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OBJECTIVES: Global brain volume changes in patients with myelin oligodendrocyte glycoprotein antibody-associated disease compared with healthy controls (HC) could be revealed by magnetic resonance imaging, but specific atrophy patterns of cortical structures and relation to cognitive impairment are not yet comprehensively known. Thus, we aimed to investigate cortical thickness differences in patients with myelin oligodendrocyte glycoprotein antibody-associated disease compared with HC. METHODS: 3-Tesla brain magnetic resonance imaging was performed in 23 patients with myelin oligodendrocyte glycoprotein antibody-associated disease and 49 HC for voxel-wise group comparisons and neuropsychological testing in patients. Surface-based morphometry with region of interest-based surface analysis and region of interest-based extraction of cortical thickness was performed in patients compared with HC and in patient subgroups with and without cognitive impairment. RESULTS: Comparing patients with myelin oligodendrocyte glycoprotein antibody-associated disease with HC, exploratory surface-based morphometry demonstrated cortical volume reduction in pericalcarine and lingual cortical regions. Region of interest-based surface analysis specified reduced cortical thickness in the adjacent pericalcarine and orbitofrontal regions in myelin oligodendrocyte glycoprotein antibody-associated disease, as well as reduced temporal cortical thickness in patients with cognitive impairment (n = 10). Patients without cognitive impairment (n = 13) showed only circumscribed cortical brain volume loss compared with HC in the pericalcarine region. INTERPRETATION: In conclusion, cortical atrophy in myelin oligodendrocyte glycoprotein antibody-associated disease was characterized by cortical thickness reduction in the adjacent pericalcarine and orbitofrontal regions, with a tendency of temporal thickness reduction in cognitively impaired patients.

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BACKGROUND AND OBJECTIVES: Progressive multifocal leukoencephalopathy (PML) is a severe neurologic disease resulting from JC virus reactivation in immunocompromised patients. Certain multiple sclerosis (MS) disease-modifying therapies (DMTs) are associated with PML risk, such as natalizumab and, more rarely, sphingosine-1-phosphate receptor modulators (S1P-RMs). Although natalizumab-associated PML is well documented, information on S1P-RM-associated PML is limited. The aim of this study is to compare clinical presentations and outcomes between the 2 groups. METHODS: A retrospective multicenter cohort study included patients with PML from 2009 to 2022 treated with S1P-RMs or natalizumab. Data on clinical and radiologic presentation, outcomes, immune reconstitution inflammatory syndrome (IRIS), survival, disability (using the modified Ranking scale-mRS), and MS relapses post-PML were analyzed. RESULTS: Of 88 patients, 84 were analyzed (20 S1P-RM, 64 natalizumab). S1P-RM-associated PML was diagnosed in older patients (median age 52 vs 44 years, p < 0.001) and after longer treatment duration (median 63.9 vs 40 months, p < 0.001). Similarly, S1P-RM patients were more prone to show symptoms at diagnosis (100 vs 80.6%, p = 0.035), had more disseminated lesions (80% vs 34.9%, p = 0.002), and had higher gadolinium enhancement (65% vs 39.1%, p = 0.042). Natalizumab patients had a higher IRIS development rate (OR: 8.3 [1.92-33.3]). Overall, the outcome (mRS) at 12 months was similar in the 2 groups (OR: 0.81 [0.32-2.0]). Yet, post-treatment MS activity was higher in S1P-RM cases (OR: 5.7 [1.4-22.2]). DISCUSSION: S1P-RM-associated PML shows reduced IRIS risk but higher post-treatment MS activity. Clinicians should tailor post-PML treatment based on pre-PML medication.

