BACKGROUND AND OBJECTIVES:Previous studies have reported inconsistent findings regarding the impact of age at onset on relapse risk in aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-IgG NMOSD), although older disease onset has been linked to more rapid disability accrual. This is in contrast to multiple sclerosis, where advancing age and older onset are associated with reduced relapse activity, allowing for treatment de-escalation or discontinuation in some older patients. The aim of this study was to clarify the influence of age at onset on relapse risk as well as disability accrual in a large, international cohort of patients with NMOSD. METHODS:We conducted a retrospective, multicenter cohort study using the MSBase data registry to evaluate annualized relapse rates (ARRs), time to first relapse, and time to Expanded Disability Status Scale (EDSS) scores of 4 and 6. For inclusion, a diagnosis of AQP4-IgG NMOSD according to the latest iteration of the criteria and availability of the minimum data set were required. Patients were stratified as pediatric onset (<18 years of age), early onset (18-55 years inclusive) or late onset (>55 years of age). Analyses included patients on high-efficacy therapy (HET), those on low-efficacy therapy (LET), and an incident cohort with the first clinical visit within 12 months from disease onset. Predictors of first relapse and EDSS 4/6 thresholds were analyzed using Cox proportional models. RESULTS:Data from 539 patients (42 pediatric, 421 with early onset, 76 with late onset; 85.2% female) with a median age at onset of 35 years (Q1 25.10, Q3 47.60) and a disease duration of 7.42 years (Q1 3.23, Q3 13.10) were analyzed. ARR and time to first relapse were not influenced by age at disease onset. Patients on HET had fewer relapses than those on LET (p < 0.001). Older age was linked to faster disability accumulation. In addition, higher baseline EDSS scores and delayed treatment were independent predictors of future disability. DISCUSSION:Our study demonstrates that while age at onset does not affect relapse risk, older patients experience more rapid disability accrual. These findings underscore the importance of early initiation of effective preventive immunotherapy in all age groups. The primary limitations of this study pertain to its retrospective design and the sole reliance on EDSS for disability assessment.

Background:As knowledge is limited about the real-world impact of relapse among patients with neuromyelitis optica spectrum disorder (NMOSD), we aimed to assess the impact of relapse(s) on patient disability, clinical outcomes, and patient and caregiver burden in a real-world setting. Objective:To assess how NMOSD relapses impacts patient and caregiver burden. Methods:Data were drawn retrospectively from the Adelphi Real World NMOSD Disease Specific Programme, a cross-sectional survey of neurologists and patients with NMOSD patients in five European countries from January-June 2023. Neurologists reported patients' demographics, caregiver involvement and clinical outcomes. Analyses were bivariate. Results:Overall, 99 neurologists provided data for 433 patients. In total, 128 patients had a relapse since their initial attack (1 relapse, 64.1%; 2 relapses, 18.8%; ≥ 3 relapses, 17.2%). Patients who had relapsed once had higher rates of control deficit for bladder (40.2% vs. 25.6%, p < .001) and bowel (8.5% vs. 5.6%, p = .042), which increased with additional relapses. Relapsed patients also required more caregiver support (41.4% vs. 31.1%, p = .048), often their partner (41.4% vs. 31.1%, p = .046). Conclusions:NMOSD relapse occurrence was associated with debilitating symptoms and more caregiver support, highlighting the need for more highly effective interventions to prevent patient and caregiver burden.

