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Neuromyelitis optica spectrum disorders (NMOSD) are chronic inflammatory diseases of the central nervous system, characterized by autoantibodies against aquaporin-4. The symptoms primarily involve severe optic neuritis and longitudinally extensive transverse myelitis. Although the disease progression is typically relapse-dependent, recent studies revealed retinal neuroaxonal degeneration unrelated to relapse activity, potentially due to anti-aquaporin-4-positive antibodies interacting with retinal glial cells such as Müller cells. In this exploratory study, we analysed the response of mouse retinal explants to NMOSD immunoglobulins (IgG). Mouse retinal explants were treated with purified IgG from patient or control sera for one and three days. We characterized tissue response patterns through morphological changes, chemokine secretion, and complement expression. Mouse retinal explants exhibited a basic proinflammatory response ex vivo, modified by IgG addition. NMOSD IgG, unlike control IgG, increased gliosis and decreased chemokine release (CCL2, CCL3, CCL4, and CXCL-10). Complement component expression by retinal cells remained unaltered by either IgG fraction. We conclude that human NMOSD IgG can possibly bind in the mouse retina, altering the local cellular environment. This intraretinal stress may contribute to retinal degeneration independent of relapse activity in NMOSD, suggesting a primary retinopathy.

Background: Antibodies against glutamic acid decarboxylase (GAD-abs) at high serum levels are associated with diverse autoimmune neurological syndromes (AINS), including cerebellar ataxia, epilepsy, limbic encephalitis and stiff-person syndrome. The impact of low serum GAD-ab levels in patients with suspected AINS remains controversial. Specific intrathecal GAD-ab synthesis may serve as a marker for GAD-ab-associated nervous system autoimmunity. We present characteristics of a multicentric patient cohort with suspected AINS associated with GAD antibodies (SAINS-GAD+) and explore the relevance of serum GAD-ab levels and intrathecal GAD-ab synthesis., Methods: All patients with SAINS-GAD+ included in the registry of the German Network for Research on Autoimmune Encephalitis (GENERATE) from 2011 to 2019 were analyzed. High serum GAD-ab levels were defined as RIA>2000 U/mL, ELISA>1000 U/mL, or as a positive staining pattern on cell-based assays., Results: One-hundred-one patients were analyzed. In descending order they presented with epilepsy/limbic encephalitis (39%), cerebellar ataxia (28%), stiff person syndrome (22%), and overlap syndrome (12%). Immunotherapy was administered in 89% of cases with improvements in 46%. 35% of SAINS-GAD+ patients had low GAD-ab serum levels. Notably, unmatched oligoclonal bands in CSF but not in serum were more frequent in patients with low GAD-ab serum levels. GAD-ab-levels (high/low) and intrathecal GAD-ab synthesis (present or not) did not impact clinical characteristics and outcome., Conclusions: Overall, immunotherapy in SAINS-GAD+ was moderately effective. Serum GAD-ab levels and the absence or presence of intrathecal GAD-ab synthesis did not predict clinical characteristics or outcomes in SAINS-GAD+. The detection of unmatched oligoclonal bands might outweigh low GAD-ab serum levels., Competing Interests: Declaration of Competing Interest Madlener, Doppler, Finke, Gerner, Lewerenz, Linsa, Mues, Paliantonis, Priller, Prüß, Rössling, Schirotzek, Senel, Sommer, Strippel, Süße, Tauber, Wandinger, Wickel: Nothing to report. Fink: Bayer, Desitin, GSK, Novartis, Pfizer: lectures. Kellingshaus: UCB Pharma, Eisai GmbH, LivaNova Europe: lectures, consultancies. Kraft: Böhringer-Ingelheim, Daichii-Sankyo, Pfitzer/BMS, Bayer: travel expenses, lectures. Kümpfel: Bayer Healthcare, Merck, Novartis Pharma, Roche Pharma: lectures, consultancies. Leypoldt: Alexion, Roche and Biogen AdvisoryBoard, Novartis, Bayer, Roche: lectures. Malter: UCB Pharma, EISAI GmbH: lectures, consultancies. Melzer: Biogen Idec, GlaxoSmith Kline, Teva, Novartis Pharma, Bayer Healthcare, Genzyme, Alexion Pharamceuticals, Fresenius Medical Care, Diamed, and BIAL: lectures, Euroimmun, Fresenius Medical Care, Diamed, Alexion Pharamceuticals, and Novartis Pharma: funding. Menge: Biogen, Novartis, Teva: lectures, Biogen: consultancies, travel expenses. Ringelstein: Novartis, Bayer, Roche, Alexion, Ipsen: lectures, Bayer Schering, Biogen Idec, Merz, Genzyme, Teva, Grifols, Roche and Merck: travel expenses. Urbanek: Böhringer-Ingelheim: lectures, Daichii-Sankyo: lectures, travel expenses, sPfitzer/BMS: travel expenses. Senel: Bayer, Biogen, Merck, Roche, and Sanofi Genzyme: lectures and/or consultancies; Celgene, TEVA: travel expenses. Sühs: Merck: lectures, travel expenses. Tauber: Teva, Biogen, Merck Serono und Roche: lectures, travel expenses. Thaler: Novartis: funding. Then Bergh: Actelion, Novartis: funding; Actelion, Bayer, Merck, Roche: lectures; Merck, Roche, Sanofi-Genzyme: Advisory Board; Actelion, Merck: travel expenses., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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.)

Objective: Patients with myelin oligodendrocyte glycoprotein antibody (MOG-IgG)-associated disease (MOGAD) suffer from severe optic neuritis (ON) leading to retinal neuro-axonal loss, which can be quantified by optical coherence tomography (OCT). We assessed whether ON-independent retinal atrophy can be detected in MOGAD., Methods: Eighty patients with MOGAD and 139 healthy controls (HCs) were included. OCT data was acquired with (1) Spectralis spectral domain OCT (MOGAD: N = 66 and HCs: N = 103) and (2) Cirrus high-definition OCT (MOGAD: N = 14 and HCs: N = 36). Macular combined ganglion cell and inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (pRNFL) were quantified., Results: At baseline, GCIPL and pRNFL were lower in MOGAD eyes with a history of ON (MOGAD-ON) compared with MOGAD eyes without a history of ON (MOGAD-NON) and HCs (p < 0.001). MOGAD-NON eyes had lower GCIPL volume compared to HCs (p < 0.001) in the Spectralis, but not in the Cirrus cohort. Longitudinally (follow-up up to 3 years), MOGAD-ON with ON within the last 6-12 months before baseline exhibited greater pRNFL thinning than MOGAD-ON with an ON greater than 12 months ago (p < 0.001). The overall MOGAD cohort did not exhibit faster GCIPL thinning compared with the HC cohort., Interpretation: Our study suggests the absence of attack-independent retinal damage in patients with MOGAD. Yet, ongoing neuroaxonal damage or edema resolution seems to occur for up to 12 months after ON, which is longer than what has been reported with other ON forms. These findings support that the pathomechanisms underlying optic nerve involvement and the evolution of OCT retinal changes after ON is distinct in patients with MOGAD. ANN NEUROL 2022;92:476-485., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Neurological disorders with IgG antibodies against myelin-oligodendrocyte glycoprotein (MOG-IgG) have been increasingly recognised as a new type of neuroinflammatory disorder., Objective: The study aimed to identify regional and ethnic differences in clinical profiles of MOG-IgG-associated disorders between East Asian (Japanese) and Caucasian (German) patients., Methods: Demographic, clinical and therapeutic data from 68 MOG-IgG-positive adults were collected (Japanese, n=44; German, n=24)., Results: Age and sex were similar between cohorts, with optic neuritis occurring most frequently at onset (Japanese: 61%; German: 58%). However, Japanese patients had a lower annualised relapse rate (0.4 vs 0.8, p=0.019; no relapse, 64% vs 25%, p=0.002) and lower Expanded Disability Status Scale score at the last visit (1.0 vs 2.0; p = 0.008), despite similar follow-up periods (mean, 73.9 months vs 73.4 months), than those of German patients, respectively. Cerebral syndromes were more common (27% vs 4%; p=0.021) and myelitis less common (21% vs 50%; p=0.012) in Japanese than in German patients, respectively. Japanese patients were more commonly treated with long-term corticosteroids (73%), whereas German patients were more commonly treated with rituximab or other immunosuppressants (63%)., Conclusions: Among patients with MOG-IgG, Japanese tended to have a monophasic milder disease, whereas the majority of German patients had a relapsing course and more frequent myelitis, findings compatible with neuromyelitis optica spectrum disorder. Although the attack-prevention treatment regimens were considerably different, genetic and environmental factors may be important to determine clinical phenotypes and disease activity., Competing Interests: Competing interests: HZ received research grants from Novartis and speaking honoraria from Bayer Healthcare. JH is reviewing editor in the Frontiers in Neurology/Frontiers in Immunology. JH reports grants for neurovisual research from the Friedrich-Baur-Stiftung and Merck, personal fees and non-financial support from Celgene, Merck, Alexion, Novartis, Roche, Santhera, Biogen, Heidelberg Engineering, Sanofi Genzyme and non-financial support of the Guthy-Jackson Charitable Foundation, all outside the submitted work. SA received travel grant from Celgene and speaker’s honorary from Roche and Bayer, unrelated to this project. GC received speaker honoraria from Merck Serono and Bayer Healthcare, unrelated to this project. EM is reviewing editor in the Journal of Biological Chemistry, editor in the Journal of Pathology, associate editor in Frontiers in Neurology and Frontiers in Immunology, editor in PLOS-One, received honorarium from Roche, Novartis, Sanofi, Biogen and Bioeq and grant support from Novartis, Sanofi and Merck. SJ was indirectly supported by research grants from the Dietmar Hopp