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BackgroundCorticosteroid treatment of multiple sclerosis (MS) relapses is assumed to improve the speed of relapse recovery, without modifying long-term disability risk. We aimed to re-evaluate this assumption in a large cohort of individuals with MS.MethodsIndividuals with clinically definite MS and ≥3 Expanded Disability Status Scale (EDSS) measurements over ≥12 months were identified within the international neuroimmunology registry MSBase. Individuals were required to have ≥1 relapse, with complete information on relapse treatment, phenotype and severity for all documented relapses. The primary outcome was disability worsening confirmed over 12 months. The association of the cumulative number of steroid-treated and untreated relapses (as a time-varying exposure) with disability worsening was evaluated with Cox proportional hazards.ResultsIn total, 3673 individuals met the inclusion criteria (71% female, mean age 38 years, mean disability EDSS step 2); 5809 relapses (4671 treated/1138 untreated) were captured (annualised relapse rate 0.19). Over the study period (total 30 175 person-years), 32.7% reached the outcome of confirmed disability worsening (median survival time 5.2 years). Non-treated relapses were associated with a higher risk of disability worsening (HR 1.72, 95% CI 1.57 to 1.88) than steroid-treated relapses (HR 1.50, 95% CI 1.43 to 1.57). This association was modified by the efficacy of disease-modifying therapy at the time of relapse.ConclusionsOur results suggest that a lack of steroid treatment of MS relapses is associated with a higher risk of future disability worsening. Hence, corticosteroid treatment of MS relapses may impact not only the speed of recovery but also the severity of residual structural damage.

Multiple sclerosis (MS) is characterized as an immune-mediated central nervous system disease marked by chronic inflammation, demyelination, and progressive neurodegeneration. In this study, we evaluated the contribution of low-frequency and rare genetic variants to MS susceptibility within one of the largest family-based MS cohorts to date, comprising 215 individuals from 59 Turkish multiplex MS families. Whole exome sequencing was conducted on all samples including affected and unaffected members, followed by investigation of the effect of well-established human leukocyte antigen loci for MS on the elevated MS risk observed in our families. Subsequently, a gene-based burden analysis was performed on candidate genes identified through both our segregation analysis and existing literature. To prioritize the genes and pathways that are potentially associated with MS, a segregation-based analysis of the variants was conducted and complemented by gene-based pathway enrichment analysis. Our results highlighted the significance of the extracellular matrix in MS pathogenesis, as we identified laminin-related genes including LAMA5 and LAMB1 from both the segregation analysis and gene-based burden test. Hemidesmosome assembly emerged as a key pathway in our analysis, primarily driven by the identification of DST and PLEC as significant genes in the gene-based segregation analysis. Finally, we identified two rare coding variants passing our allele frequency and deleteriousness score-based filters, rs41266745 (C> T) in the CD109 gene with CADD phred score 24 and rs143093165 (T> G) in the ITPR1 gene with CADD phred score 22 and LOEUF 0.325, segregating within more than one family. Overall, this is one of the first and largest family-based MS studies from Turkey that features a unique cohort from an admixed population that enabled the detection of novel low-frequency and rare variants associated with MS. The findings from this study offer valuable insights that could guide future research aimed at further exploring and understanding the factors contributing to MS risk.

ObjectiveTo evaluate variability and predictability of disability trajectories in moderately advanced and advanced multiple sclerosis (MS), and their modifiability with immunomodulatory therapy.MethodsThe epochs between Expanded Disability Status Scale (EDSS) steps 3–6, 4–6 and 6–6.5 were analysed. Patients with relapse-onset MS and having reached 6-month confirmed baseline EDSS step (3/4/6) were identified in MSBase, a global observational MS cohort study. We used multivariable survival models to examine the impact of disease-modifying therapy, clinical and demographic factors on progression to the outcome EDSS step (6/6.5). Sensitivity analyses with varying outcome definitions and inclusion criteria were conducted.ResultsFor the EDSS 3–6, 4–6 and 6–6.5 epochs, 1560, 1504 and 1231 patients were identified, respectively. Disability trajectories showed large coefficients of variance prebaseline (0.92–1.11) and postbaseline (2.15–2.50), with no significant correlations. The probability of reaching the outcome step was not associated with prebaseline variables, but was increased by higher relapse rates during each epoch (HRs 1.58–3.07; p<0.001). A greater proportion of each epoch treated with higher efficacy therapies was associated with lower risk of reaching the outcome disability step (HRs 0.72–0.91 per 25%; p≤0.02). 3 sensitivity analyses confirmed these results.ConclusionsDisease progression during moderately advanced and advanced MS is highly variable and amnesic to prior disease activity. Lower relapse rates and greater time on higher efficacy immunomodulatory therapy after reaching EDSS steps 3, 4 and 6 are associated with a decreased risk of accumulating further disability. Highly effective immunomodulatory therapy ameliorates accumulation of disability in moderately advanced and advanced relapse-onset MS.

