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BACKGROUND: The reason why some multiple sclerosis (MS) patients show disease activity after alemtuzumab (ALM) is still unclear, but ocrelizumab (OCR) could represent an interesting sequential therapeutic approach. OBJECTIVES: To investigate safety and efficacy of OCR in MS patients with disease activity after two ALM courses. METHODS: Observational retrospective multi-centers Italian cohort study. RESULTS: Seventy-two subjects were included. Mean follow-up (FU) was 2.4 (±1) years. Forty-five patients (62.5%) experienced at least one adverse event (AE), with infections accounting for 96.7% of cases. A reduction in total lymphocytes was observed between OCR start and 6 months FU, driven by BCD19+ lymphocytes depletion (p < 0.001). Immunoglobulin M (IgM) levels decreased between OCR start and 6 months FU (p < 0.001). At 2-year FU, relapse, magnetic resonance imaging (MRI) activity and disability worsening-free survival were 92.1%, 90.8%, and 89.2%. The evidence of inflammatory activity between the two ALM courses was associated with higher risk of relapse, MRI activity, and NEDA-3 status loss in relapsing-remitting multiple sclerosis (RRMS; p = 0.02, p = 0.05, p = 0.01, respectively). CONCLUSIONS: OCR after two ALM courses seemed to be safe and effective. Early IgM hypogammaglobulinemia occurred in a high proportion of patients. The evidence of inflammatory activity between ALM courses seemed to increase the risk of MS re-activation on OCR treatment.

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Over the past decades, several effective disease-modifying therapies have been approved for the treatment of multiple sclerosis (MS); however, achieving long-term disease remission remains challenging, particularly for patients with aggressive forms of MS. Intense immunosuppression followed by hematopoietic stem cell transplantation (HSCT) has been increasingly explored as a treatment strategy for aggressive MS. To date, more than 1800 MS patients have undergone HSCT worldwide. In this chapter, we provide a brief overview of the HSCT procedure, with a special focus on the unique considerations for transplanting MS patients (such as fertility preservation, prior therapy washout, and posttransplant monitoring). We also discuss the main evidence of efficacy and safety of the procedure in this context, as well as present preliminary data on the impact of HSCT on cerebrospinal fluid findings, magnetic resonance imaging metrics, and novel serum biomarkers of neurodegeneration and demyelination. In addition, we provide recommendations for patient selection from international guidelines.

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Recent advances in neuroimmunology have shed light on the pathogenic mechanisms underlying rare neuroimmunologic conditions such as myasthenia gravis (MG) and stiff person syndrome (SPS). Despite the rarity of these conditions, their complex manifestations and potential for irreversible disability necessitate effective therapeutic strategies. This chapter reviews the current understanding of the safety and efficacy of hematopoietic stem cell transplantation (HSCT) in MG and SPS. Several case reports and retrospective studies have demonstrated promising outcomes following HSCT in refractory MG and SPS, with significant clinical improvement and even discontinuation of chronic immunomodulatory therapy in some cases. Furthermore, HSCT may offer insights into the underlying pathophysiologic mechanisms of these conditions, particularly the role of cellular immunity. Although more research is needed to fully understand the impact of HSCT on disease pathology and outcomes, current evidence suggests that HSCT could be a valuable therapeutic option for patients with refractory MG and SPS.

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The use of hematopoietic stem cell transplantation (HSCT) as a treatment option for severe autoimmune diseases originated from animal studies, with promising results in human patients reported through clinical responses seen in individuals who underwent HSCT for other reasons. Currently, over 3800 HSCT procedures have been performed specifically for autoimmune disorders and the procedure has become a standard of care for conditions such as multiple sclerosis and systemic sclerosis. Despite the growing interest among the neurology community in using HSCT to treat refractory autoimmune disorders, several obstacles must still be overcome for the procedure to become widely accepted. These include increasing the safety of the procedure, determining the most effective conditioning regimen, fostering collaboration between neurology and hematology teams, and providing robust phase III study data to demonstrate the superiority of HSCT over standard immunotherapy. This Handbook aims to provide a valuable resource for all those involved in the care of patients undergoing HSCT, and we hope it will contribute to the efforts to find the correct placement of HSCT in the therapeutic strategy of the treatment of autoimmune disorders of the nervous system.

