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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 Patients with neuromyelitis optica spectrum disorder (NMOSD) are often seropositive for antibodies against aquaporin-4 (AQP4). The importance of MRI monitoring in this disease requires evaluation. Purpose To profile MRI features from a large international cohort with AQP4 immunoglobulin G (IgG)-seropositive NMOSD (from the Parallel MRI in NMOSD [PAMRINO] study) and to evaluate and confirm existing knowledge regarding the incidence, location, and longitudinal development of characteristic lesions in the central nervous system associated with AQP4-IgG-seropositive NMOSD. Materials and Methods In this retrospective study (from August 2016 to January 2019), MRI and clinical data were collected from 17 NMOSD expert sites in 11 countries across four continents. Clinical features and lesions identified at cross-sectional and longitudinal MRI were assessed. No formal statistical tests were used to compare observations; however, means, SDs, and 95% CIs are reported when evaluating lesion frequencies. Results Available T1-weighted and T2-weighted MRI scans in patients with AQP4-IgG-seropositive NMOSD ( n = 525) were read. Among the 525 patients, 320 underwent cerebral MRI examinations with T2-weighted hyperintense cerebral (264 of 320; 82.5%), cerebellar (44 of 320; 13.8%), and brainstem (158 of 321 [49.2%], including one lesion observed at cervical spinal cord [SC] MRI) lesions. Lesions in the optic nerves, analyzed from 152 MRI examinations, were mainly found in the central (81 of 92; 88%) and posterior (79 of 92; 86%) sections (bilaterally in 39 of 92; 42%). Longitudinally extensive transverse myelitis was the predominant SC lesion pattern (upper compartment from 322 MRI examinations, 133 of 210 [63.3%]; and lower compartment from 301 MRI examinations, 149 of 212 [70.3%]). However, nonlongitudinal extensive transverse myelitis lesions were also observed frequently (105 of 210; 50.0%) in the cervical SC. Clinical data ( n = 349; mean age, 44 years ± 14 [SD]; 202 female patients) and acute lesions at contrast-enhanced (CE) MRI ( n = 58, performed within 30 days of the last attack) were evaluated. CE lesions were detected in the cerebrum (eight of 13; 62%), optic nerves (14 of 19; 74%), or chiasm (three of four; 75%) within 15 days of any relapse. In the upper SC (29 of 44; 66%), CE lesions were frequently observed up to 20 days after a clinical myelitis event. Conclusion A high incidence of abnormal brain MRI examinations and nonlongitudinal extensive SC lesions was found in patients in PAMRINO with AQP4-IgG-seropositive NMOSD. © RSNA, 2024 Supplemental material is available for this article.

Neuromyelitis optica (NMO) spectrum disorder (NMOSD) is a relapsing inflammatory disease of the CNS, characterized by the presence of serum aquaporin 4 (AQP4) autoantibodies (AQP4-IgGs) and core clinical manifestations such as optic neuritis, myelitis, and brain or brainstem syndromes. Some people exhibit clinical characteristics of NMOSD but test negative for AQP4-IgG, and a subset of these individuals are now recognized to have serum autoantibodies against myelin oligodendrocyte glycoprotein (MOG) - a condition termed MOG antibody-associated disease (MOGAD). Therefore, the concept of NMOSD is changing, with a disease spectrum emerging that includes AQP4-IgG-seropositive NMOSD, MOGAD and double-seronegative NMOSD. MOGAD shares features with NMOSD, including optic neuritis and myelitis, but has distinct pathophysiology, clinical profiles, neuroimaging findings (including acute disseminated encephalomyelitis and/or cortical encephalitis) and biomarkers. AQP4-IgG-seronegative NMOSD seems to be a heterogeneous condition and requires further study. MOGAD can manifest as either a monophasic or a relapsing disease, whereas NMOSD is usually relapsing. This Review summarizes the history and current concepts of NMOSD and MOGAD, comparing epidemiology, clinical features, neuroimaging, pathology and immunology. In addition, we discuss new monoclonal antibody therapies for AQP4-IgG-seropositive NMOSD that target complement, B cells or IL-6 receptors, which might be applied to MOGAD in the near future., (© 2024. Springer Nature Limited.)

This post hoc analysis of the randomized, placebo-controlled N-MOmentum study (NCT02200770) of inebilizumab in neuromyelitis optica spectrum disorder (NMOSD) evaluated relationships between circulating B-cell subsets and aquaporin-4 immunoglobulin G (AQP4-lgG) titers and attacks. Among participants receiving placebo, CD20 + and CD27 + B-cell counts were modestly increased from the pre-attack visit to attack; plasmablast/plasma cell gene signature was increased from baseline to the pre-attack visit (p = 0.016) and from baseline to attack (p = 0.009). With inebilizumab treatment, B-cell subset counts decreased and did not increase with attacks. No difference in change of AQP4-IgG titers from baseline to time of attack was observed., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Introduction: Neuromyelitis Optica Spectrum Disorders (NMOSD) is a neuroinflammatory condition characterized by optic neuritis and transverse myelitis. While the current approach to NMOSD focuses on relapse-associated worsening (RAW), recent evidence indicates Relapse-Independent Disease Activity (RIDA) in patients., Method: Databases including Embase, PubMed, Scopus, and Web of Sciences were systematically searched up to December 2023. No restrictions were applied. Inclusion criteria focused on studies reporting evidence of RIDA in NMOSD patients. Data extraction involved details such as study title, author, participant characteristics, treatment, evaluation methods, positive findings according to RIDA, and prevalence of findings in NMOSD patients. This study is conducted following the PRISMA guidelines with a registered protocol on PROSPERO (ID = CRD42023492352)., Result: Of 802 studies, 38 were included in the systematic review, covering 1881 NMOSD patients. AQP4-IGg status was positive in 90.6 % of the patients. Ocular findings indicative of RIDA were reported in 23 studies, including thinning of GCIPL, RNFL, GCC, and GCL layers, foveal and macular shape and volume abnormalities, vessel loss, and visual evoked potentials (VEPs) abnormalities. MRI findings supporting the RIDA were reported in 13 studies, including new lesion incidence and brain and spinal cord atrophy. Serum and CSF RIDA-supporting findings were reported in five studies, including elevation in sGFAP and sNFL. Biopsies and autopsies suggested inflammatory processes in relapse-free patients in 2 studies. The predominant manifestation of RIDA in NMOSD was identified in the visual system, suggesting the impaired retinal glial cells like Müller cells during the relapse-free period in NMOSD., Interpretation: Our systematic review provides valuable insights into RIDA in NMOSD. Establishing guidelines for the diagnosis and treatment of RIDA is crucial. Further studies are needed to provide robust evidence on RIDA in NMOSD patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Objectives: To systematically describe the clinical picture of double-antibody seronegative neuromyelitis optica spectrum disorders (DN-NMOSD) with specific emphasis on retinal involvement., Methods: Cross-sectional data of 25 people with DN-NMOSD (48 eyes) with and without a history of optic neuritis (ON) were included in this study along with data from 25 people with aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorder (AQP4-NMOSD, 46 eyes) and from 25 healthy controls (HCs, 49 eyes) for comparison. All groups were matched for age and sex and included from the collaborative retrospective study of retinal optical coherence tomography (OCT) in neuromyelitis optica (CROCTINO). Participants underwent OCT with central postprocessing and local neurologic examination and antibody testing. Retinal neurodegeneration was quantified as peripapillary retinal nerve fiber layer thickness (pRNFL) and combined ganglion cell and inner plexiform layer thickness (GCIPL)., Results: This DN-NMOSD cohort had a history of [median (inter-quartile range)] 6 (5; 9) attacks within their 5 ± 4 years since onset. Myelitis and ON were the most common attack types. In DN-NMOSD eyes after ON, pRNFL ( p < 0.001) and GCIPL ( p = 0.023) were thinner compared with eyes of HCs. Even after only one ON episode, DN-NMOSD eyes already had considerable neuroaxonal loss compared with HCs. In DN-NMOSD eyes without a history of ON, pRNFL ( p = 0.027) and GCIPL ( p = 0.022) were also reduced compared with eyes of HCs. However, there was no difference in pRNFL and GCIPL between DN-NMOSD and AQP4-NMOSD for the whole group and for subsets with a history of ON and without a history of ON-as well as between variances of retinal layer thicknesses., Discussion: DN-NMOSD is characterized by severe retinal damage after ON and attack-independent retinal neurodegeneration. Most of the damage occurs during the first ON episode, which highlights the need for better diagnostic markers in DN-NMOSD to facilitate an earlier diagnosis as well as for effective and early treatments. In this study, people with DN-NMOSD presented with homogeneous clinical and imaging findings potentially suggesting a common retinal pathology in these patients.

Objective: To evaluate: (1) the distribution of gray matter (GM) atrophy in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD), and relapsing-remitting multiple sclerosis (RRMS); and (2) the relationship between GM volumes and white matter lesions in various brain regions within each disease., Methods: A retrospective, multicenter analysis of magnetic resonance imaging data included patients with MOGAD/AQP4+NMOSD/RRMS in non-acute disease stage. Voxel-wise analyses and general linear models were used to evaluate the relevance of regional GM atrophy. For significant results (p < 0.05), volumes of atrophic areas are reported., Results: We studied 135 MOGAD patients, 135 AQP4+NMOSD, 175 RRMS, and 144 healthy controls (HC). Compared with HC, MOGAD showed lower GM volumes in the temporal lobes, deep GM, insula, and cingulate cortex (75.79 cm 3 ); AQP4+NMOSD in the occipital cortex (32.83 cm 3 ); and RRMS diffusely in the GM (260.61 cm 3 ). MOGAD showed more pronounced temporal cortex atrophy than RRMS (6.71 cm 3 ), whereas AQP4+NMOSD displayed greater occipital cortex atrophy than RRMS (19.82 cm 3 ). RRMS demonstrated more pronounced deep GM atrophy in comparison with MOGAD (27.90 cm 3 ) and AQP4+NMOSD (47.04 cm 3 ). In MOGAD, higher periventricular and cortical/juxtacortical lesions were linked to reduced temporal cortex, deep GM, and insula volumes. In RRMS, the diffuse GM atrophy was associated with lesions in all locations. AQP4+NMOSD showed no lesion/GM volume correlation., Interpretation: GM atrophy is more widespread in RRMS compared with the other two conditions. MOGAD primarily affects the temporal cortex, whereas AQP4+NMOSD mainly involves the occipital cortex. In MOGAD and RRMS, lesion-related tract degeneration is associated with atrophy, but this link is absent in AQP4+NMOSD. ANN NEUROL 2024;96:276-288., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Aquaporin-4 (AQP4) antibody-associated neuromyelitis optica spectrum disorder (NMOSD) is an antibody-mediated inflammatory disease of the central nervous system. We have undertaken a systematic review and meta-analysis to ascertain the sex ratio and mean age of onset for AQP4 antibody associated NMOSD. We have also explored factors that impact on these demographic data., Methods: A systematic search of databases was conducted according to the PRISMA guidelines. Articles reporting sex distribution and age of onset for AQP4 antibody-associated NMSOD were reviewed. An initially inclusive approach involving exploration with regression meta-analysis was followed by an analysis of just AQP4 antibody positive cases., Results: A total of 528 articles were screened to yield 89 articles covering 19,415 individuals from 88 population samples. The female:male sex ratio was significantly influenced by the proportion of AQP4 antibody positive cases in the samples studied (p < 0.001). For AQP4 antibody-positive cases the overall estimate of the sex ratio was 8.89 (95% CI 7.78-10.15). For paediatric populations the estimate was 5.68 (95% CI 4.01-8.03) and for late-onset cases, it was 5.48 (95% CI 4.10-7.33). The mean age of onset was significantly associated with the mean life expectancy of the population sampled (p < 0.001). The mean age of onset for AQP4 antibody-positive cases in long-lived populations was 41.7 years versus 33.3 years in the remainder., Conclusions: The female:male sex ratio and the mean age of onset of AQP4 antibody-associated NMOSD are significantly higher than MS. The sex ratio increases with the proportion of cases that are positive for AQP4 antibodies and the mean age of onset increases with population life expectancy., (© 2024. Crown.)

Comorbidities in patients with multiple sclerosis (MS) and antibody-mediated diseases of the central nervous system (CNS) including neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein (MOG)-antibody-associated disease (MOGAD) are common and may influence the course of their neurological disease. Comorbidity may contribute to neuronal injury and therefore limit recovery from attacks, accelerate disease progression, and increase disability. This study aims to explore the impact of comorbidity, particularly vascular comorbidity, and related risk factors on clinical and paraclinical parameters of MS, NMOSD and MOGAD. We propose COMMIT, a prospective multicenter study with longitudinal follow-up of patients with MS, NMOSD, and MOGAD, with or without comorbidities, as well as healthy subjects as controls. Subjects will be stratified by age, sex and ethnicity. In consecutive samples we will analyze levels of inflammation and neurodegeneration markers in both fluid and cellular compartments of the peripheral blood and cerebrospinal fluid (CSF) using multiple state-of-the-art technologies, including untargeted proteomics and targeted ultrasensitive ELISA assays and quantitative reverse transcription polymerase chain reaction (RT-qPCR) as well as high-dimensional single-cell technologies i.e., mass cytometry and single-cell RNA sequencing. Algorithm-based data analyses will be used to unravel the relationship between these markers, optical coherence tomography (OCT) and magnetic resonance imaging (MRI), and clinical outcomes including frequency and severity of relapses, long-term disability, and quality of life. The goal is to evaluate the impact of comorbidities on MS, NMOSD, and MOGAD which may lead to development of treatment approaches to improve outcomes of inflammatory demyelinating diseases of the CNS., Competing Interests: STS as received personal fees from Munksgaard, TrustMe-Ed, and Nestlé Health Science outside the submitted work; is a co-founder of GLA:D®, a not-for-profit initiative hosted at the University of Southern Denmark aimed at implementing clinical guidelines for osteoarthritis in clinical practice; and has received a program grant from Region Zealand Exercise First and two grants from the European Union’s Horizon 2020 research and innovation program, one from the European Research Council MOBILIZE, grant agreement No. 801790 and the other under grant agreement No. 945377 ESCAPE. ML has received consulting fees and research grants from Alexion AstraZeneca, Horizon Amgen, and Genentech Roche. AP has received grant support for remyelination trials in multiple sclerosis from the Amsterdam University Medicam Centre, Department of Neurology, MS Centre RESTORE trial and UCL, London RECOVER trial and from Fight for Sight nimodipine in optic neuritis trial; has received royalties or licenses from UptoDate Wolters Kluwer on a book chapter and speaker fees from the Heidelberg Academy; has participated in the Advisory Board SC Zeiss OCTA Angi-Network; is the chairman of ERN-EYE Neuro-ophthalmology until OCT-2020 and a board member of the National Dutch Neuro-ophthalmology Association; and has received equipment OCTA from Zeiss Plex Elite. JP has received support for scientific meetings and honorariums for advisory work from Merck Serono, Novartis, Chugai, Alexion, Roche, Medimmune, Argenx, UCB, Mitsubishi, Amplo, Janssen, and Sanofi; grants from Alexion, Roche, Medimmune, UCB, and Amplo Biotechnology; and patent ref P37347WO and license agreement Numares multimarker MS diagnostics shares in AstraZeneca. She also acknowledges partial funding from the highly specialized services of NHS England. SMe has received travel grants from Merck, Roche, and Sanofi and speaking honoraria from UCB. RG has received support for scientific meetings and courses and honoraria for advisory work from Bayer, Biogen, Merck, Novartis, and Jasen. EF has served on advisory boards for Alexion, Genentech, Horizon Therapeutics, and UCB. He has received speaker honoraria from Pharmacy Times and royalties from UpToDate. He was a site primary investigator in a randomized clinical trial on inebilizumab in neuromyelitis optica spectrum disorder run by Medimmune/Viela-Bio/Horizon Therapeutics. He has received funding from the NIH R01NS113828 and is a member of the medical advisory board of the MOG project and an editorial board member of the Journal of the Neurological Sciences and Neuroimmunology Reports. SMa has received speaker honoraria from Biogen, Novartis, Horizon, and Sanofi. SA has received speaker’s honoraria from Alexion, Bayer, and Roche. HS-K has received support for scientific meetings from Roche. FO has received grants from the National Multiple Sclerosis Society US, American Academy of Neurology, Hertie Foundation for Excellence in Clinical Neuroscience, and Novartis—all independent of this project. HK has received a grant from the National Research Foundation of Korea and research support from AprilBio, Eisai, and UCB; has received consultancy/speaker fees from Alexion, Altos Biologics, AstraZeneca, Biogen, Daewoong Pharmaceutical, Eisai, GC Pharma, Handok Pharmaceutical, Kaigene, Kolon Life Science, MDimune, Merck Serono, Mitsubishi Tanabe Pharma, Roche, and Sanofi Genzyme; and is a co-editor for the Multiple Sclerosis Journal and an associated editor for the Journal of Clinical Neurology. MS and VS has received educational research grants, lecture honorarium, and travel support to attend scientific meetings from Biogen-Idec, Merck, Bayer, Novartis, Cinnagen, Osveh, Zistdaru, Zahravi, Abidi, and NanoAvland. JB reported personal fees from Roche, Genentech, Horizon, Chugai Pharma, Clene Nanoscience, Reistone-Bio, Beigene, and Imcyse; grants and personal fees from Alexion; and grants from the National Institutes of Health. JB has a patent aquaporumab issued. CB has received a grant from Roche, unrelated to this study. HZ has received grants from Novartis, unrelated to this study. BW has received royalties from RSR Ltd, Oxford University, Hospices Civil de Lyon, and MVZ Labor PD Dr. Volkmann und Kollegen GbR for a patent of NMO-IgG as a diagnostic test for neuromyelitis optica spectrum disorders; served on the adjudication committee for clinical trials conducted by MedImmune/VielaBio, Alexion, and UCB Biosciences; and consulted for Chugai/Roche/Genentech, Horizon Therapeutics, Mitsubishi-Tanabe, and CANbridge Pharmaceuticals regarding neuromyelitis optica spectrum disorders. He has received honoraria for speaking at internal meetings of Genentech, Novartis, and Horizon and at external meetings for Roche. FP served on the scientific advisory boards of Novartis and MedImmune; received travel funding and/or speaker honoraria from Bayer, Novartis, Biogen, Teva, Sanofi-Aventis/Genzyme, Merck Serono, Alexion, Chugai, MedImmune, and Shire; is an associate editor of Neurology: Neuroimmunology & Neuroinflammation; is an academic editor of PLoS ONE; consulted for Sanofi Genzyme, Biogen, MedImmune, Shire, and Alexion; received research support from Bayer, Novartis, Biogen, Teva, Sanofi-Aventis/Genzyme, Alexion, and Merck Serono; and received research support from the German Research Council, Werth Stiftung of the City of Cologne, German Ministry of Education and Research, Arthur Arnstein Stiftung Berlin, EU FP7 Framework Program, Arthur Arnstein Foundation Berlin, Guthy-Jackson Charitable Foundation, and NMSS. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Samadzadeh, Adnan, Berglova, Barzegar, Debrabant, Roikjaer, Levy, Petzold, Palace, Flanagan, Mariotto, Skou, Froelich, Lotan, Messina, Geraldes, Asseyer, Stiebel-Kalish, Oertel, Shaygannejad, Sahraian, Kim, Bennett, Böttcher, Zimmermann, Weinshenker, Paul and Asgari.)

