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Abstract Over the past few years, new-generation cell-based assays have demonstrated a robust association of autoantibodies to full-length human myelin oligodendrocyte glycoprotein (MOG-IgG) with (mostly recurrent) optic neuritis, myelitis and brainstem encephalitis, as well as with acute disseminated encephalomyelitis (ADEM)-like presentations. Most experts now consider MOG-IgG-associated encephalomyelitis (MOG-EM) a disease entity in its own right, immunopathogenetically distinct from both classic multiple sclerosis (MS) and aquaporin-4 (AQP4)-IgG-positive neuromyelitis optica spectrum disorders (NMOSD). Owing to a substantial overlap in clinicoradiological presentation, MOG-EM was often unwittingly misdiagnosed as MS in the past. Accordingly, increasing numbers of patients with suspected or established MS are currently being tested for MOG-IgG. However, screening of large unselected cohorts for rare biomarkers can significantly reduce the positive predictive value of a test. To lessen the hazard of overdiagnosing MOG-EM, which may lead to inappropriate treatment, more selective criteria for MOG-IgG testing are urgently needed. In this paper, we propose indications for MOG-IgG testing based on expert consensus. In addition, we give a list of conditions atypical for MOG-EM (“red flags”) that should prompt physicians to challenge a positive MOG-IgG test result. Finally, we provide recommendations regarding assay methodology, specimen sampling and data interpretation.

Abstract Background Antibodies to human full-length myelin oligodendrocyte glycoprotein (MOG-IgG) as detected by new-generation cell-based assays have recently been described in patients presenting with acute demyelinating disease of the central nervous system, including patients previously diagnosed with multiple sclerosis (MS). However, only limited data are available on the relevance of MOG-IgG testing in patients with chronic progressive demyelinating disease. It is unclear if patients with primary progressive MS (PPMS) or secondary progressive MS (SPMS) should routinely be tested for MOG-IgG. Objective To evaluate the frequency of MOG-IgG among patients classified as having PPMS or SPMS based on current diagnostic criteria. Methods For this purpose, we retrospectively tested serum samples of 200 patients with PPMS or SPMS for MOG-IgG using cell-based assays. In addition, we performed a review of the entire English language literature on MOG-IgG published between 2011 and 2017. Results None of 139 PPMS and 61 SPMS patients tested was positive for MOG-IgG. Based on a review of the literature, we identified 35 further MOG-IgG tests in patients with PPMS and 55 in patients with SPMS; the only reportedly positive sample was positive just at threshold level and was tested in a non-IgG-specific assay. In total, a single borderline positive result was observed among 290 tests. Conclusion Our data suggest that MOG-IgG is absent or extremely rare among patients with PPMS or SPMS. Routine screening of patients with typical PPMS/SPMS for MOG-IgG seems not to be justified.

The pathogenesis and development of lesions in multiple sclerosis (MS) are still unexplained and are the subject of some controversy. On the basis of histopathological analysis of a small set of MS cases, a recently published study postulates primary oligodendroglial damage as the initiator of MS lesions, with infiltration of leukocytes into the central nervous system (CNS) as a secondary phenomenon. In this paper we outline the current controversial discussion and different concepts of lesion development in MS. We conclude that demyelination can result from different pathogenic mechanisms, with either primary autoimmune inflammation or primary oligodendroglial damage and a secondary inflammatory reaction. Lesions can be divided into four subtypes (patterns I–IV) on the basis of histopathological characteristics, which supports the idea that MS lesions develop in different ways. These new aspects may have major implications for treatment. However, except in a few specific forms, most MS patients cannot currently be assigned to one of these lesion subtypes by means of clinical and paraclinical parameters. Without this, individual treatments tailored to the pathogenesis will not be possible. [ABSTRACT FROM AUTHOR]

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Background: Recurrent attacks in neuromyelitis optica spectrum disorders (NMOSDs) or myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) can lead to severe disability. We aimed to analyse the real-world use of immunotherapies in patients with NMOSD and MOGAD, focusing on changes in treatment strategies, effects on attack rates (ARR) and risk factors for attacks., Methods: This longitudinal registry-based cohort study included 493 patients (320 with aquaporin-4 immunoglobulin G (AQP4-IgG) seropositive NMOSD (65%), 44 with AQP4-IgG seronegative NMOSD (9%) and 129 MOGAD (26%)) with 1247 treatments from 19 German and one Austrian centre from the registry of the neuromyelitis optica study group (NEMOS). We analysed unadjusted ARR and implemented survival analyses and Cox proportional hazard regression to assess efficiency and risk factors for subsequent attacks over time., Results: Rituximab and azathioprine are the most widely used immunotherapies in NMOSD as well as in MOGAD, with changes in distribution over the last decade. Immunotherapy demonstrated significant therapeutic effects in NMOSD but less pronounced effects in MOGAD. Risk factors for attacks included younger age and prior attacks under the same therapy. Efficacy varied among the different immunotherapies, with azathioprine, rituximab and eculizumab showing significant risk reductions in AQP4-IgG seropositive NMOSD., Conclusions: This study provides insights into the evolving treatment landscape and effectiveness of immunotherapies in NMOSD and MOGAD. Established off-label therapies continue to play an important role, especially for patients with stable disease, with emerging evidence supporting newly approved therapies. Future studies are needed to refine treatment algorithms and address the ongoing uncertainties in MOGAD management., Competing Interests: Competing interests: VH has received research support from NEMOS e.V. for this project. CT received honoraria for consultation and expert testimony from Alexion Pharma Germany GmbH. None of this interfered with the current report. DE received speaker honoraria and/or travel reimbursement from Alexion, Amgen/Horizon and Merck, all not related to the presented work. DE received speaker honoraria from Alexion. HP has nothing to disclose. JH reports grants from the Friedrich-Baur-Stiftung, Merck and Horizon, personal fees and non-financial support from Alexion, Horizon, Roche, Merck, Novartis, Biogen, BMS and Janssen and non-financial support from the Guthy-Jackson Charitable Foundation and the Sumaira Foundation. AD has received research support from NEMOS e.V. independent of this project. PS received travel support from UCB, received speaker‘s honoraria from Roche and Alexion and served on advisory boards by Alexion. CS has received speaker honoraria from Alexion and travel support from Novartis and UCB. TP has nothing to disclose. KF has nothing to disclose. MR received speaker honoraria and travel reimbursement from Roche, Alexion and Horizon, not related to this study. GL has nothing to disclose. MWH received institutional research support from Myelitis e. V., the German Federal Joint Committee/Innovation Fund, and NEMOS e. V. Speaker honoraria from selpers og, AMGEN/Horizon, and Alexion, and travel grants and compensation for serving on an advisory board from Alexion. DT has nothing to disclose. FB has nothing to disclose. KG has nothing to disclose. MF has nothing to disclose. IS has nothing to disclose. MKK speaker honoraria from BMS, Novartis, Merck. SJ has nothing to disclose. ED has nothing to disclose. LR has nothing to disclose. MS has received consulting and/or speaker honoraria from Alexion, Bayer, Biogen, Bristol-Myers-Squibb/Celgene, Janssen, Merck, Horizon, Roche and Sanofi Genzyme. None of this interfered with the current report. MH has nothing to disclose. AW has nothing to disclose. MP has nothing to disclose. IK has received personal compensation for consulting, serving on a scientific advisory board, speaking or other activities with Alexion, Almirall, Bayer, Biogen, GlaxoSmithKline, Hexal, Horizon, Merck, Neuraxpharm, Roche/Chugai and Sanofi. IK is the editorial board member of BMC Neurology, Frontiers in Neurology and Frontiers in Immunology. KA received travel support from Alexion, Bayer, BiogenIdec, MerckSerono, Novartis, Teva and honoria from Biogen and TEVA; he supported neuroimmunological studies for Alexion, Bayer, BiogenIdec, MerckSerono, Roche and Novartis. MK has nothing to disclose. MG has received consulting and/or speaker honoraria from Biogen, BMS, JJ, Merck, Novartis, Roche, Sanofi Genzyme and Teva. JW has nothing to disclose. PSR has received honoraria for lectures/consultancy from Alexion (Astra Zeneca), Allmiral, Amicus, Biogen, Genzyme, Horizon (AMGEN), Merck, Novartis, Roche and Teva served von advisory boards for Alexion (Astra Zeneca), Amicus, Genzyme, Horizon (AMGEN), Merck, Roche and Sandoz and received research grants from Amicus, Roche, Merck and the Austrian Science Fund (FWF). JPS has nothing to disclose. MK has received honoraria from Novartis Pharma, Chugai Pharma and Roche Pharma for presentations unrelated to the topic of this article. FTB has received, over his academic career, research support and travel grants to attend scientific meetings through his institution from the German Science Fund (DFG), German Federal Ministry of Education and Science (BMBF), Bayer-Schering, Diamed, Fresenius, Merck, Novartis, Pfizer, Roche, Sanofi and Teva; speaker fees and compensation for advisory boards from Actelion, Alexion, Bayer, Biogen, CSL Behring, Fresenius, Horizon, Merck, Novartis, Roche, Sanofi-Genzyme, Takeda and Teva. None of these are related to this work. HT received institutional research support and/or consulting/speaker honoraria from Alexion, Bayer, Biogen, Bristol-Myers Squibb, Celgene, Diamed, Fresenius, Fujirebio, GlaxoSmithKline, Horizon, Janssen-Cilag, Merck, Novartis, Roche, Sanofi Genzyme and TEVA. His research is also funded by the Ministry of Education and Research (BMBF), the Ministry of Science, Research and Arts Baden Württemberg (MWK-BW), the German Society of Multiple Sclerosis (DMSG), DMS-Stiftung, AMSEL-Stiftung, Bayern-DMSG and Chemische Fabrik Karl Bucher GmbH. LK received compensation for serving on Scientific Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Genzyme, Horizon, Janssen, Merck Serono, Novartis, Roche and Viatris. She received speaker honoraria and travel support from Argenx, Bayer, Biogen, Bristol-Myers Squibb, Genzyme, Grifols, Merck Serono, Novartis, Roche, Santhera and Teva. She receives research support from the German Research Foundation, the IZKF Münster, IMF Münster, Biogen, Immunic AG, Novartis and Merck Serono. BW received grants from the German Ministry of Education and Research, Deutsche Forschungsgemeinschaft, Dietmar Hopp Foundation and Klaus Tschira Foundation, grants and personal fees from Merck, Novartis, Roche and personal fees from Alexion, INSTAND, Roche. OA reports grants from the German Ministry of Education and Research (BMBF) and the German Research Foundation (DFG); grants and personal fees from Biogen and Novartis; and travel support and personal fees from Alexion, Almirall, MedImmune, Merck Serono, Roche, Sanofi, Viela Bio/Horizon Therapeutics and Zambon. IA has received research support from Diamed and Chugai, speaking honoraria, travel grants and compensation for serving on a scientific advisory board from Alexion, Horizon, Roche, Merck and sanofi-aventis/Genzyme, all unrelated to this study. JB-S has received institutional research support from NEMOS e.V., Alexion and Bayer AG, personal compensation from Alexion; speaking honoraria and travel grants from Bayer Healthcare, Horizon/Amgen, Novartis and sanofi-aventis/Genzyme, in addition, compensation for serving on a scientific advisory board of Alexion, Roche and Merck, all unrelated to the presented work. FP provided research support to Neurosciences Clinical Research Center, German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Einstein Foundation, Guthy Jackson Charitable Foundation, EU FP7 Framework Program, Biogen, Genzyme, Merck Serono, Novartis, Bayer, Roche, Parexel and Almirall, received honoraria for lectures, presentations, speakers from Guthy Jackson Foundation, Bayer, Biogen, Merck Serono, Sanofi Genzyme, Novartis, Viela Bio, Roche, UCB, Mitsubishi Tanabe and Celgene, in addition received compensation for serving on a scientific advisory board of Celgene, Roche, UCB and Merck, is an Academic Editor PLos One and Associate Editor von Neurology Neuroimmunology and Neuroinflammation, all unrelated to the presented work. TK has received speaker honoraria and/or personal fees for advisory boards from Novartis Pharma, Roche Pharma, Alexion/Astra Zeneca, Horizon Therapeutics/Amgen, Merck, Chugai Pharma and Biogen. The institution she works for has received compensation for serving as a member of a steering committee from Roche. Furthermore, she is a site principal investigator in several randomised clinical trials and her institution has received compensation for clinical trials from Novartis Pharma, Roche Pharma and Sanofi Genzyme; all outside the present work. TF reports personal fees from Aslan, Bayer, BiosenseWebster, Bristol Myers Squibb, CSL Behring, Enanta, Fresenius Kabi, Galapagos, Immunic, IQVIA, Janssen, KyowaKirin, Lilly, LivaNova, Minoryx, Novartis, Recordati, Relaxera, Roche, Servier, Viatris, VICO Therapeutics and Vifor for statistical consultancies including data monitoring committees, all outside the submitted work. AB receives funding from the Innovationsausschuss of the German Federal Joint Committee (G-BA; grant 01VSF23040) and the German Federal Ministry of Education and Research (BMBF; grant 01ZZ2102B). He has received consulting and/or speaker fees from Alexion, Argenx, Biogen, Horizon/Amgen, Merck, Novartis, Roche and Sandoz/Hexal, and his institution has received compensation for clinical trials from Alexion, Biogen, Merck, Novartis, Roche and Sanofi Genzyme; all outside the present work. J-PS has nothing to disclose., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: In this multicentric study, we were interested in the vision-related quality of life and its association with visual impairment in neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) in comparison to multiple sclerosis (MS) and healthy controls., Methods: We analysed extracted data from the German NEMOS registry including National Eye Institute Visual Function Questionnaire (NEI-VFQ) scores, high and low contrast visual acuity (HCVA, LCVA), visually evoked potentials (VEP) and the scores for the expanded disability status scale (EDSS) and other neurological tests which assessed their disease-related impairment. The mean follow-up time of our patients was 1.2 years. We used adjusted linear mixed effect models to analyse NEI-VFQ differences and interactions with visual acuity among NMOSD, MOGAD, a matched MS cohort and healthy controls., Results: Despite a younger age in the MOGAD cohort (39 y.o.), vision and socioemotional-related quality of life reduction was similar over all patient subgroups in comparison to healthy controls. The most impacted life quality dimension was general health, followed by general vision, driving and role difficulties. Decline in some of the NEI-VFQ subscales scores is mostly predicted by age. The HCVA was the best predictor for most of the subscales of the NEI-VFQ., Discussion: Despite important age differences, NMOSD, MOGAD and MS seem to share a rather similar perception on their vision and quality of life impairment, which is overall poorer than that of healthy controls., Competing Interests: Declarations. Conflict of interest: MN: no conflict of interest. VH: received research support from NEMOS e.V. independent of this project. FP: received research support from NeuroCure Clinical Research Center, the German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Einstein Foundation, Guthy Jackson Charitable Foundation, EU FP7 Framework Program, Biogen, Genzyme, Merck Serono, Novartis, Bayer, Roche; received consulting fees from Alexion, Roche, Horizon, Neuraxpharm and speaker honoraria from Almirall, Bayer, Biogen, GlaxoSmithKline, Hexal, Merck, Sanofi Genzyme, Novartis, Viela Bio, UCB, Mitsubishi Tanabe, Celgene, Guthy Jackson Foundation, Serono, Roche. He received travel grants from Merck, Guthy Jackson Foundation, Bayer, Biogen, Merck Serono, Sanofi Genzyme, Novartis, Alexion, Viela Bio, Roche, UCB, Mitsubishi Tanabe, Celgene. He participated on Data Safety Monitoring Board at Celgene AdBoard, Roche AdBoard, UCB AdBoard, Merck AdBoard Academic Editor PLos One, Celgene AdBoard, Roche AdBoard, UCB AdBoard, Merck AdBoard Academic Editor PLos One. He is Academic Editor at PLoS ONE and Associate Editor of Neurology® Neuroimmunology and Neuroinflammation. FCO: currently received research support by Deutsche Forschungsgemeinschaft (DFG), Hertie foundation and Novartis—all unrelated to this project. She further received fellowship support from the American Academy of Neurology (AAN) and the National MS Society (NMSS) and travel support for the European Committee for Research and Treatment in Multiple Sclerosis (ECTRIMS) in the recent past, also unrelated to this project. PS: received travel support by UCB and received speaker’s honoraria by Roche and Alexion and served on advisory board by Alexion. JBS: received institutional research support from NEMOS e.V., Alexion and Bayer AG, personal compensation from Alexion, speaking honoraria and travel grants from Bayer Healthcare, Horizon/Amgen, Novartis and Sanofi-Aventis/Genzyme, in addition received compensation for serving on a scientific advisory board of Alexion, Roche and Merck, all unrelated to the presented work. ESA: received research grants from Novartis and Roche, speaker honoraria from Alexion, Amgen, Bayer and Roche, unrelated to the presented work. MK: received grants from Merck and Novartis, travel support and personal fees from Alexion, BMS, Merck, Novartis, Roche and Sanofi, all unrelated to the presented work. MWH: received institutional research support from Myelitis e. V., speaker honoraria from selpers og, Horizon, and Alexion, and travel grants and compensation for serving on an advisory board from Alexion. None of this interfered with the current manuscript. FB: no conflict of interest. DT: no conflict of interest. CT: received honoraria for consultation and expert testimony from Alexion Pharma Germany GmbH. None of this interfered with the current work. CS: received speaker honoraria from Alexion, Argenx, Desitin and TAD and served on advisory board for Alexion and Argenx, none related to this study. IA: received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities- from Roche, Horizon, Alexion, Sanofi, Merck, and received research support from Diamed, Roche and Alexion, none related to this study. CS: received speaker honoraria from Alexion and travel support from Novartis and UCB, all not related to the content of this manuscript. TP: no conflict of interest. KF: no conflict of interest. OA: reports grants from the German Ministry of Education and Research (BMBF) and the German Research Foundation (DFG); grants and personal fees from Biogen and Novartis; and travel support and personal fees from Alexion, Almirall, MedImmune, Merck Serono, Roche, Sanofi, Viela Bio/Horizon Therapeutics and Zambon. MR: received speaker honoraria from Novartis, Bayer Vital GmbH, Roche, Alexion, Horizon and Ipsen and travel reimbursement from Bayer Schering, Biogen Idec, Merz, Genzyme, Teva, Roche, Horizon, Alexion and Merck, none related to this study. MK: received honoraria from Chugai Pharma, Roche Pharma and Novartis with no relation to the content of the article. CW: received institutional support from Novartis, Biogen, Alexion, Janssen, Hexal and Roche. MG: received consulting and/or speaker honoraria from Biogen, BMS, JJ, Merck, Novartis, Roche, Sanofi Genzyme and Teva. MK: no conflict of interest. KA: received travel support (till 2014) from Alexion, Bayer, BiogenIdec, MerckSerono, Novartis, Teva and honoria from Biogen und TEVA; he supported neuroimmunological studies for Alexion, Bayer, BiogenIdec, MerckSerono, Roche and Novartis. PK: no conflict of interest. IK: received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alexion, Almirall, Bayer, Biogen, GlaxoSmithKline, Hexal, Horizon, Merck, Neuraxpharm, Roche/Chugai and Sanofi. PR: speaker or Consultant Honorary from Alexion (Astra Zeneca), Allmiral, Amicus, Biogen, Horizon (Amgen), Merck, Novartis, Sandoz, Sanofi, Roche, Teva. Received research grants from Amicus, Merck, Roche, Austrian Science Fund (FWF). AW: received speaker honoraria, consultant fees and travel reimbursement from Alexion, Bayer, Biogen, Glaxo Smith Kline, Hexal, Janssen, Merck, Novartis, Pfizer, Roche and Sanofi Genzyme, none related to this study. AW: no conflict of interest. MSW: no conflict of interest. JW: no conflict of interest. KG: reports reimbursement of travelling expenses by UCB. FTB: received, over his academic career, research support and travel grants to attend scientific meetings, through his institution, from the German Science Fund (DFG), German Federal Ministry of Education and Science (BMBF), Bayer-Schering, Diamed, Fresenius, Merck, Novartis, Pfizer, Roche, Sanofi and Teva; speaker fees and compensation for advisory boards from Actelion, Alexion, Bayer, Biogen, CSL Behring, Fresenius, Horizon, Merck, Novartis, Roche, Sanofi-Genzyme, Takeda and Teva. None of these are related to this work. MS: received consulting and/or speaker honoraria from Alexion, Bayer, Biogen, Bristol-Myers-Squibb/Celgene, Janssen, Merck, Horizon, Roche, and Sanofi Genzyme. HT: participated in meetings sponsored by or received honoraria for acting as an advisor/speaker for Alexion, Bayer, Biogen, Bristol-Myers Squibb, Celgene, Diamed, Fresenius, Fujirebio, GlaxoSmithKline, Horizon, Janssen-Cilag, Merck, Novartis, Roche, Sanofi-Genzyme, Siemens, and Teva. He also acknowledges research support by DMSG (German Multiple Sclerosis Society), MWK-BW (Ministry of Science, Research and Arts of the State Baden-Württemberg), University of Ulm, and Chemische Fabrik Karl Bucher. IV: received travel support from Alexion. ED: no conflict of interest. LR: no conflict of interest. LK: received compensation for serving on Scientific Advisory Boards for Alexion, Genzyme, Janssen, Merck, Novartis, and Roche; she received speaker honoraria and travel support from Bayer, Biogen, Genzyme, Grifols, Merck, Novartis, Roche, Santhera, and Teva; she receives research support from DFG, the German Ministry for Education and Research (BMBF), the IZKF Münster, IMF Münster, Biogen, Novartis and Merck. MKK: received speaker honoraria from BMS, Merck and Novartis. SJ: no conflict of interest. BW: received research grants from Deutsche Forschungsgemeinschaft, German Ministry of Education and Research, Dietmar Hopp Foundation, Klaus Tschira Foundation, Novartis, Roche, and personal fees from Alexion, INSTAND, Novartis, Roche, all unrelated to this work. JAG: received a research grant from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation; SFB/TRR 274, ID 408885537) and reports travel expenses and non-financial support from Merck, outside the submitted work. TK: received speaker honoraria and/or personal fees for advisory boards from Novartis Pharma, Roche Pharma, Alexion/Astra Zeneca, Horizon Therapeutics/Amgen, Merck, Chugai Pharma and Biogen. The Institution she works for has received compensation for serving as a member of a steering committee from Roche. Furthermore, she is a site principal investigator in several randomized clinical trials and her institution has received compensation for clinical trials from Novartis Pharma, Roche Pharma and Sanofi Genzyme, all outside the present work. DE: received speaker honoraria and/or travel reimbursement from Alexion, Amgen/Horizon and Merck, all not related to this work. JH: reports a grant for OCT research from the Friedrich‐Baur‐Stiftung, Horizon and Merck, personal fees and nonfinancial support from Alexion, Amgen, Bayer, Biogen, BMS, Merck, Novartis and Roche, and nonfinancial support of the Sumaira Foundation and Guthy-Jackson Charitable Foundation, all outside the submitted work. NS: no conflict of interest. JPS: no conflict of interest. Ethics approval: The data collection and its usage for the purpose of this publication was approved by the ethics committees of all NEMOS centres. For the MS and control data, we obtained ethical approval from the local ethic committee of Hamburg Chamber of Physicians (Registration Number PV5557). Also, written informed consent was obtained from all patients before entering the registry., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Objectives: Attack prevention is crucial in managing neuromyelitis optica spectrum disorders (NMOSDs). Eculizumab (ECU), an inhibitor of the terminal complement cascade, was highly effective in preventing attacks in a phase III trial of aquaporin-4 (AQP4)-IgG seropositive(+) NMOSDs. In this article, we evaluated effectiveness and safety of ECU in routine clinical care., Methods: We retrospectively evaluated patients with AQP4-IgG+ NMOSD treated with ECU between December 2014 and April 2022 at 20 German and 1 Austrian university center(s) of the Neuromyelitis Optica Study Group (NEMOS) by chart review. Primary outcomes were effectiveness (assessed using annualized attack rate [AAR], MRI activity, and disability changes [Expanded Disability Status Scale {EDSS}]) and safety (including adverse events, mortality, and attacks after meningococcal vaccinations), analyzed by descriptive statistics., Results: Fifty-two patients (87% female, age 55.0 ± 16.3 years) received ECU for 16.2 (interquartile range [IQR] 9.6 - 21.7) months. Forty-five patients (87%) received meningococcal vaccination before starting ECU, 9 with concomitant oral prednisone and 36 without. Seven of the latter (19%) experienced attacks shortly after vaccination (median: 9 days, IQR 6-10 days). No postvaccinal attack occurred in the 9 patients vaccinated while on oral prednisone before starting ECU and in 25 (re-)vaccinated while on ECU. During ECU therapy, 88% of patients were attack-free. The median AAR decreased from 1.0 (range 0-4) in the 2 years preceding ECU to 0 (range 0-0.8; p < 0.001). The EDSS score from start to the last follow-up was stable (median 6.0), and the proportion of patients with new T2-enhancing or gadolinium-enhancing MRI lesions in the brain and spinal cord decreased. Seven patients (13%) experienced serious infections. Five patients (10%; median age 53.7 years) died on ECU treatment (1 from myocardial infarction, 1 from ileus with secondary sepsis, and 3 from systemic infection, including 1 meningococcal sepsis), 4 were older than 60 years and severely disabled at ECU treatment start (EDSS score ≥ 7). The overall discontinuation rate was 19%., Discussion: Eculizumab proved to be effective in preventing NMOSD attacks. An increased risk of attacks after meningococcal vaccination before ECU start and potentially fatal systemic infections during ECU-particularly in patients with comorbidities-must be considered. Further research is necessary to explore optimal timing for meningococcal vaccinations., Classification of Evidence: This study provides Class IV evidence that eculizumab reduces annualized attack rates and new MRI lesions in AQP4-IgG+ patients with NMOSD.

