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Background and purpose: Next‐generation sequencing has greatly improved the diagnostic success rates for genetic neuromuscular disorders (NMDs). Nevertheless, most patients still remain undiagnosed, and there is a need to maximize the diagnostic yield. Methods: A retrospective study was conducted on 72 patients with NMDs who underwent exome sequencing (ES), partly followed by genotype‐guided diagnostic reassessment and secondary investigations. The diagnostic yields that would have been achieved by appropriately chosen narrow and comprehensive gene panels were also analysed. Results: The initial diagnostic yield of ES was 30.6% (n = 22/72 patients). In an additional 15.3% of patients (n = 11/72) ES results were of unknown clinical significance. After genotype‐guided diagnostic reassessment and complementary investigations, the yield was increased to 37.5% (n = 27/72). Compared to ES, targeted gene panels (<25 kilobases) reached a diagnostic yield of 22.2% (n = 16/72), whereas comprehensive gene panels achieved 34.7% (n = 25/72). Conclusion: Exome sequencing allows the detection of pathogenic variants missed by (narrowly) targeted gene panel approaches. Diagnostic reassessment after genetic testing further enhances the diagnostic outcomes for NMDs. [ABSTRACT FROM AUTHOR]

Background and Purpose: Autoimmune screening panels (ASPs) are often ordered as a part of the diagnostic workup in people with suspected multiple sclerosis (MS). However, data on the significance of ASP seropositivity in MS are scarce. This study aimed to investigate whether routine implementation of ASPs is viable in MS diagnostic workup., Methods: In this retrospective study, we included patients from the Vienna Multiple Sclerosis Database who were diagnosed with MS according to current McDonald criteria between 2014 and 2021 and had an ASP performed., Results: We analyzed 212 patients (mean age at serology = 30.4 [SD = 8.5] years, 67% female). Red flag symptoms for presence of systemic autoimmune disease were reported by 5.6% of patients during initial evaluation (sicca syndrome [n = 5], joint pain [n = 4], dermatitis [n = 4]). Complement levels (C3c and C4) were below the lower reference level in 26 of 134 (19.4%) and three of 134 (2.2%), respectively. Antinuclear antibodies (ANAs) were positive in 24 of 210 (11.4%), with 18 (8.6%), five (2.4%), and one (0.5%) having mildly, moderately, and strongly positive ANA titers. Extractable nuclear antibody subsets were positive in 10 of 211 (4.7%) patients. ASPs led to the diagnosis of mixed connective tissue disease (n = 1), psoriatic arthritis (n = 1), and Sjögren syndrome (n = 2; positive predictive value [PPV] = 4.9%, negative predictive value [NPV] = 99.3%). Among patients presenting with red flag symptoms, ASPs had better overall test performance (PPV = 100%, NPV = 88.9%)., Conclusions: The rate of ASP seropositivity in MS is low and within the range of the general population. Performance of ASPs without clinical suspicion of systemic autoimmune disease seems unwarranted., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objective: To investigate retinal layer thinning as a biomarker of disease-modifying treatment (DMT) effects in relapsing multiple sclerosis (RMS)., Methods: From an ongoing prospective observational study, we included patients with RMS, who (i) had an optical coherence tomography (OCT) scan within 6 to 12 months after DMT start (rebaseline) and ≥1 follow-up OCT ≥12 months after rebaseline and (ii) adhered to DMT during follow-up. Differences between DMT in thinning of peripapillary-retinal-nerve-fiber-layer (pRNFL) and macular ganglion cell-plus-inner plexiform-layer (GCIPL) were analyzed using mixed-effects linear regression. Eyes suffering optic neuritis during follow-up were excluded., Results: We included 291 RMS patients (mean age 30.8 years [SD 7.9], 72.9% female, median disease duration 9 months [range 6-94], median rebaseline-to-last-follow-up-interval 32 months [12-82]). Mean annualized rates of retinal layer thinning (%/year) in reference to DMF (n = 84, GCIPL 0.28, pRNFL 0.53) were similar under TERI (n = 18, GCIPL 0.34, pRNFL 0.59), GLAT (n = 24, GCIPL 0.32, pRNFL 0.56), and IFNb (n = 13, GCIPL 0.33, pRNFL 0.60) were slightly lower under S1PM (n = 27, GCIPL 0.19, pRNFL 0.42) and CLA (n = 23, GCIPL 0.20, pRNFL 0.42), and were significantly lower under NTZ (n = 47, GCIPL 0.09, pRNFL 0.24; both p < 0.001) and antiCD20 (n = 55, GCIPL 0.10, pRNFL 0.23; both p < 0.001). In patients achieving NEDA-2, observed thinning rates were lower overall, but still significantly lower under NTZ and antiCD20., Interpretation: Applying a rebaselining concept, retinal layer thinning differentiates DMT effects even in clinically stable patients and, thus, might be a useful biomarker to monitor DMT efficacy on subclinical neuroaxonal degeneration-at least on a group level., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Acute transverse myelitis (ATM) is a disease characterized by inflammation of the spinal cord and may have various causes. In the context of this work, the distinction between isolated ATM and initial manifestation of autoimmune-mediated diseases of the central nervous system such as multiple sclerosis (MS) is crucial. Hence, the aim of this work was to identify predictive factors associated with the conversion to definite MS in a collective of individuals after their initial episode of isolated ATM (no initial identified cause). In this retrospective data analysis from the Vienna MS Database, all patients from Jan. 1, 1999, to Dec. 31, 2019, with a diagnosis of isolated ATM (according to the criteria of the Transverse Myelitis Consortium Working Group) who underwent lumbar puncture were extracted. Electronic medical records were reviewed on the availability of clinical data including therapy and follow-up, laboratory results including cerebrospinal fluid (CSF) analysis, evoked potentials (EP) as well as magnetic resonance imaging data. Among 42 patients with the diagnosis of isolated ATM, 12 (29%) were subsequently diagnosed with MS over a median follow-up period of 7.7 years. Univariately, MS converters were younger (32 years [25-39] vs. 42 years [31-50], p = 0.032), had a lower CSF/serum albumin ratio (29 [24-35] vs 37 [27-52], p = 0.037), lower CSF total protein (4.5 [2.8-4.8] vs. 5.5 [3.4-8.5], p = 0.023) and a higher proportion of CSF-specific oligoclonal bands (OCB; 83% vs. 30%, p = 0.002). In the multivariate regression analysis, the presence of CSF-specific OCB emerged as the sole predictive factor of subsequent MS diagnosis (OR: 14.42, 95% CI 1.39 to 149.48, p = 0.03). In a collective of 42 patients with isolated ATM and an MS conversion rate of nearly 30%, the only but highly predictive factor were CSF-specific OCB. This emphasizes the significance of conducting timely CSF analysis in such patients and underscores the need for tailored monitoring and follow-up strategies in this specific group., (© 2024. The Author(s).)

Background and Objectives: Isolated value of MRI metrics in relapsing multiple sclerosis (RMS) as a surrogate marker of response to disease-modifying treatment (DMT) and, thus, as decision criteria for DMT escalation in the absence of clinical signs of disease activity is still a matter of debate. The aim of this study was to investigate whether DMT escalation based on isolated MRI activity affects clinical outcome., Methods: Combining data from 5 MS centers in Austria and Switzerland, we included patients with RMS aged at least 18 years who (1) had initiated first-line, low-to-moderate-efficacy DMT (interferon β, glatiramer acetate, teriflunomide, or dimethyl fumarate) continued for ≥12 months, (2) were clinically stable (no relapses or disability progression) on DMT for 12 months, (3) had MRI at baseline and after 12 months on DMT, and (4) had available clinical follow-up for ≥2 years after the second MRI. The primary endpoint was occurrence of relapse during follow-up. The number of new T2 lesions (T2L) and DMT strategy (continuing low-/moderate-efficacy DMT vs escalating DMT) were used as covariates in regression analyses., Results: A total of 131 patients with RMS, median age of 36 (25th-75th percentiles: 29-43) years, 73% women, were included and observed over a median period of 6 (5-9) years after second MRI. Sixty-two (47%) patients had relapse. Patients who continued first-line DMT had a 3-fold increased risk of relapse given 2 new T2L (hazard ratio [HR] 3.2, lower limit [LL] of 95% CI: 1.5) and a 4-fold increased risk given ≥3 new T2L (HR 4.0, LL-CI: 2.1). Escalation of DMT lowered the risk of relapse in patients with 2 new T2L by approximately 80% (HR 0.2, upper limit [UL] of 95% CI: 1.3) and with ≥3 new T2L by 70% (HR 0.3, UL-CI: 0.8). In case of only 1 new T2L, the increased risk of relapse and the treatment effect did not reach statistical significance of 5%., Discussion: In our real-world cohort of patients clinically stable under low-to-moderate-efficacy DMT, escalation of DMT based on isolated MRI activity decreased risk of further relapse when at least 2 new T2L had occurred., Classification of Evidence: This study provides Class III evidence that clinically stable patients with MS on low-/moderate-efficacy DMT with ≥3 new T2L on MRI who escalate DMT have a reduced risk of relapse and Expanded Disability Status Scale progression.