Background and Objectives: AQP4 antibody-positive NMOSD (AQP4-NMOSD), MOG antibody-associated disease (MOGAD), and seronegative NMOSD (SN-NMOSD) are neuroautoimmune conditions that have overlapping clinical manifestations. Yet, important differences exist in these diseases, particularly in B-cell depletion (BCD) efficacy. Yet, the biology driving these differences remains unclear. Our study aims to clarify biological pathways distinguishing these diseases beyond autoantibodies and investigate variable BCD effects through proteomic comparisons., Methods: In a retrospective study, 1,463 serum proteins were measured in 53 AQP4-NMOSD, 25 MOGAD, 18 SN-NMOSD, and 49 healthy individuals. To identify disease subtype-associated signatures, we examined serum proteins in patients without anti-CD20 B-cell depletion (NoBCD). We then assessed the effect of BCD treatment within each subtype by comparing proteins between BCD-treated and NoBCD-treated patients., Results: In NoBCD-treated patients, serum profiles distinguished the 3 diseases. AQP4-NMOSD showed elevated type I interferon-induced chemokines (CXCL9 and CXCL10) and TFH chemokine (CXCL13). MOGAD exhibited increased cytotoxic T-cell proteases (granzyme B and granzyme H), while SN-NMOSD displayed elevated Wnt inhibitory factor 1, a marker for nerve injury. Across all subtypes, BCD-treated patients showed reduction of B-cell-associated proteins. In AQP4-NMOSD, BCD led to a decrease in several inflammatory pathways, including IL-17 signaling, cytokine storm, and macrophage activation. By contrast, BCD elevated these pathways in patients with MOGAD. BCD had no effect on these pathways in SN-NMOSD., Discussion: Proteomic profiles show unique biological pathways that distinguish AQP4-NMOSD, MOGAD, or SN-NMOSD. Furthermore, BCD uniquely affects inflammatory pathways in each disease type, providing an explanation for the disparate therapeutic response in AQP4-NMOSD and MOGAD.

Background: Inebilizumab, an anti-CD19 B-cell-depleting antibody, demonstrated safety and efficacy in neuromyelitis optica spectrum disorder in the randomised controlled period of the N-MOmentum trial. Here, end-of-study data, including the randomised controlled period and open-label extension period, are reported., Methods: In the double-blind, randomised, placebo-controlled, phase 2/3 N-MOmentum trial, adults aged 18 years and older with an neuromyelitis optica spectrum disorder diagnosis, Expanded Disability Status Scale score of 8·0 or less, and history of either at least one acute inflammatory attack requiring rescue therapy in the past year or two attacks requiring rescue therapy in the past 2 years, were recruited from 81 outpatient specialty clinics or hospitals in 24 countries. Eligible participants were randomly assigned (3:1), using a central interactive voice system or interactive web response system, and a permuted block randomisation scheme (block size of 4), to receive intravenous inebilizumab (300 mg) or identical placebo on days 1 and 15 of the randomised period, which lasted up to 197 days. Participants and all study staff were masked to treatment assignment. The primary endpoint of the randomised period of the trial was time to onset of adjudicated neuromyelitis optica spectrum disorder attack on or before day 197. Participants in the randomised controlled period who had an adjudicated attack, completed 197 days in the study, or were in the randomised controlled period when enrolment stopped, could voluntarily enter the open-label period. In the open-label period, participants either initiated inebilizumab if assigned placebo (receiving 300 mg on days 1 and 15 of the open-label period) or continued treatment if assigned inebilizumab (receiving 300 mg on day 1 and placebo on day 15, to maintain B-cell depletion and masking of the randomised controlled period). All participants subsequently received inebilizumab 300 mg every 6 months for a minimum of 2 years. The end-of-study analysis endpoints were time to adjudicated attack and annualised attack rate (assessed in all participants who received inebilizumab at any point during the randomised controlled period or open-label period [any inebilizumab population] and the aquaporin-4 [AQP4]-IgG seropositive subgroup [any inebilizumab-AQP4-IgG seropositive population]) and safety outcomes (in all participants who were exposed to inebilizumab, analysed as-treated). This study is registered with ClinicalTrials.gov, NCT02200770, and is now complete., Findings: Between Jan 6, 2015, and Sept 24, 2018, 467 individuals were screened, 231 were randomly assigned, and 230 received at least one dose of inebilizumab (n=174) or placebo (n=56). Between May 19, 2015, and Nov 8, 2018, 165 (95%) of 174 participants in the inebilizumab group and 51 (91%) of 56 in the placebo group entered the open-label period (mean age 42·9 years [SD 12·4], 197 [91%] of 216 were female, 19 [9%] were male, 115 [53%] were White, 45 [21%] were Asian, 19 [9%] were American Indian or Alaskan Native, and 19 [9%] were Black or African American). As of data cutoff for this end of study analysis (Dec 18, 2020; median exposure 1178 days [IQR 856-1538], total exposure of 730 person-years) 225 participants formed the any inebilizumab population, and 208 (92%) participants were AQP4-IgG seropositive. Overall, 63 adjudicated neuromyelitis optica spectrum disorder attacks occurred in 47 (21%) of 225 treated participants (60 attacks occurred in 44 [21%] of 208 in the AQP4-IgG seropositive subgroup); 40 (63%) of 63 attacks occurred in 34 (15%) of 225 treated participants during the first year of treatment. Of individuals who had an adjudicated attack while receiving inebilizumab, 36 (77%) of 47 were subsequently attack-free at the end of 4 years. Annualised attack rates decreased year-on-year, with end-of-study adjusted annualised attack rates being similar in the any inebilizumab-AQP4-IgG seropositive subgroup (0·097 [95% CI 0·070-0·14]) and any inebilizumab populations (0·092 [0·067-0·13]). Overall, 208 (92%) of 225 participants who received any inebilizumab had at least one treatment-emergent adverse event, the most frequent of which were urinary tract infection (59 [26%]), nasopharyngitis (47 [21%]), and arthralgia (39 [17%]). Infection rates did not increase over 4 years. Three (1%) of 225 participants in the any inebilizumab population died during the open-label period (one each due to a CNS event of unknown cause and pneumonia, respiratory insufficiency resulting from an neuromyelitis optica spectrum disorder attack and viral pneumonia related to COVID-19), all of which were deemed to be unrelated to treatment., Interpretation: Data from the end-of-study analysis of the N-MOmentum trial showed continued and sustained clinical benefits of long-term inebilizumab treatment in individuals with neuromyelitis optica spectrum disorder, which supports the role of inebilizumab as a CD19+ B-cell-depleting therapy in neuromyelitis optica spectrum disorder., Funding: MedImmune and Viela Bio/Horizon Therapeutics, now part of Amgen., Competing Interests: Declaration of interests BACC reports personal fees for consulting from Alexion, Atara, Autobahn, Avotres, Biogen, Boston Pharma, EMD Serono, Gossamer Bio, Hexal/Sandoz, Horizon Therapeutics, Neuron23, Novartis, Sanofi, Siemens, TG Therapeutics, and Therini Bio, and has received research support from Genentech. HJK has received a grant from the National Research Foundation of Korea and research support from AprilBio, Eisai, and UCB; consultancy or speaker fees from Alexion, Altos Biologics, AstraZeneca, Biogen, Daewoong Pharmaceutical, Eisai, GC Pharma, Handok Pharmaceuticals, Kaigene, Kolon Life Science, MDimune, Merck Serono, Mitsubishi Tanabe Pharma, Roche, and Sanofi Genzyme; serves on a steering committee for MedImmune/Viela Bio; and is a co-editor for the Multiple Sclerosis Journal and an associate editor for the Journal of Clinical Neurology. BGW receives payments for serving as chair of attack adjudication committees for clinical trials in neuromyelitis optica spectrum disorder for Alexion, MedImmune, UCB Bioscience, and Viela Bio/Horizon Therapeutics; has consulted with CANbridge Pharmaceuticals, Chugai, Genentech, Horizon Therapeutics, Mitsubishi Tanabe Pharma, and Roche Pharmaceuticals; has received payments for speaking for Genentech, Horizon Therapeutics, and Roche; and has a patent for NMO-IgG for diagnosis of neuromyelitis optica, with royalties paid by Hospices Civils de Lyon, MVZ Labor PD Dr Volkmann und Kollegen GbR, RSR Limited, and the University of Oxford. SJP reports grants, personal fees, and non-financial support from Alexion; grants from Autoimmune Encephalitis Alliance and Grifols; grants, personal fees, and non-financial support from MedImmune and Viela Bio/Horizon Therapeutics; consulting support from Astellas, Genentech, and Sage Therapeutics; personal fees for consulting services from for F Hoffman-La Roche AG, Genentech, and UCB; and has a patent #9,891,219 (Application#12-573942) “Methods for Treating Neuromyelitis Optica (NMO) by Administration of Eculizumab to an individual that is Aquaporin-4 (AQP4)-IgG Autoantibody positive”. DMW reports personal fees from Alexion, AstraZeneca, Bristol Myers Squibb, Genentech, Horizon Therapeutics, Imcyse, Merck, Novartis, and Reistone Biopharma; serves on a clinical trial adjudication committee for MedImmune, Viela Bio/Horizon Therapeutics, and UCB Pharma; and serves on a data and safety monitoring board for Alexion and Abscuro. KF serves on scientific advisory boards for Alexion, Bayer Schering, Biogen, Chugai, MedImmune, Merck Serono, Mitsubishi Tanabe Pharma, Nihon Pharmaceutical, Novartis, Ono Pharmaceutical, and Viela Bio/Horizon Therapeutics; has received funding for travel and speaker fees from Asahi Kasei Medical, Astellas, Bayer Schering, Biogen, Daiichi Sankyo, Dainippon Sumitomo, Eisai, Mitsubishi Tanabe Pharma, Nihon Pharmaceutical, Novartis, and Takeda; and research support from Asahi Kasei Medical, Bayer Schering, Biogen, Chemo-Sero-Therapeutic Research Institute, Chugai, Genzyme Japan, the Ministry of Education, Culture, Sports, Science, and Technology of Japan, the Ministry of Health, Welfare, and Labor of Japan, Mitsubishi Tanabe Pharma, Nihon Pharmaceutical, Ono Pharmaceutical, Teijin, and Teva. FP has received research support, speaker fees, and travel reimbursement from Bayer, Biogen, Merck Serono, Novartis, Sanofi Genzyme, and Teva; is supported by the German Competence Network for Multiple Sclerosis and the German Research Council (DFG Exc 257); has received travel reimbursement from the Guthy–Jackson Charitable Foundation; and serves on the steering committee of the OCTiMS study sponsored by Novartis. GRC has received personal fees for participation on data and safety monitoring boards from AI Therapeutics, AMO Pharma, Applied Therapeutics, AstraZeneca, Avexis Pharmaceuticals, BioLineRx, Brainstorm Cell Therapeutics, Bristol Myers Squibb/Celgene, CSL Behring, Galmed Pharmaceuticals, Green Valley Pharma, Horizon Therapeutics, Immunic Therapeutics, Karuna Therapeutics, Mapi Pharma, Merck, Mitsubishi Tanabe Pharma, the National Heart, Lung, and Blood Institute (US; Protocol Review Committee), Novartis, OPKO Biologics, Prothena Biosciences, Reata Pharmaceuticals, Regeneron, Sanofi-Aventis, Teva Pharmaceuticals, the University of Texas Southwestern, the University of Pennsylvania, and Visioneering Technologies; personal fees for consulting or advisory board participation from Alexion, Antisense Therapeutics, Biogen, Clinical Trial Solutions, Entelexo Biotherapeutics, Genentech, Genzyme, GW Pharmaceuticals, Immunic Therapeutics, Immunosis, Klein Buendel, Merck/Serono, Novartis, Osmotica Pharmaceuticals, Perception Neurosciences, Protalix BioTherapeutics, Recursion/CereXis, Regeneron, Roche, and SAB Biotherapeutics. GRC is employed by the University of Alabama at Birmingham and is President of Pythagoras, a private consulting company based in Birmingham, AL, USA. RM serves on scientific advisory boards for MedImmune and Viela Bio/Horizon Therapeutics; and has received funding for travel and fees from Alexion, Biogen, Merck Serono, Novartis, Roche, Sanofi Genzyme, Teva, and Viela Bio/Horizon Therapeutics. AJG reports grants from the Conrad N Hilton Foundation and the Tom Sherak MS Hope Foundation; other financial relationships for activities as expert witness, associate editor, advisory board or steering committee participation, and endpoint adjudication with Bionure, Inception Sciences, JAMA Neurology, MedImmune/Viela Bio, Mylan, Synthon, and Trims Pharma; and personal fees from Pipeline Therapeutics. OA reports grants from the German Ministry of Education and Research (known as BMBF) and the German Research Foundation (known as DFG); grants and personal fees from Bayer HealthCare, Biogen, Genzyme, Novartis, Teva, and Viela Bio/Horizon Therapeutics; and personal fees from Alexion, Almirall, Horizon Therapeutics, Merck Serono, Roche, and Zambon. H-PH has received fees for consulting, speaking, and serving on steering committees from Bayer HealthCare, Biogen, Celgene Receptos, CSL Behring, GeNeuro, Genzyme, MedDay, MedImmune, Merck Serono, Novartis, Roche, Sanofi, TG Therapeutics, and Viela Bio with approval by the Rector of Heinrich Heine University Düsseldorf. DS, WR, MS, and DC hold stock or are employees of Viela Bio/Horizon Therapeutics, or both. EK was an employee of Viela Bio/Horizon Therapeutics during the preparation of this manuscript. JLB reports payment for study design or consultation from MedImmune/Viela Bio; personal fees from AbbVie, Alexion, Antigenomycs, BeiGene, Chugai, Clene Nanomedicine, EMD Serono, Genentech, Genzyme, Horizon Therapeutics, Mitsubishi Tanabe Pharma, Novartis, Reistone Biopharma, Roche, and TG Therapeutics; grants and personal fees from Novartis; grants from Alexion, the Guthy–Jackson Charitable Foundation, Mallinckrodt, and the National Institutes of Health; and has a patent for aquaporumab issued (US10654916B2: Compositions and methods for the treatment of neuromyelitis optica)., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

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.)