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

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BACKGROUND: Data on cognition in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are limited to studies with small sample sizes. Therefore, we aimed to analyse the extent, characteristics and the longitudinal course of potential cognitive deficits in patients with MOGAD. METHODS: The CogniMOG-Study is a prospective, longitudinal and multicentre observational study of 113 patients with MOGAD. Individual cognitive performance was assessed using the Paced Auditory Serial Addition Task (PASAT), the Symbol Digit Modalities Test (SDMT) and the Multiple Sclerosis Inventory Cognition (MuSIC), which are standardised against normative data from healthy controls. Cognitive performance was assessed at baseline and at 1-year and 2-year follow-up assessments. Multiple linear regression was used to analyse demographic and clinical predictors of cognitive deficits identified in previous correlation analyses. RESULTS: At baseline, the study sample of MOGAD patients showed impaired standardised performance on MuSIC semantic fluency (mean=-0.29, 95% CI (-0.47 to -0.12)) and MuSIC congruent speed (mean=-0.73, 95% CI (-1.23 to -0.23)). Around 1 in 10 patients showed deficits in two or more cognitive measures (11%). No decline in cognition was observed during the 1-year and 2-year follow-up period. Cerebral lesions were found to be negatively predictive for SDMT (B=-8.85, 95% CI (-13.57 to -4.14)) and MuSIC semantic fluency (B=-4.17, 95% CI (-6.10 to -2.25)) test performance. CONCLUSIONS: Based on these data, we conclude that MOGAD patients show reduced visuomotor processing speed and semantic fluency to the extent that the disease burden includes cerebral lesions.

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OBJECTIVES: To report CD19+ B-cell counts and possible adverse effects on infants of mothers exposed to anti-CD20 mAbs ≤6 months before/during pregnancy or lactation. METHODS: We conducted a retrospective study using data from the German nationwide neuroimmunologic pregnancy registry. Inclusion criteria involved infants whose mothers received anti-CD20 mAbs ≤6 months before/during pregnancy or lactation, with ≥1 postnatal CD19+ B-cell count. Main outcomes were absolute and relative CD19+ B-cell counts. Comparison with reference values was performed conservatively in a subgroup with maternal exposure ≤3 months before/during pregnancy. Additional outcomes included pregnancy results, severe infections, and lymphocyte counts. RESULTS: The cohort comprised 49 infants (F:M 25:24) exposed to anti-CD20 mAbs ≤6 months before/during pregnancy or lactation. CD19+ B-cell and lymphocyte counts in 40 infants with maternal exposure ≤3 months before/during pregnancy were comparable with normative values. Only 2 cases of complete CD19+ B-cell depletion occurred after second-trimester and third-trimester ocrelizumab exposure, with repopulation observed within 2 months. Exclusive lactation exposure had no significant effect on infants' absolute CD19+ B-cell counts. DISCUSSION: Administering anti-CD20 mAbs before or at the pregnancy onset, or during lactation, seems safe without significant impact on infant B-cell development. However, second-trimester or third-trimester exposure can cause CD19+ B-cell depletion due to placental transfer, necessitating monitoring and postponing live vaccines.

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Introduction: Subgroups of autoantibodies directed against voltage-gated potassium channel (Kv) complex components have been associated with immunotherapy-responsive clinical syndromes. The high prevalence and the role of autoantibodies directly binding Kv remain, however, controversial. Our objective was to determine Kv autoantibody binding requirements and to clarify their contribution to the observed immune response. Methods: Binding epitopes were studied in sera (n = 36) and cerebrospinal fluid (CSF) (n = 12) from a patient cohort positive for Kv1.2 but negative for 32 common neurological autoantigens and controls (sera n = 18 and CSF n = 5) by phospho and deep mutational scans. Autoantibody specificity and contribution to the observed immune response were resolved on recombinant cells, cerebellum slices, and nerve fibers. Results: 83% of the patients (30/36) within the studied cohort shared one out of the two major binding epitopes with Kv1.2-3 reactivity. Eleven percent (4/36) of the serum samples showed no binding. Fingerprinting resolved close to identical sequence requirements for both shared epitopes. Kv autoantibody response is directed against juxtaparanodal regions in peripheral nerves and the axon initial segment in central nervous system neurons and exclusively mediated by the shared epitopes. Discussion: Systematic mapping revealed two shared autoimmune responses, with one dominant Kv1.2-3 autoantibody epitope being unexpectedly prevalent. The conservation of the molecular binding requirements among these patients indicates a uniform autoantibody repertoire with monospecific reactivity. The enhanced sensitivity of the epitope-based (10/12) compared with that of the cell-based detection (7/12) highlights its use for detection. The determined immunodominant epitope is also the primary immune response visible in tissue, suggesting a diagnostic significance and a specific value for routine screening.

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BACKGROUND AND OBJECTIVES: To develop a composite score to assess the severity of the multiple symptoms present in anti-IgLON5 disease. METHODS: The anti-IgLON5 disease composite score (ICS) was designed to evaluate 17 symptoms divided into 5 clinical domains (bulbar, sleep, movement disorders, cognition, and others). Each symptom was scored from 0 (absent/normal) to 3 or 6 (severe) depending on the contribution of the symptom to neurologic disability with a maximum ICS of 69. The ICS was tested in patients from 2 cohorts (Barcelona, Spain, and GENERATE, Germany) that included cases personally seen by the authors (internal) and patients whose ICS was obtained from information of questionnaires completed by the referring neurologists (external). Test-retest and interrater reliabilities of the ICS were assessed by the intraclass coefficient (ICC) and the correlation between the ICS and modified Rankin scale (mRS) with the nonparametric Spearman rank coefficient. The Wilcoxon signed rank test was used to compare the ICS at diagnosis of anti-IgLON5 disease and follow-up in a subset of patients with available clinical information. RESULTS: A total of 86 patients (46 from Barcelona cohort; 40 from GENERATE cohort) were included. The median ICS was 15 (range 2-31). The ICS was higher in the Barcelona cohort than in the German cohort (18 vs 12, p < 0.001), due to higher partial scores in sleep and movement disorder domains. There were no significant differences in the ICS between internal and external patients (15 vs 14, p = 0.96). The ICS correlated with the mRS score (r = 0.429, p < 0.001). Test-retest and interrater reliabilities were excellent with an ICC of 0.997 (95% CI 0.992-0.999) and 0.973 (95% CI 0.925-0.990), respectively. ICS was retested during follow-up in 27 patients, and it was similar to that at diagnosis in 10 clinically stable patients (median ICS at diagnosis 11.5 vs 11.5 at follow-up; p = 1), higher in 8 patients who worsened (12.5 vs 18; p = 0.012), and lower in 9 patients who improved after immunotherapy (14 vs 10; p = 0.007). DISCUSSION: The ICS is a valid method to assess the extension and severity of the different clinical manifestations of anti-IgLON5 disease.

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BACKGROUND: Autoantibodies against the potassium voltage-gated channel subfamily A member 2 (KCNA2) have been described in a few cases of neuropsychiatric disorders, but their diagnostic and pathophysiological role is currently unknown, imposing challenges to medical practice. DESIGN / METHODS: We retrospectively collected comprehensive clinical and paraclinical data of 35 patients with KCNA2 IgG autoantibodies detected in cell-based and tissue-based assays. Patients' sera and cerebrospinal fluid (CSF) were used for characterization of the antigen, clinical-serological correlations, and determination of IgG subclasses. RESULTS: KCNA2 autoantibody-positive patients (n = 35, median age at disease onset of 65 years, range of 16-83 years, 74 % male) mostly presented with cognitive impairment and/or epileptic seizures but also ataxia, gait disorder and personality changes. Serum autoantibodies belonged to IgG3 and IgG1 subclasses and titers ranged from 1:32 to 1:10,000. KCNA2 IgG was found in the CSF of 8/21 (38 %) patients and in the serum of 4/96 (4.2 %) healthy blood donors. KCNA2 autoantibodies bound to characteristic anatomical areas in the cerebellum and hippocampus of mammalian brain and juxtaparanodal regions of peripheral nerves but reacted exclusively with intracellular epitopes. A subset of four KCNA2 autoantibody-positive patients responded markedly to immunotherapy alongside with conversion to seronegativity, in particular those presenting an autoimmune encephalitis phenotype and receiving early immunotherapy. An available brain biopsy showed strong immune cell invasion. KCNA2 autoantibodies occurred in less than 10 % in association with an underlying tumor. CONCLUSION: Our data suggest that KCNA2 autoimmunity is clinically heterogeneous. Future studies should determine whether KCNA2 autoantibodies are directly pathogenic or develop secondarily. Early immunotherapy should be considered, in particular if autoantibodies occur in CSF or if clinical or diagnostic findings suggest ongoing inflammation. Suspicious clinical phenotypes include autoimmune encephalitis, atypical dementia, new-onset epilepsy and unexplained epileptic seizures.

