Multiple sclerosis (MS) is a condition marked by considerable prognostic uncertainty, despite advances in therapeutic strategies and biomarker development. Current approaches to prognosis are largely focused on disease burden, failing to consider the influence of compensatory mechanisms, which complicate the evaluation of long-term outcomes. No unified framework currently exists to guide the integration of diverse prognostic factors, ranging from lesion burden and location to neuroaxonal injury, structural and cognitive reserve, lifestyle and digital biomarkers. To address this gap, a consortium from the Magnetic Resonance Imaging in MS (MAGNIMS) network has reviewed the latest research on MS prognosis and, in this Expert Recommendation, proposes a multiaxial conceptual model that incorporates the overall burden of damage, the topography of injury and the capacity for compensation. These three axes can be explored with different tools, such as clinical history and neurological examination, MRI-based tools, biofluid markers and additional techniques, including multimodal evoked potentials, optical coherence tomography and technology-based passive monitoring systems. The MAGNIMS consortium evaluated the existing tools, their limitations and potential future directions across each axis, proposing an integrated, non-prescriptive framework for individualized risk prediction. This work is intended not as a clinical guideline but as a conceptual roadmap to inform future research and refinement of prognostic models in MS.

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.

OBJECTIVE:Multiple sclerosis (MS) is a chronic autoimmune disease where B cells play a central pathogenic role. Cladribine, an oral therapy, provides durable benefits by reshaping lymphocyte populations, yet its specific long-term impact on distinct B-cell subsets is not fully understood. This study aimed to define cladribine's longitudinal effects on B-cell subsets and characterize their inflammatory properties. METHODS:We conducted a 48-month longitudinal study of 36 persons with relapsing-remitting MS treated with cladribine who had completed 2 annual treatment cycles, using high-parameter flow cytometry to track B-cell subset dynamics. In a parallel cross-sectional analysis, B cells from 16 untreated patients and 16 healthy donors were profiled for polyfunctional cytokine production granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and key surface markers. RESULTS:Cladribine induced profound, sustained depletion of memory B cells, with marginal zone-like (MZ-like) cells showing the deepest and most persistent loss, alongside reconstitution of transitional and naïve populations. Functionally, MZ-like B cells were the most potent polyfunctional producers of proinflammatory cytokines and immunoglobulin M (IgM), a capacity significantly enhanced in persons with MS compared to healthy donors, and expressed the highest levels of CD1c and CD1d, consistent with specialization in lipid antigen presentation. INTERPRETATION:MZ-like B cells are a dominant, polyfunctional inflammatory subset in MS, equipped for non-canonical lipid antigen presentation and IgM secretion. They represent a preferential pharmacological target of cladribine. Sustained reduction of this pathogenic memory pool, followed by repopulation with less inflammatory B cells, offers a mechanistic basis for cladribine's durable clinical benefit and nominates MZ-like cells as biomarkers of response and therapeutic targets. ANN NEUROL 2026.

Background: Disease-modifying drugs (DMDs) for multiple sclerosis (MS) slightly increase the risk of tuberculosis (TB) disease. The QuantiFERON-TB-Plus (QFT-Plus) test is approved for TB infection (TBI) screening. Currently, there are no data available regarding the characterization of QFT-Plus response in patients with MS. Objectives: This study aimed to compare the magnitude of QFT-Plus responses between patients with MS and TBI (MS-TBI) and TBI subjects without MS (NON-MS-TBI). Additionally, discordant responses to TB1/TB2 stimulation were documented. Results were evaluated considering demographic and clinical data, particularly the impact of DMDs and the type of TB exposure. Methods: Patients with MS (N = 810) were screened for TBI (2018–2023). Thirty (3.7%) had an MS-TBI diagnosis, and 20 were recruited for the study. As a control group, we enrolled 106 NON-MS-TBI. Results: MS-TBI showed significantly lower IFN-γ production in response to TB1 (p = 0.01) and TB2 stimulation (p = 0.02) compared to NON-MS-TBI. The 30% of TB2 results of MS-TBI fell into the QFT-Plus grey zone (0.2–0.7 IU/mL). Only 7% of NON-MS-TBI showed this profile (p = 0.002). Conclusions: MS-TBI had a lower QFT-Plus response and more borderline results compared to NON-MS-TBI. Future studies should clarify the significance of the borderline results in this vulnerable population to improve QFT-Plus accuracy regarding sensitivity, specificity, and TB prediction.

