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Microglia are innate immune cells that maintain homeostasis of the central nervous system (CNS) and affect various neurodegenerative diseases, especially multiple sclerosis (MS). MS is an autoimmune disease of the CNS characterized by persistent inflammation, diffuse axonal damage, and microglia activation. Recent studies have shown that microglia are extremely related to the pathological state of MS and play an important role in the development of MS. This article reviews the multiple roles of microglia in the progression of MS, including the regulatory role of microglia in inflammation, remyelination, oxidative stress, the influence of phagocytosis and antigen-presenting capacity of microglia, and the recent progress by using microglia as a target for MS therapy. Microglia modulation may be a potential way for better MS therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Dendritic cells (DCs) orchestrate both immune activation and immune tolerance in multiple sclerosis (MS). Manipulating the phenotypes and functions of DCs to boost their tolerogenic potential is an appealing strategy for treating MS and its animal model experimental autoimmune encephalomyelitis (EAE). Programmed cell death 1 (PD-1) delivers the immunoinhibitory signals by interacting with PD-1 ligand 1 (PD-L1), which plays a critical role in maintaining immune tolerance. So far, the effects of PD-1/PD-L1 signalling activation on DCs in EAE are poorly understood. Here, the administration of soluble PD-L1 (sPD-L1) protein significantly alleviated the clinical symptoms of myelin oligodendrocyte glycoprotein (MOG)-induced EAE, and inhibited the expression of cluster of differentiation (CD)86, C-C motif chemokine receptor 7 (CCR7) as well as CCR7-mediated trafficking of splenic DCs, accompanied by enhancing their phagocytosis. The impact of sPD-L1 on the surface morphology and mechanical properties of DCs was investigated at the nanoscale, using scanning electron microscope and atomic force microscope. The treatment of sPD-L1 was found to mitigate morphological maturation and biomechanical alterations, specifically in terms of adhesion and elasticity, in bone marrow-derived DCs from EAE. Taken together, our findings suggest that application of exogenous sPD-L1 has a marked suppressive effect on the maturation and migration of DCs in EAE. PD-L1 administration may be a promising therapy for EAE and for MS in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Recent advancements in research have significantly enhanced our comprehension of the intricate immune components that contribute to multiple sclerosis (MS) pathogenesis. By conducting an in-depth analysis of complex molecular interactions involved in the immunological cascade of the disease, researchers have successfully identified novel therapeutic targets, leading to the development of innovative therapies. Leveraging pioneering technologies in proteomics, genomics, and the assessment of environmental factors has expedited our understanding of the vulnerability and impact of these factors on the progression of MS. Furthermore, these advances have facilitated the detection of significant biomarkers for evaluating disease activity. By integrating these findings, researchers can design novel molecules to identify new targets, paving the way for improved treatments and enhanced patient care. Our review presents recent discoveries regarding the pathogenesis of MS, highlights their genetic implications, and proposes an insightful approach for engaging with newer therapeutic targets in effectively managing this debilitating condition., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Spasticity and muscle weakness are the most disabling symptoms in people with Multiple Sclerosis (pwMS), frequently affecting lower limbs and causing motor impairments, fatigue and increased risk of falls. Previous epidemiological studies on pwMS reported prevalence of spasticity and other symptoms but scarce information is available about combined patterns of muscle weakness and spasticity, symmetry and regional localization., Objectives: To describe the prevalent combined patterns of muscle weakness and spasticity in pwMS in order to focus attention on their functional balance before spasticity treatment., Methods: pwMS with lower limb spasticity, 3.5 ≤ Expanded-Disability-Status Scale (EDSS) ≤ 6.5 were recruited. Data regarding muscle weakness and spasticity, symmetry and involvement of other functional systems were collected. Prevalence analysis was performed., Results: Three-hundred pwMS were included. Muscle weakness and spasticity occurred mostly asymmetrically with a prevalence of paraparesis. Incidence of both symptoms increase with higher EDSS, particularly of muscle weakness. Twelve prevalent combined patterns were identified, with highest incidence of combinations characterized by "distal-intermediate spasticity and diffuse weakness" (29.3%), "diffuse spasticity and weakness" (13.7%), "distal spasticity and diffuse weakness" (11.7%)., Conclusions: This study highlighted the most prevalent combined patterns of weakness and spasticity, useful in clinical practice for pwMS' assessment by supporting optimal planning of specific pharmacologic and rehabilitative treatments., Competing Interests: Declarations. Conflicts of interest: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Ethical approval: This study was conducted in accordance with the Declaration of Helsinki. All patient data come from previous studies on MS spasticity in the three Italian centers already approved from the respective Ethics Committees (University of Campania “L. Vanvitelli”: 100/2018; Sapienza University of Rome: 5769/2020; University of Cagliari, ATS Sardinia: 198/2019/EC). Consent to participate: Informed consent was obtained from all individual participants included in the previous study., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating, neurodegenerative disease of the central nervous system, significantly impacting patients' quality of life. Understanding patient and healthcare professional (HCP) preferences for MS treatments is crucial for optimizing therapeutic strategies and improving adherence and outcomes. This Discrete-Choice Experiment (DCE) assesses preferences for various MS treatment attributes among Italian patients and HCPs. The sample included 1069 patients and 186 HCPs. Key attributes evaluated were treatment administration route, frequency, location, and Patient-Reported Outcome Measures (PROMs), such as cognitive impairment, fatigue, and mobility. Data were collected through questionnaires and responses were analyzed to determine the relative importance (RI) and utility of each attribute. Both patients and HCPs highly prioritized PROMs, with cognitive impairments and walking ability being the most critical factors. Patients showed a strong preference for oral administration and treatments administered biannually at home, whereas HCPs preferred hospital-based treatments. The "Time to Progression" attribute was more significant for HCPs than for patients, reflecting different priorities between the groups. The study highlighted the importance of treatment convenience, with patients favoring less-frequent administration schedules and home-based treatment options. This study underscores the necessity of incorporating both patient and HCP perspectives into MS treatment planning. Shared decision-making, which considers individual preferences, can enhance treatment adherence and outcomes. These insights into treatment preferences provide valuable guidance for personalized MS care, aiming to improve patient quality of life and optimize therapeutic efficacy., Competing Interests: Declarations. Conflict of interest: CG declares speaker honoraria and travel expenses for attending meetings from Bayer Schering Pharma, Sanofi-Aventis, Merck, Biogen, Novartis, and Almirall. VBM received personal compensation for speaking or consultancy from Biogen, Teva, Genzyme, Merck, Novartis, and Almirall. MF is the Editor-in-Chief of the Journal of Neurology, Associate Editor of Human Brain Mapping, Neurological Sciences, and Radiology; received compensation for consulting services from Alexion, Almirall, Biogen, Horizon, Merck, Novartis, Roche, and Sanofi; speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Horizon, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA; participation in Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Horizon, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, and Takeda; scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, and Sanofi-Genzyme; he receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). MAB, FB, EC, MP, and PP declare no conflict of interest. The funder had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results., (© 2024. The Author(s).)

In this observational cross-sectional study conducted in Italy, sociodemographic and disease data were collected from a multiple sclerosis (MS) population treated with disease-modifying therapies (DMTs). A prevalence-based cost-of-illness analysis was subsequently carried out. In total, 393 MS patients were enrolled, 65.9% female, average age of 45 ± 11.5 years. 94.9% had RRMS and EDSS median value of 1.5 (1.0, 2.0). The mean total cost per MS patient was estimated at €20,299.4 per year. Total costs of MS increase by disability level, varying from 16,812.0 (minor) to 20,407.0 (mild), 27,640.7 (moderate), and 44,404.0 (severe). DMT costs accounted for 62.5% of total costs, while productivity loss accounted for 22.0%. Indeed, besides having low quality of life decline and fatigue levels, most patients enrolled retained full working capacity while 31.3% had some productivity loss. The results obtained are in line with previous studies showing that as the disease progresses, the quality of life, fatigue and working capacity worsen alongside a rise in total MS costs for either the society or the healthcare service. Clinical relapses cause a significant cost increment. This cross-sectional study provides a representation of MS quality of life and MS cost in a cohort of Italian MS patients treated with DMT, among which the majority had RRMS. This cost-of-illness analysis can provide useful information for resource allocation and help estimate the savings that can be obtained by slowing the progression of the disease. It also constitutes a primary source of data useful for conducting a complete economic evaluation analysis, including cost-effectiveness and cost-utility analyses., Competing Interests: Declarations. Conflict of interest: Ponzio M. has no conflicts of interest to declare; Santoni L. is an employee of and may hold stock in Biogen; Tavazzi E. received honoraria for speaking from Biogen Idec, Bristol-Meyers-Squibb; Molina M. is an employee of and may hold stock in Biogen; Bergamaschi R. received honoraria for speaking from Biogen, Merck Serono, Roche, Novartis, Celgene, Janssen, Sanofi Genzyme; research grants from Biogen, Merck Serono, Roche, Novartis, Sanofi Genzyme; congress and travel/accommodation expenses funded by Biogen, Merck Serono, Roche, Novartis, Sanofi Genzyme. Ethical approval: The study protocol was approved by the Ethical Committee of the San Matteo Hospital in Pavia (PR 20180042426; 06/06/2018) and was conducted in accordance with the rules of the Declaration of Helsinki and all applicable local law requirements and regulations concerning the privacy and security of personal information, including the General Data Protection Regulation (GDPR) (EU) 2016/679. An informed consent form was obtained from all patients enrolled in the study., (© 2024. The Author(s).)

The role of exercise as a therapeutic intervention in multiple sclerosis (MS) has shifted over time. Early views surrounding exercise in MS advocated for caution against participation. With increasing evidence, perspectives shifted to promote exercise as a therapeutic approach for symptom management. Recent efforts have focused on understanding the potential disease-modifying effects of exercise in MS, although this work is still in its infancy. While efforts continue to optimize exercise prescriptions and unravel underlying mechanisms of exercise effects, current knowledge and implementation gaps limit the accessibility of exercise as therapy for all people living with MS. This topical review is based on an invited presentation on ' Exercise as a Therapeutic Intervention in MS ' delivered at the ACTRIMS Forum 2024. The review summarizes current evidence for the role of exercise as a therapeutic intervention in MS from symptomatic to disease-modifying potential. We highlight directions for future research efforts to advance our understanding of potential exercise benefits and translate findings into real-world contexts for people living with MS., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

People with multiple sclerosis (PwMS) experience many barriers to accessing multiple sclerosis (MS) care that lead to diagnostic delays, delayed treatment, interrupted care, and significant economic burden. These barriers include limited geographic healthcare resources, financial burden, physical limitations, and inequities within the healthcare system. Telemedicine has the potential to reduce these barriers and improve access to care. The lack of geographic proximity to neurologists and MS Centers can be overcome by leveraging telemedicine which has been shown to significantly reduce travel burden. Furthermore, cross-sectional studies have shown telemedicine reduces indirect costs for PwMS including significantly lower mean costs in parking, gas, tolls, and wages lost compared to in-person visits. Although there has been evidence that telemedicine can reduce many barriers there is still a need to demonstrate the impact of longitudinal telemedicine care and its direct impact on access to MS care., Competing Interests: Declaration of Conflicting InterestsThe author declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Marisa McGinley has received research support from the National Institutes of Health, Agency for Healthcare Research and Quality, Genentech, Novartis, and Biogen and consulting fees from Genentech and EMD Serono

Multiple sclerosis (MS) is a chronic neurological disease that causes substantial health economic impacts, however, the cost of informal care for MS is often excluded from health economic analysis. As a result there is a paucity of information for decision-making. This review aims to summarise, synthesise and where appropriate meta-analyse the global evidence regarding the health economics of informal care for people with MS. The findings will provide consolidated evidence that policymakers and other stakeholders can use to inform decisions, including the development of health economics models. This review was conducted with a pre-determined study protocol (PROSPERO- CRD42023396457). Biomedical and economic databases were searched. Costs were converted to 2022 United States dollars (USD). Mean cost was calculated and pooled with a random-effects model. Subgroup analysis and meta-regression was conducted for stratified variables such as country income level and Expanded Disability Status Scale (EDSS). Of 6,306 identified studies, 61 were retained for narrative synthesis and 50 for meta-analysis. Studies were conducted in 25 countries. Cost information was collected from the person with MS, not the caregiver. 83.6% of studies used the opportunity cost method. Average monthly caregiving time was 60.1 h. Informal care costs accounted for 15% of total societal cost of MS. Pooled mean annual cost of informal care per person was USD $6,308 (95% CI $5,022-7,594). Informal care costs were USD $6,797 and $1,478 in high- and middle-income countries. Costs for mild, moderate, and severe disability of the person with MS were $1,123, $6,643, and $15,855, respectively. Informal care cost contributes considerably to MS-related costs. Despite study heterogeneity, cost of informal care increases with MS-related disability severity, time attributed to care and country income level. These results can be used to inform health economic models for reimbursement decisions for MS. Future studies regarding the health economic burden of informal care should gather the data from the informal carers themselves., Competing Interests: Declaration of competing interest All authors declare that they have no conflict of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Background: People newly diagnosed with multiple sclerosis (MS) often pursue 'health-related' behaviour changes to feel in control of their diagnosis. However, little is known about the specific factors that may influence behaviour change during this crucial time. Therefore, we conducted an in-depth exploration of the socioecological influences impacting the diagnostic experience and self-management practices following an MS diagnosis., Methods: We followed a qualitative study design using a phenomenological approach to explore the lived experiences of people newly diagnosed with MS. Analysis was conducted via an iterative process, starting with deductive open coding to map onto the socioecological model, followed by inductive focused coding to extract key themes from participants' reported experiences., Results: Eight participants diagnosed with MS within the past 12 months were interviewed. Four themes were reported across the MS journey, reflecting the different levels of the socioecological model: (1) taking control of a new diagnosis to retain a sense of personal identity-individual level; (2) grief and acceptance guided by community-social connection, community and social environment; (3) practical management of MS in the wider society-policy and government regulation; and (4) global events that greatly upheave the MS journey-natural disasters and societal conflicts, such as a pandemic. These themes highlighted the complex interrelationship between socioecological factors and self-management abilities in people living with MS., Conclusions: The diagnostic experience of those with MS is highly complex. Although it varies for each person living with MS, there are shared experiences that often reflect a common cycle of grief. An MS diagnosis provides an opportunity for self-rediscovery, which can both influence and be influenced by socioecological factors. The social and technical nature of self-managing MS strongly shapes the diagnostic experience, underpinning many aspects of daily living, social interaction and physical and psychological well-being., Patient or Public Contribution: The research team worked closely with an MS-specific consumer panel for the study design. This project was raised with this group, and preliminary results were shared at a national conference for MS during a lived-experience consumer stream to gain additional insights., (© 2024 The Author(s). Health Expectations published by John Wiley & Sons Ltd.)

Background: Guidelines serve as practice-based decision support and recommend the use of standardized instruments to measure functional capacity in individuals with multiple sclerosis (MS). However, the extent to which a person's functioning is captured by these instruments is unclear., Objectives: The aim of this study is to link the content of the MS disease guideline with the International Classification of Functioning, Disability and Health (ICF) in order to capture the distribution of the content on the functional domains and contextual factors and to uncover existing gaps., Materials and Methods: Instruments of the S2k guideline "Diagnosis and therapy of multiple sclerosis, neuromyelitis optica spectrum diseases and MOG-IgG-associated diseases", which were available free of charge in German or English and designed for adult people, were included. The instruments were classified into their meaningful concepts (meaningful concepts = MCs) and subsequently coded using standardized ICF rules by two raters., Results: The 23 included instruments contained 351 items and 718 MCs. Of these, 663 MCs could be linked to the ICF according to the coding rules. Of these, 51% (340 MCs) related to body functions, 44% (291 MCs) to the activity and participation component, and 5% (32 MCs) to environmental factors. The most frequently coded chapter was mobility (d4) with 201 MCs. Interrater agreement was k = 0.79., Discussion: The linking of the guideline-recommended instruments to the ICF shows that the instruments cover different themes. The area of environmental factors is underrepresented. The ICF linkage reveals a broad spectrum of functioning covered by the guideline-recommended instruments and facilitates the selection of appropriate instruments for the affected persons., Competing Interests: Einhaltung ethischer Richtlinien. Interessenkonflikt: J. Bolte, E.-M. Dilger und A.L. Brütt geben an, dass kein Interessenkonflikt besteht. Im Rahmen der vorliegenden Arbeit wurden keine Daten von Menschen erhoben, sondern verschriftlichte Instrumente der MS-Leitlinie qualitativ untersucht. Das Einholen eines Ethikvotums war dementsprechend nicht erforderlich., (© 2024. The Author(s).)

