinical presentations . Epideminfection . Severalnfection . Fever iFungal infections such as coccidioidomycosis and histoplasmosis have been transmitted from donors who reside in specific geographical regions where these infections are endemic. Histoplasmosis is commonly found in the soil in certain regions of North America, particularly in the Ohio and Mississippi River valleys, whereas coccidioidomycosis is endemic to arid regions of southwest United States. It is estimated that donor-derived histoplasmosis occurs in approximately 1:10,000 transplants, and presents with symptoms of pneumonia, fever, sweats, weight loss, and lymphadenopathy . SimilarStrongyloides stercoralis and Toxoplasma gondii can cause donor-derived infection and have wide geographic distributions (Toxoplasma, as the morbidity and mortality of Toxoplasma gondii infection is unacceptably high (Similarly, parasitic infections such as ibutions , 37. Cliibutions . Symptombly high . Living Any suspected donor-derived infection should be reported promptly to the OPTN through the safety portal and to the responsible organ procurement organization, which will facilitate notification of other impacted recipient centers. Reporting a suspected donor-derived transmission event allows for timely investigation, appropriate management of potentially affected recipients, and implementation of preventative measures. Prompt reporting of a suspected donor-derived infection enables communication between transplant centers to allow for early detection of potential transmission events in other recipients from the same donor, which may mitigate or eliminate the risk of further transmission. In the United States, a passive reporting system is employed. Reported donor-derived transmission events are monitored by the OPTN Ad Hoc DTAC, with the goal of providing education and guidance to prevent future disease transmission events and to develop policies to enhance the safety of organ donation.Solid organ transplantation confers an inherent risk of infection transmission, and mitigation of donor-derived infection remains a challenging yet critical aspect of transplant medicine. Pre-transplant screening of the potential organ donor and recipient, as well as post-transplant monitoring of the recipient, is essential to promptly identify any signs or symptoms of donor-derived disease. Despite these measures, the risk of infection transmission cannot be completely eliminated, and transplant clinicians should report any potential infections to minimize adverse outcomes and prevent future disease transmission.


We assessed the effect of CSF area mask correction on the SBR for idiopathic normal pressure hydrocephalus (iNPH) characterized by CSF area dilatation.Cerebrospinal fluid (CSF) area mask correction reduces the influence of low [123I-FP-CIT single-photon emission computed tomography (SPECT) before shunt surgery or the tap test. The SBRs with and without CSF area mask correction were calculated, and changes in quantitative values were verified. Additionally, the number of voxels in the striatal and background (BG) VOI before and after CSF area mask correction were extracted. The number of voxels after correction was subtracted from that before correction, and the volume removed by the CSF area mask correction was calculated. The volumes removed from each VOI were compared to verify their effect on SBR.We enrolled 25 patients with iNPH who were assessed using The images of 20 and 5 patients with SBRs that were decreased and increased, respectively, by CSF area mask correction showed that the volumes removed from the BG region VOI were higher and lower, respectively than those in the striatal region.The SBR before and after CSF area mask correction was associated with the ratio of the volume removed from the striatal and BG VOIs, and the SBR was high or low according to the ratio. The results suggest that CSF area mask correction is effective in patients with iNPH.This study was registered in the UMIN Clinical Trials Registry (UMIN-CTR) as UMIN study ID: UMIN000044826. 11/07/2021. The accumulation in the striatal region is calculated as the ratio of the background (BG) volume of interest (VOI) [23I-N-fluretation . The spest (VOI) . The Soust (VOI)  is widel123I-FP-CIT accumulation can be mixed in the striatal VOI, which leads to an underestimation of the accumulated amount in the striatal VOI when applying the Southampton method [However, when the region of cerebrospinal fluid (CSF) has expanded because of cerebral atrophy or ventricular enlargement, a CSF region of low n method . Therefon method ; this men method .Idiopathic normal pressure hydrocephalus (iNPH) is characterized by cognitive dysfunction, gait disturbance, and urinary incontinence . Further123I-FP-CIT SPECT and investigated the effect of the correction on the SBR.Idiopathic NPH presents with ventriculomegaly and is likely to include the CSF region in the VOI in the Southampton method. However, to the best of our knowledge, the effects of CSF area mask correction on SBR in iNPH have not been determined. We compared the SBR before and after CSF area mask correction in iNPH using 123I-FP-CIT SPECT before shunt surgery or the tap test were included in this study. Furthermore, to establish the diagnosis of iNPH more reliably, only patients with an Evans index greater than 0.3 were included. This retrospective study was approved by the Ethical Review Committee of Yamagata University Faculty of Medicine .The subjects were patients with iNPH who visited Yamagata University Hospital and were diagnosed based on the guideline diagnostic criteria  between 99mTc-ethyl cysteinate dimer SPECT and 123I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy, eliminating as much as possible DLB and PD, which are characterized by decreased blood flow in the occipital lobe [The iNPH stage composition consisted of four possible cases, six probable cases, and 15 definite cases. All subjects in this study underwent tal lobe  and/or dtal lobe , 19. The123I-FP-CIT SPECT/computed tomography (CT) images over 28 min using a Symbia T2 with a rotating, dual-detector gamma camera  and a low- to medium-energy general-purpose collimator , with 360° continuous rotation (7.0 min/rotation × 4 rotations). Supine patients at rest with their eyes closed were intravenously injected with 123I-FP-CIT (167 MBq), and SPECT/CT images were acquired for 3 h under the following conditions: magnification, 1.45; matrix, 128 × 128 (3.3 mm/pixel); main window, 159 ± 12.0 keV; and sub-window, 8%.We acquired A Gaussian post-processing filter with a full width half maximum of 6.6 mm, six subsets, and eight iterations was applied for ordered subset expectation maximization reconstruction with CT-based attenuation correction, a multi-energy window, and collimator aperture correction for scatter correction.VOIs were placed on the striatum and BG regions determined using the Tossici-Bolt method  Fig. 1)1). We obThe CSF area mask correction creates a standard normal distribution for each VOI in the striatal and BG regions and excludes the low accumulation of the set standard deviation (SD) from the SBR calculation. The SD threshold was set to an average of − 1.0 SD .The SBR can be calculated using DaTView analysis , with differences between facilities corrected by applying the formula derived from the striatal phantom using SPECT/CT, y = 0.9369x + 0.0404 . The SBRRemoving a larger volume via CSF area mask correction results in a higher VOI count. Therefore, we hypothesized that the change in SBR was dependent on whether the volume removed by CSF area mask correction was larger in the striatal VOI or BG VOI. In other words, it was estimated that the SBR increased when the volume removed by the CSF area mask correction in the striatum VOI was larger than the volume removed by the CSF area mask correction in the BG VOI. Moreover, it was estimated that the SBR decreased when the volume removed by the CSF area mask correction in the striatum VOI was smaller than the volume removed by the CSF area mask correction in the BG VOI. The number of voxels in each VOI before and after CSF area mask correction was extracted from DaTView . The number of voxels after CSF area mask correction was subtracted from that before it, and the volume removed by the CSF area mask correction was calculated. The volumes difference between the striatal VOI and BG VOI removed by CSF area mask correction were calculated as follows:A database of Japanese healthy controls shows the upper and lower limits of the 95% prediction interval for each age . We compP-value of less than 0.05 was considered statistically significant.Spearman’s rank-order correlation was used to evaluate the relationship between the Evans index and the value of SBR change before and after CSF area mask correction. In addition, we analyzed the relationship between the changes in SBR before and after CSF area mask correction and the volume difference between the striatal VOI and BG VOI removed by CSF area mask correction by the same statistical analyses. Statistical analysis was performed using SPSS software , and a p = 0.11)  Fig. .p < 0.001).The volumes of the striatal and BG region VOIs removed by CSF area mask correction are shown in Table We compared the SBRs before and after CSF area mask correction using the phantom formula and the database of healthy controls by age Fig. . The SBRThis is the first study to evaluate the SBRs before and after CSF area mask correction in patients with iNPH characterized by Sylvian fissures and ventricular enlargement, i.e., disproportionately enlarged subarachnoid-space hydrocephalus. Recently, a study assessing the effect of CSF mask correction in parkinsonian syndromes with ventriculomegaly, such as PD and PSP, has been reported . In thisInterestingly, changes in SBR with CSF mask correction in patients with iNPH were not constant in the present study. The SBR with CSF area mask correction was low in 20 patients and high in five patients compared with the uncorrected SBR. The changes in SBR were related to the ratios of the volumes removed by CSF mask correction from the striatal and BG regions. That is, individual differences in the enlargement of Sylvian fissures and the anterior horn of the lateral ventricle affected the SBR. The VOI analysis of the Southampton method is based on the premise that nonspecific accumulation in the BG regions is uniform. Therefore, CSF area mask correction might be particularly useful for diseases in which there are large individual differences in the enlargement of Sylvian fissures and cerebral ventricles.It should be noted that the SBR after CSF area mask correction was below and near the lower limit of the 95% prediction interval of the normal database by age in one patient each. These findings suggest that CSF area mask correction might affect the visual and quantitative assessment of iNPH. The pathophysiology of DAT reduction, which was observed in approximately 30–60% of iNPH, has not been clarified –14. TherThis study had several limitations. First, we excluded patients with PD and DLB as much as possible based on cerebral blood flow SPECT/CT and MIBG myocardial scintigraphy; however, other iNPH-like disorders may have been included. Recently, a study reported that iNPH and α-synucleinopathy often coexist, with approximately 30% of iNPH cases meeting the diagnostic criteria for PD or PD with dementia and approximately 10% for DLB . iNPH wiThe SBR before and after CSF area mask correction was associated with the ratio of the volume removed from the striatal and BG VOIs, and the SBR was high or low according to the ratio. The results may indicate that CSF area mask correction is effective, particularly in patients with iNPH characterized by ventriculomegaly. In the future, further studies investigating the effect of CSF area mask correction for other neurodegenerative diseases are also needed.