Purpose: This study aimed to evaluate the numeric correlation between modified treatment in cerebral infarction (mTICI)>= 2b/3 and modified Rankin Scale (mRS)<= 2 in RCT and registries. Material and Methods: Literature search was performed on PubMed/OVID for studies in 2015-2021, mTICI, mRS, and sample size were recorded. Exclusion criteria were monocentric, non-human, and non-English studies. Studies qualities were assessed with MINORS/RoB2. A meta-analysis with a random-effects model was performed. Meta-logistic and meta-linear regressions were used to correlate mTICI and mRS in both RCTs and registries. The Z-test was used to compare the coefficients between RCTs/registries. Results: We evaluated thirty-four studies (17 registries; 17 RCTs) for 29540 patients (27031 from registries (median registry 1192.0 [CI95 % 698.7-1992.8]; 2509 from RCTs [median RCT 165.0 [CI95 % 98.1-234.0]). 10/17(58.8 %) registries considered also vertebrobasilar system strokes. Overall mRs <= 2 was 46.0 (CI95 % 43.8-48.3) with I-2 = 92.6 %. The odd-ratio of obtaining a mRS <= 2 for a singular increased of mTICI >= 2b rate was: 1.49(CI95 % 1.22-2.01) for all studies (for 1 % increase of mTICI >= 2b the odds for obtaining mRS <= 2 was 1.49), 1.50(CI95 % 1.00-2.23) for RCTs and 1.50(CI95 % 1.10-2.23) for registries. mTICI >= 2b and mRS had a positive correlation with coefficient of 0.49(CI95 % 0.22-0.75, p = 0.001) for all studies (for 1 % increase of mTICI >= 2b the mRS <= 2 rate augment by 0.49 %), 0.51(CI95 % 0.10-0.91) for RCTs and 0.46(CI 95 % 0.09-0.84) for registries. No differences were found in coefficients between RCTs/registries (p = 0.50; p = 0.57; respectively). Conclusions: Unitary increased of mTICI >= 2b rate correspond to an augment of mRS <= 2 by 0.49(CI95 % 0.22-0.75) with odd-ratio of obtaining mRS <= 2 of 1.49(CI95 % 1.22-2.01), without significantly differences in coefficients.

OBJECTIVE:To explore whether proxies of premorbid structural reserve-intracranial volume (ICV) and spinal cervical canal area (SCCA)-influence long-term disability accumulation in multiple sclerosis (MS), specifically through progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW). METHODS:We included 253 patients with relapsing-onset MS, ⩾5-year follow-up from first demyelinating event (FDE), and available 3D T1-weighted magnetic resonance imaging (MRI) scan enabling estimation of ICV and SCCA. To account for PIRA and RAW co-occurrence in the same individuals, we used negative binomial regression to estimate adjusted event rate ratios (adj.-ERRs) and competing risk models to derive subdistribution hazard ratios (SHRs) for PIRA and RAW events. RESULTS:Over a median 17-year follow-up, higher SCCA was associated with fewer PIRA events (adj.-ERR = 0.74, p = 0.014) and delayed PIRA onset (SHR = 0.50, p = 0.05), while larger ICV was associated with fewer RAW events (adj.-ERR = 0.70, p = 0.033) and both later occurrence (SHR = 0.41, p = 0.02) and older age at RAW (SHR = 0.30, p = 0.002). Patients with high combined reserve (both larger ICV and SCCA) reached EDSS ⩾ 6.0 later (hazard ratio (HR) = 0.33, p = 0.025) and at older age (HR = 0.37, p = 0.045) than those with low reserve. CONCLUSION:Pre-morbid structural reserve mitigates the MS-related disability accrual, supporting the integration of ICV and SCCA into prognostic models as markers of neuroanatomical resilience.

Background:Cladribine (CLAD) stands as an oral disease modifying treatment (DMT) for multiple sclerosis (MS) patients, distinguished by its unique dosing regimen and mechanism of action. However, real-world data on its effectiveness remain limited, particularly regarding the clinical and therapeutical management beyond the 2-year treatment schedule. Objectives:The aim of our study was to explore the effectiveness profile of CLAD in individuals with MS (pwMS). We assessed the proportion of patients achieving no evidence of disease activity (NEDA-3) status and identified variables associated with better outcomes. Design:In this retrospective study, we collected clinical and magnetic resonance imaging (MRI) data of MS patients across 10 MS Clinics in Central Italy who started CLAD between 2018 and 2023. Methods:We evaluated the annualized relapse rate (ARR) during treatment, and the proportion of patients who experienced relapses, radiological activity, and confirmed disability progression. Additionally, we estimated the proportion of patients achieving NEDA-3 among those with a minimum follow-up of 3 months and explored baseline variables associated with NEDA status. Results:We collected data from 1094 patients with a mean follow-up of 25.1 months, of whom 79% completed the second CLAD cycle. The mean age was 37.7 years (SD 9.7), and the mean disease duration was 6.5 years, with 40.5% being treatment naïve. Despite a significant reduction of the ARR from 0.91 to 0.04 (p < 0.01) following CLAD treatment, 8.9% of patients presented at least one relapse, while 22.0% and 7.9% of patients experienced radiological activity or disability progression, respectively. Across the entire study cohort, 70.2% of patients maintained the NEDA-3 status. Younger age (HR = 0.98, p < 0.001) and higher expanded disability status scale score (HR = 1.11, p = 0.049) were associated with a higher risk of not achieving the NEDA-3 status. Additionally, we included 131 patients who were older than 50 years at the time of CLAD initiation. Among the cohort, 116 patients switched to another DMT after CLAD, primarily anti-CD20 monoclonal antibodies following disease reactivation. Conclusion:This postmarketing experience confirms the effectiveness of CLAD in the treatment of pwMS, with a significant reduction in ARR and a high proportion of patients remaining free from disease activity. By contrast, some patients required an escalation strategy mainly with anti-CD20 monoclonal antibodies because of persisting disease activity.

The development of disease-modifying therapies (DMTs) for the treatment of multiple sclerosis (MS) has been highly successful in recent decades. It is now widely accepted that early initiation of DMTs after disease onset is associated with a better long-term prognosis. However, the question of when and how to de-escalate or discontinue DMTs remains open and critical. This topic was discussed during an international focused workshop organized by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in 2023. The aim was to review the current evidence on the rationale for, and the potential pitfalls of, treatment de-escalation in MS. Several clinical scenarios emerged, mainly driven by a change in the benefit-risk ratio of DMTs over the course of the disease and with ageing. The workshop also addressed the issue of de-escalation by the type of DMT used and in specific situations, including pregnancy and paediatric onset MS. Finally, we provide practical guidelines for selecting appropriate patients, defining de-escalation and monitoring modalities and outlining unmet needs in this field.

Importance:Early treatment choice in relapsing-remitting multiple sclerosis (RRMS) is prognostically crucial, yet robust comparative data on cladribine vs sphingosine-1-phosphate receptor modulators (S1PRMs) in treatment-naive patients with RRMS are limited. Objective:To compare the clinical effectiveness of cladribine vs S1PRMs in treatment-naive individuals with RRMS. Design, Setting, and Participants:This comparative effectiveness research study used data from 108 Italian multiple sclerosis (MS) centers affiliated with the Italian Multiple Sclerosis and Related Disorders Register. All treatment-naive patients with RRMS who initiated cladribine or an S1PRM (fingolimod, ozanimod, or ponesimod) between January 2011 and October 2021 and had at least 12 months of follow-up were included. Propensity score matching and pairwise censoring were used to balance baseline differences and follow-up duration. Patient data were extracted from the register in September 2024. Exposure:Initiation of cladribine or an S1PRM, with duration reflecting clinical practice. Main Outcomes and Measures:The primary outcome was no evidence of disease activity (NEDA-3) and its subcomponents. Secondary analyses evaluated disability accrual subdivided into progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW), plus variables associated with treatment response. Cox proportional hazards models, adjusted for visit and magnetic resonance imaging (MRI) frequency, were used to compare outcomes. Results:Of the 1587 patients (485 taking cladribine and 1102 taking S1PRMs), matching yielded 475 pairs (950 individuals; mean [SD] age, 34.7 [10.7] years; 686 female [72.2%]), with a median (IQR) follow-up period of 25 (12-60) months. For the cladribine vs S1PRM groups, no significant differences were observed in relapse rates (72 patients [15.2%] vs 76 patients [16.0%]), MRI activity (137 patients [31.3%] vs 145 patients [34.8%]), or NEDA-3 loss (194 patients [44.4% vs 219 patients [52.2%]). Cladribine was associated with a lower risk of disability worsening vs S1PRM (54 patients [11.4%] vs 70 patients [14.7%]; hazard ratio [HR], 0.64; 95% CI, 0.42-0.96; P = .03), a finding that was confirmed in sensitivity analyses for patients younger than 40 years, those whose diagnoses were made according to the 2017 McDonald Criteria, and those with Expanded Disability Status Scale score less than or equal to 3.0. This was mainly driven by reduced PIRA risk with cladribine (HR, 0.40; 95% CI, 0.20-0.79; P = .009), with no RAW difference. After 36 months, patients treated with cladribine showed higher relapse risk (HR, 1.81; 95% CI, 1.02-3.20; P = .04) and increased NEDA-3 loss (HR, 2.08; 95% CI, 1.18-3.67; P = .01). Discontinuation rates were similar (HR, 0.92; 95% CI, 0.67-1.15; P = .58). Conclusions and Relevance:These findings suggest cladribine was associated with superior effectiveness in reducing disability progression over 25 months, likely due to reduced PIRA, despite comparable short-term NEDA-3 outcomes. However, relapse prevention declined after 36 months, suggesting retreatment or therapy modification within 3 years may be needed to maintain long-term disease control.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare disease that primarily affects the optic nerve and the spinal cord but less frequently can also involve the brain. We present the case of a woman who experienced an atypical NMOSD relapse characterized by MRI white matter brain lesions with a leukodystrophy-like pattern. Additionally, lesions in the middle cerebellum peduncles exhibited a distinctive T2w hyperintense/FLAIR hypointense signal resembling the brain's bright spotty lesions (BSLs) previously described in the spinal cord. This case highlights the importance of recognizing atypical MRI patterns in NMOSD to facilitate diagnosis and appropriate timely treatment.