Background and Purpose: The rapidly evolving landscape of effective treatment options in multiple sclerosis has led to a shift of treatment objectives towards a treat-to-target approach aiming to suppress disease activity below the level of detectability early during the disease. To enable treat-to-target, a thorough reappraisal of available outcome measures with respect to their ability in this regard is required., Methods: To that end, we conducted a comprehensive systematic literature review of more than 1000 studies using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 methodology focusing on underlying evidence as well as utility and implementability in clinical practice., Results: From there, we propose a set of measurable outcomes for everyday routine clinical practice as well as advanced/aspirational measurables requiring additional resources. We also outline remaining knowledge/technology gaps that need to be overcome to enable a treat-to-target approach., Conclusions: This work provides the basis for an evidence-based definition of outcome targets for relevant stakeholders and regulatory authorities., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Evidence suggests a prodromal phase in multiple sclerosis (MS), with increased health care use preceding the first demyelinating event (FDE). Although prior studies have explored this in adults, limited data exist for pediatric cases. We aimed to analyze health care utilization and prodromal symptoms in the two years before FDE in patients with pediatric-onset MS (POMS)., Methods: From 122 patients at the Pediatric Multiple Sclerosis & Demyelinating Diseases Center at Washington University School of Medicine from 2011 to 2021, 37 POMS cases were identified. Of these, 21 with at least two years of records preceding FDE were included. Retrospective analysis covered symptoms and health care utilization in the two-year period before FDE, including ambulatory visits, hospital admissions, and office calls., Results: Patients showed increased health care utilization in the year preceding FDE (period B; 96 interactions) compared with the prior year (period A; 77 interactions) and an increase in the percentage of neurology-related encounters (P < 0.001). There was an increase in all office calls from period A to period B (P = 0.01). Neurological complaints included headaches (28.6%), visual (19.0%), sensory (14.3%), and balance (14.3%) in the two years before FDE, and 28.6% of patients presented for psychiatric complaints. Common non-neurological complaints included infection, dermatologic, and musculoskeletal issues and injury., Conclusions: Our POMS cohort showed increased health care use before FDE, consistent with population-based data. This study emphasizes diverse symptoms in prodromal POMS, with headaches being the most common neurological symptom in the two-year period before FDE., Competing Interests: Declaration of competing interest Dr. Mar is involved in clinical trials for treatment of pediatric-onset MS patients, sponsored by Biogen and Roche, and receives funding from the National MS Society. The other authors have no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Healthcare breakthroughs are extending the lives of multiple sclerosis (MS) patients and cancer survivors, creating a growing cohort of individuals navigating a dual diagnosis. Determining the relationship between MS and cancer risk remains challenging, with inconclusive findings confounded by age, risk exposures, comorbidities, genetics and the ongoing introduction of new MS disease-modifying therapies (DMTs) across study periods.This research places significant emphasis on cancer survival, with less attention given to the impact on MS outcomes. Our review explores the existing literature on MS, cancer risk and the intersection of DMTs and cancer treatments. We aim to navigate the complexities of managing MS in cancer survivors to optimise outcomes for both conditions. Continuous research and the formulation of treatment guidelines are essential for guiding future care. Collaboration between neuro-immunology and oncology is crucial, with a need to establish databases for retrospective and ultimately prospective analysis of outcomes in these rapidly evolving fields., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: CN has received education-related travel expense reimbursement from Roche, Biogen, Merck and Genzyme and speaker honoraria from Biogen and MS Australia. AVdW served on advisory boards for Novartis, Biogen, Merck and Roche and NervGen. She received unrestricted research grants from Novartis, Biogen, Merck and Roche. She is currently a co-Principal investigator on a co-sponsored observational study with Roche, evaluating a Roche-developed smartphone app, Floodlight-MS. She has received speaker’s honoraria and travel support from Novartis, Roche, Biogen and Merck. She serves as the Chief operating Officer of the MSBase Foundation (not for profit). Her primary research support is from the National Health and Medical Research Council of Australia and MS Research Australia. HB is an employee of Alfred Health and Monash University and has accepted travel funding from Merck and Novartis. In the last 3 years, his institutions (Monash University, MSBase Foundation) have received honoraria for talks, steering committee activities and research grants from Roche, Merck, Novartis, Alexion, UCB Pharma and Biogen, the Medical Research Future Fund Australia, NHMRC Australia, Trish MS Foundation, MS Australia and the Pennycook Foundation. He is funded by an NHMRC Australia Investigator Grant. VGJ receives research grant support from the National Health and Medical Research Council of Australia, Multiple Sclerosis Australia and F. Hoffmann-La Roche. She has received speaker’s honoraria from Novartis and The Limbic. BD declared no potential conflict of interest.

Introduction: Clean Intermittent Catheterization (CIC) is considered as a gold standard of treatment for bladder emptying disorders. A large amount of literature on CIC for patients suffering from neurological disorders is available, but there is a lack of research specifically concerning multiple sclerosis (MS) patients. Our primary outcome was to determine the characteristics of our population (sex, EDSS and age when CIC was introduced). Our secondary outcomes were to determine adherence of CIC., Method: As part of a multicenter, observational, retro-prospective study, data was collected from neuro-urologist consultation reports, and extracted from bladder diaries between 01/01/2000 and 31/03/24. MS patients, over 18 years, with the indication of CIC were included., Results: 195 patients (72.3% women) were included, with a mean age of 49 years old. The median of follow-up was 9 years. Median EDSS at the start of the study was 5.5. There was an adherence rate of 65.1%. Urinary leakage was present in 74.2% of patients prior to CIC and 31.6% following CIC., Conclusion: Catheterization is mainly offered to patients with an EDSS between 0 and 7. Rate of adhesion is encouraging, with most patients still continuing to use CIC by the end of follow-up. During the follow-up, we observed a reduced leakage rate but CIC alone can not explain this improvement. Following studies should include a list of constraints and reasons of halted CIC., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Purpose: Therapeutic plasma exchange (PLEX) is effective as a second-line treatment of severe relapses of multiple sclerosis (MS) that failed to respond to standard steroid therapy. Our objective was to evaluate the effectiveness of PLEX in the severe MS relapses in a cohort of patients treated at Neurology Clinic, University Clinical Centre of Serbia, Belgrade, from 2007 until 2020., Methods: This retrospective study comprised 107 MS patients with 127 severe relapses treated with PLEX. Majority of our patients suffered from relapsing remitting MS (83.2%), 12.1% had secondary progressive MS and 4.7% had primary progressive MS. Mean age was 39.2 years (range, 19-79 years), female/male ratio 2.3:1. Pulse corticosteroid treatment was used before PLEX in 99.3% of patients. Median EDSS score at nadire during relapse was 6.0 (range 2.0-10.0). After PLEX, 73.8% relapses showed a marked clinical improvement, 7.1% showed mild improvement and in 19.0% there was no improvement. Median EDSS at discharge was 4.0 (6.0 at nadir of relapse vs. 4.0 at discharge; p<0.0001) and it was sustained at the same level, 6 month after PLEX. Multivariate regression analysis showed that higher EDSS at nadir during relapse (OR=0.63, 95% CI 0.41-0.96, p=0.039) and older age (OR=1.07, 95% CI 1.02- 1.12, p=0.010) were significantly associated with poor treatment response after 6- month follow-up. Adverse events occurred in 17.3 of procedures and they were completely resolved., Conclusion: Our study in a large cohort of MS patients confirmed that PLEX is effective., Competing Interests: Ethical approval: The study was approved by the Institutional Review Board of the Clinic of Neurology, University Clinical Center of Serbia, Belgrade. Informed consent: All patients signed informed consent before entry in the study. Conflicts of interest: The authors have no relevant financial or non-financial interests to disclose., (© 2024. The Author(s) under exclusive licence to Belgian Neurological Society.)

Introduction: Sexual dysfunction (SD) is a common symptom that affects 40-90% of patients with multiple sclerosis (MS). Previous studies have highlighted the negative impact of sexual dysfunction in the mental health status and overall quality of life in patients with MS., Methods: The aim of this study was to examine the effects of transcutaneous tibial nerve stimulation (TTNS) in the primary SD symptoms in patients with MS. A total of 40 participants were randomized (1:1 ratio) to either TTNS or Sham group and received three 20 min sessions over the course of two months. Pre and post intervention SD was evaluated using the Multiple Sclerosis Intimacy Questionnaire (MISQ-15)., Results: Statistically significant improvements in the aspects of primary sexual dysfunction were observed in the TTNS group pre-post intervention (specifically erectile function (for males)/vaginal lubrication (for females) (p < .001), orgasm quality and satisfaction for both male and female patients (p < .001), sexual desire (p < .05) and bladder related symptomatology (p < .005). In the sham group pre-post intervention, the only observed improvement was in the sexual desire aspect (p < .05). Post intervention the groups significantly differed erectile function/vaginal lubrication and orgasm quality and satisfaction (p < .05)., Conclusions: Our findings underline the efficacy of TTNS in improving primary SD symptoms as well as bladder problems in both male and female patients with MS. TTNS demonstrated significant improvement in the following domains: erectile function, vaginal lubrication, orgasm quality, satisfaction, bladder-related symptoms, and sexual desire., Competing Interests: Declarations Ethical approval This study was approved by the Ethics Board of Attikon University Hospital, Greece (Ethics Board Approval: ΕΒΔ:722/23-12-2021). Conflict of interest The authors declare no potential conflict of interest., (© 2024. Fondazione Società Italiana di Neurologia.)

Despite the considerable progress in mesenchymal stem/stromal cells (MSCs)-based novel intervention of multiple sclerosis (MS), yet the disease-modifying effect of VCAM-1 - MSCs and novel VCAM-1 + counterpart is largely obscure. In this study, we took advantage of the EAE mouse model and VCAM-1 + human umbilical cord-derived MSCs (hUC-MSCs) for the evaluation of the therapeutic effect of systematic MSCs infusion. On the one hand, we compared the protective effect of VCAM-1 - and VCAM-1 + hUC-MSCs against the clinical symptoms, demyelination, active glia cells and neuroinflammation in EAE mice by conducting multifaceted detections upon spinal cord and brain tissues. On the other hand, we conducted RNA-sequencing (RNA-SEQ) and multidimensional bioinformatics analyses for the evaluation of the transcriptomic features of spinal cord tissue in EAE mice after systematic hUC-MSCs infusion. Compared to those with VCAM-1 - hUC-MSCs injection, VCAM-1 + mice showed further remission in clinical manifestations, and in particular, the inflammatory infiltration and active glial cells. Mice in all groups revealed conservations in overall gene expression profiling and somatic mutation spectrum. The differentially expressed genes (DEGs) between EAE mice and those with hUC-MSCs infusion were mainly involved in neuroinflammation and inflammatory response. Our findings indicated the feasibility of VCAM-1 + hUC-MSCs for multiple sclerosis treatment, which would supply new references for the development of novel VCAM-1 + MSCs-based cytotherapy in future., Competing Interests: Declarations. Competing interest: The authors declare there’s no competing interests and all authors consent to publish the data. Ethical Approval: Ethical approval of this research was approved by the Institutional Animal Care and Use Committee of The Second Hospital of Shandong University (approval No.: KYLL-2023LW099) according to the International Guiding Principles for Biomedical Research Involving Animals. Consent to Participate: Not applicable., (© 2024. The Author(s).)

