Sun exposure may influence MS susceptibility, but evidence in pediatric-onset MS (PedMS) is limited. We examined whether reduced early-childhood outdoor time (a proxy for lower sun exposure) is associated with PedMS risk. In the Italian multicenter PEDIGREE Study, environmental data were collected using the PEQ-IT questionnaire. We enrolled individuals < 18 years with PedMS and disease duration ≤ 5 years and controls without CNS inflammatory disorders. Outdoor time was reported by season and age (0–1, 1–2, 3–5 years); reduced activity was defined as < 60 min/week. We included 114 PedMS cases and 121 controls. Cases were 77.2

[This corrects the article DOI: 10.3389/fneur.2026.1747131.].

The recent introduction of High-Efficacy Therapies (HETs) in clinical practice has drastically reduced the frequency of acute inflammatory episodes and relapses, in patients with Multiple Sclerosis (MS), gradually shifting the interest of clinicians toward preventing disease progression and treating symptoms associated with the residual disease. This article summarizes the output of a recent meeting (June 2025, in Rome) among an Italian group of neurologists, who discussed about published evidence supporting the involvement of the endocannabinoid system (ECS) in MS spasticity and its associated symptoms. Sharing their clinical experiences about the silent progression of the disease, in patients with Relapse-Free Multiple Sclerosis (RFMS), treated with HETs, authors propose a new algorithm to treat residual disease in RFMS, by enhancing ECS with both cannabinoid agents and lifestyle interventions (diet and physical activity).

BACKGROUND:Motor and cognitive dysfunctions are common and disabling features in multiple sclerosis (MS) that remain challenging to treat. Here, we aimed to explore the effect of exergames as a stand-alone approach for people with MS and impaired processing speed. METHODS:This was a three-arm, randomised, rater-blinded, sham-controlled trial. People with MS and impaired processing speed were randomised in a 1:1:1 ratio to an 8-week home-based training with exergames (intervention of interest), adaptive Cognitive Training Kit (COGNI-TRAcK) (working memory training as comparator intervention) or sham intervention. A postintervention assessment was scheduled at week 16 postrandomisation. Statistical analyses were conducted to test the hypotheses that exergames were superior to sham intervention and non-inferior to adaptive COGNI-TRAcK on the symbol digit modalities test (SDMT). RESULTS:We screened 165 people with MS, of whom 102 were randomised (34 per arm). At week 8, both exergames and adaptive COGNI-TRAcK yielded improvements in SDMT, with adjusted mean differences versus sham intervention of 4.3 (95% CI 0.1 to 8.5) and 5.7 (95% CI 1.3 to 10.1) points, respectively. The non-inferiority analysis was inconclusive, as the mean between-arm difference (adaptive COGNI-TRAcK versus exergames) was 1.3 points (90% CI -1.7 to 4.3), crossing the predefined non-inferiority margin of 4 SDMT points. Exergames additionally demonstrated benefits on executive function, dynamic balance, fatigue and reduced work absenteeism. None of these benefits was retained at week 16. CONCLUSION:This study provides evidence that home-based exergames are suitable as a standalone approach to improve some specific MS-related cognitive and motor dysfunctions, but there is no evidence about their non-inferiority to working memory training. TRIAL REGISTRATION NUMBER:NCT04169750.

Air pollution is linked to an increased risk of multiple sclerosis (MS) in adults. To investigate the link between air pollutant exposure and pediatric MS (pedMS) in an Italian cohort. PEDIGREE (Pediatric Italian Genetic and Environment Exposure) is a multicenter case–control study investigating genetic and environmental factors in MS before the age of 18. Information on environmental and perinatal exposures was collected through the PEQ-IT questionnaire. Air pollution data during the first, second, and third years prior to MS onset (PM2.5, PM10, O3, NO2, SO2, and CO levels) were obtained from the European Monitoring and Evaluation Program database. Data were available for 113 pedMS cases and 117 controls. We found statistically significant associations between pedMS and higher exposure to ozone (O3) in the first (OR = 1.11; 95