Kidney transplantation in children in 1970 was considered by many to be unethical, as long-term survival was minimal. It was therefore risky at the time to offer transplantation to a child.eGFR 41 ml/min/1.73 m2) and no haematuria, proteinuria or hypertension. Except for benign skin lesions due to azathioprine, and undergoing an aortic valve replacement and an aortic aneurysm repair in adulthood, the now 58-year-old man has had no major complications.A 6-year-old boy with kidney failure due to haemolytic uraemic syndrome received 4 months of intermittent peritoneal dialysis followed by 6 months of haemodialysis until at 6 years and 10 months, he underwent bilateral nephrectomy and received a kidney transplant from a deceased 18-year-old donor. Despite moderate long-term immunosuppression of prednisone (20 mg/48 h) and azathioprine (62.5 mg/day), at the last visit in September 2022, he was well, normotrophic, with a serum creatinine of 157 µmol/l (We speculate that stable and unmodified immunosuppressive therapy, started before the era of calcineurin inhibitors, the lack of significant rejection episodes, the absence of donor-specific antibodies, and the young donor age have contributed to maintaining exceptional long-term kidney transplant survival. Luck, a robust health system and an adherent patient are also important. To the best of our knowledge, this is the longest functioning kidney transplant from a deceased donor performed in a child worldwide. Despite its risky nature at the time, this transplant paved the way for others. Treatment of kidney failure with haemodialysis and kidney transplantation in children began in the USA in the late 1960s, with reasonable results despite many unresolved problems . Kidney The patient, a previously healthy boy of Swiss origin, was hospitalized at the Geneva University Children’s Hospital at the age of 5 years and 10 months with haemolytic uraemic syndrome (HUS). Intermittent weekly peritoneal dialysis was initially required beginning in February 1970 as his kidneys did not recover. On June 15, 1970, the boy was transferred to the Zurich University Children’s Hospital for haemodialysis in anticipation of a deceased donor kidney transplant. The primary goal of switching to haemodialysis was to improve his poor nutritional status . Haemodialysis was performed for 5 h, 3 times weekly for 6 months, using a Gambro 6 plate (paediatric) dialyser . The 18-year-old donor had suffered brain injury. Histocompatibility testing revealed an identical blood group (A) and a negative crossmatch. HLA matching in retrospect is unclear, with 1 or 2 possible known mismatches [Bilateral nephrectomy was performed in the recipient (standard in Zurich at the time), and the graft was inserted into the right renal fossa. The two donor renal arteries were anastomosed to the aorta and the renal vein to the vena cava. Urine output started immediately. Initial immunosuppression consisted of methylprednisolone followed by prednisone (15 mg/day), azathioprine (50 mg) and 26 days of 5 ml of ALG . A mild rejection episode, diagnosed clinically with fever, tenderness over the graft and a 60% rise in serum creatinine at 2 weeks after transplantation, responded well to an increase in prednisone to 60 mg/day followed by a rapid decrease to 30 mg/day and doubling of ALG to 10 ml/day. A second mild rejection episode was clinically suspected due to tenderness over the graft despite stable kidney function at 4 weeks after transplantation. Prednisone was again increased to 60 mg and then reduced at 3-day intervals to 45 mg and 30 mg. The boy was discharged 8-week post-transplant on daily prednisone 30 mg (later slowly reduced to 15 mg) and azathioprine 37.5/50 mg on alternate days. As expected, he developed Cushing syndrome. At the age of 8 years, daily prednisone was therefore switched to alternate day (20 mg), permitting growth along the 3rd percentile. The patient attended regular school and leads a normal adult life.2. He has no haematuria, albuminuria or proteinuria, no hypertension, no lipid abnormalities and no diabetes. Immunosuppression still consists of prednisone (20 mg/48 h) and azathioprine (62.5 mg/day). Further donor HLA typing was attempted from the recipient’s urine without success. Crucially, he has no anti-HLA antibodies, except an anti-DP1 at low mean fluorescence intensity (MFI), therefore no significant donor-specific antibodies. Assessment of tolerance is not possible. Genetic analysis showed a homozygous CFHR3/CFHR deletion associated with atypical HUS (aHUS). He never experienced disease recurrence. Non-kidney complications have included surgical repair of an aneurysm of the ascending aorta at age 45 years and prosthetic aortic valve replacement for severe aortic insufficiency at age 57 years. Due to azathioprine, he has had benign keratoses.As of September 2022, the patient is well, height 168 cm (expected height on 50th percentile was 177 cm), weight 52 kg, serum creatinine 157 µmol/l and eGFR (CKD-EPI) 41 ml/min/1.73 mThe late 1960s was a pioneering time for dialysis and kidney transplantation, particularly in children . Long-teThe senior author (E. L.) had received training in 1969 in San Francisco with a view to introducing kidney replacement therapy for children in Switzerland. Long-term haemodialysis could only be offered once the transplant surgeon agreed to accept a young child for deceased donor transplantation. Living donor transplantation was not regarded as acceptable at the time because 1-year graft survival was < 50% . The chiScepticism, however, arose from several sides. The boy’s parents had to face the dilemma of the very limited perspective offered by dialysis and the unknowns of transplantation. A nephrologist elsewhere advised the family against transplantation. In addition, several colleagues within the hospital criticized this treatment. The engagement of the nurses, who first had to be trained in haemodialysis see Fig.  and thenWe now know that the numerous determinants of impaired graft survival include development of donor-specific antibodies, rejection, infection, malignancy, primary disease recurrence, and low adherence to lifelong drug intake –10. DespIt was great luck that the donor was young, the patient was not sensitized despite the multiple transfusions, and only experienced two minor rejection episodes. The immunosuppression with prednisone and azathioprine, started before the era of calcineurin inhibitors, was not modified, following the principle of “never changing a winning horse”. The kidney was therefore spared potential calcineurin toxicity. Crucially, he still has no significant  donor-specific antibodies . Additionally, despite having aHUS as a risk factor, he did not experience any disease recurrence. Furthermore, the patient has always had access to quality medical care and medication and has been adherent all his life. All of these factors contributed to graft function which remains good at 52 years of follow-up. To the best of our knowledge, this is the longest functioning kidney transplant from a deceased donor performed in a child worldwide and is testament to the importance of robust health systems that facilitate optimal health outcomes.


Before fatal complications, such as intracranial infection, occur, early recognition and prompt treatment are essential. (2) Methods: The clinical data of 475 patients who underwent MVD surgery from September 2020 to March 2023 were retrospectively analyzed. In these patients, if there were any symptoms of CSF leakage, and if CSF leakage was evident, a lumbar drainage catheter was inserted immediately. (3) Results: CSF leakage was suspected in 18 (3.8%) patients. Five of these patients (1.1%) showed signs of CSF leakage during conservative management and subsequently underwent catheter insertion for lumbar drainage. The lumbar drain was removed after an average of 5.2 days, resulting in an average hospitalization of 14.8 days. In all 5 patients, CSF leakage was resolved without reoperation. (4) Conclusions: Our treatment strategy prevented the development of fatal complications. Close observation of the symptoms and postoperative temporal bone computed tomography and audiometry are considered to be good evaluation methods for all patients. If CSF leakage is certain, it is important to perform lumbar drainage immediately. Cerebrospinal fluid (CSF) leakage after microvascular decompression (MVD) via the posterior fossa is one of the most common and significant problems ,2. In neTo date, various techniques have been suggested to prevent and treat CSF leakage. Although the incidence of CSF leakage is lower than before, it is still a major complication of MVD surgery . IncomplA retrospective analysis was performed on the clinical data of all patients who underwent MVD surgery between September 2020 and March 2023. All surgeries were performed by a single surgeon (Kwan Park). This study was approved by the institutional review board. The study involved the clinical data of 475 MVD surgeries that were performed on patients with various neurovascular conflict syndromes. Among these surgeries, 427 were performed to treat hemifacial spasm. Additionally, 47 surgeries were performed to treat trigeminal neuralgia, and one surgery was performed to treat glossopharyngeal neuralgia. The study group consisted of 131 males and 344 females. The median age of the patients was 58 years, ranging from 19 to 82 years .®; Integra Lifescience, Princeton, NJ, USA) for dural sutures was based on the check valve theory: covering with an absorbable fibrin sealant patch  and spraying fibrin glue . Finally, polymethyl methacrylate (PMMC) bone cement was fixed to the drilled out site  for careful observation of possible complications of a lumbar drain, such as overdrainage. In the sub-ICU, one nurse was assigned to each unit, allowing for more personalized patient care. In the absence of symptoms, the drainage volume was maintained. Five days after CSF drainage, the draining catheter was clamped from midnight to noon. After clamping for half a day, the presence of symptoms such as rhinorrhea and pseudomeningocele was checked. The catheter was removed if there were no symptoms. If there were symptoms, but fewer than there were before CSF diversion, we planned to maintain the catheter and CSF drainage for 2 more days, and if the symptoms were the same as before CSF drainage, we planned to consider revision surgery .In our study, which included a total of 475 patients, CSF leakage was suspected in 18 patients, representing a prevalence of 3.8%. Of the patients with suspected CSF leakage, 17 underwent MVD surgery to treat hemifacial spasm and 1 to treat trigeminal neuralgia. Of the 18 patients with suspected CSF leakage, 5 (1.1%) had a strong suspicion of CSF leakage, and all of these patients had lumbar drainage catheters; the remaining 13 patients did not have a lumbar drainage catheter. In all 18 patients, the mastoid air cell opened during surgery. Symptoms related to CSF leakage occurred within an average of 3.3 days (range: 2–6 days) after surgery. Among the 13 patients who did not have a lumbar drainage catheter, the average length of hospital stay was 8.2 days (range: 7–13 days). Meanwhile, among the five patients who underwent lumbar drainage, the average time from surgery to catheter insertion was 5.2 days (range: 3–8 days). The lumbar drainage catheter was maintained in the subarachnoid space for an average of 5.2 days (range: 4–6 days). The average length of stay for these five patients was 14.8 days (range: 13–19 days). All five patients who underwent lumbar drainage complained of hearing difficulties. Following consultation with an otolaryngologist, they were diagnosed with conductive hearing loss .As a result, both patients with a lumbar drainage catheter and those without a catheter due to mild symptoms recovered without reoperation and without recurrence of CSF leakage symptoms and did not progress to meningitis and brain abscess .A 59-year-old woman developed right eye and mouth twitching 2 years prior to admission and was diagnosed with HFS. After 3 botulinum toxin treatments, she was referred to our institution for MVD surgery. The offending vessel was a tandem type of right AICA and VA . After dIn the evaluation of CSF leakage, it is important to accurately assess the patient’s symptoms and initiate prompt evaluation and treatment when symptoms develop. We also suggested that pre- and postoperative TBCT and audiometry tests are helpful in evaluating CSF leakage. And diagnostic tests can be used in coordination with clinical symptoms to evaluate CSF leakage.The first and simplest test to assess CSF leakage is a glucose oxidase test because it is easy to carry out and not expensive. However, it is not recommended as a confirmatory test due to its high false-positive and false-negative rates . This isOther clinicopathologic diagnostic tests may include a beta-2 transferrin (β-2 trf) or a beta-trace protein (β-TP) test. Beta-2 transferrin is a specific isoform of transferrin that is found only in the CSF, vitreous humor of the eyeball, and perilymph. The presence of beta-2 transferrin in CSF can be considered a reliable indicator because it is not present in other body fluids and is not affected by the patient’s condition. The most commonly used detection technique is immunofixation electrophoresis. This test has been reported to have a sensitivity of 99% and a specificity of 97% , and othIn our institute, there were 18 suspected CSF leakage cases (3.8%), and five patients (1.1%) showed a very high possibility. In several studies, the various etiologies of CSF leakage in surgery via the retro-mastoid suboccipital approach include vascular lesions, tumors, and neurovascular compression, and the incidence of cases with such etiologies is 0–22% ,6,18. OuCSF leakage may occur as surgical site leakage, including pseudomeningocele, ottorhea, or rhinorrhea ,20,21. CWe analyzed the results of imaging tests such as TBCT, consulted with an otolaryngologist, and assessed the patients’ clinical features to determine the possibility of CSF leakage and proceed with treatment. Among these, it was relatively important to evaluate the effusion of mastoid air cells by performing a TBCT for all patients 3 days after MVD surgery. Normally, all patients who undergo cranial surgery undergo a brain CT immediately after surgery to evaluate the presence or absence of postoperative hemorrhage and the condition of the surgical site, but in addition, MVD patients undergo a TBCT on the third day after surgery. In patients with intraoperative mastoid air cell opening, the possibility of CSF leakage was assessed to be low even if the patients had symptoms such as slight rhinorrhea or hearing difficulty when there was no middle ear effusion or pseudomeningocele on follow-up TBCT. Accordingly, it is considered important to check temporal bone computed tomography (CT) scans for signs of possible subcutaneous CSF collection and the effusion of mastoid air cells. For that reason, we checked all patients by TBCT on the third day after surgery, which was useful for patient evaluation . In addiThe insertion of a lumbar drainage catheter was first mentioned by Voursh in 1960 . A lumbaLumbar drainage catheter insertion in itself is a fairly invasive procedure. In addition to mild complications such as headache, nausea, and vomiting, fatal complications such as meningitis, intracranial hemorrhage, and brain herniation due to the overdrainage of CSF may occur ,24,25,26Invasive catheterization, such as lumbar drainage and extraventricular drainage, is closely related to the occurrence of central nervous system infections, such as meningitis.p = 0.0037), longer hospitalization , and CSF leakage through the lumbar puncture site (p < 0.0001). The predominant pathogen was methicillin-resistant coagulase-negative staphylococcus (MRCNS) [Liang et al. analyzed risk factors for lumbar drain-related infections. Out of a total of 629 patients with a lumbar draining catheter, infection occurred in 36 (5.7%) patients, with significant risk factors being the in-dwelling of a lumbar drainage catheter for more than 4 days ( (MRCNS) . TherefoWe also used first-generation cephalosporin prophylactic antibiotics during the period of lumbar drainage catheter placement to prevent infections associated with lumbar drain catheters. However, it is important to recognize that the use of prophylactic antibiotics remains controversial. Some authors suggest that prophylactic antibiotics are effective in reducing the incidence of meningitis; they claim that these antibiotics help to prevent the development of infection by eliminating or suppressing potential pathogens. On the other hand, there are authors who express concern about the use of prophylactic antibiotics. They argue that these antibiotics have the potential to disrupt normal microbial communities. This disruption can lead to an increased risk of infections, including meningitis. Critics of prophylactic antibiotic use emphasize the increased potential for the development of antibiotic-resistant bacterial infections, the increased risk of drug side effects, and more ,28,29. WLimitations of this study include a small sample of patients with CSF leakage and the need for larger studies to identify more effective management strategies. Further analysis is needed to identify the risk factors for CSF leakage after MVD surgery. As more cases of CSF leakage accumulate, a comprehensive risk assessment for prognosis may be possible.Efforts have been devoted to mitigating CSF leaks during cranial surgery; however, complete prevention of CSF leaks remains challenging, particularly in MVD via posterior fossa approach. Nonetheless, significant progress has been made in reducing the occurrence of CSF leaks, thereby leading to a reduced risk of fatal complications such as cerebral abscess and meningitis. It is crucial to emphasize the importance of early and accurate diagnosis, as well as the importance of effective CSF diversion through a lumbar draining catheter.While our methods have proven to be successful in preventing serious complications associated with CSF leaks, methods to ensure complete prevention remain elusive. In our study, all patients with CSF leakage had conductive hearing loss, so it is helpful to follow up with temporal bone CT after surgery and perform pre- and postoperative audiometry on all patients for an early diagnosis. The lumbar drainage catheter was maintained for an average of 5.2 days, draining approximately 200 cc of CSF per day.In summary, while complete prevention of CSF leaks during MVD surgery remains a challenge, significant progress has been made in reducing their occurrence and associated complications. Early diagnosis, CSF drainage with lumbar drains, and implementation of the triple-layer suturing technique for closing the dura have been proven to be beneficial; however, further research is needed to improve diagnostic approaches, determine optimal protocols, and identify risk factors for CSF leakage in larger patient populations.


The fluid compartment surrounding the central nervous system (CNS) is a unique source of immune cells capable of reflecting the pathophysiology of neurologic diseases. While human clinical and experimental studies often employ cerebrospinal fluid (CSF) analysis, assessment of CSF in animal models of disease are wholly uncommon, particularly in examining the cellular component. Barriers to routine assessment of CSF in animal models of multiple sclerosis (MS) include limited sample volume, blood contamination, and lack of feasible longitudinal approaches. The few studies characterizing CSF immune cells in animal models of MS are largely outdated, but recent work employing transcriptomics have been used to explore new concepts in CNS inflammation and MS. Absence of extensive CSF data from rodent and other systems has curbed the overall impact of experimental models of MS. Future approaches, including examination of CSF myeloid subsets, single cell transcriptomics incorporating antigen receptor sequencing, and use of diverse animal models, may serve to overcome current limitations and provide critical insights into the pathogenesis of, and therapeutic developments for, MS. By a model [it is meant a] construct which, with the addition of certain verbal interpretations, describes observed phenomena. The justification of such a mathematical construct is solely and precisely that it is expected to work – that is, correctly to describe phenomena from a reasonably wide area. Furthermore, it must satisfy certain esthetic criteria – that is, in relation to how much it describes, it must be rather simple.— John von Neumann 1.1.A lumbar puncture, or spinal tap, has routinely been utilized diagnostically and/or therapeutically since its development as a modern medical procedure in the late 19th century . Examinade facto limitation of focusing solely on the blood to study the initiation and propagation of inflammatory demyelination in MS. Significant differences in lymphoid and myeloid composition and phenotypic traits between CSF and blood have been described in MS. For example, the ratio of CD4 and CD8 T cells is distorted between compartments in MS, with flow cytometric studies demonstrating a higher CD4/CD8 ratio in the CSF ] and Picornaviridae [Theiler’s murine encephalomyelitis virus (TMEV)] have been utilized to explore pathogenic mechanisms and therapies for CNS inflammatory demyelinating diseases  that develop spontaneous encephalomyelitis, OCBs can be detected  typically weigh over several kilograms, availing them to CSF studies. Indeed, more contemporary studies using EAE in rhesus monkeys include efforts to characterize the effects of disease-modifying therapy on leukocyte trafficking in the CNS. Analyzing leukocytes obtained via the cisterna magna  using flow cytometry at disease onset demonstrated that the CSF infiltrate was composed primarily of T cells and monocytes as opposed to B cells (Macaca fascicularis) do not routinely harbor unique OCB within the CSF 4 weeks after immunization with spinal cord homogenate emulsified in CFA (Important work emphasizing the contribution to MS by B cells has utilized primate models. In Japanese macaques (detected . A more  jacchus  has been jacchus , 2011. H B cells , whereas B cells . While t B cells . Again, d in CFA . While sOther animal systems for modeling MS exist but are not commonly used and have employed limited CSF assessment. For example, spinal fluid examination during canine EAE identified a conspicuous pleocytosis obtained from unmentioned quantities of CSF . An idio3.post-hoc. This would mitigate some of the negative consequences from pooling of specimens, including contamination from one or more samples and/or blunting of biological variability (The examination and characterization of CSF immune cells in various animal models is still quite insufficient relative to its potential for shedding light on the immune mechanisms of neuroinflammation in MS. Clearly, overcoming limited sample volumes obtained from different animals is essential. As shown recently in an elegant study exploring the role of alternatively activated neutrophils in neuroinflammation, diminutive anatomic tissues can still serve as a viable source of immune cells . Whetheriability . Barcodiiability , transcriability  and coul4.Cellular characterization of the CSF is important to capturing unique features of inflammatory demyelination of the CNS and a complete understanding of the nature of MS. High dimensional CSF studies have not been fully leveraged in animal models of MS, which limits the utility of modeling altogether. Given access from the compartment adjacent to the tissue injured by immune responses, CSF not only harbors key immune ingredients, but likely mirrors the events occurring in the CNS borders and parenchyma during disease. Although challenges persist, efforts to build upon current data are deemed worthwhile and several current and emerging opportunities are available for optimal analysis of CSF from animal models of MS. Future CSF studies exploring similarities and differences between models will clarify the utility of each model system and ultimately lead to translational contributions from animal modeling of MS.GFW is solely responsible for the content of this manuscript.This work was supported in part by Merit Award # I01CX002383 from the United States Department of Veterans Affairs Clinical Sciences Research and Development Service. GFW was also supported by R21 NS121818 from the NINDS.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The reviewer OS declared a past co-authorship with the author GFW to the handling editor.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Here, we utilize non-invasive MRI methods to explore surrogate measures of CSF production, bulk flow and egress in the context of independent PET measures of amyloid-β accumulation in older adults. Participants (N = 23) were scanned at 3.0 T with 3D T2-weighted turbo spin echo, 2D perfusion-weighted pseudo-continuous arterial spin labelling and phase-contrast angiography to quantify parasagittal dural space volume, choroid plexus perfusion and net CSF flow through the aqueduct of Sylvius, respectively. All participants also underwent dynamic PET imaging with amyloid-β tracer 11C-Pittsburgh Compound B to quantify global cerebral amyloid-β accumulation. Spearman’s correlation analyses revealed a significant relationship between global amyloid-β accumulation and parasagittal dural space volume , specifically in the frontal  and parietal  subsegments. No relationships were observed between amyloid-β and choroid plexus perfusion nor net CSF flow. Findings suggest that parasagittal dural space hypertrophy, and its possible role in CSF-mediated clearance, may be closely related to global amyloid-β accumulation. These findings are discussed in the context of our growing understanding of the physiological mechanisms of amyloid-β aggregation and clearance via neurofluids.One of the pathological hallmarks of Alzheimer’s and related diseases is the increased accumulation of protein amyloid-β in the brain parenchyma. As such, recent studies have focused on characterizing protein and related clearance pathways involving perivascular flow of neurofluids, but human studies of these pathways are limited owing to limited methods for evaluating neurofluid circulation non-invasively  et al. report that parasagittal dural (PSD) space hypertrophy, specifically in frontal and parietal subsegments, is associated with increasing amyloid-β accumulation in Alzheimer’s disease patients. These results suggest that PSD space may be related to cerebrospinal fluid egress and amyloid-β waste clearance.Song   Aβ accumulation can be identified using PET radioligands such as 12 The majority of CSF production occurs in the lateral and third ventricles, after which this CSF flows caudally through the aqueduct of Sylvius to the fourth ventricle and subsequently to the subarachnoid space (SAS) through the foramen of Magendie and Luschka, after which a portion of this fluid transits to the dural venous sinuses to be resorbed into the blood circulation via arachnoid granulations. There is increasing evidence that CNS waste product clearance may also occur along perivascular and interstitial spaces.11 In this explanation, CSF flows from the SAS to the periarterial space where it then transits to interstitial space, as governed by periarterial aquaporin 4 channels (AQP4).14 It has been proposed that fluid motion in the brain parenchymal interstitial space moves fluid into the perivenous space via AQP4 channels.15 Very recently, CSF egress evaluated using intrathecally administered contrast agents has also been proposed to occur along the parasagittal dural (PSD) space which surrounds the sagittal sinus.16-18 While features of these pathways remain to be elucidated, proximal and distal features of the neurofluid circulation, comprising ChP activity, CSF flow through the aqueduct and PSD anatomy likely have relevance to the clearance of neurofluids from the CNS.More specifically, CSF production primarily occurs in the choroid plexus (ChP) complexes, an extension of the ependymal epithelium located in the brain’s ventricles.in vivo and non-invasively.20 In previous work, we observed age-related hypertrophy of both the ChP and PSD. We also observed decreases in ChP perfusion and caudal CSF flow through the aqueduct of Sylvius with increasing age. Here, we apply measures of ChP activity, net CSF flow, PSD volume and Aβ plaque accumulation in sequence in patients with Alzheimer’s disease to test the hypotheses that patients with higher levels of Aβ burden have: (i) reduced ChP perfusion  reerfusion  and  and Petersen/Winblad (1 memory measure <1.5 SD) diagnostic frameworks.23 Clinical criteria were based on consensus determination following examination by a board-certified neurologist (D.O.C.) and board-certified neuropsychologist (C.M.C.) which includes a Clinical Dementia Rating (CDR) as well as a multi-domain cognitive exam .24-26 Biomarker probability criteria were based on Aβ PET read by a board-certified neuroradiologist (C.D.M.). Participants were excluded from the study if they had any contraindications to either 3 T MRI or PET as defined by the institutional standard screening criteria including pregnancy and ferrous metal implants. Participants were also excluded if radiological findings consistent with an independent neurological and/or neurovascular condition  were observed upon MRI review.The inclusion criteria for the study included participants between the ages of 55 and 80 years (inclusive) with clinic-pathological diagnosis of either amnestic mild cognitive impairment (aMCI) due to Alzheimer’s disease-intermediate likelihood or probable Alzheimer’s dementia-intermediate likelihood, per criteria based on recommendations from the National Institute on Aging and Alzheimer’s Association workgroups diagnostic guidelines.27 The RBANS is a clinical neuropsychological test battery designed specifically for the diagnosis and longitudinal monitoring of cognitive status.26 The measure was designed to optimize sensitivity for the detection of prodromal manifestation of dementia while remaining brief enough in administration length to lend itself to diverse clinical and research assessment settings. The RBANS generates age-normed scaled or percentile scores for all subtests, collapsed into index scores for five cognitive domains, along with a global cognitive functioning total index score. Clinical research has established strong associations between RBANS and performance on longer-length neuropsychological batteries, the six domains of the CDR, clinical–functional diagnosis of MCI and dementia syndromes, biomarkers in Alzheimer’s disease, as well as response to intervention in clinical trials, making the measure a gold-standard of cognitive-behavioural phenotyping in MCI/dementia research.28Immediately prior to imaging, participants underwent a neuropsychological examination consisting of the Montreal Cognitive Assessment and RBANS to characterize cognitive status. The Montreal Cognitive Assessment is a cognitive screen that incorporates items with appropriate range of difficulty to provide sensitivity to MCI and facilitate differentiation of dementia stage deficits, while also assessing a breadth of cognitive domains beyond memory, which allows for improved sensitivity to atypical/non-amnestic cognitive syndromes.1-weighted magnetization-prepared-rapid-gradient-echo  for anatomical reference, 3D T2-weighted volume isotropic-turbo-spin-echo-acquisition  for PSD volumetric measurement, and 2D T2-weighted fluid-attenuated inversion recovery  turbo-spin-echo for ChP segmentation. A 2D dual-pulse background-suppressed pseudo-continuous arterial spin labelling  sequence was applied to quantify ChP and cortical perfusion. A 2D readout was used to reduce artefacts from signal smearing in the phase encode direction, common in 3D GRASE readouts, to ensure accurate localized blood flow quantification in the ChP. For this scan, an equilibrium magnetization (M0) scan was sequentially acquired with identical geometry and scanner gain, but with pseudo-continuous arterial spin labelling preparation removed and TR = 15 000 ms. A phase-contrast angiography acquisition  was adapted to quantify net CSF flow draining from the lateral and third ventricles at the level of the aqueduct of Sylvius.20Participants were scheduled for same-day MRI and PET scans between 8:00 am and 11:00 am. All participants were scanned at 3T  using a body coil radiofrequency transmission and phased array 32-channel reception with the placement of four MRI-compatible ECG leads for cardiac phase correction as described below. The scanning protocol consisted of a 3D T11C-PIB, a 70 min dynamic PET scan was acquired . Data from the PET scans were reconstructed with a 3D-FRP (direct Fourier method with Fourier reprojection) algorithm for dynamic and a 3D-ordered subset expectation maximum algorithm for static analyses, achieving an isotropic 2.0 mm reconstructed image spatial resolution.All PET scans were acquired using a Philips Vereos Digital PET/CT scanner  with 3D emission acquisition. First, a 5 min transmission scan was also performed to enable attenuation correction. Next, following an intravenous bolus injection of 3) from 3D T2-weighted MRI.The goal of the MRI analysis was to provide quantitative measurements of ChP perfusion (ml/100 g/min) from arterial spin labelling MRI, net CSF flow (ml/min) from phase-contrast MRI and PSD volume  based on a 3D U-Net architecture adapted from Zhao et al.30 The neural network was trained on a training data set of 30 manual ChP segmentations that were visually inspected by a board-certified neuroradiologist (C.D.M.) for accuracy. The generated output masks were then back-transformed to native T1-weighted space for ChP perfusion quantification  estimated with a skull-stripped T1-weighted MPRAGE image, to calculate mean perfusion (ml/100 g/min) within the generated ChP masks.ChP perfusion was calculated using a previously published deep-learning segmentation pipeline.fication . Perfusi20Volumetric flow parameters of CSF through the aqueduct of Sylvius were derived from acquired phase-contrast data that were retrospectively cardiac phase-corrected (12 cardiac phases) from the ECG traces during acquisition. The sequence was planned such that the acquisition slice was orthogonal to the aqueduct of Sylvius in the sagittal view . A mask 2-weighted scans . The PSD was further subdivided into four subregions: the prefrontal, frontal, parietal and occipital PSD. The prefrontal PSD and the frontal PSD are distinguished by a plane crossing through the pituitary gland and the rostrum of the corpus callosum such that the prefrontal PSD lies ventral to the plane and the frontal PSD lies dorsal to the plane. The parietal region was delineated from the frontal PSD using the central sulcus and extends to the parietal–occipital fissure; finally, the occipital PSD was delineated from the parietal–occipital fissure to the most posterior portion of the PSD. The resulting masks were then transformed back to native T2-weighted space using the inverse transform. In this work, we investigated total and regional PSD volumes all expressed in cubic centimetres (cm3).PSD segmentation masks were generated using participant 3D Ted scans .19 An N41-weighted MPRAGE images were used for whole brain segmentation using the AssemblyNet segmentation framework.34 A global region of interest mask of cortical and subcortical regions susceptible to Aβ accumulation was created with the segmentation output similar to the global mask used in Klunk et al.35 A list of the brain regions included in this mask is outlined in Participant T1-weighted space for partial volume correction and Aβ quantification using FSL’s FLIRT with six degrees of freedom and mutual information cost function . Region-based voxel-wise (RBV) partial volume correction was then applied to the registered SUV data.36 Global mean values for SUV were calculated using the segmented global mask and a 10% trimmed mean value to improve robustness.36 The global mean SUV was then normalized to cerebellar grey matter (GM) SUV  to account for non-specific tracer binding and generate a SUV ratio (SUVr). Several studies have demonstrated that the use of the cerebellar GM as a reference region in quantifying Aβ burden with 11C-PIB produced the largest effect sizes in differentiating Aβ-positive and -negative scans.37Parametric standardized uptake value (SUV) maps were calculated from the last 20 min of the scan . The PMOD software package  was used to evaluate the SUV on a voxel-wise basis. Participant SUV data were rigidly registered to native T38 The first step uses the simplified reference tissue model to fit three parameters: non-displaceable binding potential (BPND), relative tracer delivery (R1) and reference region efflux constant .Statistical analyses were performed using the R software package . Anderson–Darling Goodness of Fit tests were applied to all quantitative imaging data to test if the data are normally distributed. We performed the following separate analyses with Spearman’s rank-order correlation tests:ND quantified by SRTM2 in subsequent analyses, we assessed the agreement of global Aβ burden with static (SUVr50–70) and dynamic (BPND + 1) models. BPND + 1, equivalent to the distribution volume ratio, was used in this specific hypothesis for direct comparison with SUVr50–70 as previously published.40To understand the similarity of BP11C-PIB BPND and the imaging biomarker of interest . Significance criteria for all primary hypotheses were set at P < 0.05.To test the primary hypotheses, we assessed the relationship between 11C-PIB BPND and subsegmental PSD volumes. Multiple comparison corrections were applied for post hoc analyses with a false discovery rate (FDR)-calculated P < 0.05.41In an exploratory analysis of the relationship between global Aβ burden and specific subregions of the PSD, we assessed the correlation between global To test whether PSD hypertrophy was a product of general brain atrophy, we assessed the correlation between cumulative grey matter and white matter (GM + WM) tissue volume and total PSD volume. We also assessed this relationship with volumes adjusted for total intracranial cavity volume to account for variations in intracranial size.Supplementary analyses of the above hypotheses using partial correlations were also used to test all hypotheses while covarying for age and sex; results are provided in P = 0.016) and net CSF flow . ND maps obtained from SRTM2 for a participant with higher and lower Aβ levels alongside corresponding ChP perfusion maps and PSD segmentation masks.A