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Background: Vagal atrophy is a hallmark of Parkinson's disease (PD) and has been found to be associated with autonomic dysfunction, while analyses of the vagus nerve (VN) in atypical Parkinsonian syndromes (APS) have not yet been performed. We here investigate the characteristics of the VN in multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) and, in a second step, its potential as a possible biomarker for orthostatic dysregulation., Objectives: The aim was to compare the VN pathology in MSA and PSP with healthy individuals and patients with PD as a differentiating factor and to further analyse the correlation of the VN with clinical parameters and cardiovascular response., Design: We conducted a monocentric, cross-sectional cohort study in 41 APS patients and compared nerve ultrasound (NUS) parameters with 90 PD patients and 39 healthy controls., Methods: In addition to a detailed neurological history and examination, several clinical severity and motor scores were obtained. Autonomic symptoms were reported in the Scales for Outcomes in Parkinson's Disease - Autonomic questionnaire. Further scores were used to detect other non-motor symptoms, quality of life and cognition. Additionally, we performed a head up tilt test (HUTT) and NUS of the VN. We conducted correlation analyses of the VN cross-sectional area (CSA) with clinical scores and the heart rate and blood pressure variability parameters of the HUTT., Results: The examination demonstrated a high prevalence of abnormal autonomic response in both MSA (90%) and PSP (80%). The VN CSA correlated with spectral parameters of the HUTT, which are associated with sympatho-vagal imbalance. In addition, the CSA of the VN in patients with PD and PSP were significantly smaller than in healthy controls. In MSA, however, there was no marked vagal atrophy in comparison., Conclusion: The occurrence of autonomic dysfunction was high in MSA and PSP, which underlines its impact on these syndromes. Our findings indicate a connection between vagal pathology and autonomic dysfunction and might contribute to a better comprehension of APS. To further evaluate the clinical relevance and the VN as a possible marker of autonomic dysfunction in APS, prospective longitudinal observations are necessary., (© The Author(s), 2024.)