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Autologous hematopoietic stem cell transplantation (AHSCT) is emerging as a potent treatment for highly active relapsing remitting multiple sclerosis (RRMS), potentially surpassing the efficacy of traditional disease-modifying therapies (DMTs). Phase II and III randomized controlled trials (RCTs) have demonstrated AHSCT's superiority in reducing relapse rates and delaying disability progression compared to standard DMTs. Despite the evolution of treatment guidelines, questions persist regarding patient selection criteria and optimal conditioning regimens. Notably, ongoing clinical trials in the United Kingdom, the United States, Italy, and Norway aim to address these uncertainties by evaluating the safety, efficacy, and long-term outcomes of AHSCT vs. high efficacy DMTs in both DMT-experienced and treatment-naïve patients with active RRMS or aggressive multiple sclerosis (MS). These trials promise to provide valuable insights into the positioning of AHSCT within the treatment landscape of MS.

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'Active' and 'non-active' secondary progressive MS (SPMS) have distinct pathophysiological mechanisms and clinical characteristics, but there is still no consensus regarding the frequency of these MS forms in the real-world setting. We aimed to evaluate the frequency of 'active' and 'non-active' SPMS in a large cohort of Italian MS patients and the differences in terms of clinical and MRI characteristics and disease progression. This multicenter study collected data about MS patients who have transitioned to the SP form in the period between 1st January 2014 and 31st December 2019 and followed by the MS centers contributing to the Italian MS Registry. Patients were divided into 'active SPMS' and 'non-active SPMS', based on both reported MRI data and relapse activity in the year before conversion to SPMS. Out of 68,621, 8,316 (12.1%) patients were diagnosed with SPMS. Out of them, 872 (10.5%) were classified into patients with either 'active' or 'non-active' SPMS. A total of 237 were classified into patients with 'active SPMS' (27.2%) and 635 as 'non-active SPMS' (72.8%). 'Non-active SPMS' patients were older, with a longer disease duration compared to those with 'active SPMS'. The percentages of patients showing progression independent of relapse activity (PIRA) at 24 months were similar between 'active' and 'non-active' SPMS patients (67 [27.4%] vs 188 [29.6%]; p = 0.60). In the 'active' group, 36 (15.2%) patients showed relapse-associated worsening (RAW). Comparison of the survival curves to EDSS 6 and 7 according to disease activity did not show significant differences (p = 0.68 and p = 0.71). 'Active' and 'non-active' SPMS patients had a similar risk of achieving disability milestones, suggesting that progression is primarily attributed to PIRA and only to a small extent to disease activity.

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OBJECTIVE: No direct comparisons of the effect of natalizumab and ocrelizumab on progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW) events are currently available. We aimed to compare the risk of achieving first 6 months confirmed PIRA and RAW events and irreversible Expanded Disability Status Scale (EDSS) 4.0 and 6.0 in a cohort of naïve patients treated with natalizumab or ocrelizumab from the Italian Multiple Sclerosis Register. METHODS: Patients with a first visit within 1 year from onset, treated with natalizumab or ocrelizumab, and ≥3 visits were extracted. Pairwise propensity score-matched analyses were performed. Risk of reaching the first PIRA, RAW, and EDSS 4.0 and 6.0 events were estimated using multivariable Cox proportional hazards models. Kaplan-Meier curves were used to show cumulative probabilities of reaching outcomes. RESULTS: In total, 770 subjects were included (natalizumab = 568; ocrelizumab = 212) and the propensity score-matching retrieved 195 pairs. No RAW events were found in natalizumab group and only 1 was reported in ocrelizumab group. A first PIRA event was reached by 23 natalizumab and 25 ocrelizumab exposed patients; 7 natalizumab- and 10 ocrelizumab-treated patients obtained an irreversible EDSS 4.0, while 13 natalizumab- and 15 ocrelizumab-treated patients reached an irreversible EDSS 6.0. No differences between the two groups were found in the risk (HR, 95%CI) of reaching a first PIRA (1.04, 0.59-1.84; p = 0.88) event, an irreversible EDSS 4.0 (1.23, 0.57-2.66; p = 0.60) and 6.0 (0.93, 0.32-2.68; p = 0.89). INTERPRETATION: Both medications strongly suppress RAW events and, in the short term, the risk of achieving PIRA events, EDSS 4.0 and 6.0 milestones is not significantly different.