Proinflammatory cytokines, such as (IL: interleukin) IL-6 and IL-17A, and complement fixation are critical in the immunopathogenesis of neuromyelitis optica spectrum disorders (NMOSD). Blocking the IL-6 receptor or the C5 complement pathway reduces relapse risk. However, the role of interleukin (IL)-6 and complement in aquaporin-4 (AQP4) autoimmunity remains unclear. To investigate the role of the anti-AQP4 immunoglobulin (AQP4-IgG)/AQP4 immunocomplex on the induction and profile of ex vivo cytokine and surface marker expression in peripheral blood mononuclear cells (PBMC) culture. Isolated PBMCs obtained from 18 patients with AQP4-IgG-seropositive-NMOSD (8 treatment-naive, 10 rituximab-treated) or ten healthy controls were cultured with AQP4-immunocomplex with or without complement. Changes in PBMC surface markers and cytokine expression were profiled using flow cytometry and ELISA. PBMCs derived from treatment-naive NMOSD patients stimulated with a complex mixture of serum complement proteins produced significant elevations of IL-17A and IL-6. Rituximab-treated patients also exhibited higher IL-6 but not IL-17A release. IL-6 and IL-17A elevations are not observed without complement. Co-stimulation of PBMCs with AQP4-IgG/AQP4 immunocomplex and complement prompts a Th17-biased response consistent with the inflammatory paradigm observed in NMOSD. A possible inflammation model is proposed via antigen-specific autoreactive peripheral blood cells, including NK/NKT cells., (© 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: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory autoimmune disease of the central nervous system that involves B-cell receptor signaling as well as astrocyte-microglia interaction, which both contribute to evolution of NMOSD lesions., Main Body: Through transcriptomic and flow cytometry analyses, we found that Bruton's tyrosine kinase (BTK), a crucial protein of B-cell receptor was upregulated both in the blood and cerebrospinal fluid of NMOSD patients. Blockade of BTK with zanubrutinib, a highly specific BTK inhibitor, mitigated the activation and maturation of B cells and reduced production of causal aquaporin-4 (AQP4) autoantibodies. In a mouse model of NMO, we found that both BTK and pBTK expression were significantly increased in microglia. Transmission electron microscope scan demonstrated that BTK inhibitor ameliorated demyelination, edema, and axonal injury in NMO mice. In the same mice colocalization of GFAP and Iba-1 immunofluorescence indicated a noticeable increase of astrocytes-microglia interaction, which was alleviated by zanubrutinib. The smart-seq analysis demonstrated that treatment with BTK inhibitor instigated microglial transcriptome changes including downregulation of chemokine-related genes and genes involved in the top 5 biological processes related to cell adhesion and migration, which are likely responsible for the reduced crosstalk of microglia and astrocytes., Conclusions: Our results show that BTK activity is enhanced both in B cells and microglia and BTK inhibition contributes to the amelioration of NMOSD pathology. These data collectively reveal the mechanism of action of BTK inhibition and corroborate BTK as a viable therapeutic target., (© 2023. The Author(s).)

Inebilizumab, a humanized, glycoengineered, IgG1 monoclonal antibody that depletes CD19+ B-cells, is approved to treat aquaporin 4 (AQP4) IgG-seropositive neuromyelitis optica spectrum disorder (NMOSD). Inebilizumab is afucosylated and engineered for enhanced affinity to Fc receptor III-A (FCGR3A) receptors on natural killer cells to maximize antibody-dependent cellular cytotoxicity. Previously, the F allele polymorphism at amino acid 158 of the FCGR3A gene (F158) was shown to decrease IgG-binding affinity and reduce rituximab (anti-CD20) efficacy for NMOSD attack prevention. In contrast, our current findings from inebilizumab-treated NMOSD patients indicate similar clinical outcomes between those with F158 and V158 allele genotypes., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein not previously described in the human central nervous system (CNS)., Objectives: We determined MFAP4 CNS expression and measured cerebrospinal fluid (CSF) and serum levels., Methods: Tissue was sampled at autopsy from patients with acute multiple sclerosis (MS) ( n = 3), progressive MS ( n = 3), neuromyelitis optica spectrum disorder (NMOSD) ( n = 2), and controls ( n = 9), including 6 healthy controls (HC). MFAP4 levels were measured in 152 patients: 49 MS, 62 NMOSD, 22 myelin oligodendrocyte glycoprotein-associated disease (MOGAD), and 19 isolated optic neuritis (ION)., Results: MFAP4 localized to meninges and vascular/perivascular spaces, intense in the optic nerve. At sites of active inflammation, MFAP4 reactivity was reduced in NMOSD and acute MS and less in progressive MS. CSF MFAP4 levels were reduced during relapse and at the onset of diseases (mean U/mL: MS 14.3, MOGAD 9.7, and ION 14.6 relative to HC 17.9. ( p = 0.013, p = 0.000, and p = 0.019, respectively). Patients with acute ON ( n = 68) had reduced CSF MFAP4 (mean U/mL: 14.5, p = 0.006). CSF MFAP4 levels correlated negatively with relapse severity (rho = -0.41, p = 0.017)., Conclusion: MFAP4 immunoreactivity was reduced at sites of active inflammation. CSF levels of MFAP4 were reduced following relapse and may reflect disease activity., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: S.S., M.N.O., M.W., S.M., S.T.L., K.S., and N.A. have nothing to disclose.T.M. has received speaker honoraria from Tanabe Mitsubishi Pharma, Novartis Pharma., Alexion Pharma., Teijin Pharma., Viela Bio, and Biogen Idec Japan; he has received research support from Cosmic Corporation, and Medical and Biological Laboratories Co.; and grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology.J.F. has served on scientific advisory boards for and received funding for travel related to these activities as well as honoraria from Biogen Idec, Merck Serono, Sanofi-Aventis, Teva, Novartis, and Almirall.S.H. is a scientific advisor for Alcon, Santen, Sanofi, and Thea.S.MA. has received support for attending scientific meetings by Merck and Euroimmun and received speaker honoraria from Biogen.K.F. has received grants from the Ministry of Education of Japan, Ministry of Health, Welfare and Labor of Japan, and received personal fees from Roche/Chugai, Alexion, Viela Bio/ Horizon Therapeutics, Biogen, Eisai, Mitsubishi Tanabe, Novartis, Astellas, Tejin, Takeda, UCB, Merck Biopharma, Abbvie, Japan Tobacco, and Asahi Kasei Medical.K.R. has received research support from Novartis, Merck Serono, German Ministry of Education and Research, European Union (821283-2), Stiftung Charité (BIH Clinical Fellow Program), and Arthur Arnstein Foundation; and received travel grants from the Guthy-Jackson Charitable Foundation.T.L.A. has received nonfinancial support from Amgen, and free reagents from 10X genomics and ABD bioscience for projects outside the submitted work.R.M. reports personal fees from Alexion, Horizon Therapeutics, Merck, Biogen, Roche, and UCB, outside the submitted work.E.F. has served on advisory boards for Alexion, Genentech, and Horizon Therapeutics. He has received speaker honoraria from Pharmacy Times, and royalties from UpToDate. He was a site primary investigator in a randomized clinical trial on Inebilizumab in neuromyelitis optica spectrum disorder run by Medimmune/Viela-Bio/Horizon Therapeutics. He has received funding from the NIH (R01NS113828), is a member of the medical advisory board of the MOG project, and an editorial board member of the Journal of the Neurological Sciences and Neuroimmunology Reports.S.P. has received personal compensation for serving as a consultant for Genentech, Sage Therapeutics, and Astellas. He has received personal compensation for serving on scientific advisory boards or data safety monitoring boards for F. Hoffman-LaRoche AG, Genentech, and UCB. His institution has received compensation for serving as a consultant for Astellas, Alexion, and Viela Bio/MedImmune. All compensation is paid to Mayo Clinic. He has received research support from Alexion, Viela Bio/MedImmune, Roche/Genentech. He has a patent, Patent# 8,889,102 (Application#12-678350, Neuromyelitis Optica Autoantibodies as a Marker for Neoplasia)—issued; a patent, Patent# 9,891,219B2 (Application#12-573942, Methods for Treating Neuromyelitis Optica (NMO) by Administration of Eculizumab to an individual that is Aquaporin-4 (AQP4)-IgG Autoantibody positive)—issued.H.J.K. received a grant from the National Research Foundation of Korea and research support from Aprilbio and Eisai; received consultancy/speaker fees from Alexion, Aprilbio, Altos Biologics, Biogen, Celltrion, Daewoong, Eisai, GC Pharma, HanAll BioPharma, Handok, Horizon Therapeutics (formerly Viela Bio), MDimune, Mitsubishi Tanabe Pharma, Merck Serono, Novartis, Roche, Sanofi, Teva-Handok, and UCB; is a co-editor for the Multiple Sclerosis Journal and an associate editor for the Journal of Clinical Neurology.J.B. reports personal fees from Roche, Genentech, Horizon, Chugai Pharma, Clene Nanoscience, Reistone-Bio, Beigene, grants and personal fees from Alexion, grants from National Institutes of Health, and has a patent Aquaporumab issued.F.P. has served on the scientific advisory boards of Novartis and MedImmune; received travel funding and/or speaker honoraria from Bayer, Novartis, Biogen, Teva, Sanofi-Aventis/Genzyme, Merck Serono, Alexion, Chugai, MedImmune, and Shire; is an associate editor of Neurology: Neuroimmunology & Neuroinflammation; is an academic editor of PLoS ONE; consulted for Sanofi Genzyme, Biogen, MedImmune, Shire, and Alexion; received research support from Bayer, Novartis, Biogen, Teva, Sanofi-Aventis/Geynzme, Alexion, and Merck Serono; and received research support from the German Research Council, Werth Stiftung of the City of Cologne, German Ministry of Education and Research, Arthur Arnstein Stiftung Berlin, EU FP7 Framework Program, Arthur Arnstein Foundation Berlin, Guthy-Jackson Charitable Foundation, and NMSS.G.L.S. is an inventor of patents owned by the University of Southern DenmarkWO2014114298, WO2019086580, WO2014114298.B.G.W. receives royalties from RSR Ltd, Oxford University, Hospices Civil de Lyon, and MVZ Labor PD Dr. Volkmann und Kollegen GbR for a patent of NMO-IgG as a diagnostic test for neuromyelitis optica spectrum disorders, served on the adjudication committee for clinical trials conducted by MedImmune/VielaBio, Alexion, and UCB Biosciences and consulted for Chugai/Roche/Genentech, Horizon Therapeutics and Mitsubishi Tanabe regarding neuromyelitis optica spectrum disorders. He has received honoraria for speaking at internal meetings of Genentech, Novartis, and Horizon and at external meetings for Roche.H.L. has received fees for lectures from Merck, Novartis, Bristol Myers Squibb, and Sanofi-Aventis; and served as a consultant for Biogen Idec, and Roche.

Disease-modifying therapies (DMTs) are widely used in neuroimmunological diseases such as multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). Although these treatments are known to predispose patients to infections and affect their responses to vaccination, little is known about the impact of DMTs on the myeloid cell compartment. In this study, we use mass cytometry to examine DMT-associated changes in the innate immune system in untreated and treated patients with MS (n = 39) or NMOSD (n = 23). We also investigated the association between changes in myeloid cell phenotypes and longitudinal responsiveness to homologous primary, secondary, and tertiary SARS-CoV-2 mRNA vaccinations. Multiple DMT-associated myeloid cell clusters, in particular CD64 + HLADR low granulocytes, showed significant correlations with B and T cell responses induced by vaccination. Our findings suggest the potential role of myeloid cells in cellular and humoral responses following vaccination in DMT-treated patients with neuroimmunological diseases., (© 2023. The Author(s).)

Background: We aimed to assess the frequency of new asymptomatic lesions on brain and spinal imaging (magnetic resonance imaging (MRI)) and their association with subsequent relapses in a large cohort of neuromyelitis optica spectrum disorder (NMOSD) patients in Argentina., Methods: We retrospectively reviewed 675 MRI (225 performed during an attack and 450 during the relapse-free period (performed at least 3 months from the last attack)) of NMOSD patients who had at least 2 years of clinical and MRI follow-up since disease onset. Kaplan-Meier (KM) curves were used for depicting time from remission MRI to subsequent relapse., Results: We included 135 NMOSD patients (64.4% were aquaporin-4-immunoglobulin G (AQP4-IgG)-positive). We found that 26 (19.26%) and 66 (48.88%) of patients experienced at least one new asymptomatic MRI lesion during both the relapse-free period and attacks, respectively. The most frequent asymptomatic MRI lesions were optic nerves followed by short-segment myelitis during the relapse-free period and attacks. KM curves did not show differences in the time taken to develop a new relapse., Conclusion: Our findings showed that new asymptomatic lesions are relatively frequent. However, the presence of new asymptomatic MRI lesions during the relapse-free period and at relapses was not associated with a shorter time to developing subsequent relapses.

Importance: Differential diagnosis of patients with seronegative demyelinating central nervous system (CNS) disease is challenging. In this regard, evidence suggests that immunoglobulin (Ig) A plays a role in the pathogenesis of different autoimmune diseases. Yet little is known about the presence and clinical relevance of IgA antibodies against myelin oligodendrocyte glycoprotein (MOG) in CNS demyelination., Objective: To investigate the frequency of MOG-IgA and associated clinical features in patients with demyelinating CNS disease and healthy controls., Design, Setting, and Participants: This longitudinal study comprised 1 discovery and 1 confirmation cohort derived from 5 centers. Participants included patients with suspected or confirmed demyelinating diseases and healthy controls. MOG-IgA, MOG-IgG, and MOG-IgM were measured in serum samples and cerebrospinal fluid (CSF) of patients, who were assessed from September 2012 to April 2022., Main Outcomes and Measures: Frequency and clinical features of patients who were seropositive for MOG-IgA and double-seronegative for aquaporin 4 (AQP4) IgG and MOG-IgG., Results: After the exclusion of 5 participants with coexisting AQP4-IgG and MOG-IgA, MOG-IgG, and/or MOG-IgM, 1339 patients and 110 healthy controls were included; the median follow-up time was 39 months (range, 0-227 months). Of included patients with isolated MOG-IgA, 11 of 18 were female (61%), and the median age was 31.5 years (range, 3-76 years). Among patients double-seronegative for AQP4-IgG and MOG-IgG (1126/1339; 84%), isolated MOG-IgA was identified in 3 of 50 patients (6%) with neuromyelitis optica spectrum disorder, 5 of 228 patients (2%) with other CNS demyelinating diseases, and 10 of 848 patients (1%) with multiple sclerosis but in none of the healthy controls (0/110). The most common disease manifestation in patients seropositive for isolated MOG-IgA was myelitis (11/17 [65%]), followed by more frequent brainstem syndrome (7/16 [44%] vs 14/75 [19%], respectively; P = .048), and infrequent manifestation of optic neuritis (4/15 [27%] vs 46/73 [63%], respectively; P = .02) vs patients with MOG-IgG. Among patients fulfilling 2017 McDonald criteria for multiple sclerosis, MOG-IgA was associated with less frequent CSF-specific oligoclonal bands (4/9 [44%] vs 325/351 [93%], respectively; P < .001) vs patients with multiple sclerosis who were MOG-IgG/IgA seronegative. Further, most patients with isolated MOG-IgA presented clinical attacks after recent infection or vaccination (7/11 [64%])., Conclusion and Relevance: In this study, MOG-specific IgA was identified in a subgroup of patients who were double-seronegative for AQP4-/MOG-IgG, suggesting that MOG-IgA may be a novel diagnostic biomarker for patients with CNS demyelination.

