Time to Disability Milestones and Annualized Relapse Rates in NMOSD and MOGAD.

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.

No evidence of an association of multiple sclerosis (MS) with Borna disease virus 1 (BoDV-1) infections in patients within an endemic region: a retrospective pilot study.

BACKGROUND: Borna disease virus 1 (BoDV-1) causes rare human infections within endemic regions in southern and eastern Germany. The infections reported to date have been linked to severe courses of encephalitis with high mortality and mostly irreversible symptoms. Whether BoDV-1 could act as a trigger for other neurological conditions, is, however, incompletely understood. OBJECTIVES AND METHODS: In this study, we addressed the question of whether the presentation of a clinically isolated syndrome (CIS) or of multiple sclerosis (MS) might be associated with a milder course of BoDV-1 infections. Serum samples of 100 patients with CIS or MS diagnosed at a tertiary neurological care center within an endemic region in southern Germany and of 50 control patients suffering from headache were retrospectively tested for BoDV-1 infections. RESULTS: In none of the tested sera, confirmed positive results of anti-BoDV-1-IgG antibodies were retrieved. Our results support the conclusion that human BoDV-1 infections primarily lead to severe encephalitis with high mortality.

Factors associated with depressive mood at the onset of multiple sclerosis - an analysis of 781 patients of the German NationMS cohort.

Background: Depression has a major impact on the disease burden of multiple sclerosis (MS). Analyses of overlapping MS and depression risk factors [smoking, vitamin D (25-OH-VD) and Epstein-Barr virus (EBV) infection] and sex, age, disease characteristics and neuroimaging features associated with depressive symptoms in early MS are scarce. Objectives: To assess an association of MS risk factors with depressive symptoms within the German NationMS cohort. Design: Cross-sectional analysis within a multicenter observational study. Methods: Baseline data of n = 781 adults with newly diagnosed clinically isolated syndrome or relapsing-remitting MS qualified for analysis. Global and region-specific magnetic resonance imaging (MRI)-volumetry parameters were available for n = 327 patients. Association of demographic factors, MS characteristics and risk factors [sex, age, smoking, disease course, presence of current relapse, expanded disability status scale (EDSS) score, fatigue (fatigue scale motor cognition), 25-OH-VD serum concentration, EBV nuclear antigen-1 IgG (EBNA1-IgG) serum levels] and depressive symptoms (Beck Depression Inventory-II, BDI-II) was tested as a primary outcome by multivariable linear regression. Non-parametric correlation and group comparison were performed for associations of MRI parameters and depressive symptoms. Results: Mean age was 34.3 years (95% confidence interval: 33.6-35.0). The female-to-male ratio was 2.3:1. At least minimal depressive symptoms (BDI-II > 8) were present in n = 256 (32.8%), 25-OH-VD deficiency (<20 ng/ml) in n = 398 (51.0%), n = 246 (31.5%) participants were smokers. Presence of current relapse [coefficient (c) = 1.48, p = 0.016], more severe fatigue (c = 0.26, p < 0.0001), lower 25-OH-VD (c = -0.03, p = 0.034) and smoking (c = 0.35, p = 0.008) were associated with higher BDI-II scores. Sex, age, disease course, EDSS, month of visit, EBNA1-IgG levels and brain volumes at baseline were not. Conclusion: Depressive symptoms need to be assessed in early MS. Patients during relapse seem especially vulnerable to depressive symptoms. Contributing factors such as fatigue, vitamin D deficiency and smoking, could specifically be targeted in future interventions and should be investigated in prospective studies.

The impact of disease-modifying therapies on immunoglobulin blood levels in patients with multiple sclerosis: a retrospective cross-sectional study.

Background: Although disease-modifying therapies (DMTs) in multiple sclerosis (MS) are known to target the immune system, mechanisms of action, efficacy, safety, and tolerability profiles differ. The long-term impact of DMTs on the immune system and its relation to infectious complications is still poorly understood. Objectives: To analyze the effect of DMTs on serum immunoglobulin (Ig) levels under consideration of patient demographics and therapy duration. Design: We included 483 patients on DMTs, 69 patients without DMTs, and 51 controls in this retrospective cross-sectional study. Methods: IgG, IgM, and IgG subclass 1-4 levels of patients with MS under treatment with DMTs were compared with treatment naive MS patients and controls by multivariate linear regression. Further, Ig levels stratified by DMTs were analyzed regarding therapy duration. Results: MS patients treated with fingolimod (FG), natalizumab, and B-cell depleting therapies (BCDT) demonstrated significantly lower IgG and IgM levels than healthy controls after a median treatment of 37, 31, and 23 months, respectively (p < 0.05). Treatment with dimethyl fumarate (DMF) and teriflunomide was associated with lower IgG, but not IgM levels. DMF and BCDT were also associated with lower IgG1 levels, while FG led to a reduction of IgG2. Treatment with interferon-beta (IFN) and glatiramer acetate (GA) had no impact on Ig levels. Analysis of subgroups by linear regression also showed a time-dependent decrease of Igs levels in patients treated with BCDT with a median annual reduction of IgG of 3.2% and IgM of 6.2%. Conclusion: Treatment with DMTs, except GA and IFN, was associated with a decrease in Ig levels. DMTs differed in the extent of decreasing Ig levels but also in their differential effects on Ig subclasses. Monitoring of Ig levels should be considered in patients on long-term treatment with DMTs, particularly those on BCDT, to identify patients at risk of low immunoglobulin levels.

Association of obesity with disease outcome in multiple sclerosis.

BACKGROUND: Obesity reportedly increases the risk for developing multiple sclerosis (MS), but little is known about its association with disability accumulation. METHODS: This nationwide longitudinal cohort study included 1066 individuals with newly diagnosed MS from the German National MS cohort. Expanded Disability Status Scale (EDSS) scores, relapse rates, MRI findings and choice of immunotherapy were compared at baseline and at years 2, 4 and 6 between obese (body mass index, BMI ≥30 kg/m2) and non-obese (BMI <30 kg/m2) patients and correlated with individual BMI values. RESULTS: Presence of obesity at disease onset was associated with higher disability at baseline and at 2, 4 and 6 years of follow-up (p<0.001). Median time to reach EDSS 3 was 0.99 years for patients with BMI ≥30 kg/m2 and 1.46 years for non-obese patients. Risk to reach EDSS 3 over 6 years was significantly increased in patients with BMI ≥30 kg/m2 compared with patients with BMI <30 kg/m2 after adjustment for sex, age, smoking (HR 1.87; 95% CI 1.3 to 2.6; log-rank test p<0.001) and independent of disease-modifying therapies. Obesity was not significantly associated with higher relapse rates, increased number of contrast-enhancing MRI lesions or higher MRI T2 lesion burden over 6 years of follow-up. CONCLUSIONS: Obesity in newly diagnosed patients with MS is associated with higher disease severity and poorer outcome. Obesity management could improve clinical outcome of MS.