total of 23 participants ranged in age from 56 to 78 years (mean = 70.0 ± 6.0 years) and were comprised of 10 males and 13 females. All participants met neurological and radiological inclusion criteria as defined above. The mean Montreal Cognitive Assessment and RBANS scores for all participants were 18.91 ± 4.80 and 72.57 ± 18.30, respectively. A summary of the demographics and quantitative imaging measurements is outlined in 50–70 and dynamic SRTM2 BPND values due to a participant leaving the PET scanner early. Global levels of Aβ burden as measured by SUVr50–70 and BPND + 1 were closely associated and met significance criteria . A scatterplot of SUVr50–70 and BPND + 1 and the Bland–Altman plot are displayed in ND as the representative measure for global Aβ burden.Twenty-two out of 23 participants were included in the comparison of static SUVrND values of 11C-PIB and did not meet significance criteria , and survived multiple comparison corrections of pFDR < 0.05. The prefrontal and occipital PSD volumes were not closely associated with global BPND . Overall, increases in PSD volume of specifically the frontal and parietal subregions were significantly associated with increases in global BPND of 11C-PIB.A schematic of the PSD subregions and associated scatterplots for each subregion is depicted in P = 0.441). Additionally, this relationship remained statistically insignificant after corrections for total intracranial volume .Correlation analyses revealed that total GM + WM tissue volume was not significantly associated with total PSD volume  and waste clearance activity may predispose individuals to excessive protein aggregation and contribute to the pathophysiology of Alzheimer’s disease. Consistent with this possibility, Li 45 Here, for the first time, we report a significant relationship between PSD volume and global Aβ protein aggregation, further suggesting that increased Aβ protein aggregation may relate to dysfunctional CSF clearance. Interestingly, we observed the strongest relationship between global Aβ accumulation and PSD volume in the frontal and parietal subsegments. These regions correlate with commonly observed Aβ aggregation topography in the frontal cortex, anterior and posterior cingulate, and precuneus. In contrast, we did not observe similar relationships in the prefrontal and occipital PSD subsegments. Additionally, PSD volume was not associated with whole brain tissue volume, even when correcting for total intracranial cavity volume, suggesting that hypertrophy of the PSD occurs independently of general brain atrophy. Supporting this, ultrastructural electron microscopy of human dura samples revealed that dural channels were more widely distributed in elderly patients than in younger patients, who exhibited densely concentrated channels around the superior sagittal sinus.18 These dural channels were found to lack expression of lymphatic and vascular markers, suggesting a potential reservoir-like role for CSF drainage.Previous studies have demonstrated a strong ageing effect with PSD volume, suggesting a potential compensatory mechanism or alternative evidence of decompensatory tissue dysfunction in response to worsening CSF or ISF drainage with age.16 In comparison, minimal efflux of tracer was found in the cribriform plate, another hypothesized CSF clearance pathway. Animal studies have also previously shown that complete aplasia of dural lymphatic vessels results in attenuated macromolecule clearance and abolished transport of CSF from the SAS to deep cervical lymph nodes.46 Together with the present findings, it is evident that the PSD plays an important, yet unclear role in CSF clearance and egress. A possible explanation for PSD hypertrophy may be a compensatory mechanism in response to increasing Aβ for the PSD to promote greater clearance by increasing communication with the superior sagittal sinus and/or providing increased collateral communication with alternate routes of CSF clearance such as along the cranial nerves. This may lead to channels within the frontal and parietal subsegments of the PSD space to become dilated and/or more diffusely distributed to promote greater CSF efflux. Alternatively, neuroinflammation has emerged as a possible link between Aβ and tau proteinopathies;47 and these inflammatory markers may trigger a hypertrophic response in the PSD. While the mechanisms with which these dural channels along the superior sagittal sinus are involved in CSF egress and waste clearance are not yet fully understood, it is evident that the PSD plays an important role in CSF egress, and further characterization of these channels is necessary to elucidate the potential implications of Alzheimer’s disease and neurodegenerative proteinopathies.Indeed, in human studies with intrathecal injection of gadobutrol, an MRI contrast agent serving as a CSF tracer, and high-resolution MRI demonstrated an efflux of gadobutrol into the PSD with peak enrichment at 24 h post-injection in humans.20 These findings provided support that CSF production from the ChP can be detected downstream in the CSF flow pathway and allowed us to establish surrogate markers of choroidal CSF production. In the present study, we did not observe relationships with global Aβ accumulation and either of the two measures, which may indicate that choroidal CSF production is not involved in the clearance of Aβ. Previous studies have suggested the involvement of ChP dysfunction in impaired Aβ clearance.49 The ChP is selectively permeable to Aβ in the CSF-facing membrane of the blood–CSF, barrier, thus suggesting an important role for the ChP in Aβ clearance other than CSF production. In support of this, a triple transgenic mouse model of Alzheimer’s disease demonstrated increased deposition of specifically isoform Aβ42 in the ChP epithelial cytoplasm, reflecting insufficient clearance transport from CSF to blood. It is possible that age-related downregulation of choroidal CSF production places a greater burden on waste transport via CSF clearance pathways, such as bulk CSF flow and/or egress. Further studies are required to understand Aβ accumulation in and around the ChP, and the role the blood–CSF barrier plays in global Aβ clearance. Together, the present findings suggest that CSF egress, and not production, may be related to Aβ plaque formation.We have previously shown age-related reductions in ChP perfusion and net CSF flow through the aqueduct of Sylvius in healthy adults, and further demonstrated a positive relationship between these two measures.43 Our novel techniques offer a non-contrasted, non-invasive method to capture indirect measures at both sites of production and egress of the CSF clearance pathway that can be readily implemented at other sites. Additionally, we utilize deep-learning algorithms to accurately segment both the ChP and PSD with commonly used anatomical MR sequences that can be applied to various other disease populations. These methods may further our understanding of the glymphatic system by providing accessible tools to characterize these structures in larger populations.The present findings extend our previous work showing age-related changes to PSD volume, ChP perfusion and CSF flow by applying these methods in an ageing human population with varying levels of Aβ proteinopathy. Previous studies of CSF clearance in humans have utilized invasive methods such as intrathecal injection of MRI contrast agents or intravenous injection of PET radiotracers.The findings of the present study contribute further support for a role of CSF-mediated Aβ clearance, but further research is required to fully characterize this clearance pathway. For example, longitudinal studies of preclinical/prodromal patients are required to understand the chronology of changes in the PSD with respect to Aβ aggregation and cognitive decline. Additionally, our results suggest specific regional changes to the PSD that relate to Aβ accumulation; and understanding the topography of glymphatic egress may clarify the underpinnings of commonly seen hotspots of Aβ aggregation in the brain parenchyma and vasculature. This CSF-mediated clearance pathway is also not limited to Aβ clearance; and applying these non-invasive methods to other patient populations such as Parkinson’s disease, multiple systems atrophy and Huntington’s disease may further our understanding of waste clearance in neurodegenerative diseases marked by aggregated proteins.50 We accounted for these fluctuations by ensuring that scans were between the times of 7:00 am and 9:00 am. Lastly, while 11C-PIB displays high diagnostic accuracy for the detection of Alzheimer’s disease, it is often marred by overestimation of Aβ levels using the late-uptake SUVr method. This becomes an even more important issue when attempting to assess relationships of Aβ levels with other quantitative measures. Therefore, we elected to use a dynamic PET imaging assessment and implemented the Wu SRTM2 to quantitatively assess Aβ levels.38Several limitations should be considered. While well characterized by cognitive assessment, PET and multi-contrast MRI, the present study sample size of 23 participants is modest and as such the findings will require additional, larger cohorts to understand the relevance of PSD hypertrophy of Aβ retention more fully. It is also noted that the diurnal activity of neurofluids varies throughout the day and is shown to be more active during sleep than in an awake state.We assessed surrogate measures of CSF production, flow and egress in a cohort of older adults with varying levels of Aβ by applying novel non-invasive MRI methods and analyses. Our findings suggest that hypertrophy of the parasagittal space may more closely relate to cerebral Aβ retention than ChP perfusion or bulk CSF net flow in older adults with Alzheimer’s disease.fcad128_Supplementary_DataClick here for additional data file.