Objective: To investigate relationships between serum neurofilament light chain (sNfL), ubiquitin C-terminal hydrolase L1 (sUCHL1), tau (sTau) and glial fibrillary acidic protein (sGFAP) levels and disease activity/disability in neuromyelitis optica spectrum disorder (NMOSD), and the effects of inebilizumab on these biomarkers in N-MOmentum., Methods: N-MOmentum randomised participants to receive inebilizumab or placebo with a randomised controlled period (RCP) of 28 weeks and an open-label follow-up period of ≥2 years. The sNfL, sUCHL1, sTau and sGFAP were measured using single-molecule arrays in 1260 scheduled and attack-related samples from N-MOmentum participants (immunoglobulin G (IgG) autoantibodies to aquaporin-4-positive, myelin oligodendrocyte glycoprotein-IgG-positive or double autoantibody-negative) and two control groups (healthy donors and patients with relapsing-remitting multiple sclerosis)., Results: The concentration of all four biomarkers increased during NMOSD attacks. At attack, sNfL had the strongest correlation with disability worsening during attacks (Spearman R 2 =0.40; p=0.01) and prediction of disability worsening after attacks (sNfL cut-off 32 pg/mL; area under the curve 0.71 (95% CI 0.51 to 0.89); p=0.02), but only sGFAP predicted upcoming attacks. At RCP end, fewer inebilizumab-treated than placebo-treated participants had sNfL>16 pg/mL (22% vs 45%; OR 0.36 (95% CI 0.17 to 0.76); p=0.004)., Conclusions: Compared with sGFAP, sTau and sUCHL1, sNfL at attack was the strongest predictor of disability worsening at attack and follow-up, suggesting a role for identifying participants with NMOSD at risk of limited post-relapse recovery. Treatment with inebilizumab was associated with lower levels of sGFAP and sNfL than placebo., Trial Registration Number: NCT02200770., Competing Interests: Competing interests: 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. OA is a member of the European Reference Network for Rare Eye Diseases (ERN-EYE), co-funded by the Health Program of the European Union under the Framework Partnership Agreement No 739534 'ERN-EYE. H-PH has received fees for consulting, speaking and serving on steering committees from Bayer Healthcare, Biogen Idec, Celgene Receptos, CSL Behring, GeNeuro, Genzyme, MedDay, MedImmune, Merck Serono, Novartis, Roche, Sanofi, TG Therapeutics and Viela Bio/Horizon Therapeutics, with approval by the Rector of Heinrich Heine University Düsseldorf. KF has received fees for consulting, speaking and serving on steering committees from AbbVie, Alexion, Asahi Kasei Medical, Biogen, Chugai/Roche, Eisai, Japan Tobacco, MedImmune/Viela Bio, Merck, Merck Biopharma, Mitsubishi-Tanabe, Novartis, Takeda, Teijin and UCB, and has received Grant-in-Aid for Scientific Research from the Ministry of Health, Welfare and Labor of Japan. FP has received research support, speaker fees and travel reimbursement from Bayer, Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme and Teva; is supported by the German Competence Network for Multiple Sclerosis and the German Research Council (DFG Exc 257); has received travel reimbursement from the Guthy–Jackson Charitable Foundation; and serves on the steering committee of the OCTIMS study sponsored by Novartis. RM serves on scientific advisory boards for Alexion, Roche and Viela Bio/Horizon Therapeutics; and has received funding for travel and fees from Alexion, Biogen, Merck, Novartis, Roche and Viela Bio/Horizon Therapeutics. JLB reports payment for study design/consultation from MedImmune/Viela Bio/Horizon Therapeutics; reports personal fees from AbbVie, Alexion, Beigene, Chugai, Clene Nanomedicine, Genentech, Genzyme, Mitsubishi Tanabe Pharma, Reistone Biopharma and Roche; reports grants and personal fees from EMD Serono and Novartis; reports grants from Alexion, Mallinckrodt and the National Institutes of Health; and has a patent for Aquaporumab issued. HJK has received a grant from the National Research Foundation of Korea; consultancy/speaker fees or research support from Alexion, AprilBio, ALTOS Biologics, Biogen, Celltrion, Daewoong, Eisai, GC Pharma, HanAll BioPharma, Handok, Horizon Therapeutics (formerly Viela Bio), Kolon Life Science, MDimune, Mitsubishi Tanabe Pharma, Merck Serono, Novartis, Roche, Sanofi Genzyme, Teva-Handok and UCB; and is a co-editor for the Multiple Sclerosis Journal and an associated editor for the Journal of Clinical Neurology. BGW receives payments for serving as chair of attack adjudication committees for clinical trials in NMOSD for Alexion, MedImmune, UCB Bioscience and Viela Bio/Horizon Therapeutics; has consulted with Chugai, Genentech, Horizon Pharmaceuticals, Mitsubishi Tanabe Pharma and Roche; has received payments for speaking for Genentech and Roche; and has a patent for NMO-IgG for diagnosis of neuromyelitis optica, with royalties paid by Hospices Civils de Lyon, MVZ Labor PD Dr Volkmann und Kollegen GbR, RSR and the University of Oxford. SJP has received personal compensation for serving as a consultant for Astellas, Genentech and Sage Therapeutics; has received personal compensation for serving on scientific advisory boards or data safety monitoring boards for F. Hoffman-La Roche AG, Genentech and UCB; has received research support from Alexion, Roche/Genentech and Viela Bio/MedImmune/Horizon; has a Patent# 8,889,102 (Application#12-678350, Neuromyelitis Optica Autoantibodies as a Marker for Neoplasia)—issued; has a patent, Patent# 9,891,219B2 (Application#12-573942, Methods for Treating Neuromyelitis Optica [NMO] by Administration of Eculizumab to an individual that is Aquaporin-4 (AQP4)-IgG Autoantibody positive)—issued; and his institution has received compensation for serving as a consultant for Alexion, Astellas and Viela Bio/MedImmune/Horizon. DMW reports personal fees from Biogen, Genentech, Horizon, Mitsubishi Tanabe, Roche, UCB Pharma and Viela Bio; and research support paid to Mayo Clinic by Alexion Pharmaceuticals. GC has received personal fees for participation on data and safety monitoring boards from AI Therapeutics, AMO Pharma, AstraZeneca, Avexis Pharmaceuticals, Biolinerx, Brainstorm Cell Therapeutics, Bristol Meyers Squibb/Celgene, CSL Behring, Galmed Pharmaceuticals, Green Valley Pharma, Horizon Pharmaceuticals, Immunic, Karuna Therapeutics, Mapi Pharmaceuticals, Merck, Mitsubishi Tanabe Pharma Holdings, NHLBI (Protocol Review Committee), Novartis, Opko Biologics, Prothena Biosciences, Regeneron, Sanofi-Aventis, Reata Pharmaceuticals, University of Texas Southwestern, University of Pennsylvania and Visioneering Technologies; has received personal fees for consulting or advisory board participation from Alexion, Antisense Therapeutics, Biogen, Clinical Trial Solutions, Entelexo Biotherapeutics, Genentech, Genzyme, GW Pharmaceuticals, Immunic, Klein-Buendel Incorporated, Merck/Serono, Novartis, Osmotica Pharmaceuticals, Perception Neurosciences, Protalix Biotherapeutics, Recursion/Cerexis Pharmaceuticals, Regeneron, Roche, SAB Biotherapeutics; and is employed by the University of Alabama at Birmingham and President of Pythagoras, a private consulting company located in Birmingham, Alabama. BAC reports personal compensation for consulting from Alexion, Atara Biotherapeutics, Autobahn, Avotres, Biogen, EMD Serono, Gossamer Bio, Horizon, Neuron23, Novartis, Sanofi, TG Therapeutics and Therini Bio; and has received research support from Genentech. MAS, WAR, DS and DC are employees of Horizon Therapeutics and own stock. MG and EK are former employees of Horizon Therapeutics and own stock., (© 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: The potential therapeutic benefit of intravenous immunoglobulins (IVIGs) for acute attacks of myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is unknown., Objective: The objective was to describe the outcomes of IVIG treatment for acute MOGAD attacks., Methods: A retrospective observational study involving seven tertiary neuroimmunology centers. Data collection included patients' demographics, Expanded Disability Status Scale (EDSS), and visual acuity (VA) before the attack, at the nadir of the attack before IVIG treatment, and at follow-up visits ⩾3 months after treatment., Results: Thirty-nine patients were included, of which 21 (53.8%) were female. The median age was 23 years (range 5-74 years), and the median disease duration was 4 months (range 0-93 months). The most common type of attack treated with IVIG was isolated optic neuritis (ON) (unilateral n = 14, bilateral n = 5, associated with transverse myelitis (TM), n = 1), followed by acute disseminated encephalomyelitis (ADEM) ( n = 8), multifocal ( n = 7), TM ( n = 3), brainstem ( n = 1), and other encephalitis ( n = 1). A significant improvement in both the EDSS and VA measures was observed at follow-up compared to the time of IVIG treatment initiation ( p < 0.0001 for both outcome measures)., Conclusion: IVIG may be an effective treatment option for acute MOGAD attacks. Further prospective studies are warranted to validate our results.

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: The N-MOmentum trial investigated safety and efficacy of inebilizumab in participants with neuromyelitis optica spectrum disorder (NMOSD)., Objective: Evaluate the attack identification process and adjudication committee (AC) performance in N-MOmentum., Methods: Adults ( n = 230) with NMOSD and Expanded Disability Status Scale score ⩽8 were randomized (3:1) to inebilizumab 300 mg or placebo. The randomized controlled period was 28 weeks or until adjudicated attack. Attacks were adjudicated according to 18 predefined criteria. Magnetic resonance imaging (MRI) and biomarker (serum glial fibrillary acidic protein [sGFAP]) analyses were performed., Results: A total of 64 participant-reported neurological events occurred; 51 (80%) were investigator-determined to be attacks. The AC confirmed 43 of the investigator-determined attacks (84%). There was high inter- and intra-AC-member agreement. In 25/64 events (39%) and 14/43 AC-adjudicated attacks (33%), MRI was reviewed during adjudication. Retrospective analysis revealed new domain-specific T1 and T2 MRI lesions in 90% of adjudicated attacks. Increased mean sGFAP concentrations (>2-fold change) from baseline were observed in 56% of adjudicated attacks versus 14% of investigator-determined attacks rejected by the AC and 31% of participant-reported events determined not to be attacks., Conclusion: AC adjudication of NMOSD attacks according to predefined criteria appears robust. MRI lesion correlates and sGFAP elevations were found in most adjudicated attacks.

Background: The novel optic neuritis (ON) diagnostic criteria include intereye differences (IED) of optical coherence tomography (OCT) parameters. IED has proven valuable for ON diagnosis in multiple sclerosis but has not been evaluated in aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorders (AQP4+NMOSD). We evaluated the diagnostic accuracy of intereye absolute (IEAD) and percentage difference (IEPD) in AQP4+NMOSD after unilateral ON >6 months before OCT as compared with healthy controls (HC)., Methods: Twenty-eight AQP4+NMOSD after unilateral ON (NMOSD-ON), 62 HC and 45 AQP4+NMOSD without ON history (NMOSD-NON) were recruited by 13 centres as part of the international Collaborative Retrospective Study on retinal OCT in Neuromyelitis Optica study. Mean thickness of peripapillary retinal nerve fibre layer (pRNFL) and macular ganglion cell and inner plexiform layer (GCIPL) were quantified by Spectralis spectral domain OCT. Threshold values of the ON diagnostic criteria (pRNFL: IEAD 5 µm, IEPD 5%; GCIPL: IEAD: 4 µm, IEPD: 4%) were evaluated using receiver operating characteristics and area under the curve (AUC) metrics., Results: The discriminative power was high for NMOSD-ON versus HC for IEAD (pRNFL: AUC 0.95, specificity 82%, sensitivity 86%; GCIPL: AUC 0.93, specificity 98%, sensitivity 75%) and IEPD (pRNFL: AUC 0.96, specificity 87%, sensitivity 89%; GCIPL: AUC 0.94, specificity 96%, sensitivity 82%). The discriminative power was high/moderate for NMOSD-ON versus NMOSD-NON for IEAD (pRNFL: AUC 0.92, specificity 77%, sensitivity 86%; GCIP: AUC 0.87, specificity 85%, sensitivity 75%) and for IEPD (pRNFL: AUC 0.94, specificity 82%, sensitivity 89%; GCIP: AUC 0.88, specificity 82%, sensitivity 82%)., Conclusions: Results support the validation of the IED metrics as OCT parameters of the novel diagnostic ON criteria in AQP4+NMOSD., Competing Interests: Competing interests: The authors have stated explicitly that there are no conflicts of interest in connection with this article., (© 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: CHAMPION-NMOSD (NCT04201262) is a phase 3, open-label, externally controlled interventional study evaluating the efficacy and safety of the terminal complement inhibitor ravulizumab in adult patients with anti-aquaporin-4 antibody-positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD). Ravulizumab binds the same complement component 5 epitope as the approved therapeutic eculizumab but has a longer half-life, enabling an extended dosing interval (8 vs 2 weeks)., Methods: The availability of eculizumab precluded the use of a concurrent placebo control in CHAMPION-NMOSD; consequently, the placebo group of the eculizumab phase 3 trial PREVENT (n = 47) was used as an external comparator. Patients received weight-based intravenous ravulizumab on day 1 and maintenance doses on day 15, then once every 8 weeks. The primary endpoint was time to first adjudicated on-trial relapse., Results: The primary endpoint was met; no patients taking ravulizumab (n = 58) had an adjudicated relapse (during 84.0 patient-years of treatment) versus 20 patients with adjudicated relapses in the placebo group of PREVENT (during 46.9 patient-years; relapse risk reduction = 98.6%, 95% confidence interval = 89.7%-100.0%, p < 0.0001). Median (range) study period follow-up time was 73.5 (11.0-117.7) weeks for ravulizumab. Most treatment-emergent adverse events were mild/moderate; no deaths were reported. Two patients taking ravulizumab experienced meningococcal infections. Both recovered with no sequelae; one continued ravulizumab treatment., Interpretation: Ravulizumab significantly reduced relapse risk in patients with AQP4+ NMOSD, with a safety profile consistent with those of eculizumab and ravulizumab across all approved indications. ANN NEUROL 2023;93:1053-1068., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

MRI and clinical features of myelin oligodendrocyte glycoprotein (MOG)-antibody disease may overlap with those of other inflammatory demyelinating conditions posing diagnostic challenges, especially in non-acute phases and when serologic testing for MOG antibodies is unavailable or shows uncertain results. We aimed to identify MRI and clinical markers that differentiate non-acute MOG-antibody disease from aquaporin 4 (AQP4)-antibody neuromyelitis optica spectrum disorder and relapsing remitting multiple sclerosis, guiding in the identification of patients with MOG-antibody disease in clinical practice. In this cross-sectional retrospective study, data from 16 MAGNIMS centres were included. Data collection and analyses were conducted from 2019 to 2021. Inclusion criteria were: diagnosis of MOG-antibody disease; AQP4-neuromyelitis optica spectrum disorder and multiple sclerosis; brain and cord MRI at least 6 months from relapse; and Expanded Disability Status Scale (EDSS) score on the day of MRI. Brain white matter T2 lesions, T1-hypointense lesions, cortical and cord lesions were identified. Random forest models were constructed to classify patients as MOG-antibody disease/AQP4-neuromyelitis optica spectrum disorder/multiple sclerosis; a leave one out cross-validation procedure assessed the performance of the models. Based on the best discriminators between diseases, we proposed a guide to target investigations for MOG-antibody disease. One hundred and sixty-two patients with MOG-antibody disease [99 females, mean age: 41 (±14) years, median EDSS: 2 (0-7.5)], 162 with AQP4-neuromyelitis optica spectrum disorder [132 females, mean age: 51 (±14) years, median EDSS: 3.5 (0-8)], 189 with multiple sclerosis (132 females, mean age: 40 (±10) years, median EDSS: 2 (0-8)] and 152 healthy controls (91 females) were studied. In young patients (<34 years), with low disability (EDSS < 3), the absence of Dawson's fingers, temporal lobe lesions and longitudinally extensive lesions in the cervical cord pointed towards a diagnosis of MOG-antibody disease instead of the other two diseases (accuracy: 76%, sensitivity: 81%, specificity: 84%, P < 0.001). In these non-acute patients, the number of brain lesions < 6 predicted MOG-antibody disease versus multiple sclerosis (accuracy: 83%, sensitivity: 82%, specificity: 83%, P < 0.001). An EDSS < 3 and the absence of longitudinally extensive lesions in the cervical cord predicted MOG-antibody disease versus AQP4-neuromyelitis optica spectrum disorder (accuracy: 76%, sensitivity: 89%, specificity: 62%, P < 0.001). A workflow with sequential tests and supporting features is proposed to guide better identification of patients with MOG-antibody disease. Adult patients with non-acute MOG-antibody disease showed distinctive clinical and MRI features when compared to AQP4-neuromyelitis optica spectrum disorder and multiple sclerosis. A careful inspection of the morphology of brain and cord lesions together with clinical information can guide further analyses towards the diagnosis of MOG-antibody disease in clinical practice., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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 and Objectives: Neuromyelitis optica spectrum disorder (NMOSD) is a rare debilitating autoimmune disease of the CNS. Three monoclonal antibodies were recently approved as maintenance therapies for aquaporin-4 immunoglobulin G (AQP4-IgG)-seropositive NMOSD (eculizumab, inebilizumab, and satralizumab), prompting the need to consider best practice therapeutic decision-making for this indication. Our objective was to develop validated statements for the management of AQP4-IgG-seropositive NMOSD, through an evidence-based Delphi consensus process, with a focus on recommendations for eculizumab, inebilizumab, and satralizumab., Methods: We recruited an international panel of clinical experts in NMOSD and asked them to complete a questionnaire on NMOSD management. Panel members received a summary of evidence identified through a targeted literature review and provided free-text responses to the questionnaire based on both the data provided and their clinical experience. Responses were used to generate draft statements on NMOSD-related themes. Statements were voted on over a maximum of 3 rounds; participation in at least 1 of the first 2 rounds was mandatory. Panel members anonymously provided their level of agreement (6-point Likert scale) on each statement. Statements that failed to reach a predefined consensus threshold (≥67%) were revised based on feedback and then voted on in the next round. Final statements were those that met the consensus threshold (≥67%)., Results: The Delphi panel comprised 24 experts, who completed the Delphi process in November 2021 after 2 voting rounds. In round 1, 23/25 statements reached consensus and were accepted as final. The 2 statements that failed to reach consensus were revised. In round 2, both revised statements reached consensus. Twenty-five statements were agreed in total: 11 on initiation of or switching between eculizumab, inebilizumab, and satralizumab; 3 on monotherapy/combination therapy; 7 on safety and patient population considerations; 3 on biomarkers/patient-reported outcomes; and 1 on research gaps., Discussion: An established consensus method was used to develop statements relevant to the management of AQP4-IgG-seropositive NMOSD. These international statements will be valuable for informing individualized therapeutic decision-making and could form the basis for standardized practice guidelines., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Serum antibodies directed against myelin oligodendrocyte glycoprotein (MOG) are found in patients with acquired CNS demyelinating syndromes that are distinct from multiple sclerosis and aquaporin-4-seropositive neuromyelitis optica spectrum disorder. Based on an extensive literature review and a structured consensus process, we propose diagnostic criteria for MOG antibody-associated disease (MOGAD) in which the presence of MOG-IgG is a core criterion. According to our proposed criteria, MOGAD is typically associated with acute disseminated encephalomyelitis, optic neuritis, or transverse myelitis, and is less commonly associated with cerebral cortical encephalitis, brainstem presentations, or cerebellar presentations. MOGAD can present as either a monophasic or relapsing disease course, and MOG-IgG cell-based assays are important for diagnostic accuracy. Diagnoses such as multiple sclerosis need to be excluded, but not all patients with multiple sclerosis should undergo screening for MOG-IgG. These proposed diagnostic criteria require validation but have the potential to improve identification of individuals with MOGAD, which is essential to define long-term clinical outcomes, refine inclusion criteria for clinical trials, and identify predictors of a relapsing versus a monophasic disease course., Competing Interests: Declaration of interests BB has or will potentially receive financial compensation for consultancy effort for Novartis, Roche, UCB, Horizon Therapeutics, Biogen, and Immunic Therapeutics for advice on clinical trial design. BB is funded by the National Multiple Sclerosis Society, National Institute of Health, and has been previously funded by the Canadian Multiple Sclerosis Society. JLB has received research grants from Novartis, Mallinckrodt Pharmaceuticals, Alexion, and the National Institutes of Health, license fees from a US patent (2014/0170140); consulting fees from Horizon Therapeutics, Alexion, BeiGene Chugai Pharmaceutical, Genentech, Genzyme, Mitsubishi-Tanabe Pharma, Reistone Biopharma, Roche, and AbbVie; and serves on Data Safety Monitoring Boards for Roche, Genentech, and Clene Nanomedicine. RM reports personal fees from Horizon Therapeutics, Alexion, Roche, and UCB and non-financial support from Horizon Therapeutics, Merck, Biogen, and Roche, outside the submitted work. HJK received a grant from the National Research Foundation of Korea and research support from Aprilbio and Eisai; received consultancy and speaker fees from Alexion, Aprilbio, Altos Biologics, Biogen, Celltrion, Daewoong, Eisai, GC Pharma, HanAll BioPharma, Handok, Horizon Therapeutics (formerly Viela Bio), Kolon Life Science, Mdimune, Merck Serono, Mitsubishi Tanabe Pharma, Novartis, Roche, Sanofi Genzyme, Teva-Handok, and UCB; and is a co-editor for the Multiple Sclerosis Journal and an associated editor for the Journal of Clinical Neurology. FB has received research funding from the National Health and Medical Research Council (Australia), Multiple Sclerosis Research Australia, New South Wales Health, Novartis, and the University of Sydney (Sydney, NSW, Australia). She has received speaker honoraria from Novartis, Biogen, Merck, and Limbic Neurology, and has been on advisory boards for Merck and Novartis. She works at the University of Sydney and at the Children's Hospital at Westmead, Westmead, New South Wales, Australia, which offers MOG-IgG testing. EPF has served on advisory boards for Alexion, Genentech, and Horizon Therapeutics. He has received speaker honoraria from Pharmacy Times and royalties from UpToDate for a topic on MOGAD. He was a site primary investigator in a randomised clinical trial on inebilizumab in neuromyelitis optica spectrum disorder run by Horizon Therapeutics. He is principal investigator on an RO1 on MOG-IgG disease. He works at Mayo Clinic, Rochester, MN, USA, which offers commercial MOG-IgG testing but he receives no royalties from such testing. SR has received research funding from the National Health and Medical Research Council (Australia), the Brain Foundation (Australia), the Royal Australasian College of Physicians, and the University of Sydney. She was supported by an National Health and Medicine Research Council Neil Hamilton Fairley Early Career Fellowship (APP1141169) and is currently supported by an NHMRC Emerging Leadership (EL2) Investigator Grant (APP2008339). She serves as a consultant on an advisory board for UCB and Limbic Neurology, and has been an invited speaker for Biogen, Limbic Neurology, and Excemed. PW has received research grants from Euroimmun AG, Commonwealth Serum Laboratories Behring and patent royalties for antibody testing (W02010046716A1). He is the co-director of the Oxford Autoimmune Neurology Diagnostic Laboratory (Oxford University, Oxford, UK) where MOG-IgG1 autoantibodies are tested and both he and the University of Oxford receive royalties (for antibody tests for LGI1 and CASPR2, W02010046716A1). He has received honoraria or consulting fees from Biogen Idec, F Hoffmann La-Roche, Mereo BioPharma, Retrogenix, UBC, Euroimmun AG, University of British Columbia, and Alexion; and travel grants from the Guthy-Jackson Charitable Foundation. Work in the Oxford Autoimmune Neurology Diagnostic Laboratory is supported by the UK National Health Service Commissioning service for NMOSD. ST has received speaker and consulting fees from Biogen-Idec Argentina, Merck SA, Genzyme-Sanofi, Roche, Novartis Argentina, and Novartis Pharma. She serves as a consultant on an advisory board for Genentech-Roche. and Alexion Pharmaceuticals. JSG has grant or contract research support from the National Multiple Sclerosis Society, Biogen, and Octave Biosciences for work unrelated to the present project. She serves on a steering committee for a trial supported by Novartis. She has received speaker fees from Alexion and Bristol Myers Sqiuibb, and served on an advisory board for Genentech. TC has received compensation for consulting from Biogen, Novartis Pharmaceuticals, Roche, Genentech, and Sanofi Genzyme. She has received research support from the National Institutes of Health, National Multiple Sclerosis Society, US Department of Defense, EMD Serono, Guthy-Jackson Charitable Foundation, I-Mab Biopharma, Mallinckrodt Pharmaceuticals, Novartis, Octave Bioscience, Roche Genentech, The Sumaira Foundation, and Tiziana Life Sciences. AUB has received grant support from Moore Foundation, Clinical and Trnaslational Awards Program, German Federal Ministry of Education and Research (BMBF). He has been named as inventor on several patents and patent applications describing multiple sclerosis serological biomarkers, drug targets for remyelination therapy, marker-less motor function analysis, and retinal image analysis methods. He serves on the Observational Study Monitoring Board for CAVS-MS. He is cofounder, board member, and currently serving as secretary treasurer of IMSVISUAL. He is cofounder and holds stocks of technology startups Motognosis GmbH and Nocturne GmbH. Motognosis GmbH develops and sells systems for assessing motor dysfunction in patients with neurological disorders. Nocturne GmbH offers analysis services for retinal optical coherence tomography. Both companies' products and services are relevant for neurology in general, but not specific to MOGAD. CH reports grant support from the Medical Research Council, Multiple Sclerosis Society, and Vasculitis UK. She serves as a consultant to Novartis, Biogen, Roche, UCB, Viela Bio, and Sanofi. She participated on an independent data safety monitoring board for the Wellcome Trust. RN reports grant support from Multiple Sclerosis Research Foundation (Netherlands). He has participated on a data safety monitoring board or advisory board for EXCEL study (neurofibromatosis). He is board member of the Dutch Pediatric Neurology Society. LP has received speaker honoraria and travel grants from Biogen, and has consulted for Biogen, Novartis, and Sanofi. Her university holds a patent for her invention: Live cell based assay for detection of autoantibodies for NMOSD and related disorders (Indian patent number 202141055841). MR is supported by research grants from the Austrian Science Fund (FWF project P32699), the Austrian Research Promotion Agency, Euroimmun, and Roche, and consulting fees and advisory board from Roche (to institution). MR works at the Clinical Department of the Medical University of Innsbruck (Innsbruck, Austria), which offers diagnostic testing for MOG-IgG and other autoantibodies. AS received personal compensation for consulting, serving on a scientific advisory board, speaking activities with Merck, Sanofi, Biogen, Roche, TEVA Pharmaceuticals, Novartis, Alexion, and Janssen. DKS has received research support from National council for Scientific and Technological Development CNPq Brazil (425331/2016-4 and 308636/2019-8), Fundacao de Amparo Pesquisa do Estado do Rio Grande do Sul (17/2551-0001391-3 and 21/2551-0000077-5), TEVA Pharmaceuticals, Merck, Biogen, and Euroimmun AG; speaker honoraria from Biogen, Novartis, Genzyme, TEVA Pharmaceuticals, Merck, Roche, and Bayer; and participates in advisory boards for Biogen, Roche, and Merck. KR has been an invited speaker for Merck and serves as a consultant for an advisory board for Roche. FP has received honoraria and research support from Alexion, Bayer, Biogen, Chugai, MerckSerono, Novartis, Genyzme, MedImmune, Shire, and Teva Pharmaceuticals, and serves on scientific advisory boards for Alexion, MedImmune, Novartis, and UCB. He has received funding from Deutsche Forschungsgemeinschaft (DFG Exc 257), Bundesministerium für Bildung und Forschung (Competence Network Multiple Sclerosis), Guthy-Jackson Charitable Foundation, EU Framework Program 7, and National Multiple Sclerosis Society of the USA. He serves on the steering committee of the N-Momentum study with inebilizumab (Horizon Therapeutics) and the OCTiMS Study (Novartis). He is an associatee editor with Neurology, Neuroimmunology, and Neuroinflammation and academic editor with PloS One. SJP reports grants, personal fees, and non-financial support from Alexion Pharmaceuticals; grants, personal fees, and non-financial support from MedImmune /Viela Bio; and personal fees for consulting from Genentech, Roche, UCB, and Astellas. He has two patents issued (8889102; application 12-678350; Neuromyelitis Optica Autoantibodies as a Marker for Neoplasia; and 9891219B2; application 12-573942; Methods for Treating Neuromyelitis Optica [NMO] by Administration of Eculizumab to an individual that is Aquaporin-4 [AQP4]-IgG Autoantibody positive). SJP also has patents pending for IgGs to the following proteins as biomarkers of autoimmune neurological disorders: septin-5, kelch-like protein 11, GFAP, PDE10A, and MAP1B. He works at Mayo Clinic, which offers commercial MOG-IgG testing. He receives no royalties from the sale of tests done at the neuroimmunology Laboratory at Mayo Clinic. KF serves as an advisor or on scientific advisory boards for Biogen, Mitsubishi Tanabe, Novartis, Chugai, Roche, Alexion, VielaBio/Horizon Therapeutics, UCB, Merck Biopharma, Japan Tobacco and Abbvie; has received funding for travel and speaker honoraria from Biogen, Eisai, Mitsubishi Tanabe, Novartis, Chugai, Roche, Alexion, VielaBio, Teijin, Asahi Kasei Medical, Merck, and Takeda; and has received the Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and the Grants-in-Aid for Scientific Research from the Ministry of Health, Welfare and Labor of Japan. JP has received consulting fees from Merck, Novartis, Roche, Mitsubishi Tnabe Pharma, UCB, Alexion, Vitaccess, and Argenx, and MRI support from Medimmune, Merck, and Roche. She has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Merck, VielaBio, Roche and Alexion. She has participated on a data safety monitoring board or advisory board for Novartis, Roche, Argenx, UCB, Alexion, and Sanofi. She is member of the Charcot Foundation Board, Magnetic Resonance in Multiple Sclerosis steering committee, and National Health Service England Intravenous Immune Globulin Committee. She holds stock for AstraZeneca for a product that is not related to MOG-antibody associated disease. She has a patent for Diagnosing Multiple Sclerosis (application no PCT/GB2013/050285, final patent number 13704627.2–1408; client reference 4440; MS reference P37347WO; patent published Sept 13, 2021)., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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.)

Introduction: Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing, often debilitating neuroinflammatory disease, whose predominant clinical manifestations are longitudinally extensive transverse myelitis and optic neuritis. About 80% of the patients with an NMOSD phenotype have pathogenic autoantibodies against the astrocyte water channel aquaporin-4 (AQP4-IgG). While therapeutic options for NMOSD have greatly expanded in recent years, well-established biomarkers for prognosis or treatment response are still lacking. Glial fibrillary acidic protein (GFAP) is mainly expressed in astrocytes and can be detected in cerebrospinal fluid (CSF) and blood of patients with NMOSD., Areas Covered: Here, we comprehensively review the current knowledge on GFAP as a biomarker in NMOSD., Expert Opinion: In patients with AQP4-IgG + NMOSD, GFAP levels are elevated in CSF and serum during acute attacks and correlate with disability, consistent with the pathophysiology of this antibody-mediated astrocytopathy. Serum GFAP levels tend to be higher in AQP4-IgG + NMOSD than in its differential diagnoses, multiple sclerosis, and myelin oligodendrocyte antibody-associated disease. Importantly, serum GFAP levels in AQP4-IgG + NMOSD during remission may be predictive of future disease activity. Serial serum GFAP measurements are emerging as a biomarker to monitor disease activity in AQP4-IgG + NMOSD and could have the potential for application in clinical practice.

Background: Large-scale disease overarching longitudinal data are rare in the field of neuroimmunology. However, such data could aid early disease stratification, understanding disease etiology and ultimately improve treatment decisions. The Berlin Registry of Neuroimmunological Entities (BERLimmun) is a longitudinal prospective observational study, which aims to identify diagnostic, disease activity and prognostic markers and to elucidate the underlying pathobiology of neuroimmunological diseases., Methods: BERLimmun is a single-center prospective observational study of planned 650 patients with neuroimmunological disease entity (e.g. but not confined to: multiple sclerosis, isolated syndromes, neuromyelitis optica spectrum disorders) and 85 healthy participants with 15 years of follow-up. The protocol comprises annual in-person visits with multimodal standardized assessments of medical history, rater-based disability staging, patient-report of lifestyle, diet, general health and disease specific symptoms, tests of motor, cognitive and visual functions, structural imaging of the neuroaxis and retina and extensive sampling of biological specimen., Discussion: The BERLimmun database allows to investigate multiple key aspects of neuroimmunological diseases, such as immunological differences between diagnoses or compared to healthy participants, interrelations between findings of functional impairment and structural change, trajectories of change for different biomarkers over time and, importantly, to study determinants of the long-term disease course. BERLimmun opens an opportunity to a better understanding and distinction of neuroimmunological diseases., (© 2022. The Author(s).)

Background and Objectives: Inhibition of terminal complement in neuromyelitis optica spectrum disorder (NMOSD) using eculizumab helps prevent relapses, but the exact mechanism of action of the drug remains unclear. Similarly, genetic variants in the Fc Gamma receptor 3A (FCGR3A), also known as CD16, are correlated with outcomes in NMOSD, but the immune cells expressing those CD16 are unknown. We compared CD16 expression on immune cells modulated by complement activity in natural killer (NK) cells and natural killer-T (NKT) cells in NMOSD to disease and normal-healthy controls., Methods: Peripheral blood cell (PBMC) samples from 45 patients with NMOSD with aquaporin 4 (AQP4)-IgG, 18 disease controls, and 19 normal controls were analyzed for CD16 expression and complement receptors in vitro., Results: At baseline, the number of NKT cells was increased in NMOSD (p < 0.001), but the proportion that was CD16 positive was lower compared to normal and disease controls (p = 0.0012). NK cell count was normal, but the ratio that was CD16 positive was also significantly lower (p < 0.001). In both NK cells and NKT cells from NMOSD, C5 complement receptor expression was much higher than normal and disease controls (p < 0.001 for both). We also evaluated activation markers CD69 and CD83, which were also significantly higher in NK and NKT cells from NMOSD patients. FCGR3A p158 V/V genotype group in NMOSD patients showed decreased NK cell proportion with activation, and fewer CD16-expressing NKT cells than the F/F genotype group., Discussion: Our results support an immunopathogenesis model in which complement pathway activation in NK/NKT cells upregulates CD16 expression that binds to antibody/antigen complexes. In the context of NMOSD, these complement-sensitive cells may be responsible for the escalating autoimmune activity., (© 2022. The Author(s).)