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OBJECTIVES: neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease mainly affecting optic nerves and the spinal cord. Due to the potentially irreversible tissue damage, prevention of relapses is of utmost importance. METHODS: We describe the atypical clinical course and pathology results of a patient with anti-aquaporin-4 antibody (anti-AQP4-Ab)-associated NMOSD who developed aseptic meningitis followed by limbic-encephalitis-like presentation with extensive brain lesions upon treatment with rituximab and tocilizumab. RESULTS: The patient developed subacute cognitive decline with magnetic resonance imaging (MRI) evidence of extensive brain white matter lesions. In the hypothesis of an opportunistic brain infection, she underwent brain biopsy of the temporal pole. Pathology results revealed typical NMOSD findings with complement activation, supporting the hypothesis of an atypical presentation of anti-AQP-Ab-associated NMOSD. Accordingly, treatment with the complement-targeting drug eculizumab was started, leading to a dramatic clinical and MRI improvement. DISCUSSION: aseptic meningitis and limbic encephalitis could represent a rare phenotype of anti-AQP4-Ab-associated NMOSD.

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BACKGROUND AND PURPOSE: Pediatric multiple sclerosis (MS) displays different pathological features compared to adult MS, which can be studied in vivo by assessing tissue magnetic susceptibility with 3T-MRI. We aimed to assess different white matter lesions (WMLs) phenotypes in pediatric MS patients using quantitative susceptibility mapping (QSM) and susceptibility mapping weighted imaging (SMWI) over 12 months. METHODS: Eleven pediatric MS patients [female: 63.6%; mean ± standard deviation (SD) age and disease duration: 16.3 ± 2.2 and 2.4 ± 1.5; median (range) Expanded Disability Status Scale (EDSS) 1 (0-2)] underwent 3 Tesla-MRI exams and EDSS assessments at baseline and after 1 year. QSM and SMWI were obtained using 3-dimensional (3D)-segmented echo-planar-imaging with submillimetric spatial resolution. WMLs were classified according to their QSM appearance and SMWI was used to identify QSM hyperintensities ascribable to veins. Total brain volumes at baseline and follow-up were computed using high-resolution 3D T1-weighted images. RESULTS: Mean ± SD paramagnetic rim lesions (PRLs) prevalence was 7.0% ± 9.0. Fifty-four percent (6/11) of patients exhibited at least one PRL, with one patient exhibiting ≥ 4 PRLs. All patients showed QSM-iso-/hypo-intense lesions, which represented a mean ± SD of 65.8% ± 22.7 of total WMLs. QSM-hyperintense WMLs showed a positive correlation with total brain volume reduction at follow-up (r = 0.705; p =  .02). No lesion was classified as different between baseline and follow-up. CONCLUSION: Chronic compartmentalized inflammation seems to occur early in pediatric MS patients with short disease duration. A high prevalence of iso-/hypo-intense lesions was found, which could account for the higher remyelination potential in pediatric MS.

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BACKGROUND: Multiple sclerosis (MS), because of its early age at onset, greatly impacts the working lives of those affected by it in ways linked to different factors, both professional and personal. It has been observed that only a small percentage (20-40%) of workers with MS retain their jobs after the diagnosis. When identifying factors determining job retention or loss in this setting, it is essential to consider the direct perspectives of people with MS (PwMS). METHODS: A qualitative study, based on the conduction of two focus groups, was conducted to explore the personal experiences of PwMS who work. RESULTS: The results show that there are numerous factors, both positive and negative, that can influence these people's ability to retain their jobs. The climate established in the workplace and the relationship between workers with MS and their colleagues were fundamentally important aspects, as was knowledge of the disease at the level of public opinion. CONCLUSIONS: Managing work is a complex undertaking for people with a disabling condition like MS. There needs to be greater awareness of the employment rights of PwMS. Improving these knowledge-based aspects could undoubtedly improve the quality of the working lives of PwM.

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BACKGROUND: This study, conducted on a sample of Italian occupational physicians (OPs), aimed to gather data regarding professional activity and their needs in managing workers with multiple sclerosis. METHODS: A convenience sample of OPs recruited by e-mail invitation to the list of Italian Society of Occupational Medicine members was considered. A total of 220 OPs participated between July and October 2022. An ad hoc questionnaire was developed based on previous survey experiences. It investigated, among others, the characteristics of OP respondents, the evaluation of fitness for work issues, and the OP training and updating needs on multiple sclerosis and work. RESULTS: Ninety-one percent of OPs had to assess the fitness for work of workers with multiple sclerosis during their activity. Sixty-four percent experienced particular difficulties in issuing a fitness for work judgment. Regarding the level of knowledge on multiple sclerosis, 54% judged it sufficient. The "Assessment of fitness for work for the specific task" and the "Role of the OPs in identifying reasonable accommodations" were the most interesting training topics regarding MS management in work contexts chosen by the respondents. CONCLUSIONS: The interest in the work inclusion and job retention of people with disability, particularly the aspects linked to the Identification and implementation of reasonable accommodations, will require integration with the occupational safety and health protection system and will undoubtedly impact the OP's activities.