Background and Purpose: Nerve cross-sectional area (CSA) is not constant over the human lifespan. The relationship between an increasing CSA and age has been described as a linear positive correlation, but few studies have found a linear decrease in nerve size with older age. The aim of the present study was to analyze the development of nerve CSA in a healthy population from early childhood to old age using high-resolution ultrasound., Methods: The median, ulnar, radial and sural nerves were examined bilaterally at 18 nerve sites in 110 healthy children, adolescents and adults aged between 2 and 98 years. The CSA of every nerve site was evaluated separately and in different age groups. The correlation of CSA with age, height and weight was analyzed in a linear, logarithmic and quadratic model and correlation coefficients were compared in a goodness-of-fit analysis. Models were then adjusted for weight and height., Results: Linear CSA-age correlations showed the lowest correlation coefficients for all nerve sites. An inverted parabolic curve suggesting a quadratic correlation of CSA and age was the best-fitting model. Weight and height had a higher predictive value than age in adjusted models., Conclusions: There is an increase in nerve size during childhood and adolescence and a trend towards a decrease in old age, suggesting an inverted parabolic curve partly explained by age-related changes in weight and height. Enlarged nerves in elderly individuals should not be attributed to age alone., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Neurodegeneration in the autoimmune disease multiple sclerosis still poses a major therapeutic challenge. Effective drugs that target the inflammation can only partially reduce accumulation of neurological deficits and conversion to progressive disease forms. Diet and the associated gut microbiome are currently being discussed as crucial environmental risk factors that determine disease onset and subsequent progression. In people with multiple sclerosis, supplementation of the short-chain fatty acid propionic acid, as a microbial metabolite derived from the fermentation of a high-fiber diet, has previously been shown to regulate inflammation accompanied by neuroprotective properties. We set out to determine whether the neuroprotective impact of propionic acid is a direct mode of action of short-chain fatty acids on CNS neurons. We analysed neurite recovery in the presence of the short-chain fatty acid propionic acid and butyric acid in a reverse-translational disease-in-a-dish model of human-induced primary neurons differentiated from people with multiple sclerosis-derived induced pluripotent stem cells. We found that recovery of damaged neurites is induced by propionic acid and butyric acid. We could also show that administration of butyric acid is able to enhance propionic acid-associated neurite recovery. Whole-cell proteome analysis of induced primary neurons following recovery in the presence of propionic acid revealed abundant changes of protein groups that are associated with the chromatin assembly, translational, and metabolic processes. We further present evidence that these alterations in the chromatin assembly were associated with inhibition of histone deacetylase class I/II following both propionic acid and butyric acid treatment, mediated by free fatty acid receptor signalling. While neurite recovery in the presence of propionic acid is promoted by activation of the anti-oxidative response, administration of butyric acid increases neuronal ATP synthesis in people with multiple sclerosis-specific induced primary neurons., Competing Interests: R.G. and A.H. have filed a patent on the supportive immunomodulatory effect of C3–C8 aliphatic fatty acids., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Purpose: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease with humoral and cellular autoimmunity causing demyelination of peripheral nerves, commonly treated with intravenous immunoglobulins (IVIg). The neonatal Fc receptor (FcRn), encoded by the FCGRT gene, prevents the degradation of immunoglobulin G (IgG) by recycling circulating IgG. A variable number of tandem repeat (VNTR) polymorphism in the promoter region of the FCGRT gene is associated with different expression levels of mRNA and protein. Thus, patients with genotypes associated with relatively low FcRn expression may show a poorer treatment response to IVIg due to increased IVIg degradation., Methods: VNTR genotypes were analyzed in 144 patients with CIDP. Patients' clinical data, including neurological scores and treatment data, were collected as part of the Immune-Mediated Neuropathies Biobank registry., Results: Most patients (n = 124, 86%) were VNTR 3/3 homozygotes, and 20 patients (14%) were VNTR 2/3 heterozygotes. Both VNTR 3/3 and VNTR 2/3 genotype groups showed no difference in clinical disability and immunoglobulin dosage. However, patients with a VNTR 2 allele were more likely to receive subcutaneous immunoglobulins (SCIg) than patients homozygous for the VNTR 3 allele (25% vs. 9.7%, p = 0.02) and were more likely to receive second-line therapy (75% vs. 54%, p = 0.05)., Conclusions: The VNTR 2/3 genotype is associated with the administration of SCIg, possibly reflecting a greater benefit from SCIg due to more constant immunoglobulin levels without lower IVIg levels between the treatment circles. Also, the greater need for second-line treatment in VNTR 2/3 patients could be an indirect sign of a lower response to immunoglobulins., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objective: To evaluate magnetic resonance neurography (MRN) for the longitudinal assessment of patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)., Methods: Prospective examination of twelve CIDP patients by neurological assessment, MRN, and nerve conduction studies in 2016 and 6 years later in 2022. Imaging parameters were compared with matched healthy controls and correlated with clinical and electrophysiological markers. The MRN protocol included T2-weighted imaging, diffusion tensor imaging (DTI), T2 relaxometry, and magnetization transfer imaging (MTI)., Results: Nerve cross-sectional area (CSA) was increased in CIDP patients compared to controls (plexus: p = 0.003; sciatic nerve: p < 0.001). Over 6 years, nerve CSA decreased in CIDP patients, most pronounced at the lumbosacral plexus (p = 0.015). Longitudinally, changes in CSA correlated with changes in the inflammatory neuropathy cause and treatment validated overall disability sum score (INCAT/ODSS) (p = 0.006). High initial nerve CSA was inversely correlated with changes in the INCAT/ODSS over 6 years (p < 0.05). The DTI parameter fractional anisotropy (FA) showed robust correlations with electrodiagnostic testing both cross-sectionally and longitudinally (p < 0.05). MTI as a newly added imaging technique revealed a significantly reduced magnetization transfer ratio (MTR) in CIDP patients (p < 0.01), suggesting underlying changes in macromolecular tissue composition, and correlated significantly with electrophysiological parameters of demyelination (p < 0.05)., Interpretation: This study provides evidence that changes in nerve CSA and FA reflect the clinical and electrophysiological course of CIDP patients. Initial nerve hypertrophy might predict a rather benign course or better therapy response., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Introduction: Blood-cerebrospinal fluid (CSF) barrier dysfunction is pivotal for diagnosing immune-mediated neuropathies, especially in spinal nerve root inflammation. Typically, either total CSF protein or the CSF to serum albumin ratio (Q Alb ) is measured. Total CSF protein measurements have limitations, notably its fixed reference value regardless of age, in contrast to the age-dependent reference for Q Alb . Our goal was to evaluate both markers in patients with immune-mediated neuropathies., Methods: In our multicenter research, we collected retrospective CSF data from patients suffering from immune-mediated neuropathies across four German research centers. These parameters were analyzed in relation to their clinical characteristics., Results: Out of 419 samples, 36 (8.6%) displayed a notable variation between total CSF protein and Q Alb values. A detailed analysis revealed that patients displaying elevated Q Alb but normal total CSF protein levels were significantly younger at disease onset ( p  = 0.01), at the time of diagnosis ( p  = 0.005), and when undergoing lumbar puncture ( p  = 0.001) compared to patients with elevated CSF protein and normal Q Alb levels. These effects were especially evident for the subgroup of samples derived by female patients., Discussion: Our work confirms the crucial role of Q Alb in diagnosing immune-mediated neuropathies and particularly its efficacy as a marker for evaluating the blood-CSF barrier in patients with an earlier disease onset. Considering the significance of the albumin quotient, its assessment is especially advisable in younger patients of female sex to avoid missing a potential barrier dysfunction that might be falsely negative when using total protein., Competing Interests: TSe reports support for attending meetings by Abbvie. SG reports research support from Alnylam Pharmaceuticals, CSL Behring, Else Kröner Fresenius Foundation, Deutsche Forschungsgemeinschaft and Hannover Biomedical Research School (HBRS) and consulting and/or speaker honoraria from Alexion, Alnylam Pharmaceuticals, AstraZeneca, GSK, Pfizer and Merck all outside the submitted work. JM reports research grants by Biogen and Deutsche Forschungsgemeinschaft, stock/stock options at Biontech and CureVac, as well as support for attending meetings and/or travel by Biogen, Novartis and Alnylam. JM also received honoraria or lectures/ manuscripts by Biogen. KP reports research grants by Biogen idec, Novartis, Celgene, CSL Behring, Grifols, honoraria for lectures from CSL Behring, Grifols, participation on an Advisory Board 2021 by Celgene and non-paid consultant activity for patients organizations POTS and Dysautonomie e.V. TSk reports honoraria for lectures and travel expenses for attending meetings from Alexion, Alnylam Pharmaceuticals, argenx, Bayer Vital, Biogen, Celgene, Centogene, CSL Behring, Euroimmun, Janssen-Cilag, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Siemens, Swedish Orphan Biovitrum, Teva, Viatris. His research is supported by the German Ministry for Education and Research (BMBF), Bristol-Myers Squibb Foundation for Immuno-Oncology, Claudia von Schilling Foundation for Breast Cancer Research, Else Kröner Fresenius Foundation, Hannover Biomedical Research School (HBRS), Alnylam Pharmaceuticals, CSL Behring, Novartis, Sanofi Genzyme, VHV Foundation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Seeliger, Gingele, Güzeloglu, Heitmann, Lüling, Kohle, Preßler, Stascheit, Motte, Fisse, Grüter, Pitarokoili and Skripuletz.)