Optic neuritis (ON) is a frequent presentation at onset of multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). The pathophysiology underlying these diseases, especially MOGAD, is still being elucidated. While obesity has been reported to potentially be a risk factor for MS, this has not been explored in NMOSD or MOGAD. We aimed to investigate a possible association between obesity (body mass index [BMI] > 30 kg/m 2 ) in patients with MOGAD, aquaporin 4-IgG positive NMOSD (AQP4-IgG+ NMOSD) or MS. In this multicenter non-interventional retrospective study, data was collected from patients with a first ever demyelinating attack of ON subsequently diagnosed with MOGAD (n = 44), AQP4-IgG+ NMOSD (n = 49) or MS (n = 90) between 2005 and 2020. The following data was collected: age, sex, ethnicity, BMI (documented before corticosteroid treatment), and the ON etiology after diagnostic work-up. A mixed model analysis was performed to assess the potential of obesity or BMI to predict MOGAD-ON, and to distinguish MOGAD-ON from AQP4-IgG+ NMOSD-ON and MS-ON. Main outcome measures included BMI in patients with acute ON and subsequent diagnosis of MOGAD, AQP4-IgG+ NMOSD or MS. A higher BMI was significantly associated with a diagnosis of MOGAD-ON (p < 0.001); in MOGAD patients the mean BMI was 31.6 kg/m 2 (standard deviation (SD) 7.2), while the mean BMI was 24.7 kg/m 2 (SD 5.3) in AQP4-IgG+ NMOSD patients, and 26.9 kg/m 2 (SD 6.2) in MS patients. Mixed-effects multinomial logistic regression, adjusted for age and sex, with obesity as a binary variable, revealed that obesity was associated with a higher odds ratio (OR) of a subsequent MOGAD diagnosis (OR 5.466, 95% CI [2.039, 14.650], p = 0.001) in contradistinction with AQP4-IgG+ NMOSD. This study suggests an association between obesity and MOGAD. Our findings require further exploration, but could have significant pathophysiologic implications if confirmed in larger prospective studies., (© 2022. The Author(s).)

There is no consensus regarding the classification of optic neuritis, and precise diagnostic criteria are not available. This reality means that the diagnosis of disorders that have optic neuritis as the first manifestation can be challenging. Accurate diagnosis of optic neuritis at presentation can facilitate the timely treatment of individuals with multiple sclerosis, neuromyelitis optica spectrum disorder, or myelin oligodendrocyte glycoprotein antibody-associated disease. Epidemiological data show that, cumulatively, optic neuritis is most frequently caused by many conditions other than multiple sclerosis. Worldwide, the cause and management of optic neuritis varies with geographical location, treatment availability, and ethnic background. We have developed diagnostic criteria for optic neuritis and a classification of optic neuritis subgroups. Our diagnostic criteria are based on clinical features that permit a diagnosis of possible optic neuritis; further paraclinical tests, utilising brain, orbital, and retinal imaging, together with antibody and other protein biomarker data, can lead to a diagnosis of definite optic neuritis. Paraclinical tests can also be applied retrospectively on stored samples and historical brain or retinal scans, which will be useful for future validation studies. Our criteria have the potential to reduce the risk of misdiagnosis, provide information on optic neuritis disease course that can guide future treatment trial design, and enable physicians to judge the likelihood of a need for long-term pharmacological management, which might differ according to optic neuritis subgroups., Competing Interests: Declaration of interests AP received grant support for remyelination trials in multiple sclerosis to the Amsterdam University Medical Centre, Department of Neurology, MS Centre (RESTORE trial), and UCL, London RECOVER trial; received grant fees from Fight for Sight (nimodipine in optic neuritis trial); received royalties or licenses from Up-to-Date (Wolters Kluwer) for a book chapter; received speaker fees for the Heidelberg Academy; participates on advisory board for SC Zeiss OCTA Angi-Network, and the SC Novartis OCTiMS study; holds leadership roles for governing board IMSVISUAL; was chairman of ERN-EYE Neuro-ophthalmology (until Oct, 2020); is board member of National Dutch Neuro-ophthalmology Association; received equipment from OCTA from Zeiss (Plex Elite); and received medical writing support from Novartis for a manuscript (https://doi.org/10.1002/acn3.51473). CF received consulting fees from Invex Therapeutics; received speaker honoraria from University of Dunedin; and holds leadership as Director of Royal Australian and New Zealand College of Ophthalmologists. VB received personal fees as consultant for Gensight and Neurophoenix. PC obtained grants from Annexon, Biogen, Genentech; received royalties from Cambridge Press for an OCT book; received consulting fees from Disarm Therapeutics, Nervgen, Biogen, Avidea; received honoraria from NY Academy of Sciences; and received equipment from Myelin Repair Foundation, Academic CME, Neuraly, and Landos. FC received speaker honoraria from Alexion, Accure Therapeutics, and the Sumiara Foundation. RDe obtained consulting fees from Alexion. JdS received consulting fees from Biogen, Teva, BMS Celegen, Roche, Novartis, Janssen, Merck, Alexion, CSL Behring; and honoraria from Biogen, Teva, BMS Celegen, Roche, Novartis, Janssen, Merck, Alexion, and CSL Behring. JFR received consulting fees from Roche, and Sanofi. EF holds honoraria from Alexion, Genzyme, Biogen, Novartis, and Janssen. TF holds honoraria from Alexion. CFT received honoraria from Novartis; and received support for attending meetings and travel from Novartis and Teva. KF obtained grants from Ministry of Education, Science and Technology of Japan as well as the Ministry of Health, Welfare and Labor of Japan; received consulting fees from Alexion Chugai-Roche Mitsubishi Tanabe, Novartis, Biogen, Eisai, Takeda, Teijin, Viela Bio, UCB, Merck, Japan Tobacco Pharma, and Abbvie; received honoraria from Alexion, Chugai-Roche, Mitsubishi Tanabe, Novartis, Biogen, Eisai, Takeda, Asahi Kasei Medical, Teijin, and Bayer; participated on a data safety monitoring board or advisory board from Alexion, Chugai, Mitsubishi Tanabe, Novartis, Biogen, Eisai, Takeda, Asahi Kasei Medical, Teijin, UCB, and Viela Bio; and received medical writing support from Oxford PharmaGenesis and Apothecom. RG acquired personal fees for participation on data safety monitoring boards, and served on the advisory boards for Biogen, Hikma, Merck, Roche, and Sanofi as well as receiving a grant from Roche. FG received grants or contracts from Roche (NMO epidemiologic studies) and Novartis (MS epidemiologic studies); received honoraria from for lectures from Roche, Novartis, Stendhal, and Merck; received support for attending meetings from the European Charcot Foundation, and ECTRIMS; and reports leadership of FOCEM (Foro Centroamericano y del Caribe de la Esclerosis Múltiple y otras enfermedades desmielinizantes del Sistema Nervioso Central) and Academia Panameña de Medicina y Cirugía (both unpaid). MHab obtained honoraria from Biogen, Sanofi Genzyme, Merck, Bayer, Novartis, Pliva-Teva, Roche, and Zentiva; received support for attending meetings from Biogen, Sanofi Genzyme, Merck, Bayer, Novartis, Pliva-Teva, and Roche; and participated on advisory board for Biogen, Sanofi Genzyme, Merck, Bayer, Novartis, Pliva-Teva, and Roche. ZIl obtained grants or contracts from Biogen and Alexion; received honoraria from Biogen, Novartis, Roche, Merck, and Alexion; received payment for expert testimony from Roche; received support for attending meetings and travel from Biogen and Sanofi; and participated on a data safety monitoring board or advisory board from Biogen, Novartis, Merck, Sanofi, Roche, and Alexion. HJK received grants or contracts from National Research Foundation of Korea, Aprilbio, and Eisai; received consulting fees from Aprilbio, Daewoong, HanAll BioPharma, MDimune, Roche, Sanofi Genzyme, Teva-Handok, UCB, and Viela Bio; and received honoraria from Alexion, Biogen, Celltrion, Eisai, GC Pharma, Merck Serono, Novartis, Sanofi Genzyme, and Teva-Handok. RM received consulting fees from UCB, Alexion, Merck, Viela Bio, Novartis, and Roche; and participated on an advisory board for Viela Bio and Roche. FP obtained research support from Alexion; received grants or contracts from German Ministry for Research Support Recipient Charité 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 from the Guthy Jackson Foundation, Bayer, Biogen, Merck Serono, Sanofi Genzyme, Novartis, Viela Bio, Roche, UCB, Mitsubishi Tanabe, and Celgene; received support for attending meetings from Guthy Jackson Foundation, Bayer, Biogen, Merck Serono, Sanofi Genzyme, Novartis, Alexion, Viela Bio, Roche, UCB, Mitsubishi Tanabe, and Celgene; participated on an advisory board for Celgene, Roche, UCB, Merck; and reports leadership as academic editor for Plos One, and associate editor for Neurology, Neuroimmunology, and Neuroinflammation. MBR received support for attending meeting from Novartis. BSD received consulting fees from Chiesi; received honoraria from Chiesi and Sanofi; received support for attending meetings from Bausch + Lomb; participated on an advisory board for Chiesi; and has stock options from Accure Therapeutics. DS received grants or contracts from National Institute of Neurological Disorders and Stroke (NINDS), National Institute of Mental Health (NIMH), American Academy of Neurology (AAN), National Institute of Aging (NIA), National Multiple Sclerosis Society (NMSS), and United States Department of State; and was a committee member for Multiple Sclerosis International Federation (MSIF) and American Neurological Association (ANA). AS received grants or contracts from the Turkish MS society, and Istanbul University Research Support Grants; received consulting fees from Roche, Merck Serono, Biogen, Gen Pharma of Türkiye, Sanofi Genzyme, and Novartis; received honoraria from Sanofi Genzyme, Novartis, Roche, and Teva; and received support for attending meetings from Sanofi Genzyme. VvP obtained grants or contracts from Biogen; received consulting fees from Biogen, Merck, Sanofi, BMS, Novartis, Janssen, Almirall, and Roche; received honoraria from Biogen, Merck, Sanofi, BMS, Novartis, Roche; and received support for attending meetings from Biogen, Roche, and Almirall. MPW received royalties from Springer Healthcare and Elsevier; received consulting fees from Biogen, Roche, Biologix, Novartis, BMS-Celgene, Imcyse, Merck Serono, Sanofi Aventis, IXICO, and Icometrix; received honoraria from Bayer, Biogen, Biologix, Genilac, Novartis, Medison, Merck Serono, Roche, Sanofi Aventis, and BMS-Celgene; and participated on a data safety monitoring board for VU University Medical Center. LB received consulting fees as editor for the Journal of Neuro-Ophthalmology. GTP is an Emeritus editor for Neuro-ophthalmology. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Inebilizumab is an anti-CD19 antibody approved for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults with aquaporin-4 autoantibodies. The relationship between B-cell, plasma-cell (PC), and immunoglobulin depletion with longitudinal reductions in NMOSD activity after inebilizumab treatment was characterised post hoc in an exploratory analysis from the N-MOmentum study (NCT02200770)., Methods: Peripheral blood CD20+ B cells, PC gene signature, and immunoglobulin levels were assessed throughout N-MOmentum (follow-up ≥2.5 years); correlations with clinical metrics and magnetic resonance imaging (MRI) lesion activity were assessed., Findings: Inebilizumab induced durable B-cell and PC depletion within 1 week versus placebo. Although no association was observed between B-cell counts at time of attack and NMOSD activity, depth of B-cell depletion after the first dosing period correlated with clinical outcomes. All participants receiving inebilizumab demonstrated a robust long-term therapeutic response, and participants with ≤4 cells/μL after the first 6-month dosing interval had persistently deeper B-cell depletion, lower annualised attack rates (estimated rate [95% CI]: 0.034 [0.024-0.04] vs 0.086 [0.056-0.12]; p = 0.045), fewer new/enlarging T2 MRI lesions (0.49 [0.43-0.56] vs 1.36 [1.12-1.61]; p < 0.0001), and a trend towards decreased Expanded Disability Status Scale worsening (0.076 [0.06-0.10] vs 0.14 [0.10-0.18]; p = 0.093). Antibodies to inebilizumab, although present in a proportion of treated participants, did not alter outcomes., Interpretation: This analysis suggests that compared with placebo, inebilizumab can provide specific, rapid, and durable depletion of B cells in participants with NMOSD. Although deep and persistent CD20+ B-cell depletion correlates with long-term clinical stability, early, deep B-cell depletion correlates with improved disease activity metrics in the first 2 years., Funding: Horizon Therapeutics (formerly from Viela Bio/MedImmune)., Competing Interests: Declaration of interests J.L.Bennett reports payment for study design/consultation from MedImmune; personal fees from AbbVie, Alexion, Antigenomycs, BeiGene, Chugai, Clene Nanomedicine, Genentech, Genzyme, Reistone Bio, Roche, and TG; grants from Alexion, the National Institutes of Health, and Novartis. In addition, Dr Bennett has a patent ‘Compositions and methods for the treatment of neuromyelitis optica’. O.Aktas reports grants from the German Research Foundation (DFG) and the German Ministry of Education and Research (BMBF); grants and personal fees from Bayer HealthCare, Biogen, Genzyme, Horizon Therapeutics (formerly from Viela Bio), Novartis, and Teva; and personal fees from Almirall, MedImmune, Merck Serono, and Roche. W.A.Rees, M.A.Smith, D.She, and D.Cimbora are employees of Horizon Therapeutics (formerly Viela Bio) and own stock. L.Yan, M.Gunsior, and E.Katz are former employees of Horizon Therapeutics. S.J.Pittock reports grants, personal fees, and non-financial support from Alexion Pharmaceuticals, Inc.; grants from Autoimmune Encephalitis Alliance and Grifols; grants, personal fees, non-financial support, and other from Horizon Therapeutics (formerly from Viela Bio) and MedImmune; personal fees for consulting services from Astellas; grants, personal fees, non-financial support and other from Roche/Genentech; personal fees for consulting services from UCB; and has a patent #9,891,219 (Application#12-573942) ’Methods for Treating Neuromyelitis Optica (NMO) by Administration of Eculizumab to an individual that is Aquaporin-4 (AQP4)-IgG Autoantibody Positive’. B.G.Weinshenker received payments for serving as chair of attack adjudication committees for clinical trials in NMOSD for Alexion, MedImmune, and Viela Bio/Horizon Therapeutics; has consulted with Chugai, Genentech, Horizon Therapeutics, Mitsubishi Tanabe Pharma, and Roche Pharmaceuticals; and has a patent for NMO-IgG for diagnosis of neuromyelitis optica, with royalties paid by Hospices Civils de Lyon, MVZ Labor PD Dr. Volkmann und Kollegen GbR, University of Oxford, and RSR. F.Paul has received research support, speaker honoraria, and travel reimbursement from Bayer, Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, and Teva; is supported by the German Research Council (DFG Exc 257) and the German Competence Network for Multiple Sclerosis; has received travel reimbursement from the Guthy-Jackson Charitable Foundation; and serves on the steering committee of the OCTIMS study, sponsored by Novartis. R.Marignier reports personal fees for consulting from Alexion, Horizon Therapeutics (formerly Viela Bio), Roche, and UCB. D.Wingerchuk reports personal fees from Biogen, Celgene, Genentech, MedImmune, Mitsubishi Tanabe, Novartis, Reistone Biopharma, and TG Therapeutics; research support paid to the Mayo Clinic by Alexion and Terumo BCT; and has served on a clinical trial adjudication committee for Horizon Therapeutics (formerly Viela Bio) and MedImmune. G.Cutter has received personal fees for participation on Data and Safety Monitoring Boards from AstraZeneca, Avexis Pharmaceuticals, BioLineRx, Brainstorm Cell Therapeutics, Bristol Myers Squibb/Celgene, CSL Behring, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Obesity Policy Research Unit oversight committee), Galmed Pharmaceuticals, Hisun Pharmaceutical, Horizon Pharmaceuticals (formerly Viela Bio), Mapi Pharma, Merck, Merck/Pfizer, the National Heart, Lung, and Blood Institute (Protocol Review Committee), Neurim Pharmaceuticals, Novartis, OncoImmune, OPKO Biologics, Orphazyme, Reata Pharmaceuticals, Sanofi-Aventis, Teva Pharmaceuticals, and Vivus; personal fees for consulting or advisory board participation from BioDelivery Sciences International, Biogen, Click Therapeutics, Genentech, Genzyme, GW Pharmaceuticals, Immunic, Klein Buendel, MedDay, MedImmune, NeuroGenesis, Novartis, Osmotica Pharmaceuticals, Perception Neurosciences, Recursion/Cerexis Pharmaceuticals, Roche, and TG Therapeutics; is employed by the University of Alabama at Birmingham, AL, USA; and is President of Pythagoras, Inc., a private consulting company based in Birmingham, AL, USA. A.Green reports grants from the Conrad N. Hilton Foundation and the Tom Sherak MS Hope Foundation; other financial relationships (for activities as expert witness, associate editor, advisory board/steering committee participation, and endpoint adjudication) with Bionure, Inception Sciences, JAMA Neurology, MedImmune/Horizon Therapeutics (formerly Viela Bio), Mylan, Synthon, and Trims Pharma; and personal fees from and other financial relationships with Pipeline Therapeutics. H.-P.Hartung has received fees for consulting, speaking, and serving on steering committees from Bayer HealthCare, Biogen Idec, Celgene Receptos, CSL Behring, GeNeuro, Genzyme, Horizon Therapeutics (formerly Viela Bio), MedDay, MedImmune, Merck Serono, Novartis, Roche, Sanofi, and TG Therapeutics with approval by the Rector of Heinrich Heine University Düsseldorf. H.J.Kim has received a grant from the National Research Foundation of Korea; consultancy/speaker fees or research support from Alexion, AprilBio, Celltrion, Daewoong Pharmaceutical, Eisai, GC Pharma, HanAll Biopharma, Horizon Therapeutics (formerly Viela Bio), Kolon Life Science, MedImmune, Merck Serono, Mitsubishi Tanabe Pharma, Novartis, Sanofi Genzyme, Teva-Handok, and UCB; and is a co-editor for the Multiple Sclerosis Journal and an associate editor for the Journal of Clinical Neurology. K.Fujihara has received fees for consulting, speaking, and serving on steering committees from AbbVie, Alexion, Asahi Kasei Kuraray Medical Co., Biogen, Chugai/Roche, Eisai, Japan Tobacco, MedImmune/Viela Bio, Merck, Merck Biopharma, Mitsubishi Tanabe Pharma, Novartis, Teijin, Takeda Pharmaceutical Company, and UCB; and a grant-in-aid for scientific research from the Ministry of Health, Labour and Welfare of Japan. M.Levy currently receives research support from Acorda Therapeutics, Alexion, Alnylam Pharmaceuticals, ApoPharma, Maryland Technology Development Corporation, the National Institutes of Health, Sanofi Genzyme, and Shire/Takeda; has received personal compensation for consultation with Acorda Therapeutics, Alexion, and Genzyme; and serves on the scientific advisory boards for Acorda Therapeutics, Alexion, and Quest Diagnostics. B.A.C.Cree reports personal compensation for consulting from Alexion, Atara Biotherapeutics, Autobahn Therapeutics, Avotres Inc., Biogen, Boston Pharma, EMD Serono, Gossamer Bio, Hexal/Sandoz, Horizon Therapeutics, Neuron23, Novartis, Sanofi, Siemens, TG Therapeutics, and Therini Bio; and has received research support from Genentech., (Copyright © 2022 Horizon Therapeutics plc. Published by Elsevier B.V. All rights reserved.)