Background: Employing a rebaselining concept may reduce noise in retinal layer thinning measured by optical coherence tomography (OCT)., Methods: From an ongoing prospective observational study, we included patients with relapsing multiple sclerosis (RMS), who had OCT scans at disease-modifying treatment (DMT) start (baseline), 6-12 months after baseline (rebaseline), and ⩾12 months after rebaseline. Mean annualized percent loss (aL) rates (%/year) were calculated both from baseline and rebaseline for peripapillary-retinal-nerve-fiber-layer (aLpRNFL baseline /aLpRNFL rebaseline ) and macular-ganglion-cell-plus-inner-plexiform-layer (aLGCIPL baseline /aLGCIPL rebaseline ) by mixed-effects linear regression models., Results: We included 173 RMS patients (mean age 31.7 years (SD 8.8), 72.8% female, median disease duration 15 months (12-94) median baseline-to-last-follow-up-interval 37 months (18-71); 56.6% moderately effective DMT (M-DMT), 43.4% highly effective DMT (HE-DMT)). Both mean aLpRNFL baseline and aLGCIPL baseline significantly increased in association with relapse (0.51% and 0.26% per relapse, p < 0.001, respectively) and disability worsening (1.10% and 0.48%, p < 0.001, respectively) before baseline, but not with DMT class. Contrarily, neither aLpRNFL rebaseline nor aLGCIPL rebaseline was dependent on relapse or disability worsening before baseline, while HE-DMT significantly lowered aLpRNFL rebaseline (by 0.31%, p < 0.001) and aLGCIPL rebaseline (0.25%, p < 0.001) compared with M-DMT., Conclusions: Applying a rebaselining concept significantly improves differentiation of DMT effects on retinal layer thinning by avoiding carry-over confounding from previous disease activity., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Gabriel Bsteh has participated in meetings sponsored by, received speaker honoraria or travel funding from Biogen, Celgene/BMS, Lilly, MedWhizz, Merck, Novartis, Roche, Sanofi Genzyme and Teva, and received honoraria for consulting Biogen, Celgene/BMS, Merck, Novartis, Roche, Sanofi Genzyme, and Teva. He has received unrestricted research grants from Celgene/BMS and Novartis.Harald Hegen has participated in meetings sponsored by, received speaker honoraria or travel funding from Bayer, Biogen, Bristol Myers Squibb, Horizon, Merck, Novartis, Sanofi Genzyme, Siemens and Teva, and received honoraria for consulting Biogen, Bristol Myers Squibb, Novartis, Roche, Sanofi Genzyme, and Teva. He is associate editor of Frontiers in Neurology.Nik Krajnc has participated in meetings sponsored by, received speaker honoraria or travel funding from Alexion, BMS/Celgene, Janssen-Cilag, Merck, Novartis, Roche and Sanofi Genzyme and held a grant for a Multiple Sclerosis Clinical Training Fellowship Programme from the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).Fabian Föttinger has nothing to disclose.Patrick Altmann has participated in meetings sponsored by, received speaker honoraria or travel funding from Biogen, Merck, Roche, Sanofi Genzyme and Teva, and received honoraria for consulting from Biogen. He received a research grant from Quanterix International and was awarded a combined sponsorship from Biogen, Merck, Sanofi Genzyme, Roche, and Teva for a clinical study.Michael Auer has participated in meetings sponsored by, received speaker honoraria or travel funding from Biogen, Merck, Novartis, Sanofi Genzyme and Horizon Therapeutics.Klaus Berek has participated in meetings sponsored by and received travel funding from Biogen, Roche, Sanofi Genzyme, and Teva.Barbara Kornek has received honoraria for speaking and for consulting from Biogen, BMS-Celgene, Johnson & Johnson, Merck, Novartis, Roche, Teva, and Sanofi Genzyme outside of the submitted work. No conflict of interest with respect to the present study.Fritz Leutmezer has participated in meetings sponsored by, received speaker honoraria or travel funding from Actelion, Almirall, Biogen, Celgene, Johnson & Johnson, MedDay, Merck, Novartis, Roche, Sanofi Genzyme, and Teva, and received honoraria for consulting Biogen, Celgene, Merck, Novartis, Roche, Sanofi Genzyme, and Teva.Stefan Macher declares no conflict of interest relevant to this study.Tobias Monschein has participated in meetings sponsored by or received travel funding from Biogen, Merck, Novartis, Roche, Sanofi Genzyme, and Teva.Markus Ponleitner has participated in meetings sponsored by, received speaker or consulting honoraria or travel funding from Amicus, Merck, Novartis and Sanofi Genzyme.Paulus Rommer has received honoraria for consultancy/speaking from Alexion/Astra Zeneca, Allmiral, Amgen/Horizon, Amicus, Biogen, Merck, Novartis, Roche, Sandoz, Sanofi has received research grants from Amicus, Biogen, Merck, and Roche.Christiane Schmied declares no conflict of interest relevant to this study.Karin Zebenholzer received speaking honoraria or travel grants from Biogen, Celgene/BMS, Novartis, and Sanofi Genzyme.Gudrun Zulehner has participated in meetings sponsored by or received travel funding from Biogen, Merck, Novartis, Roche, Sanofi Genzyme, and Teva.Tobias Zrzavy has participated in meetings sponsored by or received travel funding from Biogen, Merck, Novartis, Roche, Sanofi Genzyme, and Teva.Florian Deisenhammer has participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Alexion, Almirall, Biogen, Celgene, Merck, Novartis, Roche, and Sanofi Genzyme. His institution received scientific grants from Biogen and Sanofi Genzyme.Franziska Di Pauli has participated in meetings sponsored by, received honoraria (lectures, advisory boards, consultations) or travel funding from Biogen, Celgene BMS, Horizon, Johnson & Johnson, Merck, Novartis, Sanofi Genzyme, Teva, and Roche. Her institution has received research grants from Roche.Berthold Pemp has received honoraria for consulting from Novartis, has received honoraria for advisory boards/consulting from Chiesi and GenSight, and has received speaker honoraria from Novartis, Chiesi, and Santen.Thomas Berger has participated in meetings sponsored by and received honoraria (lectures, advisory boards, consultations) from pharmaceutical companies marketing treatments for MS: Allergan, Bayer, Biogen, Bionorica, BMS/Celgene, Genesis, GSK, GW/Jazz Pharma, Horizon, Janssen-Cilag, MedDay, Merck, Novartis, Octapharma, Roche, Sandoz, Sanofi Genzyme, Teva, and UCB. His institution has received financial support in the past 12 months by unrestricted research grants (Biogen, Bayer, BMS/Celgene, Merck, Novartis, Roche, Sanofi Genzyme, Teva) and for participation in clinical trials in multiple sclerosis sponsored by Alexion, Bayer, Biogen, Merck, Novartis, Octapharma, Roche, Sanofi Genzyme, and Teva.

Background: Recent studies proposed cellular immunoprofiling as a surrogate for predicting treatment response and/or stratifying the occurrence of adverse events (AEs) in persons with multiple sclerosis (pwMS). However, applicability in real-world circumstances is not sufficiently addressed., Objective: We aimed to explore whether standard routine clinical leukocyte phenotyping before treatment initiation could help stratify patients according to treatment response or AEs in a real-world MS cohort., Methods: In this retrospective study, 150 pwMS were included, who had been newly initiated on a disease-modifying drug (DMD) and had been assessed for standard immunophenotyping before DMD initiation (baseline) and at least once during the following year. Multivariate models were used to assess an association of immune subsets and the association between immune cell profiles regarding treatment response and AEs., Results: We found that the composition of T cell subsets was associated with relapse activity, as an increased proportion of CD8 + lymphocytes at baseline indicated a higher likelihood of subsequent relapse (about 9% per 1% increase in CD8+ proportion of all CD3+ cells). This was particularly driven by patients receiving anti-CD20 therapy, where also EDSS worsening was associated with a higher number of CD8+ cells at baseline (3% increase per 10 cells). In the overall cohort, an increase in the proportion of NK cells was associated with a higher risk of EDSS worsening (5% per 1% increase). Occurrence of AEs was associated with a higher percentage of T cells and a lower number of percentual NKT cells at baseline., Conclusion: Immune cell profiles are associated with treatment response and the occurrence of AEs in pwMS. Hence, immunophenotyping may serve as a valuable biomarker to enable individually tailored treatment strategies in pwMS., Competing Interests: TZ has participated in meetings sponsored by or received travel funding from Biogen, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. HH reports grants from Glock Health Science and Research, BlueSky Immunotherapies, Neutrolis, Clickmer, Janssen-Cilag, the Austrian Federal Ministry for Education Science and Research, as well as from the Austrian Federal Ministry for Defense and Sports, all outside of the submitted work. PA has participated in meetings sponsored by, received speaker honoraria or travel funding from Biogen, Merck, Roche, Sanofi-Genzyme and Teva, and received honoraria for consulting from Biogen. He received a research grant from Quanterix International and was awarded a combined sponsorship from Biogen, Merck, Sanofi-Genzyme, Roche, and Teva for a clinical study. BK has received honoraria for speaking and for consulting from Biogen, BMSCelgene, Johnson&Johnson, Merck, Novartis, Roche, Teva and Sanofi-Genzyme outside of the submitted work. No conflict of interest with respect to the present study. NK has participated in meetings sponsored by, received speaker honoraria or travel funding from BMS/Celgene, Janssen-Cilag, Merck, Novartis, Roche and Sanofi-Genzyme and held a grant for a Multiple Sclerosis Clinical Training Fellowship Programme from the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). TM has participated in meetings sponsored by or received travel funding from Biogen, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. KZ received speaking honoraria or travel grants from Biogen, Novartis and Sanofi-Genzyme. GZ has participated in meetings sponsored by or received travel funding from Biogen, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. TB has participated in meetings sponsored by and received honoraria (lectures, advisory boards, consultations) from pharmaceutical companies marketing treatments for MS: Allergan, Bayer, Biogen, Bionorica, BMS/Celgene, Genesis, GSK, GW/Jazz Pharma, Horizon, Janssen-Cilag, MedDay, Merck, Novartis, Octapharma, Roche, Sandoz, Sanofi-Genzyme, Teva and UCB. His institution has received financial support in the past 12 months by unrestricted research grants (Biogen, Bayer, BMS/Celgene, Merck, Novartis, Roche, Sanofi-Genzyme, Teva) and for participation in clinical trials in multiple sclerosis sponsored by Alexion, Bayer, Biogen, Merck, Novartis, Octapharma, Roche, Sanofi-Genzyme, Teva. PR has received honoraria for consultancy/speaking from AbbVie, Allmiral, Alexion, Biogen, Merck, Novartis, Roche, Sandoz, Sanofi Genzyme, has received research grants from Amicus, Biogen, Merck, Roche. FL has participated in meetings sponsored by, received speaker honoraria or travel funding from Actelion, Almirall, Biogen, Celgene, Johnson&Johnson, MedDay, Merck, Novartis, Roche, Sanofi-Genzyme and Teva, and received honoraria for consulting Biogen, Celgene, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. GB has participated in meetings sponsored by, received speaker honoraria or travel funding from Biogen, Celgene/BMS, Lilly, Merck, Novartis, Roche, Sanofi-Genzyme and Teva, and received honoraria for consulting Biogen, Celgene/BMS, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. He has received financial support in the past 12 months by unrestricted research grants (Celgene/BMS, Novartis). 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 Zrzavy, Rieder, Wuketich, Thalhammer, Haslacher, Altmann, Kornek, Krajnc, Monschein, Schmied, Zebenholzer, Zulehner, Berger, Rommer, Leutmezer and Bsteh.)