Background: The relationship between coronavirus disease 2019 (COVID-19) infection and multiple sclerosis (MS) relapse and disease progression remains unclear. Previous studies are limited by small sample sizes and most lack a propensity-matched control cohort. Objective: To evaluate the effect of COVID-19 infection on MS disease course with a large propensity-matched cohort. Design: This multi-centre cohort study analysed relapse and disability outcomes post-COVID-19 infection after balancing covariates using a propensity score matching method. The study period was from the 11th of September 2019 to the 16th of February 2023. The mean follow-up period was 1.7 years. Methods: Data were retrieved from the MSBase Registry. Propensity scores were obtained based on age, sex, disease duration, baseline Expanded Disability Status Scale (EDSS), MS course, relapses pre-baseline, disease-modifying therapy (DMT) class and country. Primary outcomes were time to first relapse, annualised relapse rate (ARR) and time to confirm EDSS progression. Secondary outcomes were time to EDSS of 3, 4 or 6. Sensitivity analyses with baseline DMT classes were performed. Results: The study included 2253 cases and 6441 controls. After matching, there were 2161 cases and an equal number of matched controls. Cases had a significantly higher ARR (ARR = 0.10 [95% CI 0.09–0.11]) compared to controls (ARR = 0.07 [95% CI 0.06–0.08]). Cases had a significantly greater hazard of time to first relapse compared to controls (hazard ratio (HR) = 1.54 [95% CI 1.29–1.84]). There was no association between COVID-19 infection and 24-week EDSS progression (HR = 1.18 [95% CI 0.92–1.52]), or time to EDSS of 3, 4 or 6. For patients on interferons and glatiramer acetate (BRACE), COVID-19 infection was associated with a greater hazard of time to first relapse (HR = 1.83 [95% CI 1.25–2.68]) and greater hazard of time to EDSS of 3 (HR = 2.04 [95% CI 1.06–3.90]) compared to patients on BRACE therapy without COVID-19 infection. Conclusion: COVID-19 infection was associated with a significantly increased MS relapse rate and a shorter time to first relapse. There was no effect on confirmed EDSS progression over the short term. These results support ongoing COVID-19 risk minimisation strategies to protect patients with MS.

Early prediction of disability progression in multiple sclerosis (MS) remains challenging despite its critical importance for therapeutic decision-making. We present the first systematic evaluation of personalized federated learning (PFL) for 2-year MS disability progression prediction, leveraging multi-center real-world data from over 26,000 patients. While conventional federated learning (FL) enables privacy-aware collaborative modeling, it remains vulnerable to institutional data heterogeneity. PFL overcomes this challenge by adapting shared models to local data distributions without compromising privacy. We evaluated two personalization strategies: a novel AdaptiveDualBranchNet architecture with selective parameter sharing, and personalized fine-tuning of global models, benchmarked against centralized and client-specific approaches. Baseline FL underperformed relative to personalized methods, whereas personalization significantly improved performance, with personalized FedProx and FedAVG achieving ROC-AUC scores of 0.8398 ± 0.0019 and 0.8384 ± 0.0014, respectively. These findings establish personalization as critical for scalable, privacy-aware clinical prediction models and highlight its potential to inform earlier intervention strategies in MS and beyond.

Background The use of non-specific immunosuppressants (NSIS) to treat multiple sclerosis (MS) remains prevalent in certain geographies despite safety concerns, likely due to resource limitations. Objective To use MSBase registry data to compare real-world outcomes in adults with relapsing-remitting MS (RRMS) treated with dimethyl fumarate (DMF) or NSIS (azathioprine, cyclosporine, cyclophosphamide, methotrexate, mitoxantrone or mycophenolate mofetil) between January 1, 2014 and April 1, 2022. Methods Treatment outcomes were compared using inverse probability of treatment weighting (IPTW) Cox regression. Outcomes were annualized relapse rates (ARRs), time to discontinuation, time to first relapse (TTFR) and time to 24-week confirmed disability progression (CDP) or 24-week confirmed disability improvement (CDI; in patients with baseline Expanded Disability Status Scale [EDSS] score ≥2). Results After IPTW, ARR was similar for DMF (0.13) and NSIS (0.16; p = 0.29). There was no difference in TTFR between cohorts (hazard ratio [HR]: 0.98; p = 0.84). The DMF cohort experienced longer times to discontinuation (HR: 0.75; p = 0.001) and CDP (HR: 0.53; p = 0.001), and shorter time to CDI (HR: 1.99; p < 0.008), versus the NSIS cohort. Conclusion This analysis supports the use of DMF to treat patients with relapsing forms of MS, and may have implications for MS practices in countries where NSIS are commonly used to treat RRMS.