Evidence directly comparing ocrelizumab (OCR) and ofatumumab (OFA) after sphingosine-1-phosphate receptor modulators (S1PRMs) withdrawal is limited, even though this transition period carries an increased risk of disease reactivation and the two anti-CD20 agents differ in molecular properties that may influence post-S1PRM outcomes. We compared effectiveness, safety, and tolerability of OFA versus OCR in relapsing–remitting multiple sclerosis (RRMS) after S1PRM therapy. We retrospectively analyzed adult (> 18 years) patients with RRMS from 23 Italian centers who switched from S1PRMs to OCR or OFA (October 2016 to July 2024). Clinical outcomes included annualized relapse rate (ARR), cumulative relapse incidence, confirmed disability progression (CDP), progression independent of relapse activity (PIRA), confirmed disability improvement (CDI), and variation in the expanded disability status scale score (ΔEDSS) from baseline to last follow-up. Magnetic resonance imaging (MRI) outcomes included time to overall MRI activity, new/enlarging T2 lesions, and new T1 Gd-enhancing lesions. Persistence on anti-CD20 and safety were also assessed. We applied inverse probability of treatment weighting (IPTW) to balance baseline covariates, and used Cox, Andersen–Gill, and regression models, further adjusted for variables with residual imbalance, to compare outcomes. We included 225 subjects (mean age 43.3 ± 10.6 years; OCR = 131, OFA = 94), with a median follow-up of 33 months. After IPTW, groups were well balanced. Compared with OCR, OFA was associated with lower ARR (adjusted relative risk [aRR] 0.22, 95

Migraine is common in people with multiple sclerosis (PwMS) and substantially contributes to disability and impaired quality of life. Although (CGRP)–targeting therapies have reshaped migraine prevention, evidence on their use in PwMS remains scarce, particularly in people receiving concomitant disease-modifying therapies (DMTs). We retrospectively collected data from 17 Italian multiple sclerosis (MS) centers on adult PwMS with comorbid migraine treated with anti-CGRP monoclonal antibodies or gepants in addition to stable DMTs. Monthly headache days (MHDs) and total number of analgesics per month were compared between treatment initiation and last follow-up. MS activity was assessed through clinical relapses, Expanded Disability Status Scale (EDSS), and MRI findings. A ≥ 50

Real-world evidence on ocrelizumab in early, minimally pretreated relapsing multiple sclerosis (MS) patients remains limited. To describe baseline demographic, clinical, radiological, and treatment characteristics of the MUSPO cohort. MUSPO is a prospective, multicenter, observational study. Enrollment occurred from September 2023 to May 2025. Adults with relapsing–remitting MS (RRMS), including a rapidly evolving severe RRMS (RES) group, were enrolled 6 months after starting ocrelizumab. MRI was acquired according to clinical practice with centralized reading. NEDA-plus (absence of relapses, disability worsening, MRI activity, brain atrophy, and cognitive worsening) will be assessed at years 1–4. Baseline descriptive statistics were used. Of 208 patients enrolled across 31 Italian sites, 199 were eligible (RRMS N = 59; RES N = 140) for the interim analysis. Median Expanded Disability Status Scale was 2.0 (IQR 1.0–3.0), indicating mild disability. Prior disease-modifying therapy (DMT) exposure occurred in 59/199 patients (29.6

Clinically silent MRI lesions occur frequently in people with relapsing-remitting multiple sclerosis (RRMS) despite disease modifying therapy (DMT). Guidelines only routinely recommend DMT escalation after multiple silent lesions, and adherence is variable. We explored outcomes and the effect of treatment escalation following single and multiple on-treatment silent lesions. This cohort study and emulated target trial used MSBase registry data from 99 clinics in 26 countries between 2007 and 2025. Clinically stable participants receiving any DMT for RRMS with silent lesions versus without silent lesions were compared. Among participants with silent lesions while taking platform or moderate-efficacy DMTs, outcomes following treatment escalation within 6 months versus no treatment escalation (unless a post-MRI clinical event occurred) were compared. The primary outcome was an MS relapse, and the secondary outcome was 6-month confirmed disability worsening. A total of 10,232 participants met inclusion criteria (71.7% female, mean age 41 [SD 11]). The 2-year cumulative incidence of relapse was 27.8% (95% CI: 25.7%-29.9%) in participants with silent lesions versus 14.3% (95% CI: 13.5%-15.2%) without (adjusted hazard ratio [aHR] 1.76 [95% CI: 1.57-1.97]). The 2-year cumulative incidence of disability worsening was 13.8% (95% CI: 12.2%-15.5%) in participants with silent lesions versus 11.4% (95% CI: 10.7%-12.2%) without (aHR 1.38 [95% CI: 1.18-1.62]). Rates of relapse and disability worsening were higher following single and multiple silent lesions versus no silent lesions. The emulated trial included 2,264 participants with ≥1 silent lesion on platform or moderate efficacy DMTs, 286 of whom escalated DMT within 6 months following silent lesions. The 4-year cumulative incidence of relapse was lower following treatment escalation (16.8% [95% CI: 12.4%-23.4%]) versus continuation (38.9% [95% CI: 35.8%-42.1%]), aHR 0.34 (95% CI: 0.23-0.47), with similar aHRs following single and multiple silent lesions. The 4-year cumulative incidence of disability worsening was similar following treatment escalation (16.0% [95% CI: 10.8%-22.2%]) versus continuation (17.7% [95% CI: 15.3%-20.1%]), aHR 0.89 (95% CI: 0.56-1.33). People with RRMS with single or multiple on-treatment silent MRI lesions have higher subsequent risks of relapse and disability worsening than people without silent lesions. DMT escalation mitigates the relapse risk, though disability worsening continues at a similar rate over 4 years. Contrary to guidelines, DMT escalation should be considered after single or multiple silent lesions.