Background: Neuromuscular disorders (NMDs) are heterogeneous conditions with a considerable fraction attributed to monogenic defects. Despite the advancements in genomic medicine, many patients remain without a diagnosis. Here, we investigate whether a comprehensive reassessment strategy improves the diagnostic outcomes., Methods: We analyzed 263 patients with NMD phenotypes that underwent diagnostic exome or genome sequencing at our tertiary referral center between 2015 and 2023. We applied a comprehensive reassessment encompassing variant reclassification, re-phenotyping and NGS data reanalysis. Multivariable logistic regression was performed to identify predictive factors associated with a molecular diagnosis., Results: Initially, a molecular diagnosis was identified in 53 cases (20%), while an additional 23 (9%) had findings of uncertain significance. Following comprehensive reassessment, the diagnostic yield increased to 23%, revealing 44 distinct monogenic etiologies. Reasons for newly obtained molecular diagnoses were variant reclassifications in 7 and NGS data reanalysis in 3 cases including one recently described disease-gene association (DNAJB4). Male sex reduced the odds of receiving a molecular diagnosis (OR 0.42; 95%CI 0.21-0.82), while a positive family history (OR 5.46; 95%CI 2.60-11.76) and a myopathy phenotype (OR 2.72; 95%CI 1.11-7.14) increased the likelihood. 7% were resolved through targeted genetic testing or classified as acquired etiologies., Conclusion: Our findings reinforce the use of NGS in NMDs of suspected monogenic origin. We show that a comprehensive reassessment enhances diagnostic accuracy. However, one needs to be aware that genetic diagnoses are often made with uncertainty and can even be downgraded based on new evidence., (© 2023. The Author(s).)

Background: Critical illness polyneuropathy (CIP) commonly occurs in critical care unit (CCU) patients, but timely diagnosis can be challenging. Therefore, new biomarkers, such as serum neurofilament light chain (sNfL), could help to improve early identification of patients with this condition., Methods: CIP was diagnosed or excluded with neurological assessment and nerve conduction measurement in a prospective study of CCU patients. sNfL and secondary predictors for neuropathy (neuron-specific enolase (NSE), S100, folic acid, and vitamin B12) were measured at admission. Cases and controls were compared regarding the predictors., Results: Nineteen patients met the inclusion criteria. CIP was considered definitely or most likely present in seven (37%, cases) and definitely or most likely absent in 12 individuals (63%, controls). At admission, sNfL levels were significantly higher in the cases than in the controls: 405 (IQR 77 to 835) vs. 27 (IQR 12 to 90) pg/mL; difference of medians 375, 95% confidence interval [14, 736], pg/mL; P=0.04. We found no significant differences regarding the secondary predictors at baseline. Cases had longer durations of CCU stay (median 19 (IQR 11 to 44) vs. 8 (IQR five to ten) and increased mortality (57% vs. 33% deceased) compared to controls., Conclusions: Levels of serum neurofilament light chain are higher in patients who develop CIP soon after CCU admission and might be helpful in identifying those individuals early.

Critical illness polyneuropathy (CIP) is a frequent and underdiagnosed phenomenon among intensive care unit patients. The lipophilic nature of neuronal synapses may result in the association of low serum cholesterol levels with a higher rate of CIP development. We aimed to investigate this issue in critically ill patients. All cases diagnosed with CIP in our tertiary care hospital between 2013 and 2017 were 1:1 matched with controls without the condition by age, sex, and ICD diagnoses. The main risk factors examined were the differences in change between initial and minimum serum total cholesterol levels, and minimum serum total cholesterol levels between matched pairs. Other predictors were serum markers of acute inflammation. We included 67 cases and 67 controls (134 critically ill patients, 49% female, 46% medical). Serum total cholesterol levels decreased more profoundly in cases than controls (median: -74 (IQR -115 to -24) vs. -39 (IQR -82 to -4), median difference: -28, 95% CI [-51, -5]), mg/dl). Minimum serum total cholesterol levels were lower in the cases (median difference: -24, 95% CI [-39, -9], mg/dl). We found significant median differences across matched pairs in maximum serum C-reactive protein (8.9, 95% CI [4.6, 13.2], mg/dl), minimum albumin (-4.2, 95% CI [-6.7, -1.7], g/l), decrease in albumin (-3.9, 95% CI [-7.6, -0.2], g/l), and lowest cholinesterase levels (-0.72, 95% CI [-1.05, -0.39], U/l). Subsequently, more pronounced decreases in serum total cholesterol levels and lower minimum total cholesterol levels during critical care unit hospitalizations may be a risk factor for CIP., (© 2023. The Author(s).)

Background and Purpose: Following increasing demands of patients with suspected neurological symptoms after infection with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the Department of Neurology at the Medical University of Vienna established a new outpatient clinic to systematically assess, diagnose, and document neurological complaints potentially associated with a prior SARS-CoV-2 infection., Methods: The data presented here include prospectively collected 156 outpatients from May 2021 to April 2022. Patients underwent semistandardized interviewing about symptoms with reported onset after SARS-CoV-2 infection, neurological examination, and comprehensive diagnostic workup., Results: Reported new onset symptoms after infection included fatigue (77.6%), subjective cognitive impairment (72.4%), headache (47.7%), loss of smell and/or taste (43.2%), and sleep disturbances (42.2%). Most patients had a mild coronavirus disease (COVID-19) disease course (84%) and reported comorbidities (71%), of which the most frequent were psychiatric disorders (34%). Frequency of symptoms was not associated with age, sex, or severity of COVID-19 course. A comprehensive diagnostic workup revealed no neurological abnormalities in the clinical examination, or electrophysiological or imaging assessments in the majority of patients (n = 143, 91.7%). Neuropsychological assessment of a subgroup of patients (n = 28, 17.9%) showed that cognitive impairments in executive functions and attention, anxiety, depression, and somatization symptoms were highly common., Conclusions: In this systematic registry, we identified fatigue, cognitive impairment, and headache as the most frequently reported persisting complaints after SARS-CoV-2 infection. Structural neurological findings were rare. We also suspect a link between the growing burden of the COVID-19 pandemic on personal lives and the increase in reported neurological and psychiatric complaints., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Objectives: The optic nerve has been recommended as an additional region for demonstrating dissemination in space (DIS) in diagnostic criteria for multiple sclerosis (MS). The aim of this study was to investigate whether adding the optic nerve region as determined by optical coherence tomography (OCT) as part of the DIS criteria improves the 2017 diagnostic criteria., Methods: From a prospective observational study, we included patients with a first demyelinating event who had complete information to assess DIS and a spectral domain OCT scan obtained within 180 days. Modified DIS criteria (DIS + OCT) were constructed by adding the optic nerve to the current DIS regions based on validated thresholds for OCT intereye differences. Time to second clinical attack was the primary endpoint., Results: We analyzed 267 patients with MS (mean age 31.3 years [SD 8.1], 69% female) during a median observation period of 59 months (range: 13-98). Adding the optic nerve as a fifth region improved the diagnostic performance by increasing accuracy (DIS + OCT 81.2% vs DIS 65.6%) and sensitivity (DIS + OCT 84.2% vs DIS 77.9%) without lowering specificity (DIS + OCT 52.2% vs DIS 52.2%). Fulfilling DIS + OCT criteria (≥2 of 5 DIS + OCT regions involved) indicated a similar risk of a second clinical attack (hazard ratio [HR] 3.6, CI 1.4-14.5) compared with a 2.5-fold increased risk when fulfilling DIS criteria (HR 2.5, CI 1.2-11.8). When the analysis was conducted according to topography of the first demyelinating event, DIS + OCT criteria performed similarly in both optic neuritis and nonoptic neuritis., Discussion: Addition of the optic nerve, assessed by OCT, as a fifth region in the current DIS criteria improves diagnostic performance by increasing sensitivity without lowering specificity., Classification of Evidence: This study provides Class II evidence that adding the optic nerve as determined by OCT as a fifth DIS criterion to the 2017 McDonald criteria improves diagnostic accuracy., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Purpose: This study was undertaken to investigate baseline peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell and inner plexiform layer (GCIPL) thickness for prediction of disability accumulation in early relapsing multiple sclerosis (RMS)., Methods: From a prospective observational study, we included patients with newly diagnosed RMS and obtained spectral-domain optical coherence tomography scan within 90 days after RMS diagnosis. Impact of pRNFL and GCIPL thickness for prediction of disability accumulation (confirmed Expanded Disability Status Scale [EDSS] score ≥ 3.0) was tested by multivariate (adjusted hazard ratio [HR] with 95% confidence interval [CI]) Cox regression models., Results: We analyzed 231 MS patients (mean age = 30.3 years, SD = 8.1, 74% female) during a median observation period of 61 months (range = 12-93). Mean pRNFL thickness was 92.6 μm (SD = 12.1), and mean GCIPL thickness was 81.4 μm (SD = 11.8). EDSS ≥ 3 was reached by 28 patients (12.1%) after a median 49 months (range = 9-92). EDSS ≥ 3 was predicted with GCIPL < 77 μm (HR = 2.7, 95% CI = 1.6-4.2, p < 0.001) and pRNFL thickness ≤ 88 μm (HR = 2.0, 95% CI = 1.4-3.3, p < 0.001). Higher age (HR = 1.4 per 10 years, p < 0.001), incomplete remission of first clinical attack (HR = 2.2, p < 0.001), ≥10 magnetic resonance imaging (MRI) lesions (HR = 2.0, p < 0.001), and infratentorial MRI lesions (HR = 1.9, p < 0.001) were associated with increased risk of disability accumulation, whereas highly effective disease-modifying treatment was protective (HR = 0.6, p < 0.001). Type of first clinical attack and presence of oligoclonal bands were not significantly associated., Conclusions: Retinal layer thickness (GCIPL more than pRNFL) is a useful predictor of future disability accumulation in RMS, independently adding to established markers., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Repetitive nerve stimulation (RNS) is a standard test for the diagnosis of myasthenia gravis (MG), where decrement of compound muscle action potentials (CMAP) corresponds to clinical muscle fatigability. Our aim was to ascertain the diagnostic and prognostic utility of RNS in MG patients. This study included MG patients treated between 01/2000 and 12/2016, with an observational period of at least one year and a minimum of two neurological examinations. Clinical and electrophysiological data were retrospectively gathered from patient records, and CMAP decrement was correlated with autoantibody titers and clinical disease severity at different time points. Ninety-four patients were included, with 88.3% of the cohort testing positive for acetylcholine receptor autoantibodies (AChR-Abs). RNS sensitivity was higher in patients with generalized disease (71.6%) than in purely ocular MG (38.5%). CMAP decrement did not significantly correlate with AChR-Ab titers, nor with clinical symptom severity at the time of testing or last follow up. However, there was a significant correlation between CMAP decrement and the worst recorded clinical status on a group level. RNS testing is more sensitive in generalized disease and AChR-Ab positive patients, but our data do not support RNS as a tool for long-term outcome prediction. Future studies with a prospective study design could help to overcome a number of limiting factors discussed in our study., (© 2023. The Author(s).)