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BACKGROUND AND PURPOSE: Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) diagnosis are based on the presence of serological and magnetic resonance imaging (MRI) biomarkers. Diffusion tensor imaging (DTI), neurites orientation dispersion and density imaging (NODDI), and the Spherical Mean Technique (SMT) may be helpful to provide a microstructural characterization of the different types of white matter lesions and give an insight about their different pathological mechanisms. The aim of the study was to characterize microstructural differences between brain typical lesions (TLs) and nontypical lesions (nTLs). METHODS: A total of 17 NMOSD and MOGAD patients [9 Aquaporin4 (AQP4) + NMO, 2 seronegative-NMO, 6 MOGAD] underwent MRI scans on a 3 Tesla MAGNETON PRISMA. Diffusion parameters (fractional anisotropy; mean diffusivity [MD]; intracellular volume fraction [ICVF]; extra-neurite transverse diffusivity; and extra-neurite MD; neurite signal fraction) were obtained using DTI, NODDI, and SMT. Microstructural parameters within lesions were compared through a generalized linear model using age, sex, and total lesion volume as covariates. RESULTS: In NMOSD/MOGAD whole cohort (total lesions = 477), TLs showed increased MD and decreased ICVF compared to nTLs (p < .05), indicating higher inflammation and axonal loss. Similar results were found also in the AQP4 + NMO subgroup (decreased ICVF, p < .05). Furthermore, in NMOSD/MOGAD whole cohort and in AQP4 + NMO subgroup, TLs showed a trend toward higher EXRATRANS than nTLs, suggesting a more severe degree of demyelination within TLs. CONCLUSIONS: TLs and nTLs in NMOSD/MOGAD showed different diffusion MRI-derived microstructural features, with TLs showing a more severe degree of inflammation and fiber disruption with respect to nTLs.

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BACKGROUND AND PURPOSE: MS lesions exhibit varying degrees of axonal and myelin damage. A comprehensive description of lesion phenotypes could contribute to an improved radiologic evaluation of smoldering inflammation and remyelination processes. This study aimed to identify in vivo distinct MS lesion types using quantitative susceptibility mapping and susceptibility mapping-weighted imaging and to characterize them through T1-relaxometry, myelin mapping, and diffusion MR imaging. The spatial distribution of lesion phenotypes in relation to ventricular CSF was investigated. MATERIALS AND METHODS: MS lesions of 53 individuals were categorized into iso- or hypointense lesions, hyperintense lesions, and paramagnetic rim lesions, on the basis of their appearance on quantitative susceptibility mapping alone, according to published criteria, and with the additional support of susceptibility mapping-weighted imaging. Susceptibility values, T1-relaxation times, myelin and free water fractions, intracellular volume fraction, and the orientation dispersion index were compared among lesion phenotypes. The distance of the geometric center of each lesion from the ventricular CSF was calculated. RESULTS: Eight hundred ninety-six MS lesions underwent the categorization process using quantitative susceptibility mapping and susceptibility mapping-weighted imaging. The novel use of susceptibility mapping-weighted images, which revealed additional microvasculature details, led us to re-allocate several lesions to different categories, resulting in a 35.6% decrease in the number of paramagnetic rim lesions, a 22.5% decrease in hyperintense lesions, and a 17.2% increase in iso- or hypointense lesions, with respect to the categorization based on quantitative susceptibility mapping only. The outcome of the categorization based on the joint use of quantitative susceptibility mapping and susceptibility mapping-weighted imaging was that 44.4% of lesions were iso- or hypointense lesions, 47.9% were hyperintense lesions, and 7.7% were paramagnetic rim lesions. A worsening gradient was observed from iso- or hypointense lesions to hyperintense lesions to paramagnetic rim lesions in T1-relaxation times, myelin water fraction, free water fraction, and intracellular volume fraction. Paramagnetic rim lesions were located closer to ventricular CSF than iso- or hypointense lesions. The volume of hyperintense lesions was associated with a more severe disease course. CONCLUSIONS: Quantitative susceptibility mapping and susceptibility mapping-weighted imaging allow in vivo classification of MS lesions into different phenotypes, characterized by different levels of axonal and myelin loss and spatial distribution. Hyperintense lesions and paramagnetic rim lesions, which have the most severe microstructural damage, were more often observed in the periventricular WM and were associated with a more severe disease course.