Introduction: Serum neurofilament light chain (sNfL) is a marker for axonal degeneration. Patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) often report a fluctuation of symptoms throughout one treatment cycle with intravenous immunoglobulins (IVIG). The aim of this study was to determine whether sNfL is suitable to quantify patient-reported symptom fluctuations., Methods: Twenty-nine patients with the diagnosis of CIDP or a CIDP-variant under treatment with IVIG were recruited in this study and underwent examination before IVIG infusion, in the middle of the treatment interval, and before their next IVIG infusion. Patients were surveyed regarding symptom fluctuations at the last visit and divided into two groups: those with and without fluctuations of symptoms. At the first visit, sociodemographic and disease-specific data were collected. Clinical scores were assessed at every examination. sNfL values were compared between both groups at the different time points after conversion into Z-scores-adjusted for age and body mass index., Results: Patients with CIDP show elevated sNfL Z-scores (median at baseline: 2.14, IQR: 1.0). There was no significant change in sNfL Z-scores or questionnaire scores within the treatment cycle in either group. There was no significant difference in sNfL levels between the patients with and without symptom fluctuations., Conclusions: CIDP patients show elevated sNfL levels. However, sNfL is not suitable to reflect patient-reported fluctuations of symptoms. This indicates that symptom fluctuations during treatment with IVIG in patients with CIDP are not caused by a neuroaxonal injury. Furthermore, repeated sNfL measurements within one treatment cycle with IVIG seem to have no benefit for symptom monitoring., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Depression has a major impact on the disease burden of multiple sclerosis (MS). Analyses of overlapping MS and depression risk factors [smoking, vitamin D (25-OH-VD) and Epstein-Barr virus (EBV) infection] and sex, age, disease characteristics and neuroimaging features associated with depressive symptoms in early MS are scarce., Objectives: To assess an association of MS risk factors with depressive symptoms within the German NationMS cohort., Design: Cross-sectional analysis within a multicenter observational study., Methods: Baseline data of n  = 781 adults with newly diagnosed clinically isolated syndrome or relapsing-remitting MS qualified for analysis. Global and region-specific magnetic resonance imaging (MRI)-volumetry parameters were available for n  = 327 patients. Association of demographic factors, MS characteristics and risk factors [sex, age, smoking, disease course, presence of current relapse, expanded disability status scale (EDSS) score, fatigue (fatigue scale motor cognition), 25-OH-VD serum concentration, EBV nuclear antigen-1 IgG (EBNA1-IgG) serum levels] and depressive symptoms (Beck Depression Inventory-II, BDI-II) was tested as a primary outcome by multivariable linear regression. Non-parametric correlation and group comparison were performed for associations of MRI parameters and depressive symptoms., Results: Mean age was 34.3 years (95% confidence interval: 33.6-35.0). The female-to-male ratio was 2.3:1. At least minimal depressive symptoms (BDI-II > 8) were present in n  = 256 (32.8%), 25-OH-VD deficiency (<20 ng/ml) in n  = 398 (51.0%), n  = 246 (31.5%) participants were smokers. Presence of current relapse [coefficient ( c ) = 1.48, p  = 0.016], more severe fatigue ( c  = 0.26, p  < 0.0001), lower 25-OH-VD ( c  = -0.03, p  = 0.034) and smoking ( c  = 0.35, p  = 0.008) were associated with higher BDI-II scores. Sex, age, disease course, EDSS, month of visit, EBNA1-IgG levels and brain volumes at baseline were not., Conclusion: Depressive symptoms need to be assessed in early MS. Patients during relapse seem especially vulnerable to depressive symptoms. Contributing factors such as fatigue, vitamin D deficiency and smoking, could specifically be targeted in future interventions and should be investigated in prospective studies., (© The Author(s), 2023.)

Autoimmune neuropathy associated with antibodies against pan-neurofascin is a new subtype of nodo-paranodopathy. It is relevant because it is associated with high morbidity and mortality. Affected patients often require intensive care unit treatment for several months, and data on the reversibility and long-term prognosis are limited. The pathogenicity including IgG subclass-associated mechanisms has not been unravelled, nor directly compared to anti-neurofascin-155 IgG4-related pathology. Understanding the underlying pathology might have a direct impact on treatment of these severely affected patients. By a multicentre combined prospective and retrospective approach, we provide clinical data of a large cohort of patients with anti-neurofascin-associated neuropathy (n = 18) including longitudinal titre and neurofilament light chain assessment via Ella® and relate clinical data to in vitro pathogenicity studies of anti-neurofascin antibodies. We assessed antibody binding characteristics and the pathogenic effects of anti-pan-neurofascin versus neurofascin-155 antibodies on living myelinating dorsal root ganglia co-cultures. Additionally, we analysed the IgG subclass profile and the complement binding capacity and effector functions considering the effects of intravenous immunoglobulin preparations via enzyme-linked immunosorbent and cell-based assays. In contrast to chronic neurofascin-155 IgG4-associated neuropathy, anti-pan-neurofascin-associated disease presented with a high morbidity and mortality, but as a monophasic and potentially reversible disorder. During follow-up, antibodies were no longer detectable in 8 of 11 patients. Anti-pan-neurofascin had direct access to the nodes of Ranvier in myelinating cultures titre-dependently, most probably inducing this severe phenotype. Antibody preincubation led to impaired paranode formation, destruction of paranodal architecture and alterations on paranodal myelin and sensory neurons in the cultures, with more severe effects than neurofascin-155 antibodies. Besides IgG4, subclass IgG3 was detected and associated with complement binding and cytotoxic effects in vitro. As a possible correlate of axonal damage in vivo, we detected highly increased serum neurofilament light chain levels (sNF-L), correlating to serum C3a. Still, sNF-L was not identified as a marker for poor prognosis, but rather as an intra- and interindividual marker for acuteness, severity and course, with a strong decrease during recovery. Our data provide evidence that anti-pan-neurofascin antibodies directly attack the node and induce severe and acute, but potentially reversible, nodo-paranodal pathology, possibly involving complement-mediated mechanisms. Screening for autoantibodies thus is crucial to identify this subset of patients who benefit from early antibody-depleting therapy. Titre and sNF-L might serve as valuable follow-up parameters. The prospect of a favourable outcome has high relevance for physicians, patients and relatives during months of critical care., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

In inflammatory neuropathies, oxidative stress results in neuronal and Schwann cell (SC) death promoting early neurodegeneration and clinical disability. Treatment with the short-chain fatty acid propionate showed a significant immunoregulatory and neuroprotective effect in multiple sclerosis patients. Similar effects have been described for patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Therefore, Schwann cell's survival and dorsal root ganglia (DRG) outgrowth were evaluated in vitro after propionate treatment and application of H2O2 or S-nitroso-N-acetyl-D-L-penicillamine (SNAP) to evaluate neuroprotection. In addition, DRG resistance was evaluated by the application of oxidative stress by SNAP ex vivo after in vivo propionate treatment. Propionate treatment secondary to SNAP application on DRG served as a neuroregeneration model. Histone acetylation as well as expression of the free fatty acid receptor (FFAR) 2 and 3, histone deacetylases, neuroregeneration markers, and antioxidative mediators were investigated. β-hydroxybutyrate was used as a second FFAR3 ligand, and pertussis toxin was used as an FFAR3 antagonist. FFAR3, but not FFAR2, expression was evident on SC and DRG. Propionate-mediated activation of FFAR3 and histone 3 hyperacetylation resulted in increased catalase expression and increased resistance to oxidative stress. In addition, propionate treatment resulted in enhanced neuroregeneration with concomitant growth-associated protein 43 expression. We were able to demonstrate an antioxidative and neuroregenerative effect of propionate on SC and DRG mediated by FFAR3-induced histone acetylases expression. Our results describe a pathway to achieve neuroprotection/neuroregeneration relevant for patients with immune-mediated neuropathies.

The aim of this prospective study was to investigate autonomic function in Parkinson's disease with a multidimensional approach including clinical evaluation tools, head-up tilt test and morphological studies of the vagus nerve. Head-up tilt test parameters including high frequency power of the heart frequency interval, the ratio of low frequency power of the distance between two consecutive R waves in electrocardiogram (RR interval) to the high frequency and low frequency power of systolic blood pressure were used to evaluate parasympathetic, cardiac sympathetic and vasomotor sympathetic functions, respectively, in 80 patients with Parkinson's disease. We examined the cross-sectional area of the vagus nerves bilaterally using nerve ultrasound and compared mean values with a control group of healthy subjects ( n = 40) as well as patients with chronic inflammatory demyelinating polyneuropathy ( n = 76). The cross-sectional area of right/left vagus nerve of Parkinson's patients was significantly lower compared to the right/left vagus nerve of the control group and of chronic demyelinating polyneuropathy patients. Furthermore, the cross-sectional area of the right vagus nerve was significantly larger from the one of the left vagus nerve for all groups. Based on tilt test, 43 patients (disease duration 7 ± 5, age at evaluation 71 ± 9, Hoehn and Yahr score 2.8 ± 8) were diagnosed with autonomic dysfunction (orthostatic hypertension n = 11, chronotropic incompetence n = 31, postural orthostatic tachycardia syndrome n = 1). Patients with orthostatic hypotension showed significantly higher Unified Parkinson's Disease Rating Scale-III values than those with chronotropic incompetence. The cross-sectional area of the vagus nerve correlated inversely with heart rate in rest and supine position and positively with tilt test parameters representing parasympathetic modulation through vagal activity [high frequency power of the distance between two consecutive R waves in electrocardiogram (RR interval)] at rest. We demonstrate for the first time that morphological characteristics of the vagus nerve correlate with parameters of parasympathetic function from the spectral analysis of cardiovascular parameters in tilt test for Parkinson's patients. This correlation reveals the impact of the atrophy of vagal atrophy for autonomic function in Parkinson's disease. Nerve ultrasound of the vagus nerve could potentially be used as an adjunct to tilt table examination to diagnose autonomic dysfunction., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Echogenicity of peripheral nerves in high-resolution ultrasound (HRUS) provides insight into the structural damage of peripheral nerves in various polyneuropathies. The aim of this study was to compare nerve echogenicity in different primarily axonal or demyelinating polyneuropathies to examine the significance of this parameter. Performing semi-automated echogenicity analysis and applying Image J, we retrospectively used HRUS images of 19 patients with critical illness polyneuropathy (CIP), and 27 patients with chemotherapy-induced polyneuropathy (CIN) and compared them to 20 patients with chronic inflammatory demyelinating polyneuropathy (CIDP). The fraction of black representing echogenicity was measured after converting the images into black and white. The nerves of patients with progressive CIDP significantly differed from the hyperechogenic nerves of patients with other polyneuropathies at the following sites: the median nerve at the forearm (p < 0.001), the median nerve at the upper arm (p < 0.004), and the ulnar nerve at the upper arm (p < 0.001). The other polyneuropathies showed no notable differences. Altogether, the comparison of echogenicity between different polyneuropathies supports the assumption that there are differences depending on the genesis of the structural nerve damage. However, these differences are slight, and cannot be used to show clear differences between each polyneuropathy form.

Introduction: Chronic inflammatory demyelinating polyneuropathy (CIDP) may have a similar clinical and electrophysiological presentation to non-inflammatory axonal polyneuropathies (NIAPs) when secondary axonal damage occurs. We aimed to investigate if nerve ultrasound can help to differentiate CIDP with additional secondary axonal damage from NIAP., Methods: In a retrospective analysis, the cross-sectional area (CSA) of the peripheral nerves measured by ultrasound at six suitable nerve sites was compared in 95 patients with CIDP and 82 patients with NIAP. We developed the adjusted Bochum ultrasound score (aBUS) ranging from 0 to 6 resulting from the number of sites with enlarged CSA (median, ulnar, radial, and sural nerve)., Results: The mean CSA of patients with CIDP was enlarged at all six nerve sites compared with the mean CSA of patients with NIAP. A total of 21 patients with CIDP did not meet 2010 electrophysiological diagnostic criteria (European Academy of Neurology/Peripheral Nerve Society Guideline, EFNS/PNS criteria) for CIDP at examination timepoint but only in further follow-up, while 25 patients with NIAP fulfilled electrophysiological EFNS/PNS criteria for CIDP as "possible" or "probable" CIDP. To increase diagnostic power, we included aBUS measured by ultrasound in patients classified as "possible" or "probable" resulting in an improved specificity of 94% and a sensitivity of 59%, compared to a specificity of the EFNS/PNS criteria alone of 60% and sensitivity of 78%., Conclusion: Using nerve ultrasound and the aBUS as a complementary method to distinguish CIDP from NIAP in case of secondary axonal damage can facilitate the diagnosis of CIDP., Competing Interests: JM has no personal pecuniary interests to disclose, received travel grants and supply from Biogen, Novartis, Celgene (BristolMyersSquibb), Teva and Eisai, and the author's research is funded by Klaus Tschira Foundation, Hertie Foundation and Ruhr-University, Bochum (FORUM-program), none related to this study. TG received travel reimbursement from Sanofi Genzyme and Biogen Idec, none related to this manuscript. M-SY has received speaker honoraria from CSL Behring and Grifols, a scientific grant from CSL Behring, none related to this manuscript. RG serves on scientific advisory boards for Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, and Novartis; has received speaker honoraria from Biogen Idec, Teva Pharmaceutical Industries Ltd., Bayer Schering Pharma, and Novartis; serves as an editor for Therapeutic Advances in Neurological Diseases and on the editorial boards of Experimental Neurology and the Journal of Neuroimmunology; and receives research support from Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, Genzyme, Merck Serono, and Novartis, none related to this manuscript. KP received travel funding and speaker honoraria from Biogen Idec, Novartis and Bayer Schering Pharma and funding from the Ruhr-University, Bochum (FORUM-program), none related to this study. AF received research funding from Georgius Agricola Stiftung Ruhr and Ruhr-University, Bochum (FORUM-program), received honoraria and travel grants from Novartis AG, Sanofi and Eisai GmbH, none related to this study, and owns shares of Fresenius SE & Co., Gilead Sciences, Medtronic PLC and Novartis AG. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Brünger, Motte, Grüter, Mork, Bulut, Carolus, Athanasopoulos, Yoon, Gold, Pitarokoili and Fisse.)