Background: Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders caused by genetic defects resulting in impaired neuromuscular transmission. Although effective treatments are available, CMS is probably underdiagnosed, and systematic clinico-genetic investigations are warranted., Methods: We used a nationwide approach to collect Austrian patients with genetically confirmed CMS. We provide a clinical and molecular characterization of this cohort and aimed to ascertain the current frequency of CMS in Austria., Results: Twenty-eight cases with genetically confirmed CMS were identified, corresponding to an overall prevalence of 3.1 per million (95% CI 2.0-4.3) in Austria. The most frequent genetic etiology was CHRNE (n = 13), accounting for 46.4% of the cohort. Within this subgroup, the variant c.1327del, p.(Glu443Lysfs*64) was detected in nine individuals. Moreover, causative variants were found in DOK7 (n = 4), RAPSN (n = 3), COLQ (n = 2), GMPPB (n = 2), CHAT (n = 1), COL13A1 (n = 1), MUSK (n = 1) and AGRN (n = 1). Clinical onset within the first year of life was reported in one half of the patients. Across all subtypes, the most common symptoms were ptosis (85.7%), lower limb (67.9%), upper limb (60.7%) and facial weakness (60.7%). The majority of patients (96.4%) received specific treatment, including acetylcholinesterase inhibitors in 20, adrenergic agonists in 11 and 3,4-diaminopyridine in nine patients., Conclusions: Our study presents the first systematic characterization of individuals with CMS in Austria, providing prevalence estimates and genotype-phenotype correlations that may help to improve the diagnostic approach and patient management., (© 2022. The Author(s).)

Background: Monitoring of patient outcomes in multiple sclerosis (MS) is fundamental for individualized treatment decisions. So far, these decisions have been motivated by conventional outcomes, i.e., relapses or clinical disability supported by radiological disease activity. Complementing this concept, patient reported outcomes (PROs) assess individual health-related quality of life, among other constructs. Their inclusion in clinical routine, however, has been challenging as assessing them requires resources of time and personnel., Objective: This interventional feasibility study investigated the haMSter app, a mobile health solution for remote and longitudinal monitoring of PROs in a sample of people with MS (pwMS)., Methods: The core feature of haMSter is the provision of three PRO questionnaires relevant to MS (anxiety/depression, MS-related quality of life, and fatigue) that patients can fill out once a month. For this feasibility trial, we offered 50 volunteers to use the haMSter app over six months and to take part in a haMSter study visit. This consultation concluded the study and participants had the opportunity to discuss their graphically plotted PRO results with their treating physician., Results: The main outcome was overall patient adherence to monthly completion of the PRO questionnaires, which remained high up to 4 months (98%) and dropped over time (months 5: 83% and 6: 66%). Exploratory outcomes included patient satisfaction as estimated on the Telemedicine Perception Questionnaire (TMPQ, 17-85 points). The mean TMPQ score was 64 (95%CI: 62-66) points, indicating a high degree of approval. Ancillary tests included subgroup analyses of participants with particularly high or low satisfaction and upper extremity disability as a potential obstacle to utility or acceptance. We found no distinct characteristics separating participants with high or low satisfaction., Conclusions: In this first feasibility trial, the haMSter app for longitudinal PRO monitoring was well received in terms of adherence and satisfaction. ClinicalTrials.gov identifier: NCT04555863., Competing Interests: The ethics review board at the Medical University of Vienna approved this study (EK1798/2019)., (© The Author(s) 2022.)

Background and Objectives: Remission of relapses is an important contributor to both short- and long-term prognosis in relapsing multiple sclerosis (RMS). In MS-associated acute optic neuritis (MS-ON), retinal layer thinning measured by optical coherence tomography (OCT) is a reliable biomarker of both functional recovery and the degree of neuroaxonal damage. However, prediction of non-ON relapse remission is challenging. We aimed to investigate whether retinal thinning after ON is associated with relapse remission after subsequent non-ON relapses., Methods: For this longitudinal observational study from the Vienna MS database, we included patients with MS with (1) an episode of acute ON, (2) available spectral domain OCT scans within 12 months before ON onset (OCT baseline ), within 1 week after ON onset (OCT acute ), and 3-6 months after ON (OCT follow-up ), and (3) at least 1 non-ON relapse after the ON episode. Subsequent non-ON relapses were classified as displaying either complete or incomplete remission based on change in the Expanded Disability Status Scale score assessed 6 months after relapse. Association of retinal thinning in the peripapillary retinal nerve fiber layer (ΔpRNFL) and macular ganglion cell and inner plexiform layer (ΔGCIPL) with incomplete remission was tested by multivariate logistic regression models adjusting for age, sex, disease duration, relapse severity, time to steroid treatment, and disease-modifying treatment status., Results: We analyzed 167 patients with MS (mean age 36.5 years [SD 12.3], 71.3% women, mean disease duration 3.1 years [SD 4.5]) during a mean observation period of 3.4 years (SD 2.8) after the ON episode. In 61 patients (36.5%), at least 1 relapse showed incomplete remission. In the multivariable analyses, incomplete remission of non-ON relapse was associated with ΔGCIPL thinning both from OCT baseline to OCT follow-up and from OCT acute to OCT follow-up (OR 2.4 per 5 μm, p < 0.001, respectively), independently explaining 29% and 27% of variance, respectively. ΔpRNFL was also associated with incomplete relapse remission when measured from OCT baseline to OCT follow-up (OR 1.9 per 10 μm, p < 0.001), independently accounting for 22% of variance, but not when measured from OCT acute to OCT follow-up. DISCUSSION: Retinal layer thinning after optic neuritis may be useful as a marker of future relapse remission in RMS., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Third vaccination against SARS-CoV-2 is recommended for patients with multiple sclerosis (pwMS), usually six months after the last vaccination., Methods: In this prospective multicenter study on 292 pwMS and 46 healthy controls (HC), who had all received two vaccinations prior to study enrollment, SARS-CoV-2 IgG response was measured in the month before and 2-4 months after third vaccination. PwMS were categorized as follows: untreated (N-DMT, n = 32), receiving disease-modifying therapy (DMT) with expected humoral response (er-DMT: interferon-beta preparations, glatiramer acetate, dimethyl fumarate, teriflunomide, natalizumab, cladribine, alemtuzumab; n = 120) or no expected humoral response (nr-DMT: S1PMs, CD20mAb; n = 140)., Results: PwMS on nr-DMT had significantly lower median antibody levels before (12.1 U/ml [0.4-2500]) and after third vaccination (305 U/ml [0.4-2500]) in comparison to other groups (p<0.001). We did not find differences in antibody levels after homologous (n = 281; 2500 [0.4-2500]) and heterologous (n = 57; 2500 [0.4-2500]) vaccination regime regardless of the DMT group. The DMT group (β= -0.60; 95% CI -1195.73, -799.10; p<0.001) was associated with antibody levels after third vaccination, while time to revaccination (6 months [1-13]) was not. After third vaccination, seropositivity was reached in 75.8% and 82.2% of pwMS on anti-CD20 mAbs and S1PMs, respectively. Complete B-cell depletion significantly decreased the probability of seroconversion even after the third vaccination (OR 0.14; p = 0.021), whereas time interval to last DMT intake and time to revaccination did not. Twenty-two patients reported a SARS-CoV-2 infection (3 N-DMT, 9 er-DMT, 10 nr-DMT), one being asymptomatic and the rest having a mild course., Conclusion: Humoral response to SARS-CoV-2 third vaccination in pwMS is excellent. While reduced by S1PMs and CD20mAb, protective response is still expected in the majority of patients., (Copyright © 2022. Published by Elsevier B.V.)