Background: Incomplete attack remission is the main cause of disability in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Apheresis therapies such as plasma exchange and immunoadsorption are widely used in neuroimmunology. Data on apheresis outcomes in MOGAD attacks remain limited., Methods: We retrospectively evaluated all apheresis treated attacks occurring in patients with MOGAD between 2008 and 2023 at 18 Neuromyelitis Optica Study Group centres. Treatment response was categorised as complete, partial or no remission. Preattack and follow-up Expanded Disability Status Scale (EDSS) and visual Functional System Scores (FSS) were used to calculate absolute outcomes (ΔEDSS/Δvisual FSS). Predictors of complete remission were analysed using a generalised linear mixed model., Results: Apheresis was used for 117/571 (20.5%) attacks in 85/209 (40.7%) patients. Attacks with simultaneous optic neuritis and myelitis were treated more often with apheresis (42.4%, n=14) than isolated myelitis (25.2%, n=35), cerebral manifestation (21.0%, n=17) or isolated optic neuritis (17.6%, n=51). Apheresis was initiated as first-line therapy in 12% (4.5 (IQR 0-11) days after attack onset), second-line therapy in 62% (15 (IQR 6.75-31) days) and third-line therapy in 26% (30 (IQR 19-42) days). Complete remission was achieved in 21%, partial remission in 70% and no remission in 9% of patients. First-line apheresis (OR 2.5, p=0.040) and concomitant disease-modifying therapy (OR 1.5, p=0.011) were associated with complete remission. Both parameters were also associated with a favourable ΔEDSS. No differences in outcomes were observed between the apheresis types., Conclusion: Apheresis is frequently used in MOGAD attacks. An early start as first-line therapy and concomitant disease-modifying therapy predict full attack recovery., Competing Interests: Competing interests: CS has received speaker honoraria from Alexion and travel support from Novartis and UCB, all not related to the content of this manuscript, as well as research support from FORUM (clinician scientist position), medical faculty Ruhr-Universität Bochum. TL has received travel support from UCB. VH has received research support from NEMOS independent of this project. IK has received personal compensation for consulting, serving on a scientific advisory board, speaking or other activities with Alexion, Almirall, Bayer, Biogen, GlaxoSmithKline, Hexal, Horizon, Merck, Neuraxpharm, Roche/Chugai and Sanofi, none related to this study. MR received speaker honoraria from Novartis, Bayer Vital, Roche, Alexion, Horizon and Ipsen and travel reimbursement from Bayer Schering, Biogen Idec, Merz, Genzyme, Teva, Roche, Alexion, Horizon and Merck, none related to this study. OA has received personal fees from Alexion, Bayer HealthCare, Biogen, Celgene, Merck Serono, MedImmune, Novartis, Roche, Teva and Zambon, outside the submitted work. TK has received speaker honoraria and/or personal fees for advisory boards from Novartis Pharma, Roche Pharma, Alexion/AstraZeneca, Horizon Therapeutics/Amgen, Merck, Chugai Pharma and Biogen. The institution she works for has received compensation for serving as a member of a steering committee from Roche. TK is a site principal investigator in several randomised clinical trials and her institution has received compensation for clinical trials from Novartis Pharma, Roche Pharma and Sanofi Genzyme; all outside the present work. DE received speaker honoraria and/or travel reimbursement from Alexion, Amgen/Horizon and Merck, all not related to the presented work. JH reports a grant for OCT research from the Friedrich‐Baur‐Stiftung, Horizon and Merck, personal fees and non-financial support from Alexion, Amgen, Bayer, Biogen, BMS, Merck, Novartis and Roche and non-financial support from the Sumaira Foundation and Guthy‐Jackson Charitable Foundation, all outside the submitted work. MWH received institutional research support from Myelitis, German Federal Joint Committee/Innovation Fund and NEMOS, speaker honoraria from selpers og, Horizon and Alexion and travel grants and compensation for serving on an advisory board from Alexion. None of these interfered with the current manuscript. CT received honoraria for consultation and expert testimony from Alexion Pharma Germany. None of these interfered with the current report. MK-K received speaker honoraria from BMS, Merck and Novartis. BW received research grants from Deutsche Forschungsgemeinschaft, German Ministry of Education and Research, Dietmar Hopp Foundation, Klaus Tschira Foundation, Novartis and Roche, and personal fees from Alexion, INSTAND, Novartis and Roche, all unrelated to this work. ABAGRG has received travel grants from Roche and Biogen, outside the submitted work. A-KP received speaker honoraria and research support from Biogen, none related to this study. RP received honoraria for lectures from Alexion, Bayer Healthcare, Biogen, Celgene, Horizon/Amgen, Novartis, Merck, Roche, Sanofi-Aventis and Teva. He received research grants from HERZ Burgdorf, Novartis and Merck. MK received honoraria from Roche Pharma and Chugai Pharma. FTB has received, over his academic career, research support and travel grants for attending scientific meetings, through his institution, from the German Science Fund (DFG), German Federal Ministry of Education and Science (BMBF), Bayer-Schering, Diamed, Fresenius, Merck, Novartis, Pfizer, Roche, Sanofi and Teva; speaker fees and compensation for advisory boards from Actelion, Alexion, Bayer, Biogen, CSL Behring, Fresenius, Horizon, Merck, Novartis, Roche, Sanofi-Genzyme, Takeda and Teva. None of these are related to this work. CG received honoraria from Merck. MCK has served on advisory boards and received speaker fees/travel grants from Merck, Sanofi-Genzyme, Novartis, Biogen, Janssen, Alexion, Celgene/Bristol-Myers Squibb and Roche. He has received research grants from Merck, Roche, Novartis, Sanofi-Genzyme, Janssen and Celgene/Bristol-Myers Squibb. PSR has received honoraria for lectures/consultancy from Alexion (AstraZeneca), Allmiral, Amicus, Biogen, Genzyme, Horizon (Amgen), Merck, Novartis, Roche and Teva, served on advisory boards for Alexion (AstraZeneca), Amicus, Genzyme, Horizon (Amgen), Merck, Roche and Sandoz and received research grants from Amicus, Roche, Merck and the Austrian Science Fund (FWF). IV has received travel support from Alexion. MS has received consulting and/or speaker honoraria from Alexion, Bayer, Biogen, Bristol-Myers Squibb/Celgene, Merck, Horizon, Roche and Sanofi-Genzyme. AW received speaker honoraria, consultant fees and travel reimbursement from Alexion, Bayer, Biogen, GlaxoSmithKline, Hexal, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi-Genzyme and UCB, none related to this study. MSW Our research is supported by research grants (Startförderung) of the Universitätsmedizin Göttingen, the National Multiple Sclerosis Society (NMSS; PP 1660), Novartis, Teva, Biogen Idec, Roche, Merck, the ProFutura Programme of the Universitätsmedizin Göttingen and the Deutsche Forschungsgemeinschaft (WE 3547/4-1; WE 3547/5-1; WE3547/7-1; project A8, SFB TRR 274). LH has received research support and speaker honoraria from Novartis. She is supported by the Deutsche Forschungsgemeinschaft (DFG Clinician Scientist Kolleg 'Zelldynamik in Pathogenese und Therapie'). AWa received speaker honoraria and meeting expenses from Novartis, Bayer, Biogen, Sanofi-Genzyme, Teva, Roche and Merck. PSchi received travel reimbursement from UCB. FP has received research support, speaker honoraria and travel reimbursement from Bayer, Biogen Idec, Merck Serono, Novartis, Sanofi-Genzyme, UCB and Teva; is supported by the German Research Council (DFG Exc 257) and the German Competence Network for Multiple Sclerosis; received travel reimbursement from the Guthy-Jackson Charitable Foundation; and serves on the steering committee of the OCTIMS study sponsored by Novartis. JB-S has received institutional research support from NEMOS, Alexion and Bayer, personal fees from Alexion, speaker honoraria and travel grants from Bayer Healthcare, Horizon/Amgen, Novartis and Sanofi-Aventis/Genzyme, as well as grants for participating in a scientific advisory board from Roche and Merck, all unrelated to the present work. RG has received speaker and board honoraria from Baxter, Bayer Schering, Biogen Idec, CLB Behring, Genzyme, Merck Serono, Novartis, Stendhal, Talecris and Teva. His department received grant support from Bayer Schering, Biogen Idec, Genzyme, Merck Serono, Novartis and Teva. All not related to the content of this manuscript. IA received personal fees from Roche, Alexion, Horizon, Sanofi-Aventis/Genzyme and Merck and received research support from Diamed, none related to this study., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Data on cognition in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are limited to studies with small sample sizes. Therefore, we aimed to analyse the extent, characteristics and the longitudinal course of potential cognitive deficits in patients with MOGAD., Methods: The CogniMOG-Study is a prospective, longitudinal and multicentre observational study of 113 patients with MOGAD. Individual cognitive performance was assessed using the Paced Auditory Serial Addition Task (PASAT), the Symbol Digit Modalities Test (SDMT) and the Multiple Sclerosis Inventory Cognition (MuSIC), which are standardised against normative data from healthy controls. Cognitive performance was assessed at baseline and at 1-year and 2-year