Predicting disease progression at the individual level is essential for personalized medicine. We previously developed machine-learning tools to estimate 5-year progression risk in people with multiple sclerosis (PwMS). Such models should account for disease-modifying therapy (DMT) and objective outcome definitions. In a retrospective multicenter case–control study, we evaluated adults with relapsing–remitting multiple sclerosis (RRMS) at baseline. Using machine-learning, we developed two complementary tools for individualized 5-year risk estimation: DAAE-M, optimized for transparency, software-neutral use, and mitigation of indication bias, and ELIE, optimized for dynamic landmark-based modeling, complex treatment histories, and mitigation of immortal-time bias. Disease progression was defined using both a clinical outcome (RRMS-to-progressive MS) and an objective outcome (late-stage confirmed progression independent of relapse activity). Among 34,510 people with RRMS (72.6

Abstract Background The thalamus has emerged as a key region involved in cognitive dysfunction in multiple sclerosis (MS). While previous studies have identified associations between thalamic structural damage, altered functional connectivity, and cognitive performance, the specific contributions of individual thalamic nuclei and the added value of integrating structural and functional metrics remain poorly understood. Methods T1-weighted MRI, diffusion MRI, resting-state fMRI, and neuropsychological data were collected from 102 individuals with MS and 27 healthy controls. Thalamic grey matter volume, white matter microstructural integrity, and functional controllability were calculated for each nucleus and compared between individuals with MS and healthy controls, as well as between MS cognitive subgroups. Partial Spearman correlations were used to examine the relationship between imaging metrics across the three modalities, and also between imaging metrics and cognitive performance in MS. Sparse canonical correlation analysis models were used to examine the covariance between thalamic imaging metrics and cognitive performance in MS. Results Widespread atrophy and microstructural damage were observed across all thalamic nuclei in individuals with MS, regardless of cognitive status. In contrast, alterations in functional controllability were more spatially specific, primarily affecting the medial dorsal anterior nuclei, and were most pronounced in cognitively impaired individuals. These functional controllability metrics were independent of grey matter volume, white matter integrity, and lesion load. Combining thalamic functional controllability with structural metrics yielded a stronger association with cognitive performance in MS than either modality alone. Conclusion This study provides novel evidence that functional controllability in the thalamus, particularly within the medial dorsal anterior nuclei, plays a critical role in cognitive impairment in MS. By applying a network control framework, our findings offer a dynamic systems perspective that extends beyond traditional connectivity analyses, capturing the thalamus’s role in supporting flexible cognitive transitions. The integration of structural and functional controllability metrics enhances the ability to characterise individual differences in cognitive performance and may inform future efforts to identify biomarkers of cognitive dysfunction in MS.

Background and objectivesProgression independent of relapse activity (PIRA) is increasingly recognized as a major driver of disability accumulation in multiple sclerosis (MS). However, the factors associated with PIRA occurring after initiation of high-efficacy therapies (HETs) remain poorly investigated. We aimed to identify clinical predictors of subsequent PIRA following first HET initiation.MethodsWe retrospectively analyzed data from two prospectively maintained Italian MS registries. Adults with relapsing MS who initiated a HET and had at least one year of post-treatment follow-up were included. Cox proportional hazards models were used to identify predictors of PIRA after first HET initiation. A primary multivariable model included age at disease onset, sex, baseline Expanded Disability Status Scale (EDSS) score, time from symptom onset to HET initiation, and annualized relapse rate (ARR) before HET exposure. A secondary model additionally adjusted for baseline brain MRI characteristics. Exploratory analyses included risk stratification according to age and treatment timing, strategy-specific analyses, comparison of predictors of PIRA and relapse-associated worsening (RAW), risk of PIRA across first HET classes, and sensitivity analyses.ResultsAmong 466 patients with relapsing MS (71.5% female, median age at onset 32.2 years), 70 (15.0%) developed PIRA after first HET initiation. In the primary multivariable model, older age at onset (HR 1.07, 95% CI 1.05–1.10; p<0.001) and longer time from symptom onset to HET initiation (HR 1.10, 95% CI 1.05–1.16; p<0.001) independently predicted PIRA. These associations remained consistent in the complete-case MRI-adjusted model including baseline brain MRI characteristics (n=269). Patients with younger age at onset and HET initiation within two years of symptom onset had the lowest risk of PIRA. In exploratory analyses, older age at onset and delayed HET initiation predicted PIRA but not RAW, whereas higher pre-treatment relapse activity predicted RAW but not PIRA. Findings were consistent across strategy-specific, on-treatment, landmark, EDSS re-baselining, and calendar-year-adjusted analyses.ConclusionsOlder age at disease onset and delayed HET initiation were the most consistent predictors of PIRA. Our findings support the importance of early HET and suggest that clinically defined PIRA and relapse-associated worsening have partially distinct predictor profiles, while not excluding a contribution of subclinical MRI inflammatory activity to PIRA events.