BACKGROUND AND OBJECTIVES:It is currently difficult to accurately predict who, after the index event of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), will develop relapsing disease (R-MOGAD). Several clinical features have been reported as possibly predictive, but none have been validated in clinical practice. We used a prospectively designed analysis to assess a combined model of reported clinical prognosticators for developing R-MOGAD in 101 patients with MOGAD (86% with onset in adulthood) from 3 UK specialist centers. METHODS:A multivariable binary logistic regression model using variables identified from a scoping literature review was fitted in a retrospective clinical data set of patients with MOGAD (Nottingham MS & Neuroinflammation Centre [NUH]), with validation analysis in 2 independent data sets (Walton NMOSD Specialist Centre [WSC]; Imperial College London [ICL]). Secondary analysis investigated time to first relapse using Cox proportional hazards on the combined cohort. Results from the significant variables from the initial analysis were further examined in a meta-analysis of relevant literature studies. RESULTS:In the Neuroinflammation - Nottingham University Hospitals NHS Trust data set (n = 33), treatment with steroids ≥10 mg for ≥ 3 months after the index event was significantly associated with a lower likelihood of developing R-MOGAD (p = 0.006) with sensitivity 83% (95% CI 59-96) and specificity 73% (95% CI 45-92). A persistently positive MOG-IgG status, age at onset, optic neuritis at onset, and sex were not significant predictors of developing R-MOGAD. To assess generalizability, this predictor was tested in 2 independent data sets. In Walton Centre Liverpool (n = 39), not receiving prednisolone ≥10 mg ≥ 3 months was associated with R-MOGAD (OR = 9.7; 95% CI 2.1-45.4; sensitivity 63%; 95% CI 38-84; specificity 85%; 95% CI 62-97). In ICL (n = 29), the association was directionally consistent but inconclusive, with wide confidence intervals crossing unity (OR = 2.7; 95% CI 0.5-13.4; sensitivity 73%; 95% CI 39-94; specificity 50%; 95% CI 26-74). For the combined cohort (n = 101), not receiving prednisolone ≥ 10 mg for ≥3 months was associated with increased odds of developing R-MOGAD (OR = 6.2; 95% CI 2.6-14.8; p < 0.0001). Conversely, prednisolone ≥10 mg ≥ 3 months was associated with a lower hazard of relapse (HR = 0.47; 95% CI 0.24-0.91; p = 0.024). Median follow-up for monophasic patients was 42 months (IQR: 17.5-64.5). DISCUSSION:Prednisolone ≥10 mg for ≥ 3 months after the index event was associated with a lower likelihood of relapsing MOGAD. This association was supported in first external cohort and directionally consistent but inconclusive in a second, smaller cohort. Further prospective multicenter studies are required to assess the reproducibility and clinical utility of this association.

The diagnosis and treatment of multiple sclerosis (MS) remain an evolving challenge in modern neurology. Recent advances are reflected in the 2024 revision of the McDonald criteria, which aim to facilitate earlier, more accurate and biologically informed diagnosis of MS. Key updates include expansion of dissemination in space to incorporate the optic nerve, integration of relapsing and progressive onset MS within a unified diagnostic framework, provision for diagnosis in selected asymptomatic individuals, dispensing with the requirement for dissemination of time in certain situations and incorporation of more specific imaging biomarkers. These include specific radiological features such as the central vein sign and paramagnetic rim lesions, visual pathway assessments using optical coherence tomography, magnetic resonance imaging and visual evoked potentials. Furthermore, oligoclonal bands and kappa free light chain index are now acknowledged as alternative cerebrospinal fluid biomarkers of intrathecal immunoglobulin synthesis. These revisions acknowledge the evolving understanding of MS biology alongside the substantial advances in disease modifying therapies. This review uses the 2024 McDonald criteria as an overarching framework to synthesise and contextualise the recent developments in MS diagnosis and treatment, highlighting their clinical implications, current limitations and future directions.