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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.

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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.

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OBJECTIVES: Anti-IgLON5 disease is a recently discovered neurologic disorder combining autoimmunity and neurodegeneration. Core manifestations include sleep disorders, bulbar symptoms, gait abnormalities, and cognitive dysfunction, but other presentations have been reported. Hallmarks are autoantibodies targeting the neuronal surface protein IgLON5, a strong human leukocyte antigen system Class II association, and brainstem and hypothalamus-dominant tau deposits. The purpose of this cohort study was to visualize tau deposition in vivo with the second-generation tau-PET tracer. METHODS: A cohort of 4 patients with anti-IgLON5 disease underwent a dynamic PET scan with [18F]PI-2620. One patient received a follow-up scan. Z-deviation maps and a 2-sample t test in comparison with healthy controls (n = 10) were performed. Antibody titers, neurofilament light chain, and disease duration were correlated with brainstem binding potentials. RESULTS: Patients demonstrated increased [18F]PI2620 tau binding potentials in the pons, dorsal medulla, and cerebellum. The longitudinal scan after 28 months showed an increase of tracer uptake in the medulla despite immunotherapy. Higher antibody titers and neurofilament light chain correlated with higher tracer retention. DISCUSSION: The results indicate that tau depositions in anti-IgLON5 disease can be visualized with [18F]PI-2620 and might correlate with the extent of disease. For validation, a larger longitudinal study is necessary.

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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.

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Background: Despite tremendous development in the treatment of neuromyelitis optica spectrum disorder (NMOSD), less is known about the characteristics of hospitalized patients and inpatient care utilization. Objective: To investigate the development of inpatient NMOSD case numbers and implemented immunotherapies in the last decade in Germany. Methods: We conducted a nationwide retrospective study using an administrative database of all hospitalized NMOSD patients between 2010 and 2021. We evaluated yearly data on case numbers, demographics, treatment regimens, and seasonal variations of apheresis therapy as a surrogate marker of severe relapse incidence. Results: During the observational period case number of inpatients substantially increased (2010:n = 463, 2021:n = 992). The mean age was 48.1 ± 2.5 years (74% females). The pooled yearly rate of plasmapheresis/immunoadsorption was 14% (95% CI [13-15%]), without seasonal variations. Its application peaked in 2013 (18%, 95% CI [15-21%]) with decreasing trend since. Predominant immunotherapy was rituximab (40%, 95% CI [34-45%]), followed by tocilizumab (4%, 95% CI [3-5%]) since 2013 and eculizumab (4%, 95% CI [3-5%]) since 2020. Inpatient mortality ranged between 0% and 1% per year. Conclusions: Inpatient case numbers of NMOSD substantially increased during the past decade, probably reflecting improving disease awareness. In parallel with the administration of highly effective therapies rate of apheresis therapies decreased. A stable apheresis rate over the year makes seasonal variations of the steroid-refractive relapses unlikely.

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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.

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

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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 (pBon < 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.

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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.