Multiple Sclerosis (MS) severity is influenced by several factors. Understanding the impact of age at disease onset may help to better characterize clinical and disease features across age groups. This study aimed to characterize the clinical features and disability outcomes of late-onset MS (LOMS) and very late-onset MS (vLOMS), compared to adult-onset MS (AOMS). We conducted an observational study using data from the MSBase registry and categorized patients based on age at MS onset: AOMS (18–39 years), transition onset (40–49 years), LOMS (50–59 years), and vLOMS (≥ 60 years). Disease progression was assessed using the 24 week confirmed disability progression, EDSS4 and 6 milestones, conversion to secondary progressive MS(SPMS), and the first progression independent of relapse activity (PIRA) event. Cox proportional hazard regression models were used to determine unadjusted hazard ratios(HR), and propensity score inverse probability of treatment weighting(PS-IPTW) balanced covariate distributions. Among 81,236 patients, 5.2

Assessing the environmental impact on multiple sclerosis (MS) is complex because of long disease latency and potential recall bias, especially for perinatal exposures. This study aimed to investigate the association between parental smoking and the development of pediatric MS (PedMS). As part of the Italian multicenter PEDIGREE study, the PEQ-IT questionnaire was used for prospective data collection. We enrolled subjects under 18 years with PedMS (2013 Krupp criteria) and disease duration ≤ 5 years from onset, along with matched controls. The study included 114 PedMS cases and 121 controls. Female participants represented 77.2

BACKGROUND:Left-truncation is an unrecorded interval between multiple sclerosis (MS) onset and initial data in observational studies. This delay may bias estimates of disease-modifying therapy (DMT) effectiveness, especially when determined by patient or disease characteristics. OBJECTIVES:To examine whether causal effect estimates of DMTs over the full disease course can be reliably derived from left-truncated registry data. METHODS:We analysed data from MSBase (144 centres, 41 countries) to assess the impact of left-truncation on causal treatment effect estimates. Cox marginal structural models (MSMs) estimated hazard ratios (HRs) for relapses, disability worsening and improvement, considering left-truncation at random and not-at-random. Fixed-time truncation and multivariable adjustment were applied to remediate bias. RESULTS:The study included 5588 patients tracked from true MS onset. The null model, without left-truncation, estimated the DMT effect on relapse risk (HR = 0.64; 95% confidence interval (CI) = 0.54-0.77). Left-truncation inflated this estimate. Shorter random truncation (1 year) produced greater bias (HR = 0.34), decreasing with longer durations (3-year HR = 0.48). Truncation not-at-random biased relapse estimates (HR = 0.37). Disability outcomes were less sensitive. CONCLUSION:MSMs can reliably estimate DMT effectiveness in left-truncated MS registry data, although accuracy depends on truncation mechanism and duration. Both random and not-at-random truncation impact relapse estimates. Disability outcomes appear less sensitive. Fixed-time truncation and covariate adjustment mitigated bias.

The isolation and proteomics characterization of extracellular vesicles (EVs) from body fluids is challenging due to their vast heterogeneity. We have recently demonstrated that Fluorescence-activated Cell Sorting (FACS) efficiently isolates the whole EV circulating compartment directly from untouched body fluids enabling a comprehensive EV proteomics analysis. Here, we characterized, for the first time, a single-phenotype EV subset by sorting leukocyte-derived EVs (Leuko EVs) from peripheral blood and tears of healthy volunteers. Using an optimized and patented staining protocol of the whole EV compartment we identified and excluded non-EV particles, debris and damaged EVs. We further isolated, using an anti-CD45 antibody, Leuko EVs (CD45+ EVs), reaching a high level of purity (> 90

Corticosteroid 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. Individuals 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. In 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. Our 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.