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BACKGROUND: Research on cognitive rehabilitation (CR) and aerobic exercise (EX) to improve cognition in progressive multiple sclerosis (PMS) remains limited. CogEx trial investigated the effectiveness of CR and EX in PMS: here, we present MRI substudy volumetric and task-related functional MRI (fMRI) findings. METHODS: Participants were randomised to: 'CR plus EX', 'CR plus sham EX (EX-S)', 'EX plus sham CR (CR-S)' and 'CR-S plus EX-S' and attended 12-week intervention. All subjects performed physical/cognitive assessments at baseline, week 12 and 6 months post intervention (month 9). All MRI substudy participants underwent volumetric MRI and fMRI (Go-NoGo task). RESULTS: 104 PMS enrolled at four sites participated in the CogEx MRI substudy; 84 (81%) had valid volumetric MRI and valid fMRI. Week 12/month 9 cognitive performances did not differ among interventions; however, 25-62% of the patients showed Symbol Digit Modalities Test improvements. Normalised cortical grey matter volume (NcGMV) changes at week 12 versus baseline were heterogeneous among interventions (p=0.05); this was mainly driven by increased NcGMV in 'CR plus EX-S' (p=0.02). Groups performing CR (ie, 'CR plus EX' and 'CR plus EX-S') exhibited increased NcGMV over time, especially in the frontal (p=0.01), parietal (p=0.04) and temporal (p=0.04) lobes, while those performing CR-S exhibited NcGMV decrease (p=0.008). In CR groups, increased NcGMV (r=0.36, p=0.01) at week 12 versus baseline correlated with increased California Verbal Learning Test (CVLT)-II scores. 'CR plus EX-S' patients exhibited Go-NoGo activity increase (p<0.05, corrected) at week 12 versus baseline in bilateral insula. CONCLUSIONS: In PMS, CR modulated grey matter (GM) volume and insular activity. The association of GM and CVLT-II changes suggests GM plasticity contributes to cognitive improvements. TRIAL REGISTRATION NUMBER: NCT03679468.

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BACKGROUND: The management of Multiple Sclerosis (MS) has undergone transformative evolution with the introduction of high-efficacy disease-modifying therapies (DMTs), specifically anti-CD20 monoclonal antibodies, such as ocrelizumab (OCR) and ofatumumab (OFA). MATERIALS AND METHODS: This is an independent retrospective cohort study in Relapsing MS (RMS) patients followed at eight Italian MS centers who initiated treatment with OCR or OFA in the participating centers and with at least 12 months on therapy. A generalized linear regression model inverse probability of treatment weight (IPTW) PS-adjusted was performed to evaluate the relationship between annualized relapse rate (ARR) and treatment groups. No evidence of disease activity-NEDA-3 at 12-month score was also collected. Safety profile of the investigated DMTs was recorded. RESULTS: A total cohort of 396 RMS patients fulfilled the required criteria and were enrolled in the study. Out of them, 216 had a prescription of OCR and 180 of OFA. The mean follow-up was 13.2 ± 1.9 months. The estimated means for ARR did not show differences between the two groups, 0.059 for patients on OCR and 0.038 for patients on OFA (p = 0.185). The generalized regression model IPTW PS-adjusted did not reveal differences between patients on OCR and OFA (ExpBOFA 0.974, 95%CI 934-1.015, p = 0.207). NEDA-3 at 12 months was experienced by 199(92.1%) patients on OCR and 170(94.4%) patients on OFA (p = 0.368). Generally, both therapies exhibit good tolerability. CONCLUSIONS: The treatment with OCR and OFA resulted in comparable control of disease activity with good safety profile. Our results need further validation in larger multicentre studies with long-term follow-up.

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BACKGROUND: Cerebrospinal fluid (CSF) and spinal MRIs are often obtained in children with the radiologically isolated syndrome (RIS) for diagnosis and prognosis. Factors affecting the frequency and timing of these tests are unknown. OBJECTIVE: To determine whether age or sex were associated with (1) having CSF or spinal MRI obtained or (2) the timing of these tests. METHODS: We analyzed children (≤ 18 y) with RIS enrolled in an international longitudinal study. Index scans met 2010/2017 multiple sclerosis (MS) MRI criteria for dissemination in space (DIS). We used Fisher's exact test and multivariable logistic regression (covariates = age, sex, MRI date, MRI indication, 2005 MRI DIS criteria met, and race). RESULTS: We included 103 children with RIS (67% girls, median age = 14.9 y). Children ≥ 12 y were more likely than children < 12 y to have CSF obtained (58% vs. 21%, adjusted odds ratio [AOR] = 4.9, p = 0.03). Pre-2017, girls were more likely than boys to have CSF obtained (n = 70, 79% vs. 52%, AOR = 4.6, p = 0.01), but not more recently (n = 30, 75% vs. 80%, AOR = 0.2, p = 0.1; p = 0.004 for interaction). Spinal MRIs were obtained sooner in children ≥ 12 y (median 11d vs. 159d, p = 0.03). CONCLUSIONS: Younger children with RIS may be at continued risk for misdiagnosis and misclassification of MS risk. Consensus guidelines are needed.

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Clinical, pathological, and imaging evidence in multiple sclerosis (MS) suggests that a smoldering inflammatory activity is present from the earliest stages of the disease and underlies the progression of disability, which proceeds relentlessly and independently of clinical and radiological relapses (PIRA). The complex system of pathological events driving "chronic" worsening is likely linked with the early accumulation of compartmentalized inflammation within the central nervous system as well as insufficient repair phenomena and mitochondrial failure. These mechanisms are partially lesion-independent and differ from those causing clinical relapses and the formation of new focal demyelinating lesions; they lead to neuroaxonal dysfunction and death, myelin loss, glia alterations, and finally, a neuronal network dysfunction outweighing central nervous system (CNS) compensatory mechanisms. This review aims to provide an overview of the state of the art of neuropathological, immunological, and imaging knowledge about the mechanisms underlying the smoldering disease activity, focusing on possible early biomarkers and their translation into clinical practice. ANN NEUROL 2024;96:1-20.

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BACKGROUND: ChatGPT is an open-source natural language processing software that replies to users' queries. We conducted a cross-sectional study to assess people living with Multiple Sclerosis' (PwMS) preferences, satisfaction, and empathy toward two alternate responses to four frequently-asked questions, one authored by a group of neurologists, the other by ChatGPT. METHODS: An online form was sent through digital communication platforms. PwMS were blind to the author of each response and were asked to express their preference for each alternate response to the four questions. The overall satisfaction was assessed using a Likert scale (1-5); the Consultation and Relational Empathy scale was employed to assess perceived empathy. RESULTS: We included 1133 PwMS (age, 45.26 ± 11.50 years; females, 68.49%). ChatGPT's responses showed significantly higher empathy scores (Coeff = 1.38; 95% CI = 0.65, 2.11; p > z < 0.01), when compared with neurologists' responses. No association was found between ChatGPT' responses and mean satisfaction (Coeff = 0.03; 95% CI = - 0.01, 0.07; p = 0.157). College graduate, when compared with high school education responder, had significantly lower likelihood to prefer ChatGPT response (IRR = 0.87; 95% CI = 0.79, 0.95; p < 0.01). CONCLUSIONS: ChatGPT-authored responses provided higher empathy than neurologists. Although AI holds potential, physicians should prepare to interact with increasingly digitized patients and guide them on responsible AI use. Future development should consider tailoring AIs' responses to individual characteristics. Within the progressive digitalization of the population, ChatGPT could emerge as a helpful support in healthcare management rather than an alternative.