The assessment of disease activity is fundamental in the management of chronic inflammatory demyelinating polyneuropathy (CIDP). Previous studies with small patient numbers found an increase of corneal immune cell infiltrates as a potential marker of inflammation in patients with CIDP. However, its clinical relevance remained unclear. The present study aimed to determine whether the amount of corneal inflammatory cells (CIC) measured by corneal confocal microscopy (CCM) detects disease activity in CIDP. CIC were measured in 142 CCM-investigations of 97 CIDP-patients. Data on clinical disease activity, disability (INCAT-ODSS) and need for therapy escalation at the timepoint of CCM, 3 and 6 months later were analyzed depending CIC-count. Pathological spontaneous activity during electromyography was examined as another possible biomarker for disease activity in comparison to CIC-count. An increased CIC-count at baseline was found in patients with clinical disease activity and disability progression in the following 3-6 months. An increase to more than 25 CIC/mm 2 had a sensitivity of 0.73 and a specificity of 0.71 to detect clinical disease activity and a sensitivity of 0.77 and a specificity of 0.64 to detect disability progression (increasing INCAT-ODSS) in the following 6 months. An increase to more than 50 CIC/mm 2 had a sensitivity of about 0.51 and a specificity of 0.91 to detect clinical disease activity and a sensitivity of 0.53 and a specificity of 0.80 to detect disability progression. CIC count is a non-invasive biomarker for the detection of disease activity in the following 6 months in CIDP., (© 2021. The Author(s).)

Objective: To evaluate the European Federation of Neurological Societies (EFNS)/Peripheral Nerve Society (PNS) diagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP) in a cohort of patients diagnosed and treated for CIDP in a tertiary university hospital., Methods: In a monocentric retrospective study of 203 CIDP patients, diagnosed according to expert opinion, we evaluated the EFNS/PNS diagnostic criteria. Clinical course and nerve conduction studies (NCS) over 1 year from first referral were studied. Secondarily, we compared the clinical and paraclinical characteristics, including nerve ultrasound, of patients who failed with those who fulfilled the criteria in order to identify clinically relevant differences., Results: At 1 year, 182 (89.7%) patients fulfilled the criteria (156/76.9% definite, 22/10.8% probable, and 4/2% possible). Twenty-one (10.3%) patients did not because the electrodiagnostic criteria remained negative. These still showed signs of demyelination but did not reach the cut-off values. They also presented typical, albeit less pronounced, multifocal nerve enlargement in ultrasonography. Mean disability at presentation and 1 year after was significantly lower. Most importantly, a relevant proportion of these patients also responded to therapy (6/21 = 28.6% vs. 82/182 = 45.3% of those fulfilling the criteria)., Interpretation: CIDP diagnosis could be established for 89.7% of patients over the course of 1 year using EFNS/PNS criteria. The remaining patients (10.3%) presented with milder disability, less accentuated demyelination, but otherwise similar characteristics and still considerable probability of treatment response. Failure to fulfill diagnostic criteria should not automatically preclude treatment. Nerve ultrasound should be considered as a complementary diagnostic tool to detect signs of inflammation in CIDP., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Up to 20% of patients with chronic immune-mediated sensorimotor neuropathies (CIN) do not respond adequately to first-line therapies. However, studies on further treatment are scarce., Methods: We analyzed retrospectively 200 CIN patients regarding disease characteristics and response to therapy with cyclophosphamide (CYP), rituximab (RTX), and bortezomib (BTZ). Treatment response was defined as improvement or stabilization of inflammatory neuropathy cause and treatment overall disability score (INCAT-ODSS)., Results: A total of 48 of 181 patients (26.5%) received therapy with CYP, RTX, or BTZ. The most frequently and first used therapy was CYP (69%). More than 40% of patients needed a second or third treatment. Overall, 71 treatments were applied in 48 patients. The combination of up to all three treatments enhanced the response-rate to 90%. Treatment within 24 months after initial diagnosis resulted in significantly higher response rate than late treatment (79% versus 50 %, p  = 0.04, χ 2 -test, n  = 46) and in lower disability in long-term follow up (INCAT-ODSS 3.8 versus 5.8, p  = 0.02, t -test, n  = 48). Patients with Lewis-Sumner syndrome ( n  = 9) and autoantibody mediated neuropathies ( n  = 13) had excellent response rates after treatment with RTX (90-100%). In contrast, typical chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) showed a response rate of 64% in CYP, 64% in RTX, and 75% in BTZ., Conclusion: Treatment with CYP, RTX, or BTZ was effective in this cohort of CIN refractory to first-line treatment. Our data increase evidence for an early use of these therapies. High efficacy of RTX in Lewis-Sumner syndrome in contrast to typical CIDP suggests a distinct pathophysiology., Competing Interests: Conflict of interest statement: Jeremias Motte: received travel grants from Biogen idec, Novartis AG, Teva, and Eisai GmbH, his research is funded by Klaus Tschira Foundation and Ruhr-University, Bochum (FoRUM-program); none related to this work. Anna Lena Fisse: received research funding by Georgius Agricola Stiftung Ruhr and Ruhr-University, Bochum (FoRUM-program), received honoraria and travel grants from Novartis AG, Sanofi, and Eisai GmbH, none related to this work. Owns shares of Fresenius SE & Co., Gilead Sciences, Medtronic PLC, and Novartis AG. Nuray Köse: none Thomas Grüter: received travel reimbursement from Sanofi Genzyme and Biogen Idec, none related to this manuscript. Hannah Mork: none Diamantis Athanasopoulos: none Miriam Fels: none Susanne Otto: none Ines Siglienti: none Christiane Schneider-Gold: has received a FoRUM grant (F 701-2010) from the Ruhr-University of Bochum and consulting and speaker’s honoraria from Alexion Pharmaceuticals, Amicus Therapeutics, Bayer Schering, CSL Behring, Grünenthal, Lupin Pharmaceuticals, and TEVA. Kerstin Hellwig: Received speaker honoraria, consultancy fees and research support from Bayer Healthcare, Biogen, Novartis, Merck, Teva, and Roche. Min-Suk Yoon has received speaker honoraria from CSL Behring and Grifols, a scientific grant from CSL Behring, none related to this manuscript. Ralf Gold: Serves on scientific advisory boards for Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, and Novartis; has received speaker honoraria from Biogen Idec, Teva Pharmaceutical Industries Ltd., Bayer Schering Pharma, and Novartis; serves as editor for Therapeutic Advances in Neurological Diseases and on the editorial boards of Experimental Neurology and the Journal of Neuroimmunology; and receives research support from Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, Genzyme, Merck Serono, and Novartis, none related to this manuscript. Because this author is the Editor-in-Chief of Therapeutic Advances in Neurological Disorders, the peer review process was managed by alternative members of the Board and the submitting Editor was not involved in the decision-making process. Kalliopi Pitarokoili: received travel funding and speaker honoraria from Biogen Idec, Novartis and Bayer Schering Pharma and funding from the Ruhr-University, Bochum (FORUM-Program), none related to this work., (© The Author(s), 2021.)