Background and Purpose: This study was undertaken to investigate short- and long-term outcome following thymectomy in patients with acetylcholine receptor antibody (AChR-Ab)-positive myasthenia gravis (MG)., Methods: Rates of clinical response (defined as minimal manifestation, pharmacological remission, or complete stable remission) lasting for at least 1 year were retrospectively analyzed using Cox proportional hazard models. The occurrence of relapses was recorded during follow-up. Clinical factors associated with achieving an initial or a sustained response were analyzed., Results: Ninety-four patients with a median age of 33 years (interquartile range [IQR] = 22-51), 68% with nonthymomatous MG and 32% with thymoma-associated MG, were included. An initial clinical response was reached in 72% (68/94). Neither sex, age at onset, thymus histology, delay to surgery after disease onset, surgical approach, corticosteroid treatment, nor clinical severity before thymectomy was significantly associated with achieving this endpoint. During long-term follow-up (median = 89.5 months, IQR = 46-189.5), only half of the patients with an initial response (34/68) had a sustained response without relapses. No clinical factors predicted whether the response would become sustained. In patients without immunosuppressive treatment before thymectomy (n = 24), a high AChR-Ab reduction rate after thymectomy was associated with a higher likelihood of achieving an initial response (p = 0.03)., Conclusions: Sustained long-term clinical response of MG patients after thymectomy is significantly lower than the initial response rates would suggest. The observation that none of the evaluated clinical factors was associated with a worse outcome supports the current clinical practice of patient selection for thymectomy. The relative decline of AChR-Abs after surgery appears to be a promising prognostic marker., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: COVID-19 continues to challenge neurologists in counselling persons with multiple sclerosis (pwMS) regarding disease-modifying treatment (DMT) and vaccination. The objective here was to characterize predictors of COVID-19 outcome in pwMS., Methods: We included pwMS with PCR-confirmed COVID-19 diagnosis from a nationwide population-based registry. COVID-19 outcome was classified as either mild or severe. Impact of DMT, specifically anti-CD20 monoclonal antibodies, and vaccination on COVID-19 outcome was determined by multivariable models adjusted for a-priori-risk (determined by a cumulative risk score comprising age, disability and comorbidities)., Results: Of 317 pwMS with COVID-19 (mean age 41.8 years [SD 12.4], 72.9% female, median EDSS 1.5 [range 0-8.5], 77% on DMT [16% on antiCD20]), 92.7% had a mild course and 7.3% a severe course with 2.2% dying from COVID-19. Ninety-seven pwMS (30.6%) were fully vaccinated. After a median 5 months from vaccination to SARS-CoV-2 infection (range 1-9), severe COVID-19 occurred in 2.1% of fully vaccinated pwMS compared to 9.5% in unvaccinated pwMS (p=0.018). A-priori-risk robustly predicted COVID-19 severity (R 2 0.605; p<0.001). Adjusting for a-priori-risk, anti-CD20 treatment was associated with increased COVID-19 severity (odds ratio [OR] 3.3; R 2 0.113; p=0.003), but exposure to any other DMT was not. Fully vaccinated pwMS showed a significantly decreased risk for severe COVID-19 (OR 0.21, R 2 0.144, p<0.001)., Conclusions: In a population-based MS cohort, COVID-19 course is primarily predicted by a-priori-risk (depending on age, disability and comorbidities) explaining about 60% of variance. Anti-CD20 treatment is associated with a moderately increased risk, while reassuringly vaccination provides protection from severe COVID-19., (This article is protected by copyright. All rights reserved.)

Background: Social distancing measures during the Covid-19 pandemic reduced access to health care and concerns were raised over the safety of immunosuppressive disease modifying treatments (DMT) for multiple sclerosis (MS)., Objective: To investigate changes in DMT prescription before and during the pandemic in a large and well-characterized real-world cohort of MS patients., Methods: From the Vienna MS database (VMSD) we extracted MS patients who were initiated on a new DMT (both treatment-naïve and switching) between January 1st 2017 and December 31st 2021. Two time periods were defined: 1) the preCovid-19 era (January 1st 2017 to March 15th 2020, i.e. the day of the first lockdown in Austria) and the Covid-19 era (March 16th 2020 to December 31st 2021). Average annualized DMT prescription rates were descriptively compared between the two periods., Results: The average annualized number of prescriptions in the preCovid-19 era was 90.3/year and dropped to 74.8/year (-17.2%) in the Covid-19 era, driven by a marked reduction to 41.7/year (-54%) in the first nine months of the Covid-19 era, partly offset by a rise to 101 in 2021. Use of alemtuzumab (-64%), antiCD20 (-49%), cladribine (-46%), and S1PM (-38%) was reduced, while natalizumab increased by 24%. Lower efficacy treatments remained stable., Conclusions: The pandemic coincides with a drop in DMT prescription, most markedly for immunosuppressive high-efficacy treatments, strongly suggesting the pandemic as the causal factor. If and how much this affects long-term outcome is yet to be determined., (Copyright © 2022. Published by Elsevier B.V.)

Background: Long-term outcome after COVID-19 in patients with multiple sclerosis (pwMS) is scarcely studied and controlled data are lacking., Objective: To compare long-term outcome after COVID-19 in pwMS to a matched control group of pwMS without COVID-19., Methods: We included pwMS with PCR-confirmed diagnosis of COVID-19 and ≥6 months of follow-up available and, as a control group, pwMS matched 1:1 for age, sex, disability level and disease-modifying treatment type., Results: Of 211 pwMS with COVID-19 (mean age 42.6 years [SD 12.2], 69% female, median EDSS 1.5 [range: 0-7.5], 16% antiCD20), 90.5% initially had a mild COVID-19 course. At follow-up, 70% had recovered completely 3 months (M3) after COVID-19, 83% after 6 months (M6) and 94% after 12 months (M12). Mild initial COVID-19 course was the only significant predictor of complete recovery (odds ratio [OR]: 10.5; p<0.001). Most frequent residual symptoms were fatigue (M3: 18.5%, M6: 13.7%, M12: 7.3%), hyposmia (M3: 13.7%, M6: 5.2%, M12: 1.7%) and dyspnea (M3: 7.1%, M6: 6.6%, M12: 2.8%). Compared to matched controls, fatigue, hyposmia and dyspnea were significantly more frequent at M3 and still slightly at M6, while there was no difference at M12. PwMS with COVID-19 had neither a significantly increased risk for relapses (OR 1.1; p=0.70) nor disability worsening (OR 0.96; p=0.60)., Discussion: Long-term outcome of COVID-19 is favourable in a large majority of pwMS with only a small proportion of patients suffering from persistent symptoms usually resolving after 3-6 months. COVID-19 is not associated with increased risk of relapse or disability., (This article is protected by copyright. All rights reserved.)