The molecular mechanisms underlying the development of posthemorrhagic hydrocephalus (PHH) remain incompletely understood. As the disease pathogenesis often cannot be attributed to visible cerebrospinal fluid (CSF) drainage obstructions, we here aimed to elucidate whether elevated CSF osmolality following subarachnoid hemorrhage (SAH) could potentiate the formation of ventricular fluid, and thereby contribute to the pathological CSF accumulation observed in PHH. The CSF osmolality was determined in 32 patients with acute SAH after external ventricular drainage (EVD) placement and again upon EVD removal and compared with the CSF osmolality from 14 healthy control subjects undergoing vascular clipping of an unruptured aneurism. However, we found no evidence of elevated CSF osmolality or electrolyte concentration in patients with SAH when compared to that of healthy control subjects. We detected no difference in CSF osmolality and electrolyte content in patients with successful EVD weaning versus those that were shunted due to PHH. Taken together, elevated CSF osmolality does not appear to underlie the development of PHH following SAH. The pathological CSF accumulation observed in this patient group must thus instead be attributed to other pathological alterations associated with the abnormal presence of blood within the CSF compartments following SAH.  Cerebrospinal fluid (CSF) continuously circulates through the central ventricular system and subarachnoid space of the mammalian brain. Disturbances in CSF homeostasis causing an imbalance between the production and reabsorption of CSF may promote pathological CSF accumulation, dilation of the cerebral ventricles, and the clinical entity hydrocephalus . The patCSF osmolality disturbances have long been speculated to play a role in the development of hydrocephalus . AlthougCSF osmolality could, if associated with PHH, also serve as a potential biomarker of PHH severity. At present, many patients with PHH undergo shunt insertion due to the development of chronic hydrocephalus after the acute phase. A need to shunt patients is determined by clinical assessment and unsuccessful weaning from external ventricular drains (EVDs) . In thisWe here tested the hypotheses that CSF osmolality is associated with PHH or with chronic hydrocephalus after acute PHH. We assessed the CSF osmolality in patients with aneurysmal SAH, one of the most common causes of PHH, by comparison to CSF collected from healthy control subjects and determined whether CSF osmolality was associated with the development of chronic hydrocephalus requiring permanent CSF diversion. n = 29) was not significantly different from that obtained in healthy control subjects  and the group of healthy control subjects  to that obtained from the cisternal compartment in healthy control subjects undergoing vascular clipping for an un-ruptured aneurysm. The CSF osmolality in patients with SAH  did not differ from that obtained from patients with successful EVD weaning . However, the CSF osmolality in patients with SAH who underwent shunt insertion due to chronic PHH development  grading scale was assessed using the CSF samples collected upon hospitalization (start samples) from the entire SAH group (weaned and shunted). The CSF osmolality did not differ across the modified Fisher’s scale  and just prior to EVD removal (end samples) were compared by assessing CSF osmolality, Na samples . Quantifapparent , substanWe found no evidence of elevated CSF osmolality in patients with SAH when compared to healthy control subjects and no detectable CSF osmolality difference between shunted SAH patients and patients with successful EVD weaning. We thus conclude that PHH following SAH appeared un-associated with elevated CSF osmolality, promoting water flow into the CSF compartments, and thereby does not contribute to the development of SAH-related hydrocephalus.+ (and Ca2+) concentration was, likewise, similar in the two SAH patient groups, suggesting no overall electrolyte disturbance, which aligns with the gross similarity of the ionic content of blood entering during the hemorrhagic event and the resident CSF. The CSF osmolality is dominated by the electrolyte contribution, as illustrated by the nearly 150 mM Na+ detected in the CSF samples. According to the principle of electroneutrality, this cationic contribution must be matched by an accompanying anion; in the CSF, mainly Cl− and HCO3−, when taken together approach the ~290 mOsm observed in human CSF . It d others , and hemd others . With thd others , mainly d others , which id others , the hemd others , we suspd others . Both std others ,36, whicd others  or compad others . Howeverd others . + and Ca2+). We, therefore, cannot exclude that the concentration of other prominent CSF electrolytes, such as Cl− or HCO3−, may have been altered. However, such an anionic increase would require a matching cation contribution, which, if substantial, should be reflected in the CSF osmolality. At present, it remains unclear why some patients with SAH can be successfully weaned from their EVDs, while a considerable patient cohort fail EVD weaning and need to undergo shunt insertion due to chronic PHH development. Identification of prognostic biomarkers for the development of PHH is thus greatly needed. However, as the present study revealed similar CSF osmolality in shunted SAH patients and patients with successful EVD weaning, CSF osmolality cannot be employed as a prognostic biomarker of PHH development, nor explain why some patients require a shunt and others not. Moreover, CSF osmolality did not reflect the severity of the SAH nor the patient’s neurological status upon hospitalization. It must be noted that division of the patients into the weaned and the shunted groups was based on clinical management; patients who failed 2–3 attempts of weaning or closure of an EVD underwent shunting. Another limitation lies in the retrospective nature of the study and the small study groups that were not matched for age or sex, which can induce variability and subsequent failure to detect small differences between groups. However, with the low osmotic water permeability of the rodent choroid plexus epithelium , we predThe present findings of 1–2 mM elevation in CSF glucose and lactate in patients with SAH may derive from the extravasation of blood into the CSF compartments. Presence of living red blood cells within the CSF could, in addition, elevate the lactate levels as a result of their anaerobic metabolism . AlternaIn conclusion, elevated CSF osmolality does not appear to underlie the development of PHH following SAH. The pathological CSF accumulation observed in this patient group may thus instead be attributed to other pathological alterations associated with the abnormal presence of blood within the CSF compartments, such as choroid plexus CSF hypersecretion or impaired CSF drainage, possibly driven by post-hemorrhagic inflammation ,11,16,18n = 10; Grade 2: n = 8; Grade 3: n = 0; Grade 4: n = 7; Grade 5: n = 7) [n = 2; Grade 2: n = 4; Grade 3: n = 7; Grade 4: n = 19) [Patients with SAH who were treated with EVD between June 2019 and September 2021 at the Department of Neurosurgery, The Neuroscience Centre, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark, were retrospectively included in the present study, which employed CSF samples stored as part of a prospective trial on EVD weaning . Only a: n = 7)  and the  n = 19) . All patn = 21) or as soon as possible hereafter as a sample taken directly from the EVD system . The last CSF sample  was obtained either just before the removal of the EVD, or during the placement of a ventriculoperitoneal shunt. The interval between the start and end samples was on average 19 days, with a range of 5–45 days. After collection, the CSF samples were immediately centrifuged at 2000× g for 10 min the supernatant aliquoted in polypropylene microtubes  before storage at −80 °C [CSF samples were collected from a total of 32 patients with SAH  through their EVD into a sterile collection tube. The first CSF sample  was obtained in the acute phase after placement of the EVD, either within 24 h of ictus , while the remaining 12 patients underwent ventriculoperitoneal shunt surgery due to chronic PHH (‘shunt’). The control group was 14 patients with unruptured aneurysms undergoing preventive surgery (vascular clipping) , from whom CSF was collected from the basal cisterns during surgery prior to clipping of the aneurysm.The study was approved by the Ethics committee of the Capital Region of Denmark  and the Danish Data Protection Agency . Oral and written informed consent were obtained from all patients or their next of kin depending on the capacity of the patients. Aliquots of the CSF samples have been analyzed for other components in unrelated studies ,64,65. +, Ca2+, glucose, and lactate levels were quantified with an ABL90 FLEX blood gas analyzer .To prevent breakdown of CSF solutes, the CSF samples were stored at −80 °C upon collection and care was taken to only thaw the CSF samples again right before the measurements. For the CSF osmolality measurements, 100 µL of each CSF sample was transferred to osmometer Eppendorf tubes  and the CSF osmolality determined with a freezing point depression osmometer  with an accuracy of ±1 mOsm. As soon as the CSF samples were thawed and aliquoted for osmolality determination, the remaining CSF was immediately put back on ice and CSF Nat-test or a Mann–Whitney test was conducted. For paired data, a paired two-tailed t-test or a Wilcoxon matched-pairs signed rank test was conducted. For determination of average CSF changes , a one-sample two-tailed t-test or a one-sample Wilcoxon signed rank test was conducted. For more than two groups, a Kruskal–Wallis test was conducted followed by Dunn’s multiple comparisons test. Statistical tests are indicated in the figure legend. p < 0.05 was considered statistically significant. All data are presented as mean ± standard deviation, and n corresponds to the number of individual patients , while CSF Na+, Ca2+, glucose, and lactate levels could not be quantified in one CSF end sample) due to insufficient sample volumes. Data analysis and statistical tests were conducted in GraphPad Prism . Data were tested for normality with the Shapiro–Wilk test. For unpaired data, an unpaired two-tailed