BACKGROUND AND OBJECTIVES:Double seronegative NMOSD (DS-NMOSD) lacks approved disease-modifying treatments, and limited data exist on optimal relapse-prevention strategies. In this multicenter, international, retrospective cohort study, we sought to compare the real-world effectiveness of anti-CD20 agents vs nonspecific immunosuppressants as disease-modifying strategies for relapse prevention in DS-NMOSD. METHODS:A retrospective cohort database was constructed using standardized data collection from medical records across collaborating centers in the United States, Brazil, the United Kingdom, Thailand, Turkiye, and China. Patients meeting IPND-2015 NMOSD criteria with negative serum aquaporin-4 and myelin oligodendrocyte glycoprotein antibody testing via cell-based assays and at least 12 months of follow-up were reviewed. The primary outcome was the incidence rate ratio (IRR) of relapses; secondary outcomes included the annualized relapse rate (ARR) and time to relapse. RESULTS:A total of 103 patients with DS-NMOSD met study criteria, with a median follow-up of 6 years. Anti-CD20 therapy was associated with a significantly lower IRR (0.02, 95% CI 0.01-0.04) and ARR (0.17, 95% CI 0.07-0.40) compared with nonspecific immunosuppressants (0.76, 95% CI 0.40-1.43) after adjusting for covariates. Survival analysis demonstrated a prolonged relapse-free interval with anti-CD20 agents. DISCUSSION:Our findings support the use of B-cell depletion as a potentially superior relapse-prevention strategy in DS-NMOSD, highlighting its potential as a first-line therapy. CLASSIFICATION OF EVIDENCE:This study provides Class IV evidence that, in patients with DS-NMOSD, treatment with a DMT reduces relapse incidence rate ratio compared with no treatment and anti-CD20 DMTs are associated with a lower relapse incidence rate ratio compared with nonspecific immunosuppressants.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare antibody-mediated neuro-autoimmune disease. Monoclonal antibodies targeting B cell antigens CD19 and CD20, the interleukin-6 receptor, or the complement cascade are used as preventive therapies to reduce relapse rates. We conducted a network meta-analysis (NMA) to compare the effect of rituximab on time to first relapse with ravulizumab, eculizumab, inebilizumab, and satralizumab in patients with NMOSD who are aquaporin-4 (AQP4)-IgG-positive. A systematic search was conducted in PubMed, Scopus, CINAHL, EMBASE, Web of Science, the Cochrane Library, and gray literature sources up to October 31, 2024, and updated on November 1, 2025, following PRISMA guidelines. A network meta-analysis of randomized and open-label trials was conducted to compare time to first relapse between rituximab and other monoclonal antibody therapies. From 6337 records, 3825 duplicates were removed; 2512 were screened, 2327 excluded, leaving eight trials. The prior treatment, relapse history, and definitions and adjudication of relapse varied across studies. Rituximab showed higher hazard ratio (HR) point estimates for time to first relapse compared with ravulizumab with or without immunosuppressive therapies (IST) (HR 5.00, 95

BACKGROUND AND OBJECTIVES:Disability in aquaporin-4 antibody-positive neuromyelitis optica spectrum disease (AQP4-IgG NMOSD) is considered relapse-driven although subclinical injury has been suggested by neuroimaging and visual pathway assessments. We investigated longitudinal changes in serum glial fibrillar acidic protein (sGFAP) and neurofilament light chain (sNfL) during relapse-free periods. METHODS:We conducted a retrospective longitudinal study (2008-2025) at a UK national referral centre for NMOSD. Patients with ≥3 serum samples collected over ≥3 years were included; samples within 3 months of relapses were excluded. Longitudinal changes in sGFAP and sNfL were assessed using linear mixed-effects models with random intercepts and generalised estimating equations, adjusting for age, sex and time. RESULTS:40 patients (87.5% females; 162 samples; median onset age 40.1 years) and 28 matched controls were included. Over the course of four measurements and a median sampling over 9 years, stability was observed in sGFAP levels (99.2 pg/mL at 0-2.5 years (95% CI 84.2 to 117.0) to 90.3 pg/mL at 7.5-10 years (95% CI 74.7 to 109.0), p=0.65) and sNfL levels (12.0 pg/mL at 0-2.5 years (95% CI 10.8 to 13.3) to 10.4 pg/mL (9.1 to 11.8) at 7.5-10 years, p=0.12) after adjustment for covariates. DISCUSSION:In this longitudinal study, mean sGFAP and sNfL levels remained stable over 9 years of sequential measurements during relapse-free periods, supporting the relapse-driven nature of NMOSD pathology.

BACKGROUND:Comorbidities occur in aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and double seronegative NMOSD (DN-NMOSD), potentially contributing to a less favorable disease course. OBJECTIVES:To characterize comorbidities in AQP4-NMOSD, MOGAD, and DN-NMOSD and assess their association with optic neuritis (ON) outcomes by optical coherence tomography (OCT) in AQP4-NMOSD. METHODS:Four hundred and forty-two participants from the CROCTINO cohort were evaluated for comorbidities. RESULTS:In AQP4-NMOSD patients (n = 360), 43.5% (n = 161) had comorbidities, equally divided between single and multiple. In MOGAD (n = 49), 40.8% had comorbidities, with 75% (n = 15) single and 25% (n = 5) multiple. In DN-NMOSD (n = 33), 36.4% (n = 12) had comorbidities equally split. AQP4-NMOSD patients had more multiple comorbidities (50%, n = 81/161) than MOGAD (25%, n = 5/20, p = 0.03) and more autoimmune disorders (AID) (40.4%, n = 65) than MOGAD (20%, n = 4, p = 0.09) and DN-NMOSD (none, p = 0.004). Cardiovascular comorbidities and related risk factors (CVC/RF) occurred in 34.8% (n = 56) of AQP4-NMOSD, 50% (n = 10) of MOGAD, and 33.3% (n = 4) of DN-NMOSD. Expanded Disability Status Scale was higher in MOGAD (3.0 vs. 2.0, p = 0.006) and DN-NMOSD (5.0 vs. 2.0, p = 0.008) with comorbidities. AQP4-NMOSD patients with CVC/RF had higher ON relapse rates than those with AID (1.06 ± 3.33 vs. 0.49 ± 0.98, p < 0.001). OCT revealed reduced inner nuclear layer thickness in AQP4-NMOSD with comorbidities compared to non-comorbidity (B = -1.52, p = 0.047), more pronounced with CVC/RF (B = -2.96, p = 0.009). CONCLUSION:Comorbidities are frequent in AQP4-NMOSD and MOGAD and are associated with ON frequency and disability. These findings highlight the need for proactive comorbidity management to improve patient care.