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is the most common chronic inflammatory neuropathy. CIDP is diagnosed according to the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) criteria, which combine clinical features with the electrophysiological evidence of demyelination. However, firstly, diagnosis is challenging, as some patients e.g. with severe early axonal damage do not fulfil the criteria. Secondly, objective and reliable tools to monitor the disease course are lacking. Thirdly, about 25% of CIDP patients do not respond to evidence-based first-line therapy. Recognition of these patients is difficult and treatment beyond first-line therapy is based on observational studies and case series only. Individualized immunomodulatory treatment does not exist due to the lack of understanding of essential aspects of the underlying pathophysiology. Novel diagnostic imaging techniques and molecular approaches can help to solve these problems but do not find enough implementation. This review gives a comprehensive overview of novel diagnostic techniques and monitoring approaches for CIDP and how these can lead to individualized treatment and better understanding of pathophysiology., Competing Interests: Competing interestsThe authors declare that they have no competing interest., (© The Author(s) 2020.)

Objective: Previous studies in Parkinson's disease (PD) patients have demonstrated a high prevalence of polyneuropathy (PNP) and pronounced alpha-Synuclein pathology in dermal nerve fibers already at early disease stages. The aim of this study was to analyze associations between the prevalence and severity of PNP with nonmotor and motor symptoms in PD patients., Methods: Fifty PD patients were characterized comprehensively for the presence of clinical symptoms (nonmotor and motor), electrophysiologic alterations and - for the first time - using high-resolution ultrasound of peripheral nerves., Results: Sixty-two percent of PD patients showed electrophysiological pathology of PNP. The prevalence of patient-reported PNP symptoms was 86% and was particularly present in patients with longer disease duration, compromised scores of nonmotor and motor symptoms as well as with a negative evaluation of quality of life. Seventy-five percent of patients showed morphologic alterations similar to axonal PNP in high-resolution ultrasound compared to healthy controls., Interpretation: The study demonstrates the high burden of peripheral nervous system disease in Parkinson's disease. It advocates further studies to delineate the underlying pathophysiological mechanisms in order to optimize treatment approaches for PD, including the associated PNP., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Hyperprolinemia type 2 (HPII) is a rare autosomal recessive disorder of the proline metabolism, that affects the ALDH4A1 gene. So far only four different pathogenic mutations are known. The manifestation is mostly in neonatal age, in early infancy or early childhood., Case Presentation: The 64-years female patient had a long history of abdominal pain, and episode of an acute neuritis. Ten years later she was admitted into the neurological intensive-care-unit with acute abdominal pain, multiple generalized epileptic seizures, a vertical gaze palsy accompanied by extensive lactic acidosis in serum 26.0 mmol/l (reference: 0.55-2.2 mmol/l) and CSF 12.01 mmol/l (reference: 1.12-2.47 mmol/l). Due to repeated epileptic seizures and secondary complications a long-term sedation with a ventilation therapy over 20 days was administered. A diagnostic work-up revealed up to 400-times increased prolin-level in urine CSF and blood. Furthermore, a low vitamin-B 6 serum value was found, consistent with a HPII causing secondary pyridoxine deficiency and seizures. The ALDH4A1 gene sequencing confirmed two previously unknown compound heterozygous variants (ALDH4A1 gene (NM&#95;003748.3) Intron 1: c.62 + 1G > A - heterozygous and ALDH4A1 gene (NM&#95;003748.3) Exon 5 c.349G > C, p.(Asp117His) - heterozygous). Under high-dose vitamin-B 6 therapy no further seizures occurred., Conclusion: We describe two novel ALDH4A1-variants in an adult patient with hyperprolinemia type II causing secondary pyridoxine deficiency and seizures. Severe and potentially life-threatening course of this treatable disease emphasizes the importance of diagnostic vigilance and thorough laboratory work-up including gene analysis even in cases with atypical late manifestation.

Background: One of the main goals of novel, noninvasive imaging techniques like high-resolution nerve ultrasound (HRUS) and corneal confocal microscopy (CCM) is the prediction of treatment response for patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)., Methods: A total of 17 patients with CIDP were examined prospectively at baseline and every 9 months over a period of 18 months using CCM to quantify corneal nerve degeneration markers and immune cell infiltration as well as HRUS to detect changes of the cross-sectional area (CSA) of the peripheral nerves. Additionally, skin biopsy of the distal and proximal leg as well as quantitative sensory testing were performed at the first follow-up visit., Results: A value of more than 30 total corneal cells/mm 2 in CCM at baseline identified patients with clinical progression with a sensitivity/specificity of 100% in our cohort. Corneal nerve fiber density and length remained low and stable over the study period and intra-epidermal fiber density was markedly reduced in the majority of the patients. Furthermore, an increase in Bochum ultrasound score (BUS), which summarizes the CSA of the ulnar nerve in Guyons' canal, the ulnar nerve in the upper arm, the radial nerve in the spiral groove and the sural nerve between the gastrocnemius muscle, and a maximum BUS of 4 at study initiation identified patients with disease progression (sensitivity 80%, specificity 88%)., Conclusions: BUS and corneal total cell infiltration seem to represent early markers for clinical progression in CIDP, thus having the potential to identify at-risk patients and impact treatment decisions., Competing Interests: Conflicts of interest: Nina Kumowski, Lynn Eitner, Tineke Greiner, Anna Lena Fisse and Adnan Labedi report no disclosures. Dietrich Sturm received funding from the Ruhr University, Bochum (FoRUM-Program). Kalliopi Pitarokoili received travel funding and speaker honoraria from Biogen Idec, Novartis and Bayer Schering Pharma and funding from the Ruhr University, Bochum (FoRUM-Program). R. Gold has received consultation fees and speaker honoraria from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis and TEVA. He also acknowledges grant support from Bayer Schering, Biogen Idec, Merck Serono, Sanofi-Aventis and TEVA, none related to this manuscript. Elena K. Enax-Krumova is member of the German Research Network on Neuropathic pain e.V. (BMBF, grants 01EM0107 & 01EM0502), members of the European Collaboration, which has received support from the Innovative Medicines Initiative Joint Undertaking, under grant agreement no 11507, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies (AstraZeneca, Pfizer, Esteve, UCB-Pharma, Sanofi-Aventis, Grünenthal, Eli Lilly und Boehringer Ingelheim) inkind contribution, was supported by intramural funding of the Ruhr University Bochum (FoRUM: grant number K046-10, Heinemann Award 2013) and has received a travel grant from Mundipharma GmbH and Bayer Vital GmbH, speaker fees from Grünenthal GmbH and Pfizer GmbH. Christoph Maier has received honoraria for speaking and advisory board membership from Gruenenthal, MSD, Köhler Chemie, Mundipharma, Pfizer, and Wyeth. Martin Tegenthoff has received speaker honoraria from Pfizer, Novartis and Mundipharma. He also acknowledges a grant support from Genzyme, not related to this manuscript. Tobias Schmidt-Wilcke received consulting fees from Daiichi Sankyo. Min-Suk Yoon has received speaker honoraria from CSL Behring and Grifols, a scientific grant from CSL Behring, none related to this manuscript.

Background and Purpose- Given inconclusive studies, it is debated whether clinical and imaging characteristics, as well as functional outcome, differ among patients with intracerebral hemorrhage (ICH) related to vitamin K antagonists (VKA) versus non-vitamin K antagonist (NOAC)-related ICH. Notably, clinical characteristics according to different NOAC agents and dosages are not established. Methods- Multicenter observational cohort study integrating individual patient data of 1328 patients with oral anticoagulation-associated ICH, including 190 NOAC-related ICH patients, recruited from 2011 to 2015 at 19 tertiary centers across Germany. Imaging, clinical characteristics, and 3-months modified Rankin Scale (mRS) outcomes were compared in NOAC- versus VKA-related ICH patients. Propensity score matching was conducted to adjust for clinically relevant differences in baseline parameters. Subgroup analyses were performed regarding NOAC agent, dosing and present clinically relevant anticoagulatory activity (last intake <12h/24h or NOAC level >30 ng/mL). Results- Despite older age in NOAC patients, there were no relevant differences in clinical and hematoma characteristics between NOAC- and VKA-related ICH regarding baseline hematoma volume (median [interquartile range]: NOAC, 14.7 [5.1-42.3] mL versus VKA, 16.4 [5.8-40.6] mL; P=0.33), rate of hematoma expansion (NOAC, 49/146 [33.6%] versus VKA, 235/688 [34.2%]; P=0.89), and the proportion of patients with unfavorable outcome at 3 months (mRS, 4-6: NOAC 126/179 [70.4%] versus VKA 473/682 [69.4%]; P=0.79). Subgroup analyses revealed that NOAC patients with clinically relevant anticoagulatory effect had higher rates of intraventricular hemorrhage (n/N [%]: present 52/109 [47.7%] versus absent 9/35 [25.7%]; P=0.022) and hematoma expansion (present 35/90 [38.9%] versus absent 5/30 [16.7%]; P=0.040), whereas type of NOAC agent or different NOAC-dosing regimens did not result in relevant differences in imaging characteristics or outcome. Conclusions- If effectively anticoagulated, there are no differences in hematoma characteristics and functional outcome among patients with NOAC- or VKA-related ICH. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT03093233.