Background: Evidence suggests that illness perceptions held by people living with multiple sclerosis (MS) impact affective distress and physical health outcomes. In a randomized controlled trial, we developed 2 MS Online Courses-the standard care course and the intervention course (IC). The IC was adapted from an evidence-based lifestyle program. Modifying lifestyle risk factors offers an opportunity to impact illness perceptions. Research on illness perceptions in people living with MS has focused predominately on quantitative methods., Objective: This study aimed to explore the experiences and health outcomes of randomized controlled trial participants, including individuals' perceived changes in attitudes toward MS and their health (ie, illness perceptions)., Methods: Qualitative responses provided by 38 participants (22 in the IC and 16 in the standard care course) were derived from semistructured interviews 1 month after completing the MS Online Course. The impact of course engagement and lifestyle modification on illness perceptions was explored using inductive thematic analysis., Results: Themes of changes in illness perceptions were most prominent in the IC arm. Qualitative responses from 22 people living with MS informed the development of three themes: "self-efficacy for disease management," "personal control," and "illness coherence.", Conclusions: Findings provide novel insights into the formation and modification of illness perceptions. Lifestyle modification may serve as a valuable adjunct to clinician-administered therapies, improving the sense of personal control over MS, illness coherence, and self-efficacy for disease management., Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12621001605886; https://tinyurl.com/2vyve9p9., International Registered Report Identifier (irrid): RR2-10.1186/s12883-023-03298-0., (©Rebekah Davenport, William Bevens, Sandra Neate, Pia Jelinek, Maggie Yu, George Jelinek, Jeanette Reece. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 29.11.2024.)

Introduction: Reactivation of thymopoiesis in adult patients with autoimmune disorders treated with autologous haematopoietic stem cell transplantation (AHSCT) is supported by studies exploring immunoreconstitution. Radiological evidence of thymic hyperplasia after AHSCT was previously reported in patients with systemic sclerosis, but, to our knowledge, it has not been described in multiple sclerosis (MS), where premature thymic involution has been observed and immunosenescence might be accelerated by disease-modifying treatments (DMTs)., Participants and Methods: monocentric case series including MS patients who performed a chest CT scan for clinical purposes after having received AHSCT (BEAM/ATG regimen) for aggressive MS failing DMTs. Chest CT exams were reviewed by a thoracic radiologist: thymic hyperplasia was defined as a rounded mass in the thymic loggia with a density around 40 Hounsfield Units (HU) and thickness >1.3 cm., Results: Fifteen MS patients were included; the median time interval between AHSCT and chest CT scan was 2 (range 1-18) months. All the patients were free from new inflammatory events and DMTs over a median follow-up of 36 months (range 12-84) after AHSCT. Thymic hyperplasia was detected in 3/15 (20%) cases in an exam taken 1 to 3 months after AHSCT; all these patients were females, and aged 30 to 40 years. Lung infections and secondary autoimmunity were diagnosed in 5 and 1 cases, respectively, none of which showed thymic hyperplasia. No associations between thymic hyperplasia and clinical-demographic characteristics or post-AHSCT outcomes were observed., Conclusions: Thymic hyperplasia was detected in 20% of MS patients recently treated with AHSCT. These results are consistent with previous immunological studies showing that AHSCT promotes thymus reactivation in MS patients, further supporting de-novo thymopoiesis as a cornerstone of immune reconstitution after AHSCT in this population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Author Contributions The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Mariottini, Boncompagni, Cozzi, Simonetti, Repice, Damato, Giordano, Miele, Nozzoli and Massacesi.)

Objectives: To collaboratively develop a music-supported video-based exercise programme for people with multiple sclerosis (pwMS) with mild to severe disability., Design and Setting: We performed this participatory mixed methods study from 15 March 2022 to 22 July 2023 at two Austrian multiple sclerosis (MS) centres., Participants: This research included 67 pwMS, of whom 18 pwMS (including two patient representatives and five MS support group leaders/members) and an additional three family members served as stakeholders. Six neurologists and six physiotherapists, each with >5 years of experience in treating pwMS were interviewed., Intervention: Stakeholders actively participated as members of study advisory, project steering and research groups. Researcher-supported peer-to-peer focus groups and individual interviews, conducted in three stages, gathered information on musical preferences and exercise needs. We co-developed, co-evaluated and co-adapted the music-supported exercise programme with the stakeholders. Involvement levels were measured using the Participation Check and Patient Public Involvement (PPI) Assessment Survey, self-efficacy with the Unidimensional Self-Efficacy Scale for Multiple Sclerosis and emotional states with the Self-Assessment Manikin., Results: We identified four themes through reflexive thematic analysis: (1) engagement; (2) ease; (3) autonomy; (4) musical meaning. Integration of qualitative and quantitative components highlighted the success of PPI activities: (a) 148 co-created, free videos are publicly available; (b) four videos provide expert interviews with general information, while 144 offer music-supported exercises tailored to pwMS with mild to severe disability; (c) patients found the videos relevant, feasible and usable in interviews and focus groups; (d) 'easy' category exercises (seated or lying) are suitable for severely affected pwMS; (e) stakeholders felt included, respected and heard, as shown by quantitative PPI assessments., Conclusions: Stakeholders were essential in identifying key aspects, preferences and constraints early on. Their feedback on music and exercise shaped the project. This study transformed our approach to exercise for pwMS. Future studies are required to evaluate the programme's efficacy., Trial Registration Number: DRKS00027979., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Multiple sclerosis (MS) is a complex autoimmune disorder of the central nervous system (CNS) with an unknown etiology and pathophysiology that is not completely understood. Although great strides have been made in developing disease-modifying therapies (DMTs) that have significantly improved the quality of life for MS patients, these treatments do not entirely prevent disease progression or relapse. Identifying the unaddressed pathophysiological aspects of MS and developing targeted therapies to fill in these gaps are essential in providing long-term relief for patients. Recent research has uncovered some aspects of MS that remain outside the scope of available DMTs, and as such, yield only limited benefits. Despite most MS pathophysiology being targeted by DMTs, many patients still experience disease progression or relapse, indicating that a more detailed understanding is necessary. Thus, this literature review seeks to explore the known aspects of MS pathophysiology, identify the gaps in present DMTs, and explain why current treatments cannot entirely arrest MS progression., (© 2024 The Author(s). Published by IMR Press.)