BACKGROUND:Aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG+ NMOSD) can cause significant disability after a single attack. Long-term immunotherapy reduces disability accumulation, but the choice of first-line therapy varies. In the United Kingdom, rituximab is typically used as escalation therapy after conventional immunosuppressants fail, while in Germany, it is widely used as first-line treatment. METHODS:We compared attack risk and disability outcomes based on the Expanded Disability Status Scale (EDSS) in AQP4-IgG+ NMOSD patients treated with rituximab as first-line versus escalation therapy. Furthermore, attack suppression and risk factors for attacks in individuals who received treatment with azathioprine and mycophenolate mofetil (with/without escalating to rituximab) were analyzed. RESULTS:The risk of attack was lower in individuals who received rituximab as first-line therapy (n = 52) compared to escalation therapy (n = 81, HR = 0.45, 95% CI = 0.30-0.67). Once escalated to rituximab, there was no altered risk of attack between first-line rituximab and escalation therapy (HR = 1.15, 95% CI = 0.64-2.08). Rituximab as first-line compared to escalation therapy was associated with lower EDSS scores at therapy start (3.0 vs. 6.0, p = 1.10 × 10-3). In patients who remained on azathioprine or mycophenolate mofetil (n = 45), age < 50 years and treatment with azathioprine were identified as risk factors for attacks. CONCLUSIONS:Rituximab as a first-line therapy shows significant reduction in disability accumulation compared to escalation treatments. However, a subgroup of patients with AQP4-IgG+ NMOSD may still respond well to conventional immunosuppression-specifically older patients treated with mycophenolate mofetil.

BACKGROUND AND OBJECTIVES:Data on the plasma exchange (PLEX) in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are limited. Herein, we evaluate outcomes after PLEX in MOGAD. METHODS:This international multicenter retrospective cohort study included patients from 18 tertiary care centers in 6 countries. Inclusion criteria included fulfillment of the 2023 International MOGAD panel criteria, receipt of at least 3 sessions of PLEX, and follow-up of ≥3 months after PLEX. Patients with coexisting neuroinflammatory disorders were excluded. We assessed the frequency of complete recovery (CR), clinically significant improvement (CSI), visual acuity (VA), and Expanded Disability Status Scale (EDSS). Logistic regression analyses were performed to identify predictors of CR and CSI. RESULTS:Of 234 patients, 135 (58%) were female. The median (interquartile range [IQR]) age at attack was 34 (IQR 22-49) years, and 42 (17%) were children. In 165 of 243 (68%), the attack treated with PLEX was the first attack. Attack phenotypes included 161 optic neuritis (235 eyes), 77 myelitis, 24 acute disseminated encephalomyelitis, 15 brainstem/cerebellar, 3 cerebral-cortical encephalitis attack, and 1 cerebral polyfocal deficit-36 with >1 core phenotypes. A total of 239 (99%) attacks were also treated with corticosteroids and 32 (13%) with IV immunoglobulins. VA in optic neuritis improved from 20/400 (20/70-hand motion) to 20/20 (20/20-20/30), p < 0.001, and EDSS decreased from a median of 4.0 (3.0-6.5) to 1.0 (0.0-2.5), p < 0.001. Of 229 attacks without subsequent attacks within 3 months, 100 (44%) achieved CR and 213 (93%) CSI. The probability of CR was decreased with advanced age (adjusted odd ratio [95% CI] 0.97 [0.96-0.99] per year), higher EDSS worsening from baseline (0.66 [0.54-0.81] per 0.5 increment) and delayed PLEX (0.98 [0.96-0.99] per day). Advanced age (0.97 [0.96-0.99] per year) and delayed PLEX (0.95 [0.94-0.96] per day) decreased the probability of CSI. DISCUSSION:We observed favorable outcomes after PLEX in MOGAD attacks. However, advanced age and delayed initiation of PLEX were associated with a reduced probability of improvement. The absence of a control group limits our ability to differentiate PLEX effects from spontaneous recovery, prior corticosteroid response, or long-term immunotherapy. Future prospective studies are needed to assess the impact of PLEX on improvement. CLASSIFICATION OF EVIDENCE:This study provides Class IV evidence that PLEX is associated with favorable clinical outcomes in patients with MOGAD.