Background: The aim of this work was to report a case of an acute motor and sensory axonal neuropathy (AMSAN) treated with propionate to evaluate its therapeutic potential in AMSAN., Materials and Methods: The patient was investigated by clinical examination, electroneurography, high-resolution nerve ultrasound and confocal corneal microscopy at baseline and the 2 month follow up. We compared the outcome with those of five other patients with acute motor axonal neuropathy (AMAN) and AMSAN of who were referred to our neurology department in the past 5 years., Results: Considering the poor prognosis of patients with acute axonal neuropathies and in comparison with the previously treated patients with AMAN or AMSAN in our clinic, the regression of our patient's symptoms and the improvement in the additional examinations under propionate seemed exceptionally good., Conclusion: Propionate may have an additional therapeutic effect in autoimmune inflammatory neuropathies., Competing Interests: Conflict of interest statement: Min-Suk Yoon: received speakers’ honoraria from CSL Behring, Grifols and a scientific grant from CSL Behring, not related to the manuscript. Kalliopi Pitarokoili: received travel grants and speakers’ honoraria from Novartis, Biogen idec, Teva, Bayer and Grifols, all not related to the manuscript. Dietrich Sturm: received funding from the Ruhr University, Bochum (FORUM-Program), not related to the manuscript. Aiden Haghikia: received speaker’s honoraria from Bayer Healthcare, Biogen Idec, Merck Serono, Novartis and Teva. Ralf Gold: received consultation fees and speaker honoraria from Bayer Schering, Biogen idec, Merck Serono, Novartis, Sanofi-Aventis and Teva. He also acknowledges grant support from Bayer Schering, Biogen idec, Merck Serono, Sanofi-Aventis and Teva, none related to this manuscript. Anna Lena Fisse: none.

Aims: Evidence is lacking regarding acute anticoagulation management in patients after intracerebral haemorrhage (ICH) with implanted mechanical heart valves (MHVs). Our objective was to investigate anticoagulation reversal and resumption strategies by evaluating incidences of haemorrhagic and thromboembolic complications, thereby defining an optimal time-window when to restart therapeutic anticoagulation (TA) in patients with MHV and ICH., Methods and Results: We pooled individual patient-data (n = 2504) from a nationwide multicentre cohort-study (RETRACE, conducted at 22 German centres) and eventually identified MHV-patients (n = 137) with anticoagulation-associated ICH for outcome analyses. The primary outcome consisted of major haemorrhagic complications analysed during hospital stay according to treatment exposure (restarted TA vs. no-TA). Secondary outcomes comprised thromboembolic complications, the composite outcome (haemorrhagic and thromboembolic complications), timing of TA, and mortality. Adjusted analyses involved propensity-score matching and multivariable cox-regressions to identify optimal timing of TA. In 66/137 (48%) of patients TA was restarted, being associated with increased haemorrhagic (TA = 17/66 (26%) vs. no-TA = 4/71 (6%); P < 0.01) and a trend to decreased thromboembolic complications (TA = 1/66 (2%) vs. no-TA = 7/71 (10%); P = 0.06). Controlling treatment crossovers provided an incidence rate-ratio [hazard ratio (HR) 10.31, 95% confidence interval (CI) 3.67-35.70; P < 0.01] in disadvantage of TA for haemorrhagic complications. Analyses of TA-timing displayed significant harm until Day 13 after ICH (HR 7.06, 95% CI 2.33-21.37; P < 0.01). The hazard for the composite-balancing both complications, was increased for restarted TA until Day 6 (HR 2.51, 95% CI 1.10-5.70; P = 0.03)., Conclusion: Restarting TA within less than 2 weeks after ICH in patients with MHV was associated with increased haemorrhagic complications. Optimal weighing-between least risks for thromboembolic and haemorrhagic complications-provided an earliest starting point of TA at Day 6, reserved only for patients at high thromboembolic risk.

Objective: To report a rare case of incipient granulomatous hypophysitis presenting by atypical trigemino-autonomic cephalalgia (TAC) and Horner syndrome., Methods: The patient was investigated with repeated brain MRI, CSF examination, thoracic CT, Doppler and duplex ultrasound of the cerebral arteries, and extensive serologic screening for endocrine and autoimmune markers. Written informed consent was obtained from the patient for access to clinical files for research purposes and for publication., Results: We present a middle-aged woman with a history of an autoimmune pancreatitis type 2 who had therapy-refractory TAC with Horner syndrome. Initial cerebral MRI showed only indistinct and unspecific signs of a pathologic process. A biopsy revealed a granulomatous hypophysitis. The symptoms disappeared after transsphenoidal subtotal resection of the pituitary mass and anti-inflammatory therapy., Conclusions: This case elucidates that inflammatory pituitary diseases must be taken into account in case of atypical and refractory TAC, especially in patients with a history of autoimmune diseases. To our knowledge, the association between TAC accompanied by Horner syndrome and hypophysitis has not yet been described before.

Background and Aims: Sleep related breathing disorders (SRBD) are common in patients with ischemic stroke and are associated with poor outcome. SRBD after stroke were assumed to be a direct consequence of injury of specific central nervous system structures. However, whether specific locations of ischemic infarcts cause SRBD is yet unknown. We therefore investigated the association of ischemic lesion location with SRBD., Methods: Patients with acute ischemic stroke treated on our stroke unit were included in a prospective observational study. All patients underwent magnetic resonance imaging (MRI) and polygraphy in the acute phase after stroke. SRBD was defined by an apnea-hypopnea index (AHI) ≥10. MRI were evaluated using standardized maps to depict voxel-wise probability distribution of infarction for patients with and without SRBD. Groups were compared using logistic regression analysis., Results: Of 142 patients included, 86 (59%) had a SRBD. Age, body mass index and prevalence of arterial hypertension were significantly higher in patients with SRBD. There was no statistically significant association between any lesion location and SRBD., Conclusion: We found no association of lesion location and SRBD in stroke patients, whereas established risk factors for SRBD, known from general population, were significantly associated with SRBD. Given the high prevalence of SRBD in stroke patients, these findings suggest that cerebral ischemia facilitates the occurrence of SRBD in patients with pre-existing risk factors rather than causing it by damaging specific central nervous system structures. Our findings can be used to identify stroke patients who might benefit from polygraphy screening., Competing Interests: Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: PY received honoraries for invited talks and advisory boards meetings from Heinen und Löwenstein, ResMed, UCB, GENZYME, Medice and Vanda. This does not alter our adherence to PLOS ONE policies on sharing data and materials.