Background and Purpose: Hereditary myopathies with limb-girdle muscular weakness (LGW) are a genetically heterogeneous group of disorders, in which molecular diagnosis remains challenging. Our aim was to present a detailed clinical and genetic characterization of a large cohort of patients with LGW., Methods: This nationwide cohort study included patients with LGW suspected to be associated with hereditary myopathies. Parameters associated with specific genetic aetiologies were evaluated, and we further assessed how they predicted the detection of causative variants by conducting genetic analyses., Results: Molecular diagnoses were identified in 62.0% (75/121) of the cohort, with a higher proportion of patients diagnosed by next-generation sequencing (NGS) than by single-gene testing (77.3% vs. 22.7% of solved cases). The median (interquartile range) time from onset to genetic diagnosis was 8.9 (3.7-19.9) and 17.8 (7.9-27.8) years for single-gene testing and NGS, respectively. The most common diagnoses were myopathies associated with variants in CAPN3 (n = 9), FKRP (n = 9), ANO5 (n = 8), DYSF (n = 8) and SGCA (n = 5), which together accounted for 32.2% of the cohort. Younger age at disease onset (p = 0.043), >10× elevated creatine kinase activity levels (p = 0.024) and myopathic electromyography findings (p = 0.007) were significantly associated with the detection of causative variants., Conclusions: Our findings suggest that an earlier use of NGS in patients with LGW is needed to avoid long diagnostic delays. We further present parameters predictive of a molecular diagnosis that may help to select patients for genetic analyses, especially in centres with limited access to sequencing., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: SARS-CoV2 vaccination is recommended for patients with multiple sclerosis (pwMS), but response may be limited by disease-modifying-treatments (DMTs). The aim of this study was to compare the rates of humoral immune response and safety of SARS-CoV-2 vaccines in pwMS and healthy controls (HCs)., Methods: In this multicenter prospective study on 456 pwMS and 116 HCs, SARS-CoV-2-IgG response was measured 3 months after the first vaccine dose. The primary endpoint was defined as proportion of patients developing antibodies (seroconversion). Secondary endpoints included antibody level, safety and efficacy., Results: Compared to 97.4% in HCs, seroconversion occurred in 96.7% (88/91) untreated pwMS, 97.1% of patients (135/139) on immunomodulatory DMTs and 61.1% (138/226; p < 0.001) on immunosuppressive DMTs. Seroconversion was lowest in patients on antiCD20 monoclonal antibodies (CD20 mAbs; 52.6%) followed by sphingosine-1-phosphate-receptor-modulators (S1PMs; 63.6%). In the S1PM subgroup, seroconversion increased with lymphocyte count (odds ratio [OR] 1.31 per 0.1 G/L; p = 0.035). In pwMS on CD20 mAbs, B-cell depletion decreased seroconversion (OR 0.52; p = 0.038), whereas time since last DMT did not. Safety of SARS-CoV-2 vaccines in pwMS was excellent., Conclusions: Humoral response to SARS-CoV2 vaccines in pwMS is generally excellent. While reduced by immunosuppressive DMTs, most importantly by B-cell-depleting CD20 mAbs and S1PMs, seroconversion is still expected in the majority of patients. SARS-CoV2 vaccination should be offered to every MS patient., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objective: The study was undertaken to assess the impact of B cell depletion on humoral and cellular immune responses to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccination in patients with various neuroimmunologic disorders on anti-CD20 therapy. This included an analysis of the T cell vaccine response to the SARS-CoV-2 Delta variant., Methods: We investigated prospectively humoral and cellular responses to SARS-CoV-2 mRNA vaccination in 82 patients with neuroimmunologic disorders on anti-CD20 therapy and 82 age- and sex-matched healthy controls. For quantification of antibodies, the Elecsys anti-SARS-CoV-2 viral spike (S) immunoassay against the receptor-binding domain (RBD) was used. IFN-gamma enzyme-linked immunosorbent spot assays were performed to assess T cell responses against the SARS-CoV-2 Wuhan strain and the Delta variant., Results: SARS-CoV-2-specific antibodies were found less frequently in patients (70% [57/82]) compared with controls (82/82 [100%], p < 0.001). In patients without detectable B cells (<1 B cell/mcl), seroconversion rates and antibody levels were lower compared to nondepleted (≥1 B cell/mcl) patients (p < 0.001). B cell levels ≥1 cell/mcl were sufficient to induce seroconversion in our cohort of anti-CD20 treated patients. In contrast to the antibody response, the T-cell response against the Wuhan strain and the Delta variant was more pronounced in frequency (p < 0.05) and magnitude (p < 0.01) in B-cell depleted compared to nondepleted patients., Interpretation: Antibody responses to SARS-CoV-2 mRNA vaccinnation can be attained in patients on anti-CD20 therapy by the onset of B cell repopulation. In the absence of B cells, a strong T cell response is generated which may help to protect against severe coronavirus disease 2019 (COVID-19) in this high-risk population. ANN NEUROL 2022;91:342-352., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Evidence guiding personalized decision-making with respect to disease-modifying therapy (DMT) around pregnancy in relapsing multiple sclerosis (RMS) is lacking., Objective: To generate and validate a risk score for disease reactivation intrapartum and postpartum in RMS., Methods: From the Vienna Innsbruck MS database (VIMSD), we included 343 pregnancies in patients with RMS. Primary endpoint was disease reactivation. Patients were randomly assigned 2:1 in a generation and validation dataset. A predictive score was calculated using the Cox regression and validated., Results: In the generation dataset, occurrence of relapse and type of DMT in the year before conception, DMT washout duration, the Expanded Disability Status Scale (EDSS) at conception, and time until DMT restart postpartum were identified as independent predictors of disease reactivation ( p < 0.001). The resulting 10-point risk score robustly predicted reactivation (explaining 75% of variance, p < 0.001) identifying patients at high [≥6 points; mean risk 65%; range 50-100%; hazard ratio (HR) 14.5], intermediate (3-5 points; mean risk 24%; range 15-35%; HR 4.3), and low risk (≤2 points; mean risk 6%; range 0-8%) of disease reactivation in pregnancy and up to 6 months postpartum., Conclusion: The composite Vienna Innsbruck Pregnancy Risk in Multiple Sclerosis (VIPRiMS) score is a valuable clinical tool to support patients and neurologists in anticipating risk and, thus, individualizing treatment decision-making around pregnancy., Competing Interests: GB has participated in meetings sponsored by, received speaker honoraria, or travel funding from Biogen, Celgene, Lilly, Merck, Novartis, Roche, Sanofi Genzyme, and Teva and received honoraria for consulting Biogen, Celgene, Roche, and Teva. HH has participated in meetings sponsored by, received speaker honoraria, or travel funding from Bayer, Biogen, Merck, Novartis, Sanofi Genzyme, Siemens, and Teva and received honoraria for consulting Biogen, Celgene, Novartis, and Teva. PA has participated in meetings sponsored by, received speaker honoraria, or travel funding from Biogen, Merck, Roche, Sanofi Genzyme, and Teva and received honoraria for consulting from Biogen. He received a research grant from Quanterix International and was awarded a combined sponsorship from Biogen, Merck, Roche, Sanofi Genzyme, and Teva for a clinical study. FDP has participated in meetings sponsored by, received honoraria (lectures, advisory boards, and consultations), or travel funding from Bayer, Biogen, Celgene, Merck, Novartis, Roche, Sanofi Genzyme, and Teva. RE has participated in meetings sponsored by, received speaker honoraria, or travel funding from Almirall, Biogen, Böhringer Ingelheim, Celgene, Daiichi Sankyo, Merck, Novartis, Ottobock, and Teva. GZ has participated in meetings sponsored by or received travel funding from Biogen, Merck, Novartis, Roche, Sanofi Genzyme, and Teva. PR has received honoraria for consultancy/speaking from AbbVie, Alexion, Almirall, Biogen, Merck, Novartis, Roche, Sandoz, and Sanofi Genzyme and has received research grants from Amicus, Biogen, Merck, and Roche. FL has participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Actelion, Alexion, Almirall, Bayer, Biogen, Celgene, Medday, Merck, Novartis, Octapharma, Pfizer, Roche, Sanofi-Aventis, and Teva. FD has participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Alexion, Almirall, Biogen, Celgene, Merck, Novartis, Roche, and Sanofi Genzyme. His institution received scientific grants from Biogen and Sanofi Genzyme. TB has participated in meetings sponsored by and received honoraria (lectures, advisory boards, and consultations) from pharmaceutical companies marketing treatments for MS: Allergan, Almirall, Bayer, Biogen, Biologix, Bionorica, Celgene/Bristol Myers Squibb (BMS), GlaxoSmithKline (GSK), Janssen-Cilag, Medday, Merck, Novartis, Octapharma, Roche, Sanofi Genzyme, Teva, and TG Pharmaceuticals. His institution has received financial support in the past 12 months by unrestricted research grants Biogen, Celgene/BMS, Merck, Novartis, Sanofi Genzyme, and Teva and for participation in clinical trials in MS sponsored by Alexion, Biogen, Celgene/BMS, Merck, Novartis, Octapharma, Roche, Sanofi Genzyme, and Teva. The remaining 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., (Copyright © 2022 Bsteh, Hegen, Riedl, Altmann, Di Pauli, Ehling, Zulehner, Rommer, Leutmezer, Deisenhammer and Berger.)

Background: Knowledge on immunity after SARS-CoV-2 infection in patients with multiple sclerosis (pwMS) and the impact of disease-modifying treatment (DMT) is limited., Objective: To evaluate degree, duration and potential predictors of specific humoral immune response in pwMS with prior COVID-19., Methods: Anti-SARS-CoV-2 antibody testing was performed in pwMS with PCR-confirmed diagnosis of symptomatic COVID-19 from a nation-wide registry. Predictors of seropositivity were identified by multivariate regression models., Results: In 125 pwMS (mean age = 42.4 years (SD = 12.3 years), 70% female), anti-SARS-CoV-2 antibodies were detected in 76.0% after a median of 5.2 months from positive PCR. Seropositivity rate was significantly lower in patients on IS-DMT (61.4%, p  = 0.001) than without DMT or immunomodulatory DMT (80.6%; 86.0%, respectively). In multivariate analysis, IS-DMT was associated with reduced probability of seropositivity (odds ratio (OR): 0.51; 95% confidence interval (95% CI): 0.17-0.82; p  < 0.001). Predefined subgroup analyses showed marked reduction of seropositivity in pwMS on rituximab/ocrelizumab (OR 0.15; 95% CI: 0.05-0.56; p  < 0.001). Rate of seropositivity did not change significantly over 6 months., Conclusions: Humoral immunity is stable after SARS-CoV-2 infection in MS, but is reduced by immunosuppressive DMT, particularly anti-CD20 monoclonal antibodies. This provides important evidence for advising pwMS as well as for planning and prioritizing vaccination.

The objective of this retrospective cohort study was to evaluate demographic, clinical and laboratory characteristics of patients with rhabdomyolysis as defined by a serum creatine kinase (sCK) activity > 950 U/L. A total of 248 patients were recruited from the Department of Neurology, Medical University of Vienna, between 01/2000 and 12/2017, with a median sCK activity of 2,160 U/l (IQR 1,342-4,786). Seizures (31.9%), illicit drugs/alcohol (9.7%) and exercise (8.5%) were the most common trigger factors. Rhabdomyolysis incidence rates in specific neurological diseases as estimated by the ratio between rhabdomyolysis cases and the total number of cases with the corresponding disease were highest in myopathies (49.8/1,000 person-years, 95% CI 32.3-67.4), followed by epilepsy (16.4/1,000 person-years, 95% CI 12.8-20.0) and stroke (11.9/1,000 person-years, 95% CI 8.4-15.4). The half-life of sCK activity was 1.5 days in the total cohort. In myopathies, sCK activity was significantly higher as compared to other disease entities 7 days after the peak measurement (p = 0.0023). Acute kidney injury (AKI) developed in 18 patients (7.3%) with no AKI-related deaths during the study period. In conclusion, rhabdomyolysis occurred in a broad range of neurological entities but was associated with a favorable prognosis in most cases rarely resulting in AKI and death., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

This study investigated treatment characteristics of Guillain-Barré syndrome (GBS) in a real-world setting between 2000 and 2019. We analyzed clinical improvement between nadir and last follow-up in patients with severe GBS (defined as having a GBS disability scale > 2 at nadir) and aimed to detect clinical factors associated with multiple treatments. We included 121 patients (74 male; median age 48 [IQR 35-60]) with sensorimotor (63%), pure motor (15%), pure sensory (10%) and localized GBS (6%) as well as Miller Fisher syndrome (6%). 44% of patients were severely affected. All but one patient received at least one immunomodulatory treatment with initially either intravenous immunoglobulins (88%), plasma exchange (10%) or corticosteroids (1%), and 25% of patients received more than one treatment. Severe GBS but not age, sex, GBS subtype or date of diagnosis was associated with higher odds to receive more than one treatment (OR 4.22; 95%CI 1.36-13.10; p = 0.01). Receiving multiple treatments had no adjusted effect (OR 1.30, 95%CI 0.31-5.40, p = 0.72) on clinical improvement between nadir and last follow-up in patients with severe GBS. This treatment practice did not change over the last 20 years., (© 2021. The Author(s).)