Background: Aquaporin-4 immunoglobulin-G positive (AQP4-IgG + ) neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy associated with optic neuritis (ON). Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an oligodendrocytopathy with a similar phenotype. Serum glial fibrillary acidic protein (sGFAP), an astrocyte-derived protein, is associated with disease severity in AQP4-IgG + NMOSD. Serum neurofilament light (sNfL) indicates neuroaxonal damage. The objective was to investigate the association of sGFAP and sNfL with subclinical afferent visual system damage in clinically stable AQP4-IgG + NMOSD and MOGAD patients., Methods: In this cross-sectional study, clinically stable patients with AQP4-IgG + NMOSD (N = 33) and MOGAD (N = 16), as diseased controls, underwent sGFAP and sNfL measurements by single molecule array, retinal optical coherence tomography and visually evoked potentials., Results: Higher sGFAP concentrations were associated with thinner ganglion cell-inner plexiform layer (β (95% confidence interval (CI)) = -0.75 (-1.23 to -0.27), p = 0.007) and shallower fovea (average pit depth: β (95%CI) = -0.59 (-0.63 to -0.55), p = 0.020) in NMOSD non-ON eyes. Participants with pathological P100 latency had higher sGFAP (median [interquartile range]: 131.32 [81.10-179.34] vs. 89.50 [53.46-121.91] pg/ml, p = 0.024). In MOGAD, sGFAP was not associated with retinal structural or visual functional measures., Conclusions: The association of sGFAP with structural and functional markers of afferent visual system damage in absence of ON suggests that sGFAP may be a sensitive biomarker for chronic disease severity in clinically stable AQP4-IgG + NMOSD., Competing Interests: Declaration of Competing Interest T.-Y. Lin, P. Schindler, U. Grittner, A. Lu, A.S. Duchow, S. Jarius, J. Kuhle, P. Benkert and T. Schmitz-Hübsch report no relevant disclosures. F.C. Oertel was an employee of Nocturne GmbH and receives research support by the American Academy of Neurology, the National Multiple Sclerosis Society and Deutsche Gesellschaft für Neurologie (German Neurology Society), unrelated to this work. S. Motamedi is named as co-inventor on the patent application for the foveal shape analysis method used by this manuscript (“Method for estimating shape parameters of the fovea by optical coherence tomography”, International Publication Number: “WO 2019/016319 A1”). S.K. Yadav is named as co-inventor on the patent application for the foveal shape analysis method used by this manuscript (“Method for estimating shape parameters of the fovea by optical coherence tomography”, International Publication Number: “WO 2019/016319 A1”) and a cofounder of medical technology companies Nocturne GmbH. A.U. Brandt is cofounder and shareholder of medical technology companies Nocturne GmbH and Motognosis GmbH. He is named as inventor on several patent applications describing MS biomarkers, visual perceptive computing based motor function analysis, and retinal image analysis. J. Bellmann-Strobl has received speaking honoraria and travel grants from Bayer Healthcare, and sanofi-aventis/Genzyme, in addition received compensation for serving on a scientific advisory board of Roche, unrelated to the presented work. F. Paul served on the scientific advisory boards of Novartis and MedImmune; received travel funding and/or speaker honoraria from Bayer, Novartis, Biogen, Teva, Sanofi-Aventis/Genzyme, Merck Serono, Alexion, Chugai, MedImmune, and Shire; is an associate editor of Neurology: Neuroimmunology & Neuroinflammation; is an academic editor of PLoS ONE; consulted for Sanofi Genzyme, Biogen, MedImmune, Shire, and Alexion; received research support from Bayer, Novartis, Biogen, Teva, Sanofi-Aventis/Geynzme, Alexion, and Merck Serono; and received research support from the German Research Council, Werth Stiftung of the City of Cologne, German Ministry of Education and Research, Arthur Arnstein Stiftung Berlin, EU FP7 Framework Program, Arthur Arnstein Foundation Berlin, Guthy-Jackson Charitable Foundation, and NMSS. K. Ruprecht received research support from Novartis, Merck Serono, German Ministry of Education and Research, European Union (821283-2), Stiftung Charité (BIH Clinical Fellow Program) and Arthur Arnstein Foundation; received travel grants from Guthy-Jackson Charitable Foundation. H.G. Zimmermann received research grants from Novartis and speaking honoraria from Bayer Healthcare and Novartis., (Copyright © 2022. Published by Elsevier B.V.)

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a rare demyelinating autoimmune disorder of the central nervous system. MOGAD frequently manifests with severe, bilateral, and episodes of recurrent optic neuritis (ON) and is an important differential diagnosis to multiple sclerosis and aquaporin-4-IgG seropositive neuromyelitis optica spectrum disorders. Besides ON, the clinical manifestations of MOGAD commonly include transverse myelitis, acute disseminated encephalomyelitis, and brain stem encephalitis. In this review, we summarize the current knowledge of the neuro-ophthalmological presentation of MOGAD-ON. We describe epidemiological aspects, including the association with COVID-19 and other infections or vaccinations, clinical presentation, and imaging findings of MOGAD-ON in the acute stage and during remission. Furthermore, we report findings on prognosis, treatment response, and changes in ON-unaffected eyes. We touch upon findings on visual acuity, visual fields, and visual evoked potentials, as well as structural changes assessed with optical coherence tomography. Moreover, we explain how to differentiate MOGAD from its differential diagnoses, including other neuroinflammatory disorders (multiple sclerosis and neuromyelitis optica spectrum disorders), but also idiopathic intracranial hypertension., Competing Interests: F. Paul served on the scientific advisory boards of Novartis and MedImmune; received travel funding and/or speaker honoraria from Bayer, Novartis, Biogen, Teva, Sanofi-Aventis/Genzyme, Merck Serono, Alexion, Chugai, MedImmune, and Shire; is an associate editor of Neurology: Neuroimmunology & Neuroinflammation; is an academic editor of PLoS ONE; consulted for Sanofi Genzyme, Biogen, MedImmune, Shire, and Alexion; received research support from Bayer, Novartis, Biogen, Teva, Sanofi-Aventis/Geynzme, Alexion, and Merck Serono; and received research support from the German Research Council, Werth Stiftung of the City of Cologne, German Ministry of Education and Research, Arthur Arnstein Stiftung Berlin, EU FP7 Framework Program, Arthur Arnstein Foundation Berlin, Guthy-Jackson Charitable Foundation, and NMSS. H. G. Zimmermann received research grants from Novartis and speaking honoraria from Bayer Healthcare and Novartis., (Thieme. All rights reserved.)

Aquaporin-4 antibody-seropositive neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD; also termed MOG encephalomyelitis) are autoimmune diseases of the central nervous system. The typical initial manifestations in adult patients are optic neuritis and myelitis. Patients often present with additional involvement of the brain and brainstem, more so in the later stages of the disease. While NMOSD commonly follows a relapsing course, MOGAD can sometimes be monophasic. Differential diagnosis is challenging and relies particularly on radiological and serological findings. It is very important to distinguish these rare diseases from the more common neuroinflammatory disease, multiple sclerosis (MS), since treatment and long-term prognoses for NMOSD, MOGAD and MS differ greatly. The diversity of the symptoms and the extent of the diagnostic work-up necessitate close collaboration between ophthalmology, neurology, and radiology. This article provides an overview of the typical MRI findings and serological antibody diagnostics for NMOSD and MOGAD, supplemented with two exemplary case reports from clinical practice., Competing Interests: Friedemann Paul: Vortragshonorar/Reisekosten von Alexion, Guthy Jackson Charitable Foundation, Bayer, Biogen, Merck Serono, Sanofi Genzyme, Novartis, Viela Bio, Roche, UCB, Mitsubishi Tanabe, Celgene (nicht im Zusammenhang mit diesem Artikel); Forschungsgelder von Alexion, Bundesministerium für Bildung und Forschung, Deutsche Forschungsgemeinschaft, Einstein Foundation, Guthy Jackson Charitable Foundation, EU FP7 Framework Program, Biogen, Genzyme, Merck Serono, Novartis, Bayer, Roche, Parexel, Almirall (nicht im Zusammenhang mit diesem Artikel); akademischer Editor für PLoS ONE; Associate Editor für Neurology Neuroimmunology & Neuroinflammation; wissenschaftliche Konsultation for SanofiGenzyme, Biogen Idec, MedImmune, Shire, und Alexion; wissenschaftlicher Beirat für Celgene, Roche, UCB, Merck. Claudia Chien; Vortragshonorar von Bayer und Forschungsgelder von Novartis (nicht im Zusammenhang mit diesem Artikel)./Friedemann Paul: Speaker fees/travel costs from Alexion, the Guthy Jackson Charitable Foundation, Bayer, Biogen, Merck Serono, Sanofi Genzyme, Novartis, Viela Bio, Roche, UCB, Mitsubishi Tanabe, and Celgene (not related to this article); research funding from Alexion, the Federal Ministry of Education and Research, the German Research Foundation, the Einstein Foundation, the Guthy Jackson Charitable Foundation, the EU FP7 Framework Program, Biogen, Genzyme, Merck Serono, Novartis, Bayer, Roche, Parexel, and Almirall (not related to this article); academic editor for PLoS ONE; associate editor for Neurology Neuroimmunology & Neuroinflammation; academic consultant for SanofiGenzyme, Biogen Idec, MedImmune, Shire, and Alexion; member of scientific advisory board for Celgene, Roche, UCB, and Merck. Claudia Chien; speaker fees from Bayer and research funding from Novartis (not related to this article)., (Thieme. All rights reserved.)

Optic neuritis (ON) in neuromyelitis optica spectrum disorders (NMOSD) regularly leads to more profound vision loss compared to multiple sclerosis (MS) and myelin-oligodendrocyte-glycoprotein-antibody associated disease (MOGAD). Here we investigate ON-related vision loss in NMOSD compared to MS and MOGAD in order to identify neuroaxonal and retinal contributors to visual dysfunction. In this retrospective study we included patients with aquaporin-4-antibody seropositive NMOSD (n = 28), MOGAD (n = 14), MS (n = 29) and controls (n = 14). We assessed optic nerve damage and fovea morphometry by optical coherence tomography. Visual function was assessed as high (HCVA) and low contrast visual acuity (LCVA), and visual fields' mean deviation (MD). In all diseases, lower visual function was associated with peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell and inner plexiform layer (GCIP) thinning following a broken stick model, with pRNFL and GCIP cutoff point at ca. 60 µm. HCVA loss per µm pRNFL and GCIP thinning was stronger in NMOSD compared with MOGAD. Foveal inner rim volume contributed to MD and LCVA in NMOSD eyes, only. Together these data supports that visual dysfunction in NMOSD is associated with neuroaxonal damage beyond the effect seen in MS and MOGAD. A primary retinopathy, respectively Müller cell pathology, may contribute to this effect., (© 2022. The Author(s).)

Background: In neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), neutrophils are found in CNS lesions. We previously demonstrated that NMOSD neutrophils show functional deficiencies. Thus, we hypothesized that neutrophil accumulation in the CNS may be facilitated by impairments affecting mechanisms of neutrophil death., Objective: To evaluate cell death in blood neutrophils from aquaporin-4 (AQP4)-IgG-seropositive NMOSD and MOGAD patients as well as matched healthy controls (HC) using in vitro assays., Methods: Twenty-eight AQP4 + NMOSD and 19 MOGAD patients in stable disease phase as well as 45 age- and sex-matched HC were prospectively recruited. To induce cell death, isolated neutrophils were cultured with/without phorbol 12-myristate 13-acetate (PMA). Spontaneous and PMA-induced NETosis and apoptosis were analyzed using 7-AAD and annexin-V by flow cytometry. Caspase-3 was assessed by western blot. Myeloperoxidase-DNA complexes (MPO-DNA), MPO and elastase were evaluated by ELISA, and cell-free DNA (cfDNA) by a fluorescence-based assay. Reactive oxygen species (ROS) were evaluated by a dihydrorhodamine 123-based cytometric assay. Serum GM-CSF, IL-6, IL-8, IL-15, TNF-ɑ and IL-10 were evaluated by multiplex assays, and neurofilament light chain (NfL) by single-molecule array assay., Results: In response to PMA, neutrophils from AQP4 + NMOSD but not from MOGAD patients showed an increased survival, and subsequent reduced cell death (29.6% annexin V + 7-AAD + ) when compared to HC (44.7%, p = 0.0006). However, AQP4 + NMOSD also showed a mild increase in annexin V + 7-AAD - early apoptotic neutrophils (24.5%) compared to HC (20.8%, p = 0.048). PMA-induced reduction of caspase-3 activation was more pronounced in HC (p = 0.020) than in AQP4 + NMOSD neutrophils (p = 0.052). No differences were observed in neutrophil-derived MPO-DNA or serum levels of MPO, elastase, IL-6, IL-8 and TNF-ɑ. IL-15 levels were increased in both groups of patients. In AQP4 + NMOSD, an increase in cfDNA, GM-CSF and IL-10 was found in serum. A positive correlation among cfDNA and NfL was found in AQP4 + NMOSD., Conclusions: AQP4 + NMOSD neutrophils showed an increased survival capacity in response to PMA when compared to matched HC neutrophils. Although the data indicate that the apoptotic but not the NETotic response is altered in these neutrophils, additional evaluations are required to validate this observation., (© 2022. The Author(s).)

Background: Despite rigorous confirmation with reliable assays, some individuals showing the neuromyelitis optica spectrum disorder (NMOSD) phenotype remain negative for both aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibodies., Objective: We aimed to investigate whether double seronegative NMOSD (DN-NMOSD) and NMOSD with AQP4 antibody (AQP4-NMOSD) share the same pathophysiological basis, astrocytopathy, by measurement of cerebrospinal fluid (CSF) glial fibrillary acidic protein (GFAP) levels as a marker of astrocyte damage., Methods: Seventeen participants who (1) satisfied the 2015 diagnostic criteria for NMOSD, and (2) tested negative for AQP4 and MOG antibodies confirmed with repeated cell-based assays, and (3) had available CSF samples obtained at the point of clinical attacks, were enrolled from 4 medical centers (South Korea, Germany, Thailand, and Denmark). Thirty age-matched participants with AQP4-NMOSD, 17 participants with MOG antibody associated disease (MOGAD), and 15 participants with other neurological disorders (OND) were included as controls. The concentration of CSF GFAP was measured using enzyme-linked immunosorbent assay., Results: CSF GFAP levels in the DN-NMOSD group were significantly lower than those in the AQP4-NMOSD group (median: 0.49 versus 102.9 ng/mL; p < 0.001), but similar to those in the OND (0.25 ng/mL) and MOGAD (0.39 ng/mL) control groups. The majority (90% (27/30)) of participants in the AQP4-NMOSD group showed significantly higher CSF GFAP levels than the highest level measured in the OND group, while no participant in the DN-NMOSD and MOGAD groups did., Conclusions: These results suggest that DN-NMOSD has a different underlying pathogenesis other than astrocytopathy, distinct from AQP4-NMOSD., (© 2022. The Author(s).)