Foundation and from Merck Serono to the Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany. TK has received speaker honoraria including advisory boards from Bayer Healthcare, Teva Pharma, Merck, Novartis Pharma, Sanofi-Aventis/Genzyme, Roche Pharma and Biogen as well as grant support from Novartis and Chugai Pharma in the past. FP serves as an Associate Editor for Neurology: Neuroimmunology & Neuroinflammation, reports research grants and speaker honoraria from Bayer, Teva, Genzyme, Merck, Novartis, MedImmune and is member of the steering committee of the OCTIMS study (Novartis). SK serves as the Deputy Editor of the Journal of Neurology, Neurosurgery, and Psychiatry and is an Editorial Board member of the Journal of the Neurological Sciences., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: We aim to evaluate serum neurofilament light chain (sNfL), indicating neuroaxonal damage, as a biomarker at diagnosis in a large cohort of early multiple sclerosis (MS) patients., Methods: In a multicentre prospective longitudinal observational cohort, patients with newly diagnosed relapsing-remitting MS (RRMS) or clinically isolated syndrome (CIS) were recruited between August 2010 and November 2015 in 22 centers. Clinical parameters, MRI, and sNfL levels (measured by single molecule array) were assessed at baseline and up to four-year follow-up., Findings: Of 814 patients, 54.7% (445) were diagnosed with RRMS and 45.3% (369) with CIS when applying 2010 McDonald criteria (RRMS[2010] and CIS[2010]). After reclassification of CIS[2010] patients with existing CSF analysis, according to 2017 criteria, sNfL levels were lower in CIS[2017] than RRMS[2017] patients (9.1 pg/ml, IQR 6.2-13.7 pg/ml, n = 45; 10.8 pg/ml, IQR 7.4-20.1 pg/ml, n = 213; p = 0.036). sNfL levels correlated with number of T2 and Gd+ lesions at baseline and future clinical relapses. Patients receiving disease-modifying therapy (DMT) during the first four years had higher baseline sNfL levels than DMT-naïve patients (11.8 pg/ml, IQR 7.5-20.7 pg/ml, n = 726; 9.7 pg/ml, IQR 6.4-15.3 pg/ml, n = 88). Therapy escalation decisions within this period were reflected by longitudinal changes in sNfL levels., Interpretation: Assessment of sNfL increases diagnostic accuracy, is associated with disease course prognosis and may, particularly when measured longitudinally, facilitate therapeutic decisions., Funding: Supported the German Federal Ministry for Education and Research, the German Research Council, and Hertie-Stiftung., Competing Interests: Declaration of Competing Interest Falk Steffen, Vinzenz Fleischer, Muthuraman Muthuraman, Sergiu Groppa, and Mark Mühlau declare no competing interests. Stefan Bittner has received honoria and compensation for travel from Biogen Idec, Merck Serono, Novartis, Sanofi-Genzyme and Roche. Timo Uphaus received honoria from Merck Serono. Carsten Lukas received consulting and speaker's honoraria from BiogenIdec, Bayer Schering, Novartis, Sanofi, Genzyme, and TEVA; has received research scientific grant support from Bayer Schering, TEVA, and Merck Serono; holds an endowed professorship supported by the Novartis Foundation. Anke Salmen received speaker honoraria and/or travel compensation for activities with Almirall Hermal GmbH, Biogen, Merck, Novartis, Roche, and Sanofi Genzyme and research support by the Swiss MS Society, none related to this work. Felix Luessi received consultancy fees from Roche and support with travel cost from Teva Pharma. Achim Berthele reports personal fees from Bayer Healthcare, Biogen, Merck Serono, Mylan, Roche, and Sanofi Genzyme, and his institution received compensations for clinical trials from Alexion Pharmaceuticals, Biogen, Chugai, Novartis, Roche, Sanofi Genzyme, and Teva - all outside the submitted work. Luisa Klotz received honoraria for lecturing and serving on advisory boards, as well as travel expenses for attending meetings and financial research support from Immunic AG, Biogen, Janssen, Merck Serono, Novartis, Roche, Sanofi Genzyme, Teva, Grifols, Alexion, Santhera, Bayer Healthcare, the Deutsche Forschungsgemeinschaft (DFG; German Research Society), the German Ministry for Education and Research (BMBF), the Interdisciplinary Center for Clinical Studies (IZKF) Muenster and the program Innovative Medical Research (IMF) Muenster. Sven G. Meuth receives 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 Almirall, Amicus Therapeutics Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, Merck Serono, Novartis, ONO Pharma, Roche, and Teva. Antonios Bayas received personal compensation from Merck, Biogen, Bayer Vital, Novartis, TEVA, Roche and Sanofi-Aventis/Genzyme and grants for congress trips and participation from Biogen, TEVA, Novartis, Sanofi-Aventis/Genzyme, and Merck. Friedemann Paul receives honoraria for lecturing, and travel expenses for attending meetings from Guthy Jackson Foundation, Sanofi Genzyme, Novartis, Alexion, Viela Bio, Roche, UCB, Mitsubishi Tanabe and Celgene. 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, Arthur Arnstein Foundation Berlin, Biogen, Genzyme, Merck Serono, Novartis, Bayer, Teva, Alexion, Roche, Parexel and Almirall. Hans-Peter Hartung has received fees for consulting, serving on steering committees and data monitoring committees from Bayer Healthcare, Biogen, GeNeuro, Medimmune, Merck, Novartis, Roche, Sanofi Genzyme, Teva and TG Therapeutics with approval by the Rector of Heinrich-Heine-University. Ralf Linker received Research Support and/or personal compensation for activities with Bayer Health Care, Biogen, Genzyme/Sanofi, Merck, Novartis Pharma, Roche, and TEVA Pharma; none related to this work. Christoph Heesen received research grants and speaker honoraria from Biogen, Genzyme, Roche, and Merck; none related to this work. Martin Stangel received honoraria for scientific lectures or consultancy from Alexion, Bayer Healthcare, Biogen, CSL Behring, Grifols, Janssen, Merck-Serono, Novartis, Roche, Sanofi-Aventis, Takeda, and Teva. His institution received research support from Bayer Healthcare, Biogen Idec, Genzyme, Merck-Serono, Novartis, and Teva; none related to this work. Brigitte Wildemann 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 Serono, Sanofi Genzyme, Novartis pharmaceuticals, and personal fees from Bayer Healthcare, Biogenm, Teva Pharma; none related to this work. Florian Then Bergh received travel support to attend scientific meetings, personal speaker honoraria, and consultancy fees as a speaker and advisor from Bayer Healthcare, Biogen, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA. He received, through his institution, unrestricted research grants from Novartis, TEVA, Bayer Healthcare, and Actelion; none related to this work. He received funding from the DFG and, through TRM Leipzig, from the BMBF. Björn Tackenberg received personal speaker honoraria and consultancy fees as a speaker and advisor from Bayer Healthcare, Biogen, CSL Behring, GRIFOLS, Merck Serono, Novartis, Octapharma, Roche, Sanofi Genzyme, TEVA und UCB Pharma. His University received unrestricted research grants from Biogen-idec, Novartis, TEVA, Bayer Healthcare, CSL-Behring, GRIFOLS, Octapharma, Sanofi Genzyme und UCB Pharma; none related to this work. He is currently an employee of Roche. The data collection, evaluation and drafting of the manuscript was performed before beginning employment at Roche. Tania Kuempfel has received travel expenses and personal compensations from Bayer Healthcare, Teva Pharma, Merck-Serono, Novartis, Sanofi-Aventis/Genzyme, Roche and Biogen as well as grant support from Bayer-Schering AG, Novartis and Chugai Pharma. Frank Weber received honoraria from Genzyme, Novartis TEVA and Biogen for speaking or for serving on a scientific advisory board, a travel grant for the attention of a scientific meeting from Merck-Serono and Novartis and grant support from Merck-Serono, Novartis and from the Federal Ministry of Education and Research (BMBF, Projects Biobanking and Omics in ControlMS as part of the Competence Network Multiple Sclerosis). Uwe K. Zettl received speaker fees, travel compensation and/or his section received research support from Alexion, Almirall, Bayer Health Care, Biogen, Celgene, Genzyme, Merck Serono, Novartis, Roche, Sanofi-Aventis, Teva and grants from German Ministry for Education and Research (BMBF), German Ministry for Economy (BMWi), Deutsche Forschungsgemeinschaft (DFG), European Union (EU), outside the submitted work. Ulf Ziemann received speaker honoraria and/or travel compensation from Biogen Idec GmbH, Bayer Vital GmbH, Bristol Myers Squibb GmbH, CorTec GmbH, Medtronic GmbH, and grants from Biogen Idec GmbH, Servier, and Janssen Pharmaceuticals NV; none related to this work. Hayrettin Tumani received speaker honoraria from Bayer, Biogen, Fresenius, Genzyme, Merck, Novartis, Roche, Siemens, Teva; serves as section editor for the Journal of Neurology, Psychiatry, and Brain Research; and his institution receives research support from Fresenius, Genzyme, Merck, and Novartis; none related to this work. Bernhard Hemmer served on scientific advisory boards for Novartis; he has served as DMSC member for AllergyCare, Polpharma, and TG therapeutics; he or his institution have received speaker honoraria from Desitin; his