follow-up assessments. Multiple linear regression was used to analyse demographic and clinical predictors of cognitive deficits identified in previous correlation analyses., Results: At baseline, the study sample of MOGAD patients showed impaired standardised performance on MuSIC semantic fluency (mean=-0.29, 95% CI (-0.47 to -0.12)) and MuSIC congruent speed (mean=-0.73, 95% CI (-1.23 to -0.23)). Around 1 in 10 patients showed deficits in two or more cognitive measures (11%). No decline in cognition was observed during the 1-year and 2-year follow-up period. Cerebral lesions were found to be negatively predictive for SDMT (B=-8.85, 95% CI (-13.57 to -4.14)) and MuSIC semantic fluency (B=-4.17, 95% CI (-6.10 to -2.25)) test performance., Conclusions: Based on these data, we conclude that MOGAD patients show reduced visuomotor processing speed and semantic fluency to the extent that the disease burden includes cerebral lesions., Competing Interests: Competing interests: SP, CStern, SJ, MK-K, VH, J-PS, MG, RS, JRK, AW, FTB, PSS and BK report no disclosures relevant to the manuscript. TK has received speaker honoraria and/or personal fees for advisory boards from Merck, Roche Pharma, Alexion/Astra Zeneca, Horizon, Chugai and Biogen. JH reports grants from the Friedrich-Baur-Stiftung, Merck and Horizon, personal fees and non-financial support from Alexion, Horizon, Roche, Merck, Novartis, Biogen, BMS and Janssen, and non-financial support from the Guthy-Jackson Charitable Foundation and The Sumaira Foundation. DE received speaker honoraria from Alexion and Horizon/Amgen. BW received grants from the German Ministry of Education and Research, Deutsche Forschungsgemeinschaft, Dietmar Hopp Foundation and Klaus Tschira Foundation, grants and personal fees from Merck, Novartis and personal fees from Alexion, INSTAND, Roche. MS has received consulting and/or speaker honoraria from Alexion, Bayer, Biogen, Bristol-Myers-Squibb, Merck, Horizon, Roche and Sanofi Genzyme. CW has received institutional support from Novartis, Alexion, Sanofi Genzyme, Biogen, Merck, Roche and Hexal. 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. LK received compensation for serving on Scientific Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Genzyme, Horizon, Janssen, Merck Serono, Novartis, Roche and Viatris. She received speaker honoraria and travel support from Argenx, Bayer, Biogen, Bristol-Myers Squibb, Genzyme, Grifols, Merck Serono, Novartis, Roche, Santhera and Teva. She receives research support from the German Research Foundation, the IZKF Münster, IMF Münster, Biogen, Immunic AG, Novartis and Merck Serono. OA reports grants from the German Ministry of Education and Research (BMBF) and the German Research Foundation (DFG); grants and personal fees from Biogen and Novartis; and travel support and personal fees from Alexion, Almirall, MedImmune, Merck Serono, Roche, Sanofi, Viela Bio/Horizon Therapeutics and Zambon. MR received speaker honoraria from Novartis, Bayer Vital, Roche, Alexion, Horizon and Ipsen and travel reimbursement from Bayer Schering, Biogen Idec, Merz, Genzyme, Teva, Roche, Horizon and Merck, none related to this study. IA has received research support from Diamed and Chugai, speaking honoraria, travel grants and compensation for serving on a scientific advisory board from Alexion, Horizon, Roche, Merck and Sanofi-Aventis/Genzyme, all unrelated to this study. CSchwake has received speaker honoraria from Alexion and travel support from Novartis and UCB. All not related to the content of this manuscript. IK has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alexion, Almirall, Bayer, Biogen, GlaxoSmithKline, Hexal, Horizon, Merck, Neuraxpharm, Roche/Chugai and Sanofi. RR received speaking honorar from Roche unrelated to this study. PS received travel reimbursement by UCB. JB-S has received research support from NEMOS e.V. and Bayer AG, personal compensation from Alexion, speaking honoraria and travel grants from Bayer Healthcare, Horizon, Novartis and Sanofi-Aventis/Genzyme, in addition received compensation for serving on a scientific advisory board of Roche and Merck, all unrelated to the presented work. FP receives honoraria for lecturing, and travel expenses from Guthy Jackson Foundation, Bayer, Biogen, Merck Serono, Sanofi Genzyme, Novartis, Viela Bio, Roche, UCB, Mitsubishi Tanabe, Celgene and support for attending meetings from Alexion. His research is funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Einstein Foundation, Guthy Jackson Charitable Foundation, EU FP7 Framework Program, Biogen, Genzyme, Merck Serono, Novartis, Bayer, Roche, Parexel and Almirall. FP serves on advisory boards and steering committees for Celgene, Roche, UCB and Merck and is associate editor of Neurology, Neuroimmunology & Neuroinflammation and academic editor for PLoS ONE. CT has received honoraria for consultation and expert testimony from Alexion Pharma Germany. None of this interfered with the current report. MWH received research support from Myelitis e. V., speaker honoraria from selpers og, Horizon, and Alexion, and reimbursement of travel expenses and compensation for serving on an advisory board from Alexion. None of this interfered with the current manuscript., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Epstein-Barr virus (EBV) infection has long been associated with the development of multiple sclerosis (MS). MS patients have elevated titers of EBV-specific antibodies in serum and show signs of CNS damage only after EBV infection. Regarding CD8+ T-cells, an elevated but ineffective response to EBV was suggested in MS patients, who present with a broader MHC-I-restricted EBV-specific T-cell receptor beta chain (TRB) repertoire compared to controls. It is not known whether this altered EBV response could be subject to dynamic changes, e.g., by approved MS therapies, and whether it is specific for MS. 1317 peripheral blood TRB repertoire samples of healthy donors (n=409), patients with MS (n=710) before and after treatment, patients with neuromyelitis optica spectrum disorder (n=87), myelin-oligodendrocyte-glycoprotein antibody-associated disease (n=64) and Susac's syndrome (n=47) were analyzed. Apart from MS, none of the evaluated diseases presented with a broader anti-EBV TRB repertoire. In MS patients undergoing autologous hematopoietic stem-cell transplantation, EBV reactivation coincided with elevated MHC-I-restricted EBV-specific TRB sequence matches. Therapy with ocrelizumab, teriflunomide or dimethyl fumarate reduced EBV-specific, but not CMV-specific MHC-I-restricted TRB sequence matches. Together, this data suggests that the aberrant MHC-I-restricted T-cell response directed against EBV is specific to MS with regard to NMO, MOGAD and Susac's Syndrome and that it is specifically modified by MS treatments interfering with EBV host cells or activated lymphocytes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Previous investigations of multiple sclerosis (MS)-related healthcare have focused on utilisation of specific individual health services (e.g. hospital care, office-based neurologists) by people with MS (PwMS). Meanwhile, little is known about possible patterns of utilisation across health services and their potential differences across patient characteristics., Objective: To comprehensively analyse and identify patterns of MS-related health service utilisation and detect patient characteristics explaining such patterns., Methods: In 2021, we invited all PwMS insured by the largest insurance company in Lower Saxony, Germany, to take part in an online survey. We merged respondents' survey and health insurance claims data. We analysed MS-related health service utilisation and defined individual characteristics for subgroup analyses based on Andersen's Behavioural Model. We executed non-parametric missing value imputation and conducted hierarchical clustering to find patterns in health service utilisation., Results: Of 6928 PwMS, 1935 responded to our survey and 1803 were included in the cluster analysis. We identified four distinct health service utilisation clusters: (1) regular users (n = 1130), (2) assistive care users (n = 443), (3) low users (n = 195) and (4) special services users (n = 35). Clusters differ by patient characteristics (e.g. age, impairment)., Conclusion: Our findings highlight the complexity of MS-related health service utilisation and provide relevant stakeholders with information allowing them to tailor healthcare planning according to utilisation patterns., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: CT has received honoraria for consultation and expert testimony from Alexion Pharma Germany GmbH, and Roche Pharma GmbH. None of this interfered with the current report. PF has received speaker's fees and honoraria for advisory boards from Almirall, Bayer, Biogen Idec, BMS-Celgene, Coloplast, Genzyme, GW Pharma, Hexal, Janssen-Cilag, Novartis, Merck, Roche, Sanofi, Stadapharm and Teva. AS has no personal pecuniary interests to disclose, other than being the lead of the German MS Registry, which receives (project) funding from a range of public and corporate sponsors, recently including The German Innovation Fund (G-BA), The German Retirement Insurance, The German MS Trust, The German MS Society, Biogen GmbH, BristolMyersSquibb, Merck Health care Germany GmbH, Novartis Pharma GmbH and Roche Pharma AG. None resulted in a conflict of interest. The remaining authors declare that there is no conflict of interest., (© The Author(s), 2024.)

Objective: To investigate accumulation of disability in neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD) in a changing treatment landscape. We aimed to identify risk factors for the development of disability milestones in relation to disease duration, number of attacks, and age., Methods: We analyzed data from individuals with NMOSD and MOGAD from the German Neuromyelitis Optica Study Group registry. Applying survival analyses, we estimated risk factors and computed time to disability milestones as defined by the Expanded Disability Status Score (EDSS)., Results: We included 483 patients: 298 AQP4-IgG + NMOSD, 52 AQP4-IgG - /MOG-IgG - NMOSD patients, and 133 patients with MOGAD. Despite comparable annualized attack rates, disability milestones occurred earlier and after less attacks in NMOSD patients than MOGAD patients (median time to EDSS 3: AQP4-IgG+ NMOSD 7.7 (95% CI 6.6-9.6) years, AQP4-IgG - /MOG-IgG - NMOSD 8.7) years, MOGAD 14.1 (95% CI 10.4-27.6) years; EDSS 4: 11.9 (95% CI 9.7-14.7), 11.6 (95% lower CI 7.6) and 20.4 (95% lower CI 14.1) years; EDSS 6: 20.1 (95% CI 16.5-32.1), 20.7 (95% lower CI 11.6), and 37.3 (95% lower CI 29.4) years; and EDSS 7: 34.2 (95% lower CI 31.1) for AQP4-IgG + NMOSD). Higher age at onset increased the risk for all disability milestones, while risk of disability decreased over time., Interpretation: AQP4-IgG + NMOSD, AQP4-IgG - /MOG-IgG - NMOSD, and MOGAD patients show distinctive relapse-associated disability progression, with MOGAD having a less severe disease course. Investigator-initiated research has led to increasing awareness and improved treatment strategies appearing to ameliorate disease outcomes for NMOSD and MOGAD. ANN NEUROL 2024;95:720-732., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Optic neuritis is often an initial symptom in multiple sclerosis (MS) or clinically isolated syndrome (CIS), yet comprehensive studies using the 2017 McDonald criteria for MS are scarce. Patient records from our academic centre (2010-2018) were reviewed. Using the 2017 McDonald criteria, three groups were formed: MS optic neuritis (optic neuritis with confirmed MS), CIS optic neuritis (optic neuritis without confirmed MS) and suspected optic neuritis (sON). We compared clinical and paraclinical findings among the groups to identify predictors for CIS- or MS-optic neuritis. The study included 129 MS, 108 CIS, and 44 sON cases. The combination of visual impairment, dyschromatopsia, and retrobulbar pain was observed in 47% of MS patients, 42% of CIS patients, and 30% of sON patients. Dyschromatopsia was the strongest indicator of MS or CIS diagnosis in the backward regression model. 56% of MS patients had relative afferent pupillary defect, 61% optic nerve anomalies within magnetic resonance imaging, and 81% abnormal visual evoked potentials. Our results emphasize the challenges in diagnosing optic neuritis, as not all patients with objectively diagnosed MS exhibit the triad of typical symptoms. To address potentially missing clinical features, incorporating additional paraclinical findings is proposed., (© 2024. The Author(s).)

This manuscript presents practical recommendations for managing acute attacks and implementing preventive immunotherapies for neuromyelitis optica spectrum disorders (NMOSD), a rare autoimmune disease that causes severe inflammation in the central nervous system (CNS), primarily affecting the optic nerves, spinal cord, and brainstem. The pillars of NMOSD therapy are attack treatment and attack prevention to minimize the accrual of neurological disability. Aquaporin-4 immunoglobulin G antibodies (AQP4-IgG) are a diagnostic marker of the disease and play a significant role in its pathogenicity. Recent advances in understanding NMOSD have led to the development of new therapies and the completion of randomized controlled trials. Four preventive immunotherapies have now been approved for AQP4-IgG-positive NMOSD in many regions of the world: eculizumab, ravulizumab - most recently-, inebilizumab, and satralizumab. These new drugs may potentially substitute rituximab and classical immunosuppressive therapies, which were as yet the mainstay of treatment for both, AQP4-IgG-positive and -negative NMOSD. Here, the Neuromyelitis Optica Study Group (NEMOS) provides an overview of the current state of knowledge on NMOSD treatments and offers statements and practical recommendations on the therapy management and use of all available immunotherapies for this disease. Unmet needs and AQP4-IgG-negative NMOSD are also discussed. The recommendations were developed using a Delphi-based consensus method among the core author group and at expert discussions at NEMOS meetings., (© 2023. The Author(s).)

Background: Viral and autoimmune encephalitis may present with similar symptoms, but require different treatments. Thus, there is a need for biomarkers to improve diagnosis and understanding of pathogenesis. We hypothesized that virus-host cell interactions lead to different changes in central nervous system (CNS) metabolism than autoimmune processes and searched for metabolite biomarkers in cerebrospinal fluid (CSF) to distinguish between the two conditions., Methods: We applied a targeted metabolomic/lipidomic analysis to CSF samples from patients with viral CNS infections (n = 34; due to herpes simplex virus [n = 9], varicella zoster virus [n = 15], enteroviruses [n = 10]), autoimmune neuroinflammation (n = 25; autoimmune anti-NMDA-receptor encephalitis [n = 8], multiple sclerosis [n = 17), and non-inflamed controls (n = 31; Gilles de la Tourette syndrome [n = 20], Bell's palsy with normal CSF cell count [n = 11]). 85 metabolites passed quality screening and were evaluated as biomarkers. Standard diagnostic CSF parameters were assessed for comparison., Results: Of the standard CSF parameters, the best biomarkers were: CSF cell count for viral infections vs. controls (area under the ROC curve, AUC = 0.93), Q-albumin for viral infections vs. autoimmune neuroinflammation (AUC = 0.86), and IgG index for autoimmune neuroinflammation vs. controls (AUC = 0.90). Concentrations of 2 metabolites differed significantly (p < 0.05) between autoimmune neuroinflammation and controls, with proline being the best biomarker (AUC = 0.77). In contrast, concentrations of 67 metabolites were significantly higher in viral infections than controls, with SM.C16.0 being the best biomarker (AUC = 0.94). Concentrations of 68 metabolites were significantly higher in viral infections than in autoimmune neuroinflammation, and the 10 most accurate metabolite biomarkers (AUC = 0.89-0.93) were substantially better than Q-albumin (AUC = 0.86). These biomarkers comprised six phosphatidylcholines (AUC = 0.89-0.92), two sphingomyelins (AUC = 0.89, 0.91), and acylcarnitines isobutyrylcarnitine (C4, AUC = 0.92) and isovalerylcarnitine (C5, AUC = 0.93). Elevated C4 and C5 concentrations suggested dysfunctional mitochondrial β-oxidation and correlated only moderately with CSF cell count (Spearman ρ = 0.41 and 0.44), indicating that their increase is not primarily driven by inflammation., Conclusions: Changes in CNS metabolism differ substantially between viral CNS infections and autoimmune neuroinflammation and reveal CSF metabolites as pathophysiologically relevant diagnostic biomarkers for the differentiation between the two conditions. In viral CNS infections, the observed higher concentrations of free phospholipids are consistent with disruption of host cell membranes, whereas the elevated short-chain acylcarnitines likely reflect compromised mitochondrial homeostasis and energy generation., (© 2023. The Author(s).)

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.)

The clinical implications of the presence of anti-N-methyl-D-aspartate receptor (NMDAR)-specific intrathecal immunoglobulin G synthesis and whether it determines the diagnosis of anti-NMDAR encephalitis have not been thoroughly investigated yet. Thus, the aim of this study was to investigate whether the detection of intrathecal anti-NMDAR-specific IgG synthesis contributes to the diagnostic confirmation of anti-NMDAR encephalitis, to disease severity, and to prognosis in patients with positive serum anti-NMDAR-IgG. In this study, patients with detectable anti-NMDAR IgG in serum and/or cerebrospinal fluid (CSF) were included and separated into two groups that either met the 2016 criteria by Graus et al. of definite anti-NMDAR encephalitis (n = 27) or did not (n = 15). In a total, of 80 paired CSF/serum samples, antibody titers were titrated manually and end-point titer levels were carefully determined in a blinded manner to the subgroup attribution. The disease course was assessed via the modified Rankin Scale (mRS) and prognosis was estimated by the anti-NMDAR Encephalitis One-Year Functional Status (NEOS) score. With respect to whether the diagnostic Graus criteria for definite anti-NMDAR encephalitis were fulfilled, a significantly unequal distribution of intrathecal anti-NMDAR antibody-specific synthesis could be shown with a high negative predictive value in case of a negative anti-NMDAR antibody-specific index (NMDAR AI, p = .008. OR = 23.9, sensitivity = 1.0, specificity = 0.4, negative predictive value = 1). A weak correlation was found between the CSF antibody titer and mRS value at the time of sample collection (r s  = .37, p = .008, 95% CI [.09, .59]). During the disease course a higher delta-mRS value formed of the mRS at initial presentation minus that at the last recorded presentation correlated with a higher NMDAR AI at first lumbar puncture (r s  = - .56, p = .017, 95% CI [- .83, - .11]). No association with the prognostic NEOS score was found. In conclusion, a negative antibody-specific index for anti-NMDAR IgG antibodies has a highly negative predictive value for the diagnosis of anti-NMDAR encephalitis. Yet, a positive NMDAR AI alone does not allow the diagnosis of anti-NMDAR encephalitis., (© 2023. Springer Nature Limited.)

The term 'neuromyelitis optica spectrum disorders' (NMOSD) is used as an umbrella term that refers to aquaporin-4 immunoglobulin G (AQP4-IgG)-positive neuromyelitis optica (NMO) and its formes frustes and to a number of closely related clinical syndromes without AQP4-IgG. NMOSD were originally considered subvariants of multiple sclerosis (MS) but are now widely recognized as disorders in their own right that are distinct from MS with regard to immunopathogenesis, clinical presentation, optimum treatment, and prognosis. In part 1 of this two-part article series, which ties in with our 2014 recommendations, the neuromyelitis optica study group (NEMOS) gives updated recommendations on the diagnosis and differential diagnosis of NMOSD. A key focus is on differentiating NMOSD from MS and from myelin oligodendrocyte glycoprotein antibody-associated encephalomyelitis (MOG-EM; also termed MOG antibody-associated disease, MOGAD), which shares significant similarity with NMOSD with regard to clinical and, partly, radiological presentation, but is a pathogenetically distinct disease. In part 2, we provide updated recommendations on the treatment of NMOSD, covering all newly approved drugs as well as established treatment options., (© 2023. The Author(s).)

Background: There is limited and inconsistent information on the prevalence of cognitive impairment in neuromyelitis optica spectrum disorders (NMOSD)., Objective: To assess cognitive performance and changes over time in NMOSD., Methods: This study included data from 217 aquaporin-4-IgG-seropositive (80%) and double-seronegative NMOSD patients. Cognitive functions measured by Symbol Digit Modalities Test (SDMT), Paced Auditory Serial-Addition Task (PASAT), and/or Multiple Sclerosis Inventory Cognition (MuSIC) were standardized against normative data ( N  = 157). Intraindividual cognitive performance at 1- and 2-year follow-up was analyzed. Cognitive test scores were correlated with demographic and clinical variables and assessed with a multiple linear regression model., Results: NMOSD patients were impaired in SDMT ( p  = 0.007), MuSIC semantic fluency ( p  < 0.001), and MuSIC congruent speed ( p  < 0.001). No significant cognitive deterioration was found at follow-up. SDMT scores were related to motor and visual disability ( p Bon  < 0.05). No differences were found between aquaporin-4-IgG-seropositive and double-seronegative NMOSD., Conclusions: A subset of NMOSD patients shows impairment in visual processing speed and in semantic fluency regardless of serostatus, without noticeable changes during a 2-year observation period. Neuropsychological measurements should be adapted to physical and visual disabilities.

Background: Data on the humoral vaccine response in patients on anti-interleukin-6 (IL-6) receptor therapy remain scarce., Objective: The main objective of our study was to investigate the humoral response after vaccination against SARS-CoV-2 in neuromyelitis optica spectrum disorder (NMOSD)/myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) patients treated with anti-IL-6 receptor therapy. Secondarily, we analyzed relapse activity timely associated with vaccination., Methods: In this retrospective cross-sectional multicenter study, we included 15 healthy controls and 48 adult NMOSD/MOGAD patients without previous COVID-19 infection. SARS-CoV-2 spike protein antibody titers during anti-IL-6 receptor therapy were compared to anti-CD20 antibody therapy, oral immunosuppressants, and to nonimmunosuppressed individuals., Results: We observed 100% seroconversion in the anti-IL-6 receptor treatment group. Titers of SARS-CoV-2 spike protein antibodies were lower compared to healthy controls (720 vs 2500 binding antibody units (BAU)/mL, p  = 0.004), but higher than in the anti-CD20 (720 vs 0.4 BAU/mL, p  < 0.001) and comparable to the oral immunosuppressant group (720 vs 795 BAU/mL, p  = 1.0). We found no association between mRNA-based vaccines and relapse activity in patients with or without immunotherapy., Conclusions: Despite being lower than in healthy controls, the humoral vaccine response during anti-IL-6 receptor therapy was evident in all patients and substantially stronger compared to anti-CD20 treatment. No relevant disease activity occurred after mRNA vaccination against SARS-CoV-2.

Background and Objectives: To evaluate the effects of the coronavirus disease 2019 (COVID-19) pandemic on the life of patients with neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated diseases (MOGAD)., Methods: This multicenter, cross-sectional study included data of 187 patients recruited from 19 different German and Austrian Neuromyelitis Optica Study Group (NEMOS) centers between July 2021 and March 2022. The effects of the pandemic on immunotherapeutic treatment and access to care, the possible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and the potential effect of vaccination against SARS-CoV-2 on disease incidence and relapse risk were assessed using a patient questionnaire. Health-related quality of life (HRQoL) was measured with the EuroQoL Group 5-Dimension 5-Level Scale (EQ-5D-5L). Demographic and clinical characteristics were retrieved from the NEMOS database., Results: One hundred eighty-seven patients (75% women; median age 47 [range 21-86] years; median disease duration 5.5 [range 0-67] years; median Expanded Disability Status Scale 2.0 [range 0-8.0]; 51% aquaporin-4 immunoglobulin G (AQP4-IgG)-positive, 36% myelin oligodendrocyte glycoprotein (MOG)-IgG-positive 13% double-seronegative) were analyzed. Most patients maintained excellent access to healthcare services throughout the pandemic. Immunotherapy was not changed in 88% of patients. Ninety-one percent of all patients were satisfied with medical care during the pandemic. Nearly two-thirds (64%) of patients rated their risk of infection with SARS-CoV-2 as low or moderate. Among this study sample, 23 patients (12%) knowingly acquired an infection with SARS-CoV-2 and predominantly had a nonsevere course of illness (n = 22/23, 96%). The SARS-CoV-2 vaccination rate was 89%, with 4 cases of confirmed attack or first manifestation of NMOSD/MOGAD occurring in temporal association with the vaccination (range 2-9 days). The reported HRQoL did not decline compared with a prepandemic assessment (mean EQ-5D-5L index value 0.76, 95% bootstrap confidence interval [CI] 0.72-0.80; mean EQ-VAS 66.5, 95% bootstrap CI 63.5-69.3)., Discussion: This study demonstrates that, overall, patients with NMOSD/MOGAD affiliated with specialized centers received ongoing medical care during the pandemic. Patients' satisfaction with medical care and HRQoL did not decrease., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Obesity reportedly increases the risk for developing multiple sclerosis (MS), but little is known about its association with disability accumulation., Methods: This nationwide longitudinal cohort study included 1066 individuals with newly diagnosed MS from the German National MS cohort. Expanded Disability Status Scale (EDSS) scores, relapse rates, MRI findings and choice of immunotherapy were compared at baseline and at years 2, 4 and 6 between obese (body mass index, BMI ≥30 kg/m 2 ) and non-obese (BMI <30 kg/m 2 ) patients and correlated with individual BMI values., Results: Presence of obesity at disease onset was associated with higher disability at baseline and at 2, 4 and 6 years of follow-up (p<0.001). Median time to reach EDSS 3 was 0.99 years for patients with BMI ≥30 kg/m 2  and 1.46 years for non-obese patients. Risk to reach EDSS 3 over 6 years was significantly increased in patients with BMI ≥30 kg/m 2 compared with patients with BMI <30 kg/m 2 after adjustment for sex, age, smoking (HR 1.87; 95% CI 1.3 to 2.6; log-rank test p<0.001) and independent of disease-modifying therapies. Obesity was not significantly associated with higher relapse rates, increased number of contrast-enhancing MRI lesions or higher MRI T2 lesion burden over 6 years of follow-up., Conclusions: Obesity in newly diagnosed patients with MS is associated with higher disease severity and poorer outcome. Obesity management could improve clinical outcome of MS., Competing Interests: Competing interests: SB has received honoraria from Biogen Idec, Bristol Meyer Squibbs, Merck Serono, Novartis, Sanofi-Genzyme, Roche and Teva. His research is funded by the Deutsche Forschungsgemeinschaft (DFG) and Hertie Foundation. FL has served on the advisory board of Roche and received travel funding from Teva. AS has received speaker honoraria and/or travel compensation for activities with Bristol Myers Squibb, CSL Behring, Novartis and Roche, and research support by the Swiss MS Society and Baasch Medicus Foundation, not related to this manuscript. LK has received compensation for serving on Scientific Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Genzyme, Horizon, Janssen, Merck Serono, Novartis and Roche. She has received speaker honoraria and travel support from Bayer, Biogen, Bristol-Myers Squibb, Genzyme, Grifols, Merck Serono, Novartis, Roche, Santhera and Teva. She has received research support from the German Research Foundation, the IZKF Münster, IMF Münster, Biogen, Immunic AG, Novartis and Merck Serono. CK has received speaker fees, travel support and/or served on advisory boards by Biogen, Merck, Roche and Sanofi. BW has received grants from the German Ministry of Education and Research, Deutsche Forschungsgemeinschaft, Dietmar Hopp Foundation and Klaus Tschira Foundation, grants and personal fees from Merck, and personal fees from Alexion, Bayer, Biogen, Teva; none related to this work. AB has received personal compensation from Merck Serono, Biogen, Novartis, Teva, Roche, Sanofi/Genzyme, Celgene/BMS and Janssen; he has received grants for congress travel and participation from Biogen, Teva, Novartis, Sanofi/Genzyme, Merck Serono and Celgene. None related to this report. HT has received consulting and/or speaker honoraria from Alexion, Bayer, Biogen, Celgene, GSK, Jannssen, Merck, Novartis, Roche, Sanofi Genzyme and Teva. SM has received honoraria for lecturing and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS and Teva. His research is funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Else Kröner Fresenius Foundation, German Academic Exchange Service, Hertie Foundation, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, German Foundation Neurology and by Almirall, Amicus Therapeutics Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, Merck Serono, Novartis, ONO Pharma, Roche and Teva. CT has received honoraria for consultation and expert testimony from Alexion Pharma Germany, Chugai Pharma Germany and Roche Pharma. None of this interfered with the current report. UKZ has received speaking fees, travel support and financial support for research activities from Alexion, Almirall, Bayer, Biogen, Bristol-Myers-Squibb, Janssen, Merck-Serono, Novartis, Octapharm, Roche, Sanofi-Genzyme and Teva as well as EU, BMBF, BMWi. CH has received speaker honoraria from Merck and Roche. He has received grant support from Merck, Novartis and Roche. TK has received speaker honoraria and/or personal fees for advisory boards from Bayer Healthcare, Merck, Novartis Pharma, Sanofi-Aventis/Genzyme, Roche Pharma, Alexion and Biogen as well as grant support from Novartis and Chugai Pharma in the past. None of this interfered with the current report. RG has received speaker and board honoraria from Baxter, Bayer Schering, Biogen Idec, Bristol Meyer Squibb, CSL Behring, Eisai, Genzyme, Janssen, Merck Serono, Novartis, Stendhal, Talecris and Teva. His department has received grant support from Bayer Schering, BiogenIdec, Genzyme, Merck Serono, Novartis and Teva. All of RG’s declarations are unrelated to the content of this manuscript. BH has served on scientific advisory boards for Novartis; he has served as DMSC member for AllergyCare, Polpharma, Sandoz and TG therapeutics; he or his institution has received speaker honoraria from Desitin; his institution has received research grants from Regeneron for multiple sclerosis research. He holds part of two patents: one for the detection of antibodies against KIR4.1 in a subpopulation of patients with multiple sclerosis and one for genetic determinants of neutralising antibodies to interferon. FZ has recently received research grants and/or consultation funds from Biogen, Ministry of Education and Research (BMBF), Bristol-Meyers-Squibb, Celgene, German Research Foundation (DFG), Janssen, Max-Planck-Society (MPG), Merck Serono, Novartis, Progressive MS Alliance (PMSA), Roche, Sanofi Genzyme and Sandoz. HW has received honoraria for acting as a member of Scientific Advisory Boards for Janssen, Merck and Novartis as well as speaker honoraria and travel support from Alexion, Amicus Therapeuticus, Biogen, Biologix, Bristol Myers Squibb, Cognomed, F. Hoffmann-La Roche Ltd, Gemeinnützige Hertie-Stiftung, Medison, Merck, Novartis, Roche Pharma AG, Genzyme, Teva and WebMD Global. HW is acting as a paid consultant for Biogen, Bristol Myers Squibb, EMD Serono, Idorsia, Immunic, Novartis, Roche, Sanofi, the Swiss Multiple Sclerosis Society and UCB. His research is funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgesellschaft (DFG), Deutsche Myasthenie Gesellschaft e.V., Alexion, Amicus Therapeutics, Argenx, Biogen, CSL Behring, F. Hoffmann - La Roche, Genzyme, Merck KgaA, Novartis Pharma, Roche Pharma and UCB Biopharma. JDL has received speaker fees, research support, travel support, and/or served on advisory boards by Abbvie, Alexion, Argenx, Biogen, Merck, Novartis, Roche, Sanofi and Takeda. JDL has received speaker fees, research support, travel support, and/or served on advisory boards by Abbvie, Alexion, Argenx, Biogen, Merck, Novartis, Roche, Sanofi and Takeda., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background : Since the 1990s, transplantations of hematopoietic and mesenchymal stem cells (HSCT and MSCT) and dendritic cell (DCT) have been investigated for the treatment of neurological autoimmune disorders (NADs). With the growing number of transplanted patients, awareness of neuroimmunolgical complications has increased. Therefore, an overview of SCT for the most common NADs and reports of secondary immunity after SCT is provided. Methods : For this narrative review, a literature search of the PubMed database was performed. A total of 86 articles reporting on different SCTs in NADs and 61 articles dealing with immune-mediated neurological complications after SCT were included. For multiple sclerosis (MS), only registered trials and phase I/II or II studies were considered, whereas all available articles on other disorders were included. The different transplantation procedures and efficacy and safety data are presented. Results : In MS patients, beneficial effects of HSCT, MSCT, and DCT with a decrease in disability and stabilization of disease activity have been reported. These effects were also shown in other NADs mainly in case reports. In seven of 132 reported patients with immune-mediated neurological complications, the outcome was fatal. Conclusions : Phase III trials are ongoing for MS, but the role of SCT in other NADs is currently limited to refractory patients due to occasional serious complications.

Background and Objectives: To evaluate costs and health-related quality of life (HRQoL) of neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD)., Methods: In this multicenter cross-sectional study, data on consumption of medical and nonmedical resources and work ability were assessed via patient questionnaires. Costs were analyzed in Euros for 2018 from the societal perspective. HRQoL was captured by the EuroQoL Group 5 Dimension 5 Level Scale (EQ-5D-5L) questionnaire. Clinical data were retrieved from the Neuromyelitis Optica Study Group (NEMOS) database., Results: Two hundred twelve patients (80% women, median age 50 [19-83] years, median disease duration 7 [0-43] years, median Expanded Disability Status Scale [EDSS] score 3.5 [0-8.5], 66% aquaporin-4 immunoglobulin G [IgG] positive, 22% MOG IgG positive, 12% double seronegative) were analyzed. The mean total annual per capita cost of illness accounted for €59,574 (95% CI 51,225-68,293 or US dollars [USD] 70,297, 95% CI 60,445-80,586), and the mean index value of the EQ-5D-5L was 0.693 (95% CI 0.65-0.73). The most important cost drivers were informal care costs (28% of total costs), indirect costs (23%), and drugs (16%), especially immunotherapeutics. Costs showed a positive correlation with disease severity (ρ = 0.56, 95% CI 0.45-0.65); in the EDSS score 6.5 to 8.5 subgroup, the mean annual costs were €129,687 (95% CI 101,946-160,336 or USD 153,031, 95% CI 120,296-189,196). The HRQoL revealed a negative correlation to disease severity (ρ = -0.69, 95% CI -0.76 to -0.61); in the EDSS score 6.5 to 8.5 subgroup, the EQ-5D-5L mean index value was 0.195 (95% CI 0.13-0.28). Neither antibody status nor disease duration influenced the total annual costs or HRQoL., Discussion: These German data from the era without approved preventive immunotherapies show enormous effects of the diseases on costs and quality of life. An early and cost-effective therapy should be provided to prevent long-term disability and to preserve quality of life., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)