Advances in the availability and regimen optimization of highly effective disease-modifying treatments (DMTs) for relapsing–remitting multiple sclerosis (RRMS) have led to questions about their comparative worth. This study evaluates the costs and effects of natalizumab versus other highly effective DMTs and the impact, in terms of times and costs, of the new subcutaneous natalizumab formulation versus the intravenous formulation in patients with RRMS in Italy. This is a cost-consequence analysis from the Italian national health service and societal perspectives. A Markov model was developed to assess clinical and cost outcomes related to disease and DMTs. The model simulated two scenarios: one comparing natalizumab extended-dose regimen and ofatumumab and ocrelizumab, focusing on efficacy outcomes and costs, and one comparing intravenous and subcutaneous natalizumab with a focus on administration resource consumption, times, and costs. Model input data came from the literature. DMTs had similar clinical and social outcomes: natalizumab slightly reduced disease progression, increased quality-adjusted life-years, and reduced the impact on days of productivity loss and informal care. Natalizumab also resulted in statistically significant 5-year cost reductions compared with ocrelizumab and ofatumumab. Subcutaneous natalizumab improved resource consumption compared with intravenous natalizumab, saving the time of healthcare professionals, patients, and caregivers and reducing administration costs. The subcutaneous formulation was associated with statistically significant total direct and indirect cost reductions at 5 years. 6-week dosing regimen of natalizumab showed a slight improvement of clinical and social outcomes and a statistically significant cost reduction compared with ocrelizumab and ofatumumab over a 5-year simulation. Moreover, subcutaneous administration reduced administration times and costs.

Background Physical activity (PA) has been recommended in multiple sclerosis (MS) to maintain good physical fitness and mental health, reduce the severity of symptoms and risk of relapse, and improve quality of life. Pilates has been suggested as an ideal PA to manage physical, cognitive, and psychological symptoms of MS and a useful method to maintain and improve balance and gait. Objective This paper presents the protocol for a study that aims to evaluate the efficacy on the physical domain (specifically balance and gait) of a home-based, self-managed PA intervention delivered through the MS-FIT exergame (HELAGLOBE Società a responsabilità limitata). In addition, measures of cognitive performance, quality of life, and well-being will be considered. Methods This is a 2-arm, multicenter, randomized controlled trial with 3 assessment points (baseline, 12 weeks postintervention, and 6 weeks follow-up). People with MS with mild disability, low risk of falling, preserved cognitive functions, and low anxiety and depression are potential eligible participants. The experimental group (MS-FIT) will self-administer the MS-FIT exergame at home in addition to their leisure-time physical activities. MS-FIT is an internet- and Pilates-based tool that uses the Microsoft Kinect Sensor V2. Participants in the control group will only have access to their leisure-time physical activities. Participants in the MS-FIT group will train at home with MS-FIT for 12 weeks and will be required to perform the exercises for a total of 30 minutes/day for at least 3 days/week. The primary outcome is the Timed Up and Go, a test designed to assess walking. We will also administer additional tests for motor function (visual analog scale 0-10, Timed 25-Foot Walk, Ambulation Index, 2-minute walk test, Twelve Item Multiple Sclerosis Walking Scale, Nine-Hole Peg Test), cognition (Brief International Cognitive Assessment for Multiple Sclerosis), fatigue (Modified Fatigue Impact Scale), quality of life (Multiple Sclerosis Quality of Life-54), well-being (Psychological Well-Being Scales), and PA (International Physical Activity Questionnaire and Minnesota Leisure Time Physical Activity Questionnaire). Acceptance and satisfaction with the intervention received (Client Satisfaction Questionnaire and an adapted version of the Tele-healthcare Satisfaction Questionnaire – Wearable Technology) and subjective impressions of changes in performance (Patients’ Global Impression of Change) will also be assessed. Results Recruitment for the trial started on March 16, 2022, and the first participant was randomized the same day. Data analysis and results are expected to be published in 2025. Conclusions Pilates has proven beneficial in several neurological diseases such as MS. With this study, we will provide evidence for the use in clinical practice of a digital tool for self-administered Pilates exercises at home as a complement to rehabilitation and for the continuity of care in MS. Trial Registration ClinicalTrials.gov NCT04011579; https://tinyurl.com/2p9n4d2t International Registered Report Identifier (IRRID) DERR1-10.2196/58026

Background:Epilepsy is two to three times more common in patients with multiple sclerosis (pwMS) compared to the general population. Patients with MS and epilepsy without other identifiable causes (MS + E) show greater cortical damage than those without epilepsy (MS-E). However, it's unclear whether MS + E patients exhibit distinct cognitive and neuropsychological features requiring specific management. Methods:In a cohort of pwMS from three MS centers, MS + E patients were identified and data on MS clinical features, epilepsy history, and treatments were collected. A matched group of MS-E patients was included. Assessments included cognitive and neuropsychiatric tests. Cognitive impairment (CI) was defined as scoring ≥1.5 standard deviations below normative values in ≥1 cognitive domain. Results:CI was more prevalent in MS + E (n = 33) patients than in MS-E (n = 33). MS + E patients had lower processing speed (p < 0.01) and visuospatial memory (p = 0.03). MS + E was independently associated with CI (odds ratio 3.6, 95% confidence interval 1.21-12). Somatization, phobia, anxiety, and depression were the most affected neuropsychological domains in MS + E, with global psychological distress negatively correlating with processing speed (rho -0.36, p = 0.048). Conclusions:MS + E is associated with higher CI, particularly in processing speed and visuospatial memory, alongside psychological distress, highlighting the need for targeted multidisciplinary care to improve outcomes and quality of life.

Purpose:Two analyses, a cost-minimization and a budget impact, were conducted to estimate the economic and financial impact of subcutaneous (SC) vs intravenous (IV) natalizumab in terms of administration times and costs in the Italian setting from the perspective of multiple sclerosis (MS) center, patient, and society. Patients and Methods:Cost minimization analysis (CMA) adopted a Markov model with three different states, and it is based on the results of REFINE study and its post-hoc analysis, which evaluated and demonstrated the non-inferiority of natalizumab SC vs IV formulation. The economic inputs came mainly from EASIER study, that estimated the administration time, resource consumption, and costs of natalizumab SC vs IV. A lifetime horizon was considered. Budget impact analysis (BIA) was conducted with a cost calculator approach and compared a base scenario (without SC natalizumab) with an alternative scenario (with SC natalizumab). The inputs were shared with the CMA and a 3-year time horizon was considered. A progressive increase in the number of patients treated with natalizumab SC was estimated from the 1st to the 2nd to the 3rd year after reimbursement in Italy. Results:CMA estimated that savings due to the use of SC instead of IV natalizumab would be €2,824, €1,137, and €9,170 per patient from the perspectives of MS center, patient, and society, respectively, thus depicting a weak dominance (lower costs and non-inferiority efficacy). BIA estimated that the savings were approximately 3.2 million euros from the perspective of MS centers and around 10.3 million euros from the perspective of society in the first 3 years following reimbursement. Conclusion:Administering natalizumab subcutaneously rather than intravenously to treatment-eligible patients would result in administration time and cost savings thus determining a favorable impact for the MS center, the patient and the society.