Spontaneous cerebrospinal fluid (CSF) rhinorrhea is rare and may develop secondary to inner ear malformation. A possible diagnosis of CSF leak should be considered in any Pediatric patient who presents with hearing impairment, rhinorrhea, or otorrhea.We describe a case of 13 months male infant presenting with rhinorrhoea which on evaluation found to be CSF oto-rhinorrhoea due congenital inner ear malformation. Imaging showed malformed inner ear on both sides with CSF leak on left side with bilateral profound sensory neural hearing loss. A multidisciplinary management was considered. Child underwent CSF leak repair on left side followed by Cochlear implantation on right side in another setting. This case is a perfect example to describe the cumbersome management of CSF leak with inner ear anomaly addressing the auditory habilitation on the grounds of recent innovations. As per available literature inner ear anomaly is an important subgroup of population of cochlear implant candidates with promising auditory outcomes.  Osseous labyrinthine malformations are fairly rare anomalies, representing approximately 20% of the cases of congenital sensorineural hearing loss . Rest 80As complex is this disorder, that complex is its management part. In the beginning era of cochlear implantation (CI) one of the contraindications for the surgery was IEA. However soon in 1983 Mangaberia-Albernaz reported the first CI in IEA which was a Mondini deformity . Here we are discussing a peculiar case of inner ear malformation with an odd presentation, diagnosis, management and (re)habilitation. A 13-month-old boy who had no previous history of head injury or trauma was brought by parents with chief complaints of spontaneous continuous watery nasal discharge from both sides since the age of 6 months. Parents also noticed poor responses to sound. He had no recent history of upper respiratory illness, and no history of acute otitis media or otorrhea. On clinical examination, child was not responding to loud sounds and rest of the ear, nose and throat examination was normal. He was subsequently admitted, audiology and imaging was planned. Auditory brainstem response (ABR) testing showed bilateral profound sensorineural hearing loss. The acoustic immittance (AI) test revealed a “C” shaped curve on the left and an “A” shaped curve on the right. CT and MRI scanning of the temporal bones demonstrated left side wide internal acoustic canal (IAC) with absent cribriform plate &2.Cystic cochlea was seen without any internal architecture. Vestibule was visualized separately from cochlea with figure of eight configuration- likely type-1 incomplete partition of cochlea. Lateral and posterior semicircular canals were not visualized. Left cochlear segment of VIII nerve complex was hypoplastic. Fluid signal was seen in the left mesotympanum and mastoid cavity with extension along the left Eustachian tube. On right side IAC was mildly widened, and a cribriform plate was present. Cochlea was cystic with absent modiolus. Vestibule & semicircular canals were visualized normally. The cisternal portions of the right VII-VIII nerve complex were seen normally. Child underwent left side radical mastoidectomy with CSF leak repair . Intraoperatively CSF leak was found to be from both round window and oval window. Child recovered uneventfully. After the recommended period of habilitation with hearing aid he underwent right side cochlear implantation by Veria technique via cochleostomy . Switch on was done on post operative day 21 and auditory verbal therapy was started.Inner ear anomaly masquerading as CSF rhinorrhoea is always a fascinating entity for ENT surgeons. So is the management of inner ear anomaly from the perspective of complication as well as (re) habilitation.Radical mastoidectomy is defined as canal wall down procedure with removal of the ossicles, stripping of middle ear mucosa, plugging of eustachian tube with or without cul de sac closure of external auditory canal. This procedure in a case of CSF otorrhea especially with inner ear anomaly has been a controversy . There ath nerve or aberrant course of VIIth nerve  there are varieties of malformation of cochlea with considerable architectural differences. Hence one should choose the appropriate electrode as per standard recommendation. Electrodes with complete contact ring are preferred in common cavity, IP I & III. All kind of electrodes can be used in IP II and Large vestibular aqueduct syndrome, while short electrodes are used in Cochlear hypoplasia . A speciCommon intraoperative challenges faced are CSF gusher and facial nerve anomaly. Facial nerve has a complex temporal bone course and the deciding factor for the final position of the facial nerve is the inner ear development. Preoperative radiology and intraoperative facial nerve monitoring are the steps to reduce the facial nerve injury.CSF gusher is defined as the egress of profuse clear fluid upon making an opening in inner ear. This is common in CI surgery for IEA. Phelps et al classified CSF gusher into oozing (gentle flow of clear fluid and gusher (profuse flow) . A smallInner ear anomaly can be masquerade as CSF rhinorrhoea. These individuals are considered to be a unique subgroup of candidates in CI surgery. It is important to follow a single classification system when dealing with IEA in order to standardise the treatment, follow up and (re)habilitation. Both MRI and CT should be considered during the work up of such patients and two important intraoperative challenges are aberrant facial nerve course and CSF gusher.


MenACYW-TT  is a quadrivalent  meningococcal tetanus toxoid conjugate vaccine. It is approved for use in persons aged ≥2 years in the US and persons aged ≥1 year in Europe and certain other countries; trials in infants as young as 6 weeks are ongoing. The second stage of a 2-stage study of MenACYW-TT, reported herein, evaluated immune persistence among older adults who received primary vaccination with either quadrivalent meningococcal polysaccharide vaccine (MSPV4) or MenACYW-TT five years earlier at age ≥ 56 years. The immunogenicity and safety of a MenACYW-TT booster dose given to this population were also evaluated.This was a Phase 3, 2-stage, randomized, open-label, multi-center study (NCT04142242) of adults aged ≥59 years who participated in previous studies of MenACYW-TT vs MPSV4 (NCT01732627 and NCT02842866). The study was conducted in the US and Puerto Rico. Immune persistence and response were assessed with a serum bactericidal assay using human complement (hSBA). Safety data were collected for up to 30 days after booster vaccination. All analyses were descriptive.Of the initial study population (N=471), 70 adults participated in Stage II of the study. At 5 years post-primary vaccination, seroprotection (hSBA ≥ 1:8) rates (SPRs) and hSBA geometric mean titers (GMTs) declined in both MenACYW-TT- and MPSV4-primed subjects, with SPRs and hSBA GMTs for serogroups A, C, W, and Y trending higher in MenACYW-TT- vs MPSV4-primed subjects (Table 1). Thirty days after booster vaccination, hSBA GMTs and SPRs increased from pre-booster for all serogroups and were, along with seroresponse rates, higher in MenACYW-TT-primed subjects compared to MPSV4-primed subjects (Table 2). Rates of AEs following booster vaccination were similar regardless of priming vaccine. No safety concerns were identified.Five years after primary vaccination, immune persistence tended to be greater for MenACYW-TT vs MPSV4. A MenACYW-TT booster was well tolerated and immunogenic in adults ≥ 61 years, when administered 5 years after primary vaccination with either MPSV4 or MenACYW-TT.Corwin A. Robertson, MD, MPH, FACP, Sanofi: Sanofi employee|Sanofi: Sanofi's Employee|Sanofi: Stocks/Bonds Katherine Galarza, MD, Sanofi: Sanofi employee|Sanofi: Stocks/Bonds Alexandre Selmani, PhD, Sanofi: Sanofi employee|Sanofi: Stocks/Bonds Philipp Oster, MD, Sanofi: Sanofi employee