Background: Decreased motion perception has been suggested as a marker for visual pathway demyelination in optic neuritis (ON) and/or multiple sclerosis (MS)., Objectives: To examine the influence of neuro-axonal damage on motion perception in MS and neuromyelitis optica spectrum disorders (NMOSD)., Methods: We analysed motion perception with numbers-from-motion (NFM), visual acuity, (multifocal (mf)) VEP, optical coherence tomography in patients with MS ( n = 38, confirmatory cohort n = 43), NMOSD ( n = 13) and healthy controls ( n = 33)., Results: NFM was lower compared with controls in MS ( B = -12.37, p < 0.001) and NMOSD ( B = -34.5, p < 0.001). NFM was lower in ON than in non-ON eyes ( B = -30.95, p = 0.041) in NMOSD, but not MS. In MS and NMOSD, lower NFM was associated with worse visual acuity ( B = -139.4, p < 0.001/ B = -77.2, p < 0.001) and low contrast letter acuity ( B = 0.99, p = 0.002/ B = 1.6, p < 0.001), thinner peripapillary retinal nerve fibre layer ( B = 1.0, p < 0.001/ B = 0.92, p = 0.016) and ganglion cell/inner plexiform layer ( B = 64.8, p < 0.001/ B = 79.5, p = 0.006), but not with VEP P100 latencies. In the confirmatory MS cohort, lower NFM was associated with thinner retinal nerve fibre layer ( B = 1.351, p < 0.001) and increased mfVEP P100 latencies ( B = -1.159, p < 0.001)., Conclusions: Structural neuro-axonal visual pathway damage is an important driver of motion perception impairment in MS and NMOSD.

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.)

Background and Objectives: The choroid plexus has been shown to play a crucial role in CNS inflammation. Previous studies found larger choroid plexus in multiple sclerosis (MS) compared with healthy controls. However, it is not clear whether the choroid plexus is similarly involved in MS and in neuromyelitis optica spectrum disorder (NMOSD). Thus, the aim of this study was to compare the choroid plexus volume in MS and NMOSD., Methods: In this retrospective, cross-sectional study, patients were included by convenience sampling from 4 international MS centers. The choroid plexus of the lateral ventricles was segmented fully automatically on T1-weighted MRI sequences using a deep learning algorithm (Multi-Dimensional Gated Recurrent Units). Uni- and multivariable linear models were applied to investigate associations between the choroid plexus volume, clinically meaningful disease characteristics, and MRI parameters., Results: We studied 180 patients with MS and 98 patients with NMOSD. In total, 94 healthy individuals and 47 patients with migraine served as controls. The choroid plexus volume was larger in MS (median 1,690 µL, interquartile range [IQR] 648 µL) than in NMOSD (median 1,403 µL, IQR 510 µL), healthy individuals (median 1,533 µL, IQR 570 µL), and patients with migraine (median 1,404 µL, IQR 524 µL; all p < 0.001), whereas there was no difference between NMOSD, migraine, and healthy controls. This was also true when adjusted for age, sex, and the intracranial volume. In contrast to NMOSD, the choroid plexus volume in MS was associated with the number of T2-weighted lesions in a linear model adjusted for age, sex, total intracranial volume, disease duration, relapses in the year before MRI, disease course, Expanded Disability Status Scale score, disease-modifying treatment, and treatment duration (beta 4.4; 95% CI 0.78-8.1; p = 0.018)., Discussion: This study supports an involvement of the choroid plexus in MS in contrast to NMOSD and provides clues to better understand the respective pathogenesis., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Identification of triggers that potentially instigate attacks in neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) has remained challenging. We aimed to analyze the seasonality of NMOSD and MS attacks in an Argentinean cohort seeking differences between the two disorders., Methods: A retrospective study was conducted in a cohort of NMOSD and MS patients followed in specialized centers from Argentina and enrolled in RelevarEM, a nationwide, longitudinal, observational, non-mandatory registry of MS/NMOSD patients. Patients with complete relapse data (date, month and year) at onset and during follow-up were included. Attack counts were analyzed by month using a Poisson regression model with the median monthly attack count used as reference., Results: A total of 551 patients (431 MS and 120 NMOSD), experiencing 236 NMOSD-related attacks and 558 MS-related attacks were enrolled. The mean age at disease onset in NMOSD was 39.5 ± 5.8 vs. 31.2 ± 9.6 years in MS (p < 0.01). Mean follow-up time was 6.1 ± 3.0 vs. 7.4 ± 2.4 years (p < 0.01), respectively. Most of the included patients were female in both groups (79% vs. 60%, p < 0.01). We found a peak of number of attacks in June (NMOSD: 28 attacks (11.8%) vs MS: 33 attacks (5.9%), incidence rate ratio 1.82, 95%CI 1.15-2.12, p = 0.03), but no differences were found across the months in both disorders when evaluated separately. Strikingly, we observed a significant difference in the incidence rate ratio of attacks during the winter season when comparing NMOSD vs. MS (NMOSD: 75 attacks (31.7%) vs MS: 96 attacks (17.2%), incidence rate ratio 1.82, 95%CI 1.21-2.01, p = 0.02) after applying Poisson regression model. Similar results were observed when comparing the seropositive NMOSD (n = 75) subgroup vs. MS., Conclusions: Lack of seasonal variation in MS and NMOSD attacks was observed when evaluated separately. Future epidemiological studies about the effect of different environmental factors on MS and NMOSD attacks should be evaluated prospectively in Latin America population., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Patients with anti-aquaporin-4 antibody seropositive (AQP4-IgG+) neuromyelitis optica spectrum disorders (NMOSDs) frequently suffer from optic neuritis (ON) leading to severe retinal neuroaxonal damage. Further, the relationship of this retinal damage to a primary astrocytopathy in NMOSD is uncertain. Primary astrocytopathy has been suggested to cause ON-independent retinal damage and contribute to changes particularly in the outer plexiform layer (OPL) and outer nuclear layer (ONL), as reported in some earlier studies. However, these were limited in their sample size and contradictory as to the localisation. This study assesses outer retinal layer changes using optical coherence tomography (OCT) in a multicentre cross-sectional cohort., Method: 197 patients who were AQP4-IgG+ and 32 myelin-oligodendrocyte-glycoprotein antibody seropositive (MOG-IgG+) patients were enrolled in this study along with 75 healthy controls. Participants underwent neurological examination and OCT with central postprocessing conducted at a single site., Results: No significant thinning of OPL (25.02±2.03 µm) or ONL (61.63±7.04 µm) were observed in patients who were AQP4-IgG+ compared with patients who were MOG-IgG+ with comparable neuroaxonal damage (OPL: 25.10±2.00 µm; ONL: 64.71±7.87 µm) or healthy controls (OPL: 24.58±1.64 µm; ONL: 63.59±5.78 µm). Eyes of patients who were AQP4-IgG+ (19.84±5.09 µm, p=0.027) and MOG-IgG+ (19.82±4.78 µm, p=0.004) with a history of ON showed parafoveal OPL thinning compared with healthy controls (20.99±5.14 µm); this was not observed elsewhere., Conclusion: The results suggest that outer retinal layer loss is not a consistent component of retinal astrocytic damage in AQP4-IgG+ NMOSD. Longitudinal studies are necessary to determine if OPL and ONL are damaged in late disease due to retrograde trans-synaptic axonal degeneration and whether outer retinal dysfunction occurs despite any measurable structural correlates., Competing Interests: Competing interests: HZ reports grants from Novartis and speaking honoraria from Bayer Healthcare, unrelated to this study. EHM-L received funding from the Instituto de Salud Carlos III (Spain) and Fondo Europeo de Desarrollo Regional (FEDER-JR16/00006), Grant for MS Innovation, Fundació Privada Cellex and Marató TV3 Charitable Foundation and is a researcher in the OCTIMS study, an observational study (that involves no specific drugs) to validate SD-OCT as a biomarker for MS, sponsored by Novartis and has received honoraria and travel support for international and national meetings over the last 3 years from from Biogen, Novartis, Roche, Genzyme. She is a member of the working committee of International Multiple Sclerosis Visual System (IMSVISUAL) Consortium. MAL-P has received funding for travel and speaker honoraria from Novartis, Sanofi- Genzyme and Roche. MAF has nothing to disclose. Jacqueline Palace has received support for scientific meetings and honorariums for advisory work From Merck Serono, Novartis, Chugai, Alexion, Roche, Medimmune, Argenx, UCB, Mitsubishi, Amplo, Janssen. Grants from Alexion, Amplo biotechnology. Shares in AstraZenica. Acknowledges Partial funding by Highly specialised services NHS England. MIL reported being involved in aquaporin 4 testing, receiving salary from the National Health Service National Highly Specialised Commissioning Group for Neuromyelitis Optica, UK, being supported by the National Institute for Health Research Oxford Biomedical Research Centre, UK, and receiving speaking honoraria and travel grants from Biogen Idec, and travel grant from Novartis. SMS has nothing to disclose. AR-F is sponsored by Abide Therapeutic outside of the submitted work and reports no potential conflicts of interest. SSiritho received funding for travel and speaker honoraria from Merck Serono, Pacific Healthcare (Thailand), Menarini (Thailand), Biogen Idec, UCB (Thailand), and Novartis. AA reports personal fees from received honoraria for giving educational presentations on multiple sclerosis and neuroimmunology at several national congresses or symposia from Teva Turkey, Merck-Serono, Biogen Idec-Gen Pharma of Turkey, Roche, Novartis, Bayer, Sanofi-Genzyme. She has received travel and registration coverage for attending several national and international congresses or symposia from Merck-Serono, Biogen Idec-Gen Pharma of Turkey, Roche, Sanofi-Genzyme and Bayer. AJ has received compensation for advisory board, consulting, meeting attendance and speaking from Biogen, Terumo-BCT, Genentech, Shire and Chugai Pharmaceuticals. SH has received funding from the NMO Spectrum-UK charity and was previously funded by an MGA/Watney/NIHR Oxford Biomedical research grant. RM serves on scientific advisory board for MedImmune and has received funding for travel and honoraria from Biogen, Merck Serono, Novartis, Sanofi- Genzyme, Roche and Teva. EN has nothing to disclose. ACC received funding from the Instituto de Salud Carlos III (Spain) JR19/00007 unrelated to this manuscript. DB has received speaking/consulting honoraria from Bayer Health Care, Biogen Idec, Merck, Sanofi-Genzyme, TEVA and Roche and had travel expenses to scientific meetings sponsored by Bayer Health Care, Merck Serono, TEVA and Roche. JH reports grants for OCT 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. JH is partially funded by the German Federal Ministry of Education and Research (DIFUTURE), Grant Numbers 01ZZ1603[A-D] and 01ZZ1804[A-H]. LL received honoraria for consulting services from Merck, Roche, Biogen and for speaking activities from Teva; research support from Merck, Biogen, Novartis; travel support from Merck, Roche, Biogen, Almirall. MP has nothing to disclose. OA has received honoraria for speaking/consultation and travel grants from Bayer Healthcare, Biogen Idec, Chugai, Novartis, Medimmune, Merck Serono, and Teva and research grants from Bayer Healthcare, Biogen Idec, Novartis, and Teva. MR received speaker honoraria from Novartis, Bayer, Roche, Alexion and Ipsen and travel reimbursement from Bayer, Biogen, Merz, Genzyme, Teva, Roche and Merck, none related to this study. PA reports grants, personal fees and non-financial support from Allergan, Biogen, Ipsen, Merz Pharmaceuticals, Novartis, and Roche, personal fees and non-financial support from Bayer Healthcare, and Merck, and non-financial support from Sanofi-Aventis/Genzyme. HJK reports speaking and/or consulting: Bayer Schering Pharma, Biogen, Celltrion, Eisai, HanAll BioPharma, MedImmune, Merck Serono, Novartis, Sanofi Genzyme, Teva-Handok, and UCB; research support: Ministry of Science & ICT, Sanofi Genzyme, Teva-Handok, and UCB; steering committee member: MedImmune; co-editor/associated editor: MS Journal-Experimental, Translational and Clinical; and Journal of Clinical Neurology. J-WH has received a grant from the National Research Foundation of Korea. YM-D has served as a consultant and/or received grant support from: Acorda, Bayer Pharmaceutical, Biogen Idec, Celgene, EMD Serono, Genzyme, Novartis, Questor, Chugai, and Teva Neuroscience and is currently supported by grants from NIH NIAID Autoimmune Center of Excellence: UM1-AI110557; NIH NINDS R01-NS080821. HSK has nothing to disclose. IK served on scientific advisory board for Biogen Idec and Genentech and received research support from Guthy-Jackson Charitable Foundation, National Multiple Sclerosis Society, Biogen-Idec,Serono, Genzyme and Novartis. ZR has nothing to disclose. AR has nothing to disclose. MRY is founder and a shareholder of NovaDigm Therapeutics, Inc; he receives funding from the United States National Institutes of Health and United States Department of Defense; he holds US and international patents on immunotherapeutic and anti-infective technologies, is a member of the Genentech-Roche Scientific Advisory Committee and adviser to The Guthy-Jackson Charitable Foundation. TJS was issued US patents covering the therapeutic targeting of IGF-I receptor in autoimmune diseases. He is a paid consultant for Horizon Thera and Immunovant and is a scientific advisor to the Guthy-Jackson Charitable Foundation. He receives research funding from the National Institutes of Health. AP is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Moorfields Eye Hospital National Health Service (NHS) Foundation Trust and University College London Institute of Ophthalmology. AB is cofounder and shareholder of Motognosis and Nocturne. He is named as inventor on several patent applications regarding MS serum biomarkers, OCT image analysis and perceptive visual computing. 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. FCO was employee of Nocturne GmbH and receives research support by the American Academy of Neurology and National Multiple Sclerosis Society (US), unrelated to this work as well as funding by the German Association of Neurology (Deutsche Gesellschaft für Neurologie) in context of this project.CC has received a speaking honorarium from Bayer and research funding from Novartis unrelated to this publication. All other authors have nothing to disclose., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The N-MOmentum trial, a double-blind, randomized, placebo-controlled, phase 2/3 study of inebilizumab in neuromyelitis optica spectrum disorder (NMOSD), enrolled participants who were aquaporin-4-immunoglobulin G (AQP4-IgG)-seropositive (AQP4+) or -seronegative (AQP4-). This article reports AQP4- participant outcomes., Methods: AQP4-IgG serostatus was determined for all screened participants by a central laboratory, using a validated, fluorescence-observation cell-binding assay. Medical histories and screening data for AQP4- participants were assessed independently by an eligibility committee of three clinical experts during screening. Diagnosis of NMOSD was confirmed by majority decision using the 2006 neuromyelitis optica criteria. Myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG) serology (using a clinically validated, flow cytometry assay) and annualized attack rates (AARs) were evaluated post hoc. Efficacy outcomes were assessed by comparing pre-study and on-study AARs in treated participants., Results: Only 18/50 AQP4- screened participants (36%) were initially considered eligible for randomization; 16 were randomized and received full treatment, 4 to placebo (1 MOG-IgG-seropositive [MOG+]) and 12 to inebilizumab (6 MOG+). The most common reason for failure to pass screening among prospective AQP4- participants was failure to fulfill the 2006 NMO MRI criteria. In inebilizumab-treated AQP4- participants, on-study AARs (95% confidence interval [CI]) calculated from treatment initiation (whether from randomization or when received at the start of the open-label period) to the end of study were lower than pre-study rates: for all AQP4- participants (n = 16), mean (95% CI) AAR was 0.048 (0.02-0.15) versus 1.70 (0.74-2.66), respectively. For the subset of AQP4-/MOG+ participants (n = 7), AAR was 0.043 (0.006-0.302) after treatment versus 1.93 (1.10-3.14) before the study. For the subset of AQP4-/MOG- participants (n = 9), post-treatment AAR was 0.051 (0.013-0.204) versus 1.60 (1.02-2.38). Three attacks occurred during the randomized controlled period in the AQP4- inebilizumab group and were of mild severity; no attacks occurred in the AQP4- placebo group. The low number of participants receiving placebo (n = 4) confounds direct comparison with the inebilizumab group. No attacks were seen in any AQP4- participant after the second infusion of inebilizumab. Inebilizumab was generally well tolerated by AQP4- participants and the adverse event profile observed was similar to that of AQP4+ participants., Conclusion: The high rate of rejection of AQP4- participants from enrollment into the study highlights the challenges of implementing the diagnostic criteria of AQP4- NMOSD. An apparent reduction of AAR in participants with AQP4- NMOSD who received inebilizumab warrants further investigation., (Copyright © 2021. Published by Elsevier B.V.)

Myelin oligodendrocyte glycoprotein antibody-associated disorders (MOGAD) are rare in both children and adults, and have been recently suggested to be an autoimmune neuroinflammatory group of disorders that are different from aquaporin-4 autoantibody-associated neuromyelitis optica spectrum disorder and from classic multiple sclerosis. In-vivo imaging of the MOGAD patient central nervous system has shown some distinguishing features when evaluating magnetic resonance imaging of the brain, spinal cord and optic nerves, as well as retinal imaging using optical coherence tomography. In this review, we discuss key clinical and neuroimaging characteristics of paediatric and adult MOGAD. We describe how these imaging techniques may be used to study this group of disorders and discuss how image analysis methods have led to recent insights for consideration in future studies., (© 2021 The Authors. Clinical & Experimental Immunology published by John Wiley & Sons Ltd on behalf of British Society for Immunology.)