In the 14th week of gestation, a 19-year-old female patient presented to a peripheral hospital with worsening of her symptoms of headache and meaningless somniloquy at nights. She was referred to our center after detecting extensive hyperintense lesions (most of them showing diffusion restriction) in T2 and fluid attenuated inversion recovery sections on brain magnetic resonance imaging (also including the corpus callosum) performed nearly one month after the onset of symptoms (Figure 1). The patient’s presenting neurologic examination revealed impairment in orientation to place, bilateral extensor plantar response, and hyperactive deep tendon reflexes.

Optic neuritis, myelitis, and neuromyelitis optica spectrum disorder (NMOSD) have been associated with antibodies against myelin oligodendrocyte glycoprotein-immunoglobulin G (anti-MOG-IgG). Furthermore, patients with radiological and demographic features atypical for multiple sclerosis (MS) with optic neuritis and myelitis also demonstrate antibodies against aquaporin-4 and anti-MOG-IgG. However, data on the diagnosis, treatment, follow-up, and prognosis in patients with anti-MOG-IgG are limited. To evaluate the clinical, radiological, and demographic characteristics of patients with anti-MOG-IgG. Multicenter, retrospective, observational study. Patients with blood samples demonstrating anti-MOG-IgG that had been evaluated at the Neuroimmunology laboratory at Ondokuz Mayıs University’s Faculty of Medicine were included in the study. Of the 104 patients with anti-MOG-IgG, 56.7% were women and 43.3% were men. Approximately 2.4% of the patients were diagnosed with MS, 15.8% with acute disseminated encephalomyelitis (ADEM), 39.4% with NMOSD, 31.3% with isolated optic neuritis, and 11.1% with isolated myelitis. Approximately 53.1% of patients with spinal involvement at clinical onset demonstrated a clinical course of NMOSD. Thereafter, 8.8% of these patients demonstrated a clinical course similar to MS and ADEM, and 28.1% demonstrated a clinical course of isolated myelitis. The response to acute attack treatment was lower and the disability was higher in patients aged > 40 years than patients aged < 40 years at clinical onset. Oligoclonal band was detected in 15.5% of the patients. For patients with NMOSD and without anti-NMO antibodies, the diagnosis is supported by the presence of anti-MOG-IgG. Furthermore, advanced age at clinical onset, Expanded Disability Status Scale (EDSS) score at clinical onset, spinal cord involvement, and number of attacks may be negative prognostic factors in patients with anti-MOG-IgG.

Background/ObjectivesThe COVID-19 pandemic raised concern amongst clinicians that disease-modifying therapy (DMT), particularly anti-CD20 monoclonal antibodies (mAB) and fingolimod, could worsen COVID-19 in people with multiple sclerosis (pwMS). This study aimed to examine DMT prescribing trends pre- and post-pandemic.MethodsA multi-centre longitudinal study with 8,771 participants was conducted using data from the MSBase COVID-19 sub-study. Trends in DMT prescribing between 2018–2022 were analysed using multivariable mixed-effects logistic regression. DMT-initiation referred to the first prescription of any DMT in that timeframe, DMT-switches denoted a change in DMT regimen within 6 months of last DMT use.ResultsPost-pandemic, there was a significant increase in DMT initiation/switching to natalizumab and cladribine ([Natalizumab-Initiation:OR 1.72, 95% CI 1.39–2.13;Switching:OR 1.66, 95% CI 1.40–1.98],[Cladribine-Initiation:OR 1.43, 95% CI 1.09–1.87;Switching:OR 1.67, 95% CI 1.41–1.98]). Anti-CD20 mABs initiation decreased during-pandemic but recovered post-pandemic. Overall, anti-CD20 mABs initiation/switching increased, however less than other high-efficacy DMTs(Initiation:OR 1.26, 95% CI 1.06–1.49;Switching:OR 1.15, 95% CI 1.02–1.29). Initiation/switching of fingolimod, interferon-beta, and alemtuzumab significantly decreased([Fingolimod-Initiation:OR 0.55, 95% CI 0.41–0.73;Switching:OR 0.49, 95% CI 0.41–0.58],[Interferon-Initiation:OR 0.48, 95% CI 0.41–0.57; Switching:OR 0.78, 95% CI 0.62–0.99],[Alemtuzumab-Initiation:OR 0.27, 95% CI 0.15–0.48;Switching:OR 0.27, 95% CI 0.17–0.44]). Dimethyl fumarate initiation increased, while switching decreased(Initiation: OR 1.76, 95% CI 1.49–2.09;Switching:OR 0.85, 95% CI 0.69–1.05).ConclusionPost-pandemic, clinicians preferentially prescribed natalizumab and cladribine over anti-CD20 mABs and fingolimod, likely to preserve efficacy but reduce perceived risk of immunosuppression. This has clinical implications for disease progression and highlights the importance of equitable access to DMTs and COVID-19 treatment in a pandemic to ensure continued use of high-efficacy DMTs.