institution has received research support from Regeneron; holds part of two patents; one for the detection of antibodies and T cells against KIR4.1 in a subpopulation of MS patients and one for genetic determinants of neutralising antibodies to interferon β during the last 3 years. Heinz Wiendl receives honoraria for acting as a member of Scientific Advisory Boards and as a consultant for Biogen, Evgen, MedDay Pharmaceuticals, Merck Serono, Novartis, Roche Pharma AG, Sanofi-Genzyme, as well as speaker honoraria and travel support from Alexion, Biogen, Cognomed, F. Hoffmann-La Roche Ltd., Gemeinnützige Hertie-Stiftung, Merck Serono, Novartis, Roche Pharma AG, Sanofi-Genzyme, TEVA, and WebMD Global. Prof. Wiendl is acting as a paid consultant for Abbvie, Actelion, Biogen, IGES, Novartis, Roche, Sanofi-Genzyme, and the Swiss Multiple Sclerosis Society. His research is funded by the BMBF, DFG, Else Kröner Fresenius Foundation, Fresenius Foundation, Hertie Foundation, NRW Ministry of Education and Research, Interdisciplinary Center for Clinical Studies (IZKF) Muenster and RE Children's Foundation, Biogen GmbH, GlaxoSmithKline GmbH, and Roche Pharma AG, Sanofi-Genzyme. Ralf Gold serves on scientific advisory boards for Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, and Novartis; has received speaker honoraria from Biogen Idec, Teva Pharmaceutical Industries Ltd., Bayer Schering Pharma, and Novartis; serves as editor for Therapeutic Advances in Neurological Diseases and on the editorial boards of Experimental Neurology and the Journal of Neuroimmunology; and receives research support from Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, Genzyme, Merck Serono, and Novartis; none related to this work. Frauke Zipp has recently received research grants and/or consultation funds from the DFG, BMBF, PMSA, Novartis, Octapharma, Merck Serono, ONO Pharma, Biogen, Genzyme, Celgene and Roche., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Neuromyelitis optica spectrum disorders (NMOSD) are inflammatory conditions of the central nervous system and an important differential diagnosis of multiple sclerosis (MS). Unlike MS, the course is usually relapsing, and it is unclear, if progressive neurodegeneration contributes to disability. Therefore, we aimed to investigate if progressive retinal neuroaxonal damage occurs in aquaporin4-antibody-seropositive NMOSD., Methods: Out of 157 patients with NMOSD screened, 94 eyes of 51 patients without optic neuritis (ON) during follow-up (F/U) and 56 eyes of 28 age-matched and sex-matched healthy controls (HC) were included (median F/U 2.3 years). The NMOSD cohort included 60 eyes without (Eye ON - ) and 34 eyes with a history of ON prior to enrolment (Eye ON+ ). Peripapillary retinal nerve fibre layer thickness (pRNFL), fovea thickness (FT), volumes of the combined ganglion cell and inner plexiform layer (GCIP) and the inner nuclear layer (INL) and total macular volume (TMV) were acquired by optical coherence tomography (OCT)., Results: At baseline, GCIP, FT and TMV were reduced in Eye ON+ (GCIP p<2e -16 ; FT p=3.7e -4 ; TMV p=3.7e -12 ) and in Eye ON -  (GCIP p=0.002; FT p=0.040; TMV p=6.1e -6 ) compared with HC. Longitudinally, we observed GCIP thinning in Eye ON- (p=0.044) but not in Eye ON+ . Seven patients had attacks during F/U; they presented pRNFL thickening compared with patients without attacks (p=0.003)., Conclusion: This study clearly shows GCIP loss independent of ON attacks in aquaporin4-antibody-seropositive NMOSD. Potential explanations for progressive GCIP thinning include primary retinopathy, drug-induced neurodegeneration and retrograde neuroaxonal degeneration from lesions or optic neuropathy. pRNFL thickening in the patients presenting with attacks during F/U might be indicative of pRNFL susceptibility to inflammation., Competing Interests: Competing interests: FCO has nothing to disclose. JH reports personal fees and non-financial support from Merck, grants, personal fees and non-financial support from Novartis, personal fees from Roche, non-financial support from Bayer Healthcare, personal fees from Santhera, personal fees and non-financial support from Biogen, personal fees and non-financial support from Sanofi Genzyme, all outside the submitted work. ARF is sponsored by Abide Therapeutic outside of the submitted work and reports no potential conflicts of interest. NL has nothing to disclose. HZ reports grants from Novartis, during the conduct of the study. SM has nothing to disclose; he is named as inventor on a patent application describing OCT image analysis. NB has nothing to disclose. JBS received speaking fees and travel grants from Bayer Healthcare, Sanofi-Aventis/Genzyme, Biogen and Teva Pharmaceuticals, unrelated to the present scientific work. PA reports grants, personal fees and non-financial support from Allergan, personal fees and non-financial support from Bayer Healthcare, grants, personal fees and non-financial support from Biogen, grants, personal fees and non-financial support from Ipsen, grants, personal fees and non-financial support from Merz Pharmaceuticals, personal fees and non-financial support from Merck, grants, personal fees and non-financial support from Novartis, non-financial support from Sanofi-Aventis/Genzyme, personal fees and non-financial support from Teva Pharmaceuticals, grants, personal fees and non-financial support from Roche, outside the submitted work. KR reports research support from Novartis and Merck Serono as well as speaking fees or travel grants from Bayer Healthcare, Biogen Idec, Merck Serono, Sanofi-Aventis/Genzyme, Teva Pharmaceuticals, Roche, Novartis and the Guthy-Jackson Charitable Foundation, all unrelated to this work. TK received travel expenses and personal compensations from Bayer Healthcare, Teva Pharmaceuticals, Merck, Novartis Pharma, Sanofi-Aventis/Genzyme, Roche and Biogen as well as grant support from Bayer-Schering AG, Novartis and Chugai Pharma, unrelated to this work. OW has nothing to disclose. SJ has nothing to disclose. MIL reports personal fees from Biogen Idec and grants from Novartis, outside the submitted work. JP reports grants Journal of Neurology, Neurosurgery and Psychiatry and personal fees from Merck Serono, grants and personal fees from Biogen Idec, personal fees from Teva Pharmaceuticals, grants from Chugai, grants and personal fees from MedImmun, grants and personal fees from Alexion, grants and personal fees from Novartis, personal fees from Roche, grants from Genzyme, grants and personal fees from ABIDE, personal fees from TG Therapeutics, outside the submitted work. In addition, JP has a patent Isis: Diagnosing Multiple Sclerosis. FP reports research grants and speaker honoraria from Bayer, Teva, Genzyme, Merck, Novartis, MedImmune and is member of the steering committee of the OCTIMS study (Novartis), all unrelated to this work. AUB is cofounder and holds shares of commercial entities Motognosis and Nocturne. He is named as inventor on several patent applications describing serum biomarkers for MS, perceptive visual computing for tracking of motor dysfunction and OCT image analysis., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

The presence of inflammation and demyelination in a central nervous system (CNS) biopsy points towards a limited, yet heterogeneous group of pathologies, of which multiple sclerosis (MS) represents one of the principal considerations. Inflammatory demyelination has also been reported in patients with clinically suspected primary central nervous system lymphoma (PCNSL), especially when steroids had been administered prior to biopsy acquisition. The histopathological changes induced by corticosteroid treatment can range from mild reduction to complete disappearance of lymphoma cells. It has been proposed that in the absence of neoplastic B cells, these biopsies are indistinguishable from MS, yet despite the clinical relevance, no histological studies have specifically compared the two entities. In this work, we analyzed CNS biopsies from eight patients with inflammatory demyelination in whom PCNSL was later histologically confirmed, and compared them with nine well defined early active multiple sclerosis lesions. In the patients with steroid-treated PCNSL (ST-PCNSL) the interval between first and second biopsy ranged from 3 to 32 weeks; all of the patients had received corticosteroids before the first, but not the second biopsy. ST-PCNSL patients were older than MS patients (mean age: ST-PCNSL: 62 ± 4 years, MS: 30 ± 2 years), and histological analysis revealed numerous apoptoses, patchy and incomplete rather than confluent and complete demyelination and a fuzzy lesion edge. The loss of Luxol fast blue histochemistry was more profound than that of myelin proteins in immunohistochemistry, and T cell infiltration in ST-PCNSL exceeded that in MS by around fivefold (P = 0.005). Our data indicate that in the presence of extensive inflammation and incomplete, inhomogeneous demyelination, the neuropathologist should refrain from primarily considering autoimmune inflammatory demyelination and, even in the absence of lymphoma cells, instigate close clinical follow-up of the patient to detect recurrent lymphoma., (© 2017 International Society of Neuropathology.)

Multiple sclerosis (MS), a chronic progressive inflammatory disease of the central nervous system, causes frequent disability, mood disorders, fatigue, and cognitive dysfunction. As a part of the last, social cognition is frequently disturbed in MS patients. It comprises empathy and social perception of emotions from facial, bodily and vocal cues. Social cognitive deficits worsen affect decoding, interpersonal relationship, and quality of life. Despite the impact of these deficits on global functioning, only a small number of studies have investigated its correlations and overlaps with MS symptoms. This review focuses on the definition and anatomy of social cognition and draws attention to findings of neuropsychological and neuroimaging studies on social cognitive performance in MS.Results of the available studies show that social cognitive deficits are already measurable in early stages of MS. Over time course of the disease, neuropsychological and neuroimaging studies show an increase of disease burden and social and non-social cognitive impairment following the hypothesis of a disconnection syndrome resulting from gray and white matters lesions. These structural changes might exceed a threshold of compensatory restorative and neuroplasticity mechanisms and finally lead to deficits in social cognition. Considering this burden in social functioning, a further assessment of sociocognitive deficits in MS is urgently needed to provide specific therapeutic approaches and to improve quality of life., Competing Interests: Interessenkonflikt: Frank Padberg erhielt Forschungsförderung von NeuroConn, Ilmenau, Deutschland und von Brainsway, Jerusalem, Israel.Ulrich Palm erhielt Vortragshonorare von NeuroCareGroup München, Deutschland.Die anderen Autoren geben an, dass kein Interessenkonflikt besteht., (Georg Thieme Verlag KG Stuttgart · New York.)

Neuromyelitis optica (NMO) predominantly affects women, some in childbearing age, and requires early therapeutic intervention to prevent disabling relapses. We report an anti-AQP4 antibody-seropositive patient who became pregnant seven months after low-dose (100 mg) rituximab application. Pregnancy showed no complications, and low-dose rituximab restarted two days after delivery resulted in neurological stability for 24 months. Remarkably, her otherwise healthy newborn presented with anti-AQP4 antibody and reduced B lymphocyte counts in umbilical cord blood, which normalized three months later. Confirming and extending previous reports, our case suggests that low-dose rituximab might be compatible with pregnancy and prevent rebound NMO disease activity postpartum.

Recurrent myelitis is one of the predominant characteristics in patients with neuromyelitis optica (NMO). While paresis, visual loss, sensory deficits, and bladder dysfunction are well known symptoms in NMO patients, pain has been recognized only recently as another key symptom of the disease. Although spinal cord inflammation is a defining aspect of neuromyelitis, there is an almost complete lack of data on altered somatosensory function, including pain. Therefore, eleven consecutive patients with NMO were investigated regarding the presence and clinical characteristics of pain. All patients were examined clinically as well as by Quantitative Sensory Testing (QST) following the protocol of the German Research Network on Neuropathic Pain (DFNS). Additionally, plasma endocannabinoid levels and signs of chronic stress and depression were determined. Almost all patients (10/11) suffered from NMO-associated neuropathic pain for the last three months, and 8 out of 11 patients indicated relevant pain at the time of examination. Symptoms of neuropathic pain were reported in the vast majority of patients with NMO. Psychological testing revealed signs of marked depression. Compared to age and gender-matched healthy controls, QST revealed pronounced mechanical and thermal sensory loss, strongly correlated to ongoing pain suggesting the presence of deafferentation-induced neuropathic pain. Thermal hyperalgesia correlated to MRI-verified signs of spinal cord lesion. Heat hyperalgesia was highly correlated to the time since last relapse of NMO. Patients with NMO exhibited significant mechanical and thermal dysesthesia, namely dynamic mechanical allodynia and paradoxical heat sensation. Moreover, they presented frequently with either abnormal mechanical hypoalgesia or hyperalgesia, which depended significantly on plasma levels of the endogenous cannabinoid 2-arachidonoylglycerole (2-AG). These data emphasize the high prevalence of neuropathic pain and hyperalgesia in patients with NMO. The degree of mechanical hyperalgesia reflecting central sensitization of nociceptive pathways seems to be controlled by the major brain endocannabinoid 2-AG.