Background: Albuminocytologic dissociation in cerebrospinal fluid (CSF) is a diagnostic hallmark of Guillain-Barré syndrome (GBS). Compared to CSF total protein (TP), the CSF/serum albumin quotient (Qalb) has the advantage of method-independent reference ranges. Whether the diagnostic yield differs between Qalb and CSF-TP is currently unknown., Methods: We retrospectively analyzed the diagnostic yield (i.e., a value above the URL indicating blood-nerve barrier dysfunction) of Qalb and CSF-TP levels in patients with GBS. We evaluated two different equations (Reiber's and Hegen's) for age-adjusted URLs of Qalb and compared results to CSF-TP using the standard URL of 0.45 g/L as well as age-adjusted URLs (by decade of age). Additionally, multivariable logistic regression analysis was used to assess the effect of clinical factors on the diagnostic yield., Results: We analyzed 110 patients [62% males; median age 48 (IQR 35-58)] with sensorimotor (68), motor (16), sensory (12) and localized (8) GBS as well as Miller Fisher syndrome (6). Qalb and CSF-TP were highly correlated (r = 0.95, p < 0.001). The diagnostic yield of Qalb was 65% with Reiber's and 47% with Hegen's age-adjusted URLs compared to 66% with the fixed CSF-TP URL of 0.45 g/L and 49% with age-adjusted CSF-TP URLs. A longer duration from clinical onset to lumbar puncture was associated with a higher diagnostic yield., Conclusion: Qalb strongly correlates with CSF-TP in patients with GBS with a similar diagnostic yield for the detection of a blood-nerve barrier dysfunction. However, the diagnostic yield of both values is lower when using more recent age-adjusted URLs and at earlier timepoints., (© 2021. The Author(s).)

Background: The COVID-19 pandemic challenges neurologists in counselling patients with multiple sclerosis (pwMS) regarding their risk by SARS-CoV-2 and in guiding disease-modifying treatment (DMT)., Objective: To characterize the prevalence and outcome of COVID-19 in pwMS specifically associated with different DMT in a nationwide population-based study., Methods: We included patients aged ≥18 years with a confirmed diagnosis of MS and a diagnosis of COVID-19 established between January 1, 2020 and December 31, 2020. We classified COVID-19 course as either mild, severe or fatal. Impact of DMT and specifically immunosuppressants (alemtuzumab, cladribine, fingolimod, ocrelizumab or rituximab) on COVID-19 outcome was determined by multivariable models, adjusted for a-priori-risk., Results: Of 126 MS patients with COVID-19 (mean age 43.2 years [SD 13.4], 71% female), 86.5% had a mild course, 9.5% a severe course and 3.2% died from COVID-19. A-priori-risk significantly predicted COVID-19 severity (R2 0.814; p<0.001) and mortality (R2 0.664; p<0.001). Adjusting for this a-priori-risk, neither exposure to any DMT nor exposure to specific immunosuppressive DMT were significantly associated with COVID-19 severity (odds ratio [OR] 1.6; p = 0.667 and OR 1.9; p = 0.426) or mortality (OR 0.5; p = 0.711 and 2.1; 0.233) when compared to no DMT., Conclusions: In a population-based MS cohort, COVID-19 outcome was not associated with exposure to DMT and immunosuppressive DMT when accounting for other already known risk factors. This provides reassuring evidence that COVID-19 risk can be individually anticipated in MS and-except for a very small proportion of high-risk patients-treatment decisions should be primarily focused on treating MS rather than the pandemic., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Gabriel Bsteh: has participated in meetings sponsored by, received speaker honoraria or travel funding from Biogen, Celgene, Merck, Novartis, Roche, Sanofi-Genzyme and Teva, and received honoraria for consulting Biogen, Roche and Teva. Hamid Assar: has participated in meetings sponsored by, received honoraria (advisory boards, consultations) or travel funding from Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. Harald Hegen: has participated in meetings sponsored by, received speaker honoraria or travel funding from Bayer, Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, Siemens and Teva, and received honoraria for consulting Biogen, Novartis and Teva. Bettina Heschl: has nothing to disclose. Fritz Leutmezer: has participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Bayer, Biogen, Celgene, MedDay, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. Franziska Di Pauli: has participated in meetings sponsored by, received honoraria (lectures, advisory boards, consultations) or travel funding from Bayer, Biogen, Celgene, Merck, Novartis, Sanofi-Genzyme, Roche and Teva. Christiane Gradl: has participated in meetings sponsored by, received honoraria (lectures, consultations) and/or travel funding from Biogen, D-Pharma, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. Gerhard Traxler: has participated in meetings sponsored by, received honoraria (lectures, advisory boards, consultations) or travel funding from Biogen, Celgene, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. Gudrun Zulehner: has participated in meetings sponsored by or received travel funding from Biogen, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. Paulus Rommer: has received honoraria for consultancy/speaking from AbbVie, Allmiral, Alexion, Biogen, Merck, Novartis, Roche, Sandoz, Sanofi Genzyme, has received research grants from Amicus, Biogen, Merck, Roche. Peter Wipfler: has received funding for travel and honoraria (lectures, advisory boards) from Bayer, Biogen, Celgene, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. Michael Guger: has received support and honoraria for research, consultation, lectures and education from Almirall, Bayer, Biogen, Celgene, Genzyme, MedDay, Merck, Novartis, Octapharma, Roche, Sanofi-Genzyme, Shire and Teva. Christian Enzinger: has received funding for travel and speaker honoraria from Bayer, Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, Shire and Teva. has received research support from Biogen, Celgene, Merck, and Teva; is serving on scientific advisory boards for Bayer, Biogen, Celgene, Merck, Novartis, Roche and Teva. Thomas Berger: has participated in meetings sponsored by and received honoraria (lectures, advisory boards, consultations) from pharmaceutical companies marketing treatments for MS: Allergan, Bayer, Biogen, Bionorica, Celgene, MedDay, Merck, Novartis, Octapharma, Roche, Sanofi-Genzyme, Teva. His institution has received financial support in the past 12 months by unrestricted research grants (Bayer, Biogen, Merck, Novartis, Sanofi Aventis, Teva) and for participation in clinical trials in multiple sclerosis sponsored by Alexion, Bayer, Biogen, Merck, Novartis, Octapharma, Roche, Sanofi-Genzyme, Teva. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Treatment and monitoring decisions in people with multiple sclerosis (MS) are based commonly on clinician-reported outcomes. These reflect physical and radiological disease activity and are the most relevant endpoints in clinical trials. Over the past few years, the number of studies evaluating so-called patient-reported outcomes (PROs) has been increasing. PROs are reports from patients concerning their own health perception. They are typically obtained by means of questionnaires and aim to quantify symptoms such as fatigue, depression, and sexual dysfunction. The emergence of PROs has made a tremendous contribution to understanding the individual impact of disease in people with MS and their health-related quality of life. However, the assessment of PROs consumes resources, including time and personnel. Thus, useful ways to conveniently introduce PROs into clinical practice are needed., Objective: We aim to provide a rationale and pilot study protocol for a mobile health (mHealth) solution named "haMSter" that allows for remote monitoring of PROs in people with MS., Methods: The core function of haMSter is to provide three scientifically validated PRO questionnaires relevant to MS for patients to fill out at home once a month. Thereby, longitudinal and remote documentation of PROs is enabled. A scoring algorithm graphically plots PRO scores over time and makes them available at the next visit., Results: The pilot study is currently ongoing and will evaluate adherence to this mHealth solution in 50 patients over a period of 6 months. Results from the haMSter pilot study are expected in 2021., Conclusions: haMSter is a novel mHealth-based solution for modern PRO research, which may constitute the first step in achieving the ability to integrate PROs in clinical practice. This allows for a more problem-oriented approach in monitoring visits, which addresses patient needs and ultimately saves time., Trial Registration: ClinicalTrials.gov NCT04555863; https://clinicaltrials.gov/ct2/show/NCT04555863., International Registered Report Identifier (irrid): DERR1-10.2196/25011., (©Patrick Altmann, Werner Hinterberger, Fritz Leutmezer, Markus Ponleitner, Tobias Monschein, Tobias Zrzavy, Gudrun Zulehner, Barbara Kornek, Rupert Lanzenberger, Klaus Berek, Paulus Stefan Rommer, Thomas Berger, Gabriel Bsteh. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 07.05.2021.)