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BACKGROUND: People with progressive multiple sclerosis (PMS) present motor (eg, walking) and cognitive impairments, and report fatigue. Fatigue encompasses fatigability which is objectively measured by the capacity to sustain a motor or cognitive task. OBJECTIVE: To investigate the prevalence of walking and cognitive fatigability (CF) and the associated clinical characteristics in a large sample of PMS patients. METHODS: PMS patients (25-65 years old) were included from 11 sites (Europe and North America), having cognitive impairment (1.28 standard deviation below normative data for the symbol digit modality test [SDMT]). Walking fatigability (WF) was assessed using the distance walk index (DWI) and CF using the SDMT (scores from the last 30 seconds compared to the first 30 seconds). Additional measures were: cognitive assessment-Brief International Cognitive Assessment for multiple sclerosis (MS), cardiorespiratory fitness, 6-minute walk, physical activity, depressive symptoms, perceived fatigue-Modified Fatigue Impact Scale (MFIS), MS impact-MSIS-29, and walking ability. RESULTS: Of 298 participants, 153 (51%) presented WF (DWI = -28.9 ± 22.1%) and 196 (66%) presented CF (-29.7 ± 15%). Clinical characteristics (EDSS, disease duration, and use of assistive device) were worse in patients with versus without WF. They also presented worse scores on MSIS-29 physical, MFIS total and physical and reduced physical capacity. CF patients scored better in the MSIS-29 physical and MFIS psychosocial, compared to non-CF group. Magnitude of CF and WF were not related. CONCLUSIONS: Half of the cognitively-impaired PMS population presented WF which was associated with higher disability, physical functions, and fatigue. There was a high prevalence of CF but without strong associations with clinical, cognitive, and physical functions. TRIAL REGISTRATION NUMBER: The "CogEx-study," www.clinicaltrial.gov identifier number: NCT03679468.

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BACKGROUND: High-efficacy disease-modifying therapies have been proven to slow disability accrual in adults with relapsing-remitting multiple sclerosis. However, their impact on disability worsening in paediatric-onset multiple sclerosis, particularly during the early phases, is not well understood. We evaluated how high-efficacy therapies influence transitions across five disability states, ranging from minimal disability to gait impairment and secondary progressive multiple sclerosis, in people with paediatric-onset multiple sclerosis. METHODS: Longitudinal data were obtained from the international MSBase registry, containing data from people with multiple sclerosis from 151 centres across 41 countries, and the Italian Multiple Sclerosis and Related Disorders Register, containing data from people with multiple sclerosis from 178 Italian multiple sclerosis centres. People younger than 18 years at the onset of multiple sclerosis symptoms were included, provided they had a confirmed diagnosis of relapsing-remitting multiple sclerosis and at least four Expanded Disability Status Scale (EDSS) scores recorded within 12-month intervals. The primary outcome was the time to change in disability state: minimal disability (EDSS scores 0, 1·0, and 1·5), mild disability (EDSS scores 2·0 and 2·5), moderate disability (EDSS scores 3·0 and 3·5), gait impairment (EDSS scores ≥4·0), and clinician diagnosed secondary progressive multiple sclerosis. A multi-state model was constructed to simulate the natural course of multiple sclerosis, modelling the probabilities of both disability worsening and improvement simultaneously. The impact of high-efficacy disease-modifying therapies (alemtuzumab, cladribine, daclizumab, fingolimod, mitoxantrone, natalizumab, ocrelizumab, rituximab, or autologous haematopoietic stem cell transplantation) and low-efficacy disease-modifying therapies (dimethyl fumarate, glatiramer acetate, interferon beta, or teriflunomide), compared with no treatment, on the course of disability was assessed. Apart from recruitment, individuals with lived experience of multiple sclerosis were not involved in the design and conduct of this study. FINDINGS: A total of 5224 people (3686 [70·6%] female and 1538 [29·4%] male) with mean age at onset of multiple sclerosis 15·24 years (SD 2·52) were included. High-efficacy therapies reduced the hazard of disability worsening across the disability states. The largest reduction (hazard ratio 0·41 [95% CI 0·31-0·53]) was observed in participants who were treated with high-efficacy therapies while in the minimal disability state, compared with those remained untreated. The benefit of high-efficacy therapies declined with increasing disability. Young people with minimal disability who received low-efficacy therapy also experienced a reduced hazard (hazard ratio 0·65 [95% CI 0·54-0·77]) of transitioning to mild disability, in contrast to those who remained untreated. INTERPRETATION: Treatment of paediatric-onset relapsing-remitting multiple sclerosis with high-efficacy therapy substantially reduces the risk of reaching key disability milestones. This reduction in risk is most pronounced among young people with minimal or mild disability when treatment began. Children with relapsing-remitting multiple sclerosis should be treated early with high-efficacy therapy, before developing significant neurological impairments, to better preserve their neurological capacity. FUNDING: National Health and Medical Research Council, Australia; MSBase Foundation Fellowship; MS Australia Postdoctoral Fellowship.

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