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination. Current treatment options for MS focus on immunosuppression, but their efficacy can be limited. Recent studies suggest a potential role for nerve injury-induced protein 1 (NINJ1) in MS pathogenesis. NINJ1, a protein involved in cell death and inflammation, may contribute to the infiltration and activation of inflammatory cells in the CNS, potentially through enhanced blood-brain barrier crossing; enhancing plasma membrane rupture during cell death, leading to the release of inflammatory mediators and further tissue damage. This review explores the emerging evidence for NINJ1's involvement in MS. It discusses how NINJ1 might mediate the migration of immune cells across the blood-brain barrier, exacerbate neuroinflammation, and participate in plasma membrane rupture-related damage. Finally, the review examines potential therapeutic strategies targeting NINJ1 for improved MS management. Abbreviations: MS, Multiple sclerosis; CNS, Central nervous system; BBB, Blood-brain barrier; GSDMD, Gasdermin-D; EAE, Experimental autoimmune encephalitis; HMGB-1, High mobility group box-1 protein; LDH, Lactate dehydrogenase; PMR, Plasma membrane rupture; DMF, Dimethyl fumarate; DUSP1, Dual-specificity phosphatase 1; PAMPs, Pathogen-associated molecular patterns; DAMPs, Danger-associated molecular patterns; PRRs, Pattern recognition receptors; GM-CSF, Granulocyte-macrophage colony stimulating factor; IFN-γ, Interferon gamma; TNF, Tumor necrosis factor; APCs, Antigen-presenting cells; ECs, Endothelial cells; TGF-β, Transforming growth factor-β; PBMCs, Peripheral blood mononuclear cells; FACS, Fluorescence-activated cell sorting; MCP-1, Monocyte chemoattractant protein-1; NLRP3, Pyrin domain-containing 3; TCR, T cell receptor; ROS, Reactive oxygen species; AP-1, Activator protein-1; ANG1, Angiopoietin 1; BMDMs, Bone marrow-derived macrophages; Arp2/3, actin-related protein 2/3; EMT, epithelial-mesenchymal transition; FAK, focal adhesion kinase; LIMK1, LIM domain kinase 1; PAK1, p21-activated kinases 1; Rac1, Ras-related C3 botulinum toxin substrate 1; β-cat, β-caten; MyD88, myeloid differentiation primary response gene 88; TIRAP, Toll/interleukin-1 receptor domain-containing adapter protein; TLR4, Toll-like receptor 4; IRAKs, interleukin-1 receptor-associated kinases; TRAF6, TNF receptor associated factor 6; TAB2/3, TAK1 binding protein 2/3; TAK1, transforming growth factor-β-activated kinase 1; JNK, c-Jun N-terminal kinase; ERK1/2, Extracellular Signal Regulated Kinase 1/2; IKK, inhibitor of kappa B kinase; IκB, inhibitor of NF-κB; NF-κB, nuclear factor kappa-B; AP-1, activator protein-1; ASC, Apoptosis-associated Speck-like protein containing a CARD; NEK7, NIMA-related kinase 7; NLRP3, Pyrin domain-containing 3; CREB, cAMP response element-binding protein., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Multiple sclerosis (MS) is a chronic, progressive autoimmune disease, with increasing attention on the role of B cells in its pathogenesis. Despite this growing interest, a comprehensive analysis of research trends and emerging foci on B cells in MS is currently lacking. In this research, we utilize a bibliometric approach to visualize and analyze research trends and focal points in this field, offering a valuable reference for future mechanistic studies in MS., Methods: We retrieved bibliometric data from the Web of Science Core Collection (WOSCC) for articles published between 2014 and 2023. VOSviewer 1.6.18 and CiteSpace 5.7R3 were used for co-authorship, co-occurrence, and citation analyses to identify key researchers, institutions, countries, and emerging themes in B cell research related to MS., Results: The analysis examined 5,578 articles published in 1,041 journals by 5,337 institutions globally. The United States leads in publication output, with Amit Bar-Or identified as the most influential author, and Frontiers in Immunology as the top journal in the field. Research has increasingly focused on the complex role of B cells in MS, particularly their involvement in the central nervous system (CNS) and mechanisms of anti-B cell therapy. Recent trends point to a growing focus on meningeal inflammation, kinase inhibitors, and Epstein-Barr virus, signaling a shift in research priorities., Conclusion: This bibliometric analysis highlights pivotal research trends, key contributors, and emerging areas of interest in B cell research in MS from 2013 to 2024. The findings underscore the growing recognition of the multifaceted role of B cells in MS pathogenesis, particularly their involvement in the CNS compartment and the potential of targeted therapies. The study identifies meningeal inflammation, Epstein-Barr virus infection, and kinase inhibitors as promising avenues for future research. The analyses driving the in-depth exploration of B cell mechanisms in MS and the development of novel diagnostic and therapeutic strategies provide researchers in the MS field with a comprehensive and objective perspective, serving as a valuable reference for accelerating the translation of basic research findings into clinical applications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Jiang, Zhang, Liu, Sun and Mu.)

The bidirectional interaction between the gut and the central nervous system (CNS), the so-called gut microbiota-brain axis, is reported to influence brain functions, thus having a potential impact on the development or the progression of several neurodegenerative disorders. Within this context, it has been documented that multiple sclerosis (MS), an autoimmune inflammatory, demyelinating, and neurodegenerative disease of the CNS, is associated with gastrointestinal symptoms, including constipation, dysphagia, and faecal incontinence. Moreover, some evidence suggests the existence of an altered gut microbiota (GM) composition in MS patients with respect to healthy individuals, as well as the potential influence of GM dysbiosis on typical MS features, including increased intestinal permeability, disruption of blood-brain barrier integrity, chronic inflammation, and altered T cells differentiation. Starting from these assumptions, the possible involvement of GM alteration in MS pathogenesis seems likely, and its restoration could represent a supplemental beneficial strategy against this disabling disease. In this regard, the present review will explore possible preventive approaches (including several dietary interventions, the administration of probiotics, prebiotics, synbiotics, and postbiotics, and the use of faecal microbiota transplantation) to be pursued as prophylaxis or in combination with pharmacological treatments with the aim of re-establishing a proper GM, thus helping to prevent the development of this disease or to manage it by alleviating symptoms or slowing down its progression., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Published by Elsevier Ltd.)

Background: Treatment of fatigue is important for many patients with multiple sclerosis (MS). While pharmacological options have not shown consistent benefit, psychological interventions offer another avenue of treatment. Cognitive behavioural therapy (CBT) involves strategies to change maladaptive cognition and illness behaviours that modulate how patients with MS respond to fatigue. The aim of this study was to perform a systematic review and meta-analysis to determine the effectiveness of CBT for the treatment of fatigue in patients with MS., Methods: Five databases (Cochrane Central Register of Controlled Trials, MEDLINE/PubMed, Embase, Emcare and PsycINFO) were searched up until 31 July 2023. Randomised controlled trials involving adult patients with MS and fatigue, comparing CBT with another intervention or usual treatment were included. Studies were required to measure fatigue severity and/or the impact of fatigue as the primary outcome(s). Each study was assessed for bias using the Cochrane Risk of Bias tool version 2. Studies with sufficient data were used for meta-analysis to quantify the short- and long-term effects of CBT on MS-related fatigue. The level of certainty provided by the body of evidence was evaluated using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework., Results: Eight studies were included in the review and six studies contributed to the meta-analysis. Most studies had a low overall risk of bias. CBT interventions differed in the number, duration and frequency of sessions, mode of delivery and therapist. There were significant short- (standardised mean difference (SMD) -0.58, 95% confidence interval (95%CI) -0.85 to -0.31, P-value < 0.0001) and long-term (SMD -0.36, 95%CI -0.52 to -0.19, P-value < 0.0001) effects supporting CBT. The evidence provided a low level of certainty for the short-term effect because of heterogeneity of results and possible publication bias, while there was high certainty for the long-term result., Conclusion: The study provides secondary evidence that CBT has moderate short-term and small long-term effects in reducing fatigue in patients with MS. CBT should be regarded as a viable evidence-based intervention, particularly in the absence of established alternatives. Future research should identify the ideal characteristics of a fatigue-specific CBT intervention, patient factors that predict treatment response and strategies to maintain initial improvements over time., Competing Interests: Declaration of competing interest The authors declare that no funding or research grants were received in the course of study, research or assembly of the manuscript., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Lifestyle changes have been demonstrated to impact pathophysiology in Multiple Sclerosis (MS). Various diet and exercise protocols have been reported to improve symptoms and function in persons with MS. Evidence is accumulating that interventions as early as possible in the disease course are warranted. The objective of this study was to investigate the effect of a remotely delivered lifestyle program focusing on specific diet and exercise recommendations in persons with early MS., Methods: MS patients, with disease diagnosis no more than 2 years prior, were recruited from the patient population of the MS clinic of the Pacific Neuroscience Institute. Participants followed recommendations for diet and exercise delivered via remote heath coaching. Each participant received 6 sessions with a health coach over a 12-week period. They were given parameters of a Mediterranean-type diet to follow, and specific and individualized recommendations about duration, intensity and type of exercise and physical activity. Outcome measures included Quality of Life (QOL), cognition (Symbol Digit Modalities Test, SDMT), fatigue (Multiple Sclerosis Fatigue Impact Scale, MFIS), fitness (estimated with Metabolic equivalents, METS) and other objective and patient reported outcomes (PRO). Changes in outcomes were analyzed using mixed effects general linear models and standardized pre-post differences.(Cohen's d) RESULTS: Fifteen persons with early (≤ 2 years) MS enrolled in the study, 14 of whom completed the study. We observed significant improvements in QOL (p = 0.02), SDMT (p = 0.006), fatigue(p = 0.005), fitness (p = 0.04), and other PRO and objective metrics at the end of the protocol compared to baseline. Adherence and patient satisfaction measures were high., Conclusions: Specific and individualized lifestyle recommendations can be effectively delivered remotely, and may produce improvement in symptoms and function in persons with early MS. Larger controlled trials of these interventions are warranted., Competing Interests: Declaration of competing interest NONE, (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Neurogenic lower urinary tract (NLUTD), bowel (NBD), and sexual dysfunction (SD) are commonly observed in patients with (pw) multiple sclerosis (MS) and diminish the patients' quality of life (QoL). This systematic review aim to evaluate and discuss the current algorithms for the management of these issues., Methods: A systematic review was conducted on the PubMed in June 2024. The primary search criterion was the presence of the term 'algorithm/s' or 'management/ing' in the title and/or abstract, followed by the MeSH term 'multiple sclerosis' and a combination of free-text keywords referring to NLUTD, NBD or SD., Results: Fifteen articles regarding NLUTD were considered eligible, only one regarding SD while none addressed NBD., Discussion: Numerous studies emphasize the profound impact of urinary and bowel symptoms on the QoL and morbidity in pwMS. Few algorithms addressing NLUTD are designed for first-line physicians and addresses the key priorities in MS care. Specific approaches to NBD management in pwMS are lacking. Screening for SD requires a structured assessment to deliver appropriate solutions., Conclusion: NLUTD, NBD, and SD are underdiagnosed and undertreated. The implementation of straightforward algorithms for first-line physicians could enhance the management of these common issues, improve the QoL, reduce costs, and ensure appropriate referral to specialists., Competing Interests: Declaration of competing interest The author declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Multiple sclerosis (MS) is a chronic disease characterized by dysregulated self-reactive immune responses that damage the neurons' myelin sheath, leading to progressive disability. The primary therapeutic option, immunosuppressants, inhibits pathogenic anti-myelin responses but depresses the immune system. Antigen-specific monocyte-derived autologous tolerogenic dendritic cells (tolDCs) offer alternative therapeutic approaches to restore tolerance to autoantigens without causing generalized immunosuppression. However, immune dysregulation in MS could impact the properties of the monocytes used as starting material for this cell therapy. Here, we characterized CD14+ monocytes, mature dendritic cells, and vitamin D3-tolDCs (VitD3-tolDCs) from active, treatment-naive MS patients and healthy donors (HDs). Using multiomics, we identified a switch in these cell types toward proinflammatory features characterized by alterations in the aryl hydrocarbon receptor (AhR) and NF-κB pathways. MS patient-derived VitD3-tolDCs showed reduced tolerogenic properties compared with those from HDs, which were fully restored through direct AhR agonism and by use of in vivo or in vitro dimethyl fumarate (DMF) supplementation. Additionally, in the experimental autoimmune encephalomyelitis mouse model, combined therapy of DMF and VitD3-tolDCs was more efficient than monotherapies in reducing the clinical score of mice. We propose that a combined therapy with DMF and VitD3-tolDCs offers enhanced therapeutic potential in treating MS.