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Anti-IgLON5 disease is a newly defined clinical entity characterized by a progressive course with high disability and mortality rate. While precise pathogenetic mechanisms remain unclear, features characteristic of both autoimmune and neurodegenerative diseases were reported. Data on immunotherapy are limited, and its efficacy remains controversial. In this study, we retrospectively investigated an anti-IgLON5 disease cohort with special focus on clinical, serological and genetic predictors of the immunotherapy response and long-term outcome. Patients were recruited from the GENERATE (German Network for Research on Autoimmune Encephalitis) registry. Along with clinical parameters, anti-IgLON5 immunoglobulin (Ig)G in serum and CSF, anti-IgLON5 IgG1-4, IgA and IgM in serum, neurofilament light chain and glial fibrillary acidic protein in serum as well as human leukocyte antigen-genotypes were determined. We identified 53 patients (symptom onset 63.8 ± 10.3 years, female:male 1:1.5). The most frequent initial clinical presentations were bulbar syndrome, hyperkinetic syndrome or isolated sleep disorder [at least one symptom present in 38% (20/53)]. At the time of diagnosis, the majority of patients had a generalized multi-systemic phenotype; nevertheless, 21% (11/53) still had an isolated brainstem syndrome and/or a characteristic sleep disorder only. About one third of patients [28% (15/53)] reported subacute disease onset and 51% (27/53) relapse-like exacerbations during the disease course. Inflammatory CSF changes were evident in 37% (19/51) and increased blood-CSF-barrier permeability in 46% (21/46). CSF cell count significantly decreased, while serum anti-IgLON5 IgG titre increased with disease duration. The presence of human leukocyte antigen-DRB1*10:01 [55% (24/44)] was associated with higher serum anti-IgLON5 IgG titres. Neurofilament light chain and glial fibrillary acidic protein in serum were substantially increased (71.1 ± 103.9 pg/ml and 126.7 ± 73.3 pg/ml, respectively). First-line immunotherapy of relapse-like acute-to-subacute exacerbation episodes resulted in improvement in 41% (11/27) of patients and early initiation within the first 6 weeks was a predictor for therapy response. Sixty-eight per cent (36/53) of patients were treated with long-term immunotherapy and 75% (27/36) of these experienced no further disease progression (observation period of 20.2 ± 15.4 months). Long-term immunotherapy initiation during the first year after onset and low pre-treatment neurofilament light chain were significant predictors for a better outcome. In conclusion, subacute disease onset and early inflammatory CSF changes support the primary role of autoimmune mechanisms at least at initial stages of anti-IgLON5 disease. Early immunotherapy, prior to advanced neurodegeneration, is associated with a better long-term clinical outcome. Low serum neurofilament light chain at treatment initiation may serve as a potential biomarker of the immunotherapy response.

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Autoimmune neurological syndromes (AINS) with autoantibodies against the 65 kDa isoform of the glutamic acid decarboxylase (GAD65) present with limbic encephalitis, including temporal lobe seizures or epilepsy, cerebellitis with ataxia, and stiff-person-syndrome or overlap forms. Anti-GAD65 autoantibodies are also detected in autoimmune diabetes mellitus, which has a strong genetic susceptibility conferred by human leukocyte antigen (HLA) and non-HLA genomic regions. We investigated the genetic predisposition in patients with anti-GAD65 AINS. We performed a genome-wide association study (GWAS) and an association analysis of the HLA region in a large German cohort of 1214 individuals. These included 167 patients with anti-GAD65 AINS, recruited by the German Network for Research on Autoimmune Encephalitis (GENERATE), and 1047 individuals without neurological or endocrine disease as population-based controls. Predictions of protein expression changes based on GWAS findings were further explored and validated in the CSF proteome of a virtually independent cohort of 10 patients with GAD65-AINS and 10 controls. Our GWAS identified 16 genome-wide significant (P < 5 × 10-8) loci for the susceptibility to anti-GAD65 AINS. The top variant, rs2535288 [P = 4.42 × 10-16, odds ratio (OR) = 0.26, 95% confidence interval (CI) = 0.187-0.358], localized to an intergenic segment in the middle of the HLA class I region. The great majority of variants in these loci (>90%) mapped to non-coding regions of the genome. Over 40% of the variants have known regulatory functions on the expression of 48 genes in disease relevant cells and tissues, mainly CD4+ T cells and the cerebral cortex. The annotation of epigenomic marks suggested specificity for neural and immune cells. A network analysis of the implicated protein-coding genes highlighted the role of protein kinase C beta (PRKCB) and identified an enrichment of numerous biological pathways participating in immunity and neural function. Analysis of the classical HLA alleles and haplotypes showed no genome-wide significant associations. The strongest associations were found for the DQA1*03:01-DQB1*03:02-DRB1*04:01HLA haplotype (P = 4.39 × 10-4, OR = 2.5, 95%CI = 1.499-4.157) and DRB1*04:01 allele (P = 8.3 × 10-5, OR = 2.4, 95%CI = 1.548-3.682) identified in our cohort. As predicted, the CSF proteome showed differential levels of five proteins (HLA-A/B, C4A, ATG4D and NEO1) of expression quantitative trait loci genes from our GWAS in the CSF proteome of anti-GAD65 AINS. These findings suggest a strong genetic predisposition with direct functional implications for immunity and neural function in anti-GAD65 AINS, mainly conferred by genomic regions outside the classical HLA alleles.

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