Background and Purpose: There is a lack of evidence guiding discontinuation of disease-modifying therapy (DMT) in relapsing multiple sclerosis (RMS). Thus, the objective of this study was to generate and validate a risk score for disease reactivation after DMT discontinuation in RMS., Methods: We drew a generation and validation dataset from two separate prospectively collected observational databases including RMS patients who received interferon-β or glatiramer acetate for ≥12 months, then discontinued DMT for ≥6 months and had ≥2 years of follow-up available. In the generation sample (n = 168), regression analysis was performed to identify clinical or magnetic resonance imaging (MRI) variables independently predicting disease reactivation after DMT discontinuation. A predictive score was calculated using the variables included in the multivariable model and applied to the validation sample (n = 98)., Results: The variables included in the final model as independent predictors of disease reactivation were age at discontinuation, MRI activity at discontinuation, and duration of clinical stability (all p < 0.001). The resulting score was able to robustly identify patients at high (83%-85%), moderate (36%-38%), and low risk (7%) of disease reactivation within 5 years after DMT discontinuation in both cohorts., Conclusions: The composite VIAADISC score is a valuable tool to inform and support patients and neurologists in the process of decision making to discontinue injectable DMTs., (© 2020 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Little is known on how to address sexuality in clinical care for patients with multiple sclerosis (pwMS)., Aim: To describe and contrast the perception of sexuality and associated aspects of communication in pwMS and their treating neurologists ("MSologists") and provide a standard of care., Methods: Patients were surveyed using a 13-item questionnaire investigating perception on their own sexuality and opinions on communication about sexuality in context with MS. Certified MSologists in Austria received an 18-item survey regarding their approach to taking a sexual history of their patients., Outcomes: We report the frequency of answers given in this survey and propose a possible standard of care how sexuality could be addressed in clinical routine., Results: Ninety-three pwMS (mean age 39 ± 11 years, 57% female) and 75 MSologists (mean age 43 ± 9 years, 63% male) completed this survey. Seventy-six percent of patients report their own sexuality as being (very) important to them and 95% think that sexual dysfunction would influence their quality of life. 84% would like to be asked about their sexuality by their MSologist. In contrast, only 15% of MSologists reported discussing sexuality with every patient. The most common reason for not doing so was a fear of crossing personal borders (34%). There is a strong desire for further medical education on this subject (76%)., Clinical Implications: Discussing sexuality is important to pwMS and MSologists should consider their patients' wishes and needs to talk about it., Strengths & Limitations: This is the largest survey contrasting the views of patients and their treating physicians on the topic of communication about sexuality. The use of an empirical unvalidated questionnaire may have introduced bias. Moreover, patients that are open to talk about their sexuality may be potentially overrepresented in this study., Conclusion: MSologists should offer their patients an open opportunity and appropriate framework to discuss their sexuality during a consultation. Altmann P, Leithner K, Leutmezer F, et al. Sexuality and Multiple Sclerosis: Patient and Doctor Perspectives. J Sex Med 2021;18:743-749., (Copyright © 2021 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Sexual dysfunction (SD) in people with multiple sclerosis (pwMS) has a detrimental impact on individual health-related quality of life (HRQoL). It is not clear whether SD in multiple sclerosis (MS) is an independent symptom or merely a byproduct of other symptoms such as depression or anxiety. This cross-sectional study of 93 pwMS determines risk factors for SD in MS based on prevalence, HRQoL, and associated disease outcomes. Diagnosis of SD was determined based on the Multiple Sclerosis Intimacy and Sexuality Questionnaire-19 (MSISQ-19) and correlated with physical disability (measured by Expanded Disability Status scale, EDSS), depression and anxiety [Hospital Anxiety and Depression Scale (HADS)], and HRQoL [Multiple Sclerosis Quality of Life-54 (MSQoL-54)]. Multivariate regression models were performed to determine independent risk factors for SD in pwMS. Almost half of the participants in this study (46%) reported SD. HRQoL was significantly poorer in patients with MS suffering from SD (median [IQR] MSQoL-54 scores: physical subscale 52 [41-68] vs. 81 [69-89], p < 0.001; mental subscale 50 [38-82] vs. 86 [70-89], p < 0.001). In the multivariate model, EDSS was the only independent risk factor for SD (OR 18.1 for EDSS ≥4 [95% CI 3.3-31.4, p < 0.001]), while depression and anxiety were not. We conclude that the risk for SD is growing with increasing EDSS and is independent of depression or anxiety. Screening for SD becomes particularly relevant in patients with growing disability., Competing Interests: PA has participated in meetings sponsored by and received speaker honoraria or travel funding from Biogen, Merck, Roche, Sanofi-Genzyme, and Teva and received honoraria for consulting from Biogen. He received a research grant from Quanterix International and was awarded a combined sponsorship from Biogen, Merck, Roche, Sanofi-Genzyme, and Teva for a clinical study. FL has participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Bayer, Biogen, Celgene, MedDay, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. TM has participated in meetings sponsored by or received travel funding from Biogen, Celgene, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. PR has received honoraria for consultancy/speaking from AbbVie, Alexion, Almirall, Biogen, Merck, Novartis, Roche, Sandoz, and Sanofi-Genzyme and has received research grants from Amicus, Biogen, Merck, and Roche. TZ has participated in meetings sponsored by or received travel funding from Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. KB has participated in meetings sponsored by and received travel funding from Roche. TB has participated in meetings sponsored by and received honoraria (lectures, advisory boards, consultations) from pharmaceutical companies marketing treatments for MS: Allergan, Almirall, Bayer, Biogen, Biologix, Bionorica, Celgene, MedDay, Merck, Novartis, Octapharma, Roche, Sanofi-Genzyme, Teva, and TG Pharmaceuticals. His institution has received financial support in the past 12 months by unrestricted research grants (Biogen, Merck, Novartis, Sanofi-Genzyme, and Teva and for participation in clinical trials in multiple sclerosis sponsored by Alexion, Biogen, Merck, Novartis, Octapharma, Roche, Sanofi-Genzyme, and Teva. GB has participated in meetings sponsored by and received speaker honoraria or travel funding from Biogen, Celgene, Merck, Novartis, Sanofi-Genzyme, and Teva and received honoraria for consulting Biogen, Roche, and Teva. 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 © 2021 Altmann, Leutmezer, Leithner, Monschein, Ponleitner, Stattmann, Rommer, Zrzavy, Zulehner, Berek, Berger and Bsteh.)

Objective: Nerve conduction studies (NCS) are essential to differentiate between demyelinating and axonal subtypes in Guillain-Barré syndrome (GBS). However, it is debated to which extent the delay of NCS after symptom onset and repeated measurements during the disease course influence the diagnostic accuracy., Methods: We evaluated NCS in 93 patients with a classical GBS applying two widely used criteria (Hadden's and Rajabally's). The initial measurements after symptom onset were compared to follow-up studies where available (n = 43). We analyzed the influence of NCS timing after symptom onset and clinical severity on fulfilling the electrophysiological criteria for axonal or demyelinating subtypes and evaluated the impact of repeated measurements. We further evaluated the presence of reversible conduction failure., Results: A higher GBS disability scale at nadir correlated with a successful subclassification whereas the delay of the first NCS after symptom onset did not influence the diagnostic yield (75% for Hadden's and 68% for Rajabally's criteria for the first assessment). A second measurement allowed the additional successful classification in 19% and 14% of patients, respectively. On the other hand, a repeated measurement in patients with an initial successful classification resulted in a different subtype in 5% and 7%, respectively. Reversible conduction failure was found in 7% of patients., Conclusion: Clinical severity but not timing of NCS influenced the fulfilment of electrophysiological criteria for either the axonal or demyelinating subtype. Repeated electrophysiological measurements led to a further specification or a change in subtype classification in a relevant proportion of patients., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: To investigate the frequency and characterize the clinical features of treatment-refractory myasthenia gravis in an Austrian cohort., Methods: Patient charts of 126 patients with generalized myasthenia gravis and onset between 2000 and 2016 were analyzed retrospectively. Patients were classified as treatment-refractory according to strict, predefined criteria. These mandated patients being at least moderately symptomatic (i.e., MGFA class III) or needing either maintenance immunoglobulins or plasma exchange therapy for at least 1 year in spite of two adequately dosed immunosuppressive drugs. Clinical features and outcome at last follow-up were compared to treatment-responsive patients., Results: 14 out of 126 patients (11.1%) met these criteria of treatment-refractory myasthenia gravis. Treatment-refractory patients had more frequent clinical exacerbations and more often received rescue treatments or a further escalation of immunosuppressive therapies. They also remained more severely affected at last follow-up. An early onset of myasthenia gravis was associated with a higher risk for a refractory course., Conclusion: A small subgroup of patients with generalized myasthenia gravis do not respond sufficiently to standard therapies. Refractory disease has considerable implications for both patients and health care providers and highlights an unmet need for new treatment options.

Anecdotal oculomotor disturbances have been described in spastic paraplegia type 7 (SPG7). We investigated oculomotor and vestibular dysfunction in five patients with genetically verified SPG7. All five patients exhibited significantly slower velocities of vertical saccades compared to controls, but significantly faster than in progressive supranuclear palsy, with upward saccades being particularly affected. Horizontal saccades, cerebellar oculomotor markers, and vestibuloocular reflex seem to be variably affected. Thus, albeit subclinical in some cases, slowing of the vertical saccades may belong to the phenotype of SPG7 and may serve as a valuable biomarker for differentiation from spastic ataxias and atypical parkinsonism., (© 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.)

Currently, it has not been satisfactorily established, whether modern low-osmolality iodinated contrast agents (ICAs) used in computed tomography (CT) studies are a risk factor for exacerbation of myasthenic symptoms. The rate of acute adverse events as well as delayed clinical worsening up to 30 days were analyzed in 73 patients with confirmed myasthenia gravis (MG) who underwent contrast-enhanced CT studies and compared to 52 patients who underwent unenhanced CT studies. One acute adverse event was documented. 12.3% of MG patients experienced a delayed exacerbation of symptoms after ICA administration. The rate of delayed severe exacerbation was higher in the contrast-enhanced group. Alternative causes for the exacerbation of MG-related symptoms were more likely than ICA administration in all cases. ICA administration for CT studies in MG patients should not be withheld if indicated, but patients particularly those with concomitant acute diseases should be carefully monitored for exacerbation of symptoms.