Background: Adults with multiple sclerosis (MS) frequently experience symptoms of depression and anxiety, which pose significant challenges. However, psychological support for these symptoms remains a major unmet healthcare need., Objectives: To inform the evidence base for the psychological management of adults with MS, this study examined the efficacy of cognitive behavioural therapy (CBT) interventions for improving symptoms of depression and anxiety. CBT interventions teach skills for improving the relationships between an individual's thoughts, feelings, and/or behaviours. The study also examined the role of intervention and study characteristics as moderators of treatment effects., Methods: Medline, Embase, PsycINFO, and Cochrane Central Register of Controlled Trials were searched up to August 2024 for randomised control trials., Results: A meta-analysis of 15 clinical trials (1508 participants) was conducted, which found a medium significant treatment effect size for depression symptoms (g = 0.59, 95 % Confidence Interval [CI] [0.38, 0.80]) and a small significant treatment effect size for anxiety symptoms (g = 0.38 95 % CI [0.19, 0.57]). Moderator analyses revealed treatment effects for anxiety, but not depression, were significantly larger for studies conducted in non-Western countries compared to Western countries, and for those with smaller sample sizes., Conclusions: CBT-based interventions appear efficacious for the management of depression and anxiety symptoms in adults with MS. However, future clinical trials with larger samples and more rigorous methodology are warranted. Further examination of intervention characteristics, including ways in which CBT is tailored and how this relates to outcomes, may help to refine interventions for people with MS., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Many people with MS do not meet the recommended exercise regime to elicit health benefits. This study aimed to determine the feasibility, safety, acceptability, and appropriateness of an exercise intervention delivered online to persons with MS that meets current exercise recommendations and behaviour change principles., Methods: Seventy-two participants (age: 43.3 ± 13.3 years) with mild to moderate MS were stratified according to previous exercise behaviour and block-randomised into one of three groups: Control (CON; n = 24), General Exercise (GE; n = 24) who at screening did not meet current exercise recommendations, and Advanced Exercise, (AE; n = 24) who at screening met the current exercise recommendations. GE and AE groups received a four-month online-supervised, behaviour change theory-based exercise program and were assessed at baseline, four-months, five-months, and eleven-months for physical activity participation. The feasibility of process, resources, management, and scientific outcomes was assessed., Results: Of 198 potential participants, 143 met the eligibility criteria (72 %), and 72 were randomised. Fifty-three participants completed the intervention (74 % immediate retention), and 44 were retained at the six-month follow-up (61 %). Personnel time was 369 h, and total per-participant cost was Au$1036.20. Adherence rate to ≥70 % of exercise sessions was 73 % (GE) and 38 % (AE). The GE group observed a small magnitude of improvement in physical activity (d = -0.23)., Conclusions: An online exercise program embedded with behaviour interventions for either GE or AE appears feasible, acceptable, appropriate and safe and may show long-term efficacy in increased exercise behaviours for persons with mild to moderate MS., Trial Registration: ANZCRT number ACTRN12619000228189p., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Fatigue is a pervasive and debilitating symptom of multiple sclerosis (MS) that severely impairs quality of life and daily functioning. This emphasizes the essential need for complementary therapies that go beyond conventional therapies. Although acupuncture is gaining popularity in MS management, there is a critical lack of rigorous research on its effectiveness in alleviating symptoms., Methods: A comprehensive literature search was conducted across multiple databases, focusing on studies evaluating acupuncture's effectiveness in alleviating fatigue in MS patients. Key outcomes measured in the analysis included fatigue, quality of life, and disability., Results: Six studies were included in the analysis, consisting of two observational studies and four randomized controlled trials. The analysis focused on evaluating acupuncture's efficacy in alleviating fatigue induced by MS. Despite variations in acupuncture protocols, outcome metrics, and control conditions, our meta-analysis revealed that acupuncture significantly reduces fatigue (MD: -0.92, 95 % CI: -1.36 to -0.47, p < 0.0001) and enhances quality of life (SMD: 0.91, 95 % CI: 0.07-1.74, p = 0.03), underscoring its potential as a therapeutic intervention in the management of MS., Conclusion: The meta-analysis suggests a notable improvement in MS-related fatigue following acupuncture, both compared to controls and pre-treatment levels, positioning it as a potential adjunct therapy. However, the prevalent risk of bias in these studies necessitates further high-quality research, along with studies involving larger patient cohorts, to definitively ascertain acupuncture's efficacy and safety in this context., Competing Interests: Declaration of competing interest The review authors assert the absence of discernible conflicting financial involvements or personal associations that might have seemed to exert an influence on the research findings disclosed in this manuscript., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background and Purpose: Physical exercise improves physical and psychological health. However, information on the quantitative impact of Traditional Chinese Exercise (TCE) on physical and psychological health remains limited. Therefore, this systematic review and meta-analysis aimed to quantitatively explore the effects of TCE on the physical and psychological health of patients with multiple sclerosis (MS)., Methods: A comprehensive search was conducted across seven electronic databases (PubMed, SCOPUS, CINAHL, Web of Science, Cochrane Library, China National Knowledge Infrastructure, and Wanfang) from their inception to March 7, 2024 using the terms, Taiji, Tai Chi, Tai Chi Chuan, Qigong, Baduanjin, Wuqinxi, Yijinjing, multiple sclerosis, and disseminated sclerosis. Randomized controlled trials (RCTs) and non-RCTs reporting the effects of TCE on physical function or psychological health outcomes in MS patients were included. A random-effects model and 95 % confidence intervals (95 % CI) were used to compute the effect sizes., Results: Eleven studies, including 461 subjects with MS, were included in this meta-analysis. TCE significantly increased balance (d = 0.88, 95 % CI [0.45, 1.31], p < 0.001, I 2  = 39.26 %), activities of daily living (d = 1.17, 95 % CI [0.30, 2.04], p < 0.001, I 2  = 89.15 %), Multiple Sclerosis Impact Scale (MSIS) scores (d = 0.53, 95 % CI [0.12, 0.93], p = 0.01, I 2  = 0 %), depression (d = 0.66, 95 % CI [0.003, 1.32], p = 0.049, I 2  = 62.97 %), and Activities-Specific Balance Confidence (ABC) scores (d = 1.30, 95 % CI [0.41, 2.18], p < 0.001, I 2  = 0 %) compared with control conditions., Conclusions: This meta-analysis suggests the efficacy of TCE in improving balance, activities of daily living, MSIS scores, depression, and ABC scores in MS patients. However, further high-quality research is warranted to investigate these findings., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: To investigate the acute effect of myofascial stretching exercises on spasticity, balance, ambulation status and mobility of posterior chain muscles in multiple sclerosis., Method: The study was conducted as a randomised controlled experimental study. The study included a total of 80 individuals diagnosed with multiple sclerosis (MS) with a mean age of 43.5 ± 9.62 years (experimental group) and 41.4 ± 10.4 years (control group). All individuals were treated once and evaluated before and after the session. After recording the sociodemographic characteristics, spasticity assessment was performed with the Modified Ashword Scale (MAS), balance assessment with the Berg Balance Scale (BBS), ambulation status with the Timed Up and Go Test (TUG), and posterior chain muscle mobility (PCMM) with finger-to-ground distance measurement., Results: The TUG (time to complete the distance) measurements of the experimental group after treatment were lower than those of the control group ( p  < 0.05). The value of PCMM measurements of the experimental group before the treatment was lower than that of the control group ( p  < 0.001). The difference in positive increase in PCMM measurements in the experimental group was higher than that in the control group ( p  < 0.05). After the treatment, the MAS value in the left knee of the experimental group was lower than that of the control group ( p  < 0.05)., Discussion: Myofascial stretching exercises applied to individuals with MS made an acute contribution to ambulation status and mobility of posterior chain muscles. There was no difference in the evaluation of spasticity and balance.

Introduction: Synchronous telehealth (ST) consists of the remote real-time delivery of health services. COVID-19 pandemic has pressed the use of ST and forced neurologists to deliver telehealth services. The aim of this study was to obtain the actual picture of ST accessibility/interest and to evaluate the user satisfaction in patients with multiple sclerosis (MS) during the COVID-19 pandemic. Methods: The study consisted of two phases. First, a hard-copy questionnaire ("Telehealth Identity Card" [TIC]), including only yes/no questions, filled in the presence of a neurologist, and investigating the technical/practical access and the willingness/interest of MS patients to the telehealth services, was obtained from 600 consecutive outpatients, with no time limit for answering. Second, a fully filled "Televisit Satisfaction Questionnaire" (TSQ) was obtained from 100 consecutive patients that underwent a televisit. Statistical analysis applied the t test for normally distributed variables and the Mann-Whitney U test for ordinal. Logistic univariate and multivariate regressions were applied to predict televisit availability on the base of demographic variables. Results: Statistical analysis was performed on 552/600 consecutive TIC (92%). Of them, 464/552 (84%) of the MS patients declared to possess the tools and to be interested in telehealth services. Compared with noninterested patients, they were younger (mean age: 44.0 vs. 49.8, p < 0.001) and with lower disability (mean Expanded Disability Status Scale: 2.5 vs. 3.3, p < 0.01). From TSQ, it emerged that 95% agree or strongly agree that televisit respected timelines, saved time and money, was conducted with respect to privacy, can be a useful tool for monitoring disease and therapy, and expressed their availability for further televisits. Discussion: A great majority of MS patients living in Padua Province were interested in telehealth. High satisfaction and the willingness for further televist were expressed. Telehealth services can help neurologists to manage the increasing number of MS patients and their complex therapeutic monitoring.

Aim: This study aimed to assess the impact of a positive psychotherapy-based hope placement program on life goal setting and hope levels in individuals diagnosed with multiple sclerosis (MS)., Method: A Solomon Four-Group experimental design was used, involving 50 individuals diagnosed with MS who sought treatment at a university hospital's neurology outpatient clinic. Experimental (1-2) and control (1-2) groups were randomized, and pretests were administered exclusively to the experimental and control groups. Data were collected using a Personal Information Form, the Herth Hope Scale, and the Scale for Determining Life Goals in the Context of Positive Psychotherapy. A 5-week/10-session Positive Psychotherapy-Based Hope Placement Program was conducted online for the Experimental groups. The research was conducted in the form of group therapy. Post-tests were administered to all groups upon program completion., Results: The experimental 1-2 group exhibited statistically significant improvements in the Scale for Identifying Life Goals in the Context of Positive Psychotherapy and Herth Hope Scale scores (p < .05). The Positive Psychotherapy-Based Hope Placement Program effectively enhances hope levels and life goal setting for individuals diagnosed with MS., Conclusion: The results indicate that the program increased the sense of purpose in life and elevated levels of hope among MS patients. These findings suggest that positive psychotherapy-based interventions significantly improve the quality of life for MS patients., Clinical or Methodological Significance of This Article: This study examines the impact of a Positive Psychotherapy-based hope placement program on determining hope and life purpose in patients with Multiple Sclerosis (MS). This research shows that HOPP (Hope Placement Program), an intervention based on Positive Psychotherapy, can significantly improve the quality of life of MS patients. These findings support the consideration of Positive Psychotherapy-based approaches as a potential therapeutic option that can positively influence the life experiences of MS patients. Therefore, this article makes an important contribution to researchers interested in using Positive Psychotherapy-based interventions in clinical practice and related research., (© 2024 The Author(s). Public Health Nursing published by Wiley Periodicals LLC.)

Multiple sclerosis is a demyelinating neurodegenerative disease, and its animal model, experimental autoimmune encephalomyelitis (EAE), exhibits immunological and clinical similarities. The study aimed to examine mechanisms underlying therapeutic effects of mesenchymal stem cell administration in EAE. C57BL/6 mice were separated into control and treatment groups (T1, T2, and T3); EAE was induced in all animals. Clinical examinations were conducted daily, and on 25th day, animals were sacrificed, and spinal cord was stained for histological analysis. Additionally, spleen cell proliferation assay, assessments of cytokine, and gene expression in both spinal cord and spleen cells were performed. The results indicated a significant reduction in clinical symptoms among treatment groups compared to control group. Histological analyses revealed decreased infiltration of lymphocytes into the spinal cord and reduced demyelinated areas in treatment groups compared to control group. Cytokine production of IL-10, TGF-β, and IL-4 were significantly enhanced and IFN-γ and TNF-α in treatment groups were decreased relative to control group. Also, gene expression of CTLA-4, PD-1, IL-27, and IL-33 indicated a significant increase in treatment groups. The administration of MSCs significantly improved clinical symptoms, attenuated inflammation, and reduced spinal cord demyelination in EAE, suggesting a potential protective effect on disease progression., (© 2024 Scandinavian Societies for Pathology, Medical Microbiology and Immunology.)

The aim of the study is to investigate the effect of the application of Reiki on fatigue and sleep quality in people with MS. The study is a randomised controlled study. A total of 60 people (control group = 30, intervention group = 30) participated in this study. Personal Information Form, Piper Fatigue Scale (PFS) and Pittsburg Sleep Quality Index (PSQI) were used to collect data. It was found that the PFS and PSQI total and subcomponent scores of the intervention group decreased after Reiki compared to the control group and this was statistically significant (p < 0.05). The study showed that Reiki was significantly effective in improving fatigue and sleep quality in people with MS. As Reiki is a simple, inexpensive and accessible method, it was suggested that its use in the management of MS should be encouraged and maintained in nursing practice., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This paper explores the significant role of real-world data (RWD) in advancing our understanding and management of Multiple Sclerosis (MS). RWD has proven invaluable in MS research and care, offering insights from larger and diverse patient populations. A key focus of the paper is the European Health Data Space (EHDS), a significant development that promises to change how healthcare data is managed across Europe. This initiative is particularly relevant to the MS community. The paper highlights various data initiatives, discussing their importance for those affected by MS. Despite the potential benefits, there are challenges and concerns, especially about ensuring that the growth of various data platforms remains beneficial for MS patients. The paper suggests practical actions for the global MS community to consider, aimed at optimizing the use of RWD. The emphasis of this discussion is on the secondary use of health data, particularly in the European context. The content is based on the author's own experiences and interpretations, offering a personal yet informed view on using RWD to improve MS research and patient care., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Peeters.)

Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system (CNS) with the immune system attacking myelin sheaths leading to neuronal death. While several disease-modifying therapies are available to treat MS, these therapies are not universally effective and do not stop disease progression. More personalized long-term treatment options that target specific aspects of the disease, such as reducing relapse frequency, delaying disability accumulation, and addressing symptoms that impact daily functioning, as well as therapies that can promote neuroprotection and repair are needed. Chimeric Antigen Receptor (CAR) Tcell therapies have revolutionized cancer treatment by intravenously (IV) administering a defined dose of T cells with high specificity provided by the CAR. An autologous CAR T cell therapy using suppressive regulatory T cells (Tregs) inducing long-lasting tolerance would be the ideal treatment for patients. Hence, we expanded the application of CAR-T cells by introducing a CAR into Tregs to treat MS patients. We developed a myelin oligodendrocyte glycoprotein (MOG)-specific CAR Treg cell therapy for patients with MS. MOG is expressed on the outer membrane of the myelin sheath, the insulating layer the forms around nerves, making it an ideal target for CAR Treg therapy. Our lead candidate is a 2nd generation CAR, composed of an anti-MOG scFv screened from a large human library. In vitro, we demonstrated CAR-dependent functionality and showed efficacy in vivo using a passive EAE mouse model. Additionally, the MOG-CAR Tregs have very low tonic signaling with a desirable signal-to-noise ratio resulting in a highly potent CAR. In summary our data suggest that MOG-CAR Tregs are a promising MS treatment option with the potential to induce long-lasting tolerance in patients., (© 2024. The Author(s).)

Background: The treatment of multiple sclerosis, an autoimmune disease that predominantly affects women of reproductive age, has undergone considerable advancements. Nevertheless, their unique needs, particularly those related to motherhood, continue to be disregarded. This study aims to ascertain the needs of women diagnosed with MS about motherhood., Methods: Using the Noblit and Hare methods, meta-synthesis research was conducted on 10 qualitative studies. The relevant studies were obtained by conducting a comprehensive search using keywords in the PubMed, Scopus, Web of Science (ISI), and ProQuest databases without any time limitations until June 2023. The CASP checklist was used to assess the quality of the articles, while the technique of Brown and Clark (2006) was utilized for data synthesis., Results: Four key themes emerged from this meta-synthesis, highlighting the significance of a support system, psychoeducational counseling, knowledge promotion, and continuous, comprehensive, and unique care., Conclusion: Identifying the needs of women diagnosed with MS and addressing these needs concerning motherhood can enhance the quality of services rendered and enhance women's contentment with their choice to embark on motherhood. Furthermore, recognizing these needs during subsequent stages can be utilized in formulating tailored programs catering to this specific cohort of women., (© 2024. The Author(s).)

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that progresses with demyelination and neurodegeneration. To date, many studies have revealed the key role of interleukins in the pathogenesis of MS, but their impact has not been fully explained. The aim of the present study was to collect and review the results obtained so far regarding the influence of interleukins on the development and course of MS and to assess the potential for their further use. Through the platform "PubMed", terms related to interleukins and MS were searched. The following interval was set as the time criterion: 2014-2024. A total of 12,731 articles were found, and 100 papers were subsequently used. Cells that produce IL-10 have a neuroprotective effect, whereas those that synthesize IL-6 most likely exacerbate neuroinflammation. IL-12, IL-23 and IL-18 represent pro-inflammatory cytokines. It was found that treatment with an anti-IL-12p40 monoclonal antibody in a study group of MS patients showed a beneficial effect. IL-4 is a pleiotropic cytokine that plays a significant role in type 2 immune responses and inhibits MS progression. IL-13 is an anti-inflammatory cytokine through which the processes of oligodendrogenesis and remyelination occur more efficiently. The group of interleukins discussed in our paper may represent a promising starting point for further research aimed at finding new therapies and prognostic markers for MS.

Multiple sclerosis (MS) is an immune-mediated disease characterized by inflammation, demyelination, and neurodegeneration within the central nervous system. Brain plasticity, the brain's ability to adapt its structure and function, plays a crucial role in mitigating MS's impact. This paper explores the potential benefits of lifestyle changes and nutraceuticals on brain plasticity in the MS population. Lifestyle modifications, including physical activity and dietary adjustments, can enhance brain plasticity by upregulating neurotrophic factors, promoting synaptogenesis, and reducing oxidative stress. Nutraceuticals, such as vitamin D, omega-3 fatty acids, and antioxidants like alpha lipoic acid, have shown promise in supporting brain health through anti-inflammatory and neuroprotective mechanisms. Regular physical activity has been linked to increased levels of brain-derived neurotrophic factor and improved cognitive function. Dietary interventions, including caloric restriction and the intake of polyphenols, can also positively influence brain plasticity. Integrating these lifestyle changes and nutraceuticals into the management of MS can provide a complementary approach to traditional therapies, potentially improving neurological outcomes and enhancing the quality of life for the MS population.

In Multiple Sclerosis (MS), inflammatory demyelinated lesions in the brain and spinal cord lead to neurodegeneration and progressive disability. Remyelination can restore fast saltatory conduction and neuroprotection but is inefficient in MS especially with increasing age, and is not yet treatable with therapies. Intrinsic and extrinsic inhibition of oligodendrocyte progenitor cell (OPC) function contributes to remyelination failure, and we hypothesised that the transplantation of 'improved' OPCs, genetically edited to overcome these obstacles, could improve remyelination. Here, we edit human(h) embryonic stem cell-derived OPCs to be unresponsive to a chemorepellent released from chronic MS lesions, and transplant them into rodent models of chronic lesions. Edited hOPCs display enhanced migration and remyelination compared to controls, regardless of the host age and length of time post-transplant. We show that genetic manipulation and transplantation of hOPCs overcomes the negative environment inhibiting remyelination, with translational implications for therapeutic strategies for people with progressive MS., (© 2024. The Author(s).)

Introduction: This study aimed to investigate how shared decision-making (SDM) and the use of different types of outcome information are applied in routine care management for people with multiple sclerosis (MS) in an academic outpatient clinic., Methods: This qualitative study used the following: (a) observations of clinical encounters (N = 23) between patients and healthcare professionals (HCPs), (b) interviews with those patients (N = 17) and (c) interviews with those HCPs (N = 7). HCPs were not trained in SDM before the study. Audio recordings were transcribed literally. Transcriptions were analysed using qualitative thematic analysis., Results: Outcome information was hardly discussed with patients, apart from clinical outcome information at an individual level, such as MRI or lab results. This use of clinical outcome information did not automatically lead to a process of SDM. HCPs tended to implicitly present choices to patients after signalling and discussing 'problems'. In the interviews, patients indicated that they tended to consent to the advice given by HCPs and to prefer not too much change in treatment plans. However, they also emphasized the importance of being informed about available options with benefits and harms. We observed multiple discussions about patients' preferences, especially related to patients' experiences and priorities., Conclusions: Overall, SDM and the use of different types of outcome information did not seem to be enacted in routine care management for people with MS, mostly because choices were not explicitly mentioned or discussed. However, discussions about patients' experiences and priorities did take place. Training HCPs further and developing patient information seem reasonable steps to proceed., Patient or Public Contribution: People with MS contributed as research participants and provided us with their experiences in interviews. Furthermore, representatives of two patient organizations contributed to the study by reviewing the interview protocol for people with MS., (© 2024 The Author(s). Health Expectations published by John Wiley & Sons Ltd.)

B-cell therapy using anti-CD20 antibodies significantly suppresses relapse and is therefore an important treatment option for multiple sclerosis (MS). Based on the production of inflammatory cytokines and enhanced antigen-presenting capacity, B cells trigger MS relapses via activation of pathogenic T cells. Suppression of these abnormal actions of B cells is the primary mechanism underlying relapse prevention using B-cell therapies. Treatments that target B cells are also expected to suppress chronic progression of MS through modulation of B-cell activity within the central nervous system. B-cell therapies based on novel approaches are expected to improve the regulation of acute and chronic MS pathology.

Introduction: Multiple sclerosis (MS), a leading cause of disability in young adults worldwide, including in Iran, affects their whole life so common care is no longer effective. In this regard, context-based approaches should be considered for a holistic care delivery that accords with the patients' inputs. We aimed to explore patients' understanding of MS and their personal experiences of living with this disease., Methods: A qualitative descriptive study was conducted. The data were collected through in-depth, semi-structured interviews with 17 patients. These patients were selected using a purposive sampling method, and the data were analyzed using a conventional content analysis approach., Findings: Three main categories and nine subcategories were identified: Thunder and Lightning strike in the form of Displeasure, Social wrong beliefs, Experiences of Constraints, Interference with Life Stages and Dark Spots on the Horizon of the Future; Subtle Beam consisting of Extrinsic Light Radiation, Reflection of Individual Effort and Formation of a Rainbow by Resilience and Hope for a Bright Future., Conclusion: By offering multidimensional support, patients reported a shift from fear to a vibrant life. Although research often focuses on the negative aspects of MS, this study recognizes both positive and negative aspects. These findings can contribute to future interventional research., Patient or Public Contribution: During the explanation of research goals and consent acquisition, participants were reminded that sharing their experiences could provide valuable insights benefiting others coping with or at risk of the same disease. Additionally, during data analysis, codes extracted were reviewed and improved with active participant involvement., (© 2024 The Author(s). Health Expectations published by John Wiley & Sons Ltd.)

Use of techniques derived from generative artificial intelligence (AI), specifically large language models (LLMs), offer a transformative potential on the management of multiple sclerosis (MS). Recent LLMs have exhibited remarkable skills in producing and understanding human-like texts. The integration of AI in imaging applications and the deployment of foundation models for the classification and prognosis of disease course, including disability progression and even therapy response, have received considerable attention. However, the use of LLMs within the context of MS remains relatively underexplored. LLMs have the potential to support several activities related to MS management. Clinical decision support systems could help selecting proper disease-modifying therapies; AI-based tools could leverage unstructured real-world data for research or virtual tutors may provide adaptive education materials for neurologists and people with MS in the foreseeable future. In this focused review, we explore practical applications of LLMs across the continuum of MS management as an initial scope for future analyses, reflecting on regulatory hurdles and the indispensable role of human supervision., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: H.I. received speaker honoraria from Roche and financial support for research activities from Teva, Biogen, and Alexion. S.G. declares a nonfinancial interest as an Advisory Group member of the EY-coordinated “Study on Regulatory Governance and Innovation in the Field of Medical Devices” conducted on behalf of the DG SANTE of the European Commission. S.G. declares the following competing financial interests: he has or has had consulting relationships with Una Health GmbH, Lindus Health Ltd., Flo Ltd, Thymia Ltd., FORUM Institut für Management GmbH, High-Tech Gründerfonds Management GmbH, and Ada Health GmbH and holds share options in Ada Health GmbH. S.G. and J.N.K. are supported by the German Federal Ministry of Health (DEEP LIVER, ZMVI1-2520DAT111; SWAG, 01KD2215B), the Max-Eder-Programme of the German Cancer Aid (grant no. 70113864), the German Federal Ministry of Education and Research (PEARL, 01KD2104C; CAMINO, 01EO2101; SWAG, 01KD2215A; TRANSFORM LIVER, 031L0312A; TANGERINE, 01KT2302 through ERA-NET Transcan), the German Academic Exchange Service (SECAI, 57616814), the German Federal Joint Committee (Transplant.KI, 01VSF21048) the European Union’s Horizon Europe and innovation programme (ODELIA, 101057091; GENIAL, 101096312) and the National Institute for Health and Care Research (NIHR, NIHR213331) Leeds Biomedical Research Centre. K.A. received personal compensation from Novartis, Biogen Idec, Teva, Sanofi, and Roche for consulting services. T.Z. reports scientific advisory board and/or consulting for Biogen, Roche, Novartis, Celgene, and Merck; compensation for serving on speakers bureaus for Roche, Novartis, Merck, Sanofi, Celgene, and Biogen; and research support from Biogen, Novartis, Merck, and Sanofi. E.W., I.V., D.A., J.W., I.W., and D.F. have nothing to declare.