OBJECTIVES:To assess loss of employment, work hours, and wages of people with aquaporin-4 antibody-positive or double-seronegative/antibody status unknown neuromyelitis optica spectrum disorder (NMOSD) internationally. METHODS:An investigator-designed survey was administered to adults ages 18-70 years with NMOSD and distributed by neurologists in 23 countries, July 2022 to September 2023. RESULTS:There were 897 participants (635 aquaporin-4 antibody positive, 262 double-seronegative/untested; 81.4% female, average age 42.5 years, average disease duration 7.6 years, median 2 disease attacks since diagnosis). NMOSD impact was visual loss (34.0% unilateral; 28.2% bilateral), 61.8% with spinal cord disease, 55.6% with pain, 43.6% with fatigue, 38.2% with depressed mood, and 25.0% with gait aid use. In total, 92.6% took immunosuppressive therapy. Employment rates were 62.6% before and 36.3% after NMOSD diagnosis. In a multivariable model, statistically significant independent associations with unemployment in NMOSD were older age (odds ratio (OR) = 0.97, p < 0.001), being female (OR = 0.48, p < 0.001), bilateral visual loss (OR = 0.61, p = 0.02), highest frequency of depressed mood (OR = 0.29, p < 0.001), and walking aid use (OR = 0.38, p < 0.001). DISCUSSION:Approximately 1/3 of people living with NMOSD of potential working age are in the workforce. Unemployment in NMOSD is associated with previously recognized factors but also self-reported low mood, gait aid use, and bilateral visual loss.

BackgroundNeuromyelitis optica spectrum disorder (NMOSD) can be categorised into aquaporin-4 antibody (AQP4-IgG) NMOSD or seronegative NMOSD. While our knowledge of AQP4-IgG NMOSD has evolved significantly in the past decade, seronegative NMOSD remains less understood. This study aimed to evaluate the predictors of relapses and treatment responses in AQP4-IgG NMOSD and seronegative NMOSD.MethodsThis was a multicentre, international, retrospective cohort study using the MSBase registry. Recurrent relapse risk was assessed using an Andersen-Gill model and risk of first relapse was evaluated using a Cox proportional hazards model. Covariates that putatively influence relapse risk included demographic factors, clinical characteristics and immunosuppressive therapies; the latter was assessed as a time-varying covariate.ResultsA total of 398 patients (246 AQP4-IgG NMOSD and 152 seronegative NMOSD) were included. The AQP4-IgG NMOSD and seronegative NMOSD patients did not significantly differ by age at disease onset, ethnicity or annualised relapse rate. Both low-efficacy and high-efficacy immunosuppressive therapies were associated with significant reductions in recurrent relapse risk, with notably greater protection conferred by high-efficacy therapies in both AQP4-IgG NMOSD (HR 0.27, 95% CI 0.15 to 0.49, p<0.001) and seronegative NMOSD (HR 0.21, 95% CI 0.08 to 0.51, p<0.001). Longer disease duration (HR 0.97, 95% CI 0.95 to 0.99, p<0.001) and male sex (HR 0.52, 95% CI 0.34 to 0.84, p=0.007) were additional protective variables in reducing the recurrent relapse risk for the AQP4-IgG NMOSD group.ConclusionAlthough further studies are needed to improve our understanding of seronegative NMOSD, our findings underscore the importance of aggressive treatment with high-efficacy immunotherapies in both NMOSD subtypes, regardless of serostatus.