Background: The diagnostic and pathophysiological relevance of antibodies to aquaporin-4 (AQP4-Ab) in patients with neuromyelitis optica spectrum disorders (NMOSD) has been intensively studied. However, little is known so far about the clinical impact of AQP4-Ab seropositivity., Objective: To analyse systematically the clinical and paraclinical features associated with NMO spectrum disorders in Caucasians in a stratified fashion according to the patients' AQP4-Ab serostatus., Methods: Retrospective study of 175 Caucasian patients (AQP4-Ab positive in 78.3%)., Results: Seropositive patients were found to be predominantly female (p < 0.0003), to more often have signs of co-existing autoimmunity (p < 0.00001), and to experience more severe clinical attacks. A visual acuity of ≤ 0.1 during acute optic neuritis (ON) attacks was more frequent among seropositives (p < 0.002). Similarly, motor symptoms were more common in seropositive patients, the median Medical Research Council scale (MRC) grade worse, and MRC grades ≤ 2 more frequent, in particular if patients met the 2006 revised criteria (p < 0.005, p < 0.006 and p < 0.01, respectively), the total spinal cord lesion load was higher (p < 0.006), and lesions ≥ 6 vertebral segments as well as entire spinal cord involvement more frequent (p < 0.003 and p < 0.043). By contrast, bilateral ON at onset was more common in seronegatives (p < 0.007), as was simultaneous ON and myelitis (p < 0.001); accordingly, the time to diagnosis of NMO was shorter in the seronegative group (p < 0.029). The course of disease was more often monophasic in seronegatives (p < 0.008). Seropositives and seronegatives did not differ significantly with regard to age at onset, time to relapse, annualized relapse rates, outcome from relapse (complete, partial, no recovery), annualized EDSS increase, mortality rate, supratentorial brain lesions, brainstem lesions, history of carcinoma, frequency of preceding infections, oligoclonal bands, or CSF pleocytosis. Both the time to relapse and the time to diagnosis was longer if the disease started with ON (p < 0.002 and p < 0.013). Motor symptoms or tetraparesis at first myelitis and > 1 myelitis attacks in the first year were identified as possible predictors of a worse outcome., Conclusion: This study provides an overview of the clinical and paraclinical features of NMOSD in Caucasians and demonstrates a number of distinct disease characteristics in seropositive and seronegative patients.

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease that is characterized by impaired transmission across the neuromuscular junction due to autoantibodies directed against the presynaptic voltage-gated calcium channels (VGCC-ab). Clinical symptoms are usually characterized by proximal muscle weakness and mild dysautonomia. In some patients there are signs of cerebellar dysfunction as well, usually associated with cancer. Here we report the long-term follow-up of a patient with VGCC-ab-positive LEMS and a severe cerebellar syndrome but without evidence of cancer over 5 years. While conventional immunosuppressive therapy (steroids, azathioprine) failed, he improved with plasma exchange and consecutive treatment with rituximab. Muscle Nerve 40: 305-308, 2009.

In neuromyelitis optica (NMO), the monoclonal B-cell antibody rituximab is a therapeutic option. Little is known about the course of NMO and the safety of rituximab during pregnancy. In this study, we report the clinical course of a patient with NMO after application of rituximab 1 week before inadvertent conception. Mother and child did not experience any adverse event, and the postpartum development of the baby was completely normal up to 15 months. Clinical course of NMO was stable during the entire pregnancy. This case illustrates a favorable outcome in a pregnant NMO patient and her child after therapy with rituximab.

Purpose: In view of the putative role of serotonergic neurotransmission in basal ganglia circuitry we investigated the effects of paroxetine (PXT) as a selective serotonin reuptake inhibitor (SSRI) on the motor performance in n=19 patients clinically diagnosed as MSA using a double-blind placebo-controlled randomized study design. In addition, we assessed the effects on the psychopathological status of the patients., Results: The short-term add-on treatment with PXT up to 30 mg tid for two weeks resulted in a significant improvement of the motor abilities of the upper limbs and speech when compared to placebo. The treatment with PXT was generally well tolerated. The degree of depressive symptoms was not significantly influenced by PXT or placebo during the observation period., Conclusions: Previous observations suggest that serotonergic projections may modulate the neuronal excitability of the mesolimbic system and cerebellar system. The observed effects of PXT on motor performance may therefore be due to a direct action of the drug on the motor system. However, these results should be regarded as preliminary, and further research is suggested to evaluate the long-term outcome and clinical relevance of SSRI co-medication in MSA.

Background: Parkinson disease (PD) is often difficult to distinguish from parkinsonian syndromes of other causes in early stages of the disease. In search of a suitable endocrinologic challenge test, we investigated dopaminergic sensitivity in patients with de novo parkinsonian syndromes., Objective: We measured the growth hormone (GH) response to a subthreshold dose of the dopamine 1-dopamine 2 receptor agonist apomorphine hydrochloride to differentiate parkinsonian syndromes from PD., Patients and Methods: Seventeen patients with a clinical diagnosis of PD, 16 patients with a clinical diagnosis of multiple system atrophy, and 11 healthy controls. The GH response to a subthreshold dosage of apomorphine and to somatorelin (GH-releasing factor) was tested in a randomized order; on the third day the protocol was repeated with a clinically effective dose of apomorphine., Results: The GH response to the low dose of apomorphine was significantly increased in patients with PD when compared with patients with multiple system atrophy or the control subjects (multivariate analyses of covariance; univariate F test, all P<.05). In contrast, there were no significant group differences with use of the higher dose of apomorphine or in the somatorelin-induced GH release., Conclusions: The GH response to a subthreshold dose of apomorphine appears to be a useful tool to identify patients with PD vs multiple system atrophy. The enhanced GH response to a subthreshold dopaminergic stimulus may reflect a hypersensitivity of the extrastriatal dopamine receptors in PD.