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Objective: Cognitive impairment affects approximately 30% of pediatric onset Multiple Sclerosis (POMS) patients with a negative impact on everyday life. The aim of this study was to evaluate the feasibility and effectiveness of a home-based, computer-assisted training of attention in patients with POMS., Methods: This was a randomized double-blind study. Subjects were randomized to specific training (ST) or non-specific training (n-ST), delivered through a customized module based on attention exercises (COGNI-TRAcK2). The main feature of the ST is the implementation of working load algorithms and procedures for intensiveness regulation. The effectiveness of the ST on attention was primarily assessed on the Symbol Digit Modalities Test (SDMT), using the Wilcoxon signed-rank test. Secondary objectives included effectiveness on other cognitive tests. The evaluations were performed at baseline, end of training and 3-month follow-up., Results: 22 relapsing-remitting patients were included: data of 8 subjects in n-ST and 5 subjects in ST were available. As for the primary outcome, SDMT score improved in the ST group (from 31.2 at baseline to 42.4 after 3 months, p = 0.043). There was no benefit in other neuropsychological measures., Conclusions: These preliminary findings point to a potential benefit of a home-based, computer-assisted training of attention in patients with POMS., Competing Interests: Declarations. Ethical approval: All subjects gave their informed consent for inclusion before they participated in the study. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee. The protocol of the study was written in accordance to “Norma UNI EN ISO 14155 and Good Clinical Practice”. The promoter is committed to the protection of personal sensitive data in accordance with national (D.Lgs. 196/2003) and international law (European Regulation 679/2019). Conflict of interest: E.P. received compensation for travel grants, participation in advisory board and/or speaking activities from Biogen, Merck Serono, Sanofi, Teva, and Novartis and serves on the editorial board of Frontiers in Neurology and Brain Sciences. RG received fees for Advisory Boards from UCB, Zogenix, Biocodex, GW-Jazz, Angelini, Takeda, and Rapport Therapeutics, and was an investigator in the STICLO-Italy trial of stiripentol. F.M. is employees of GeneDx. M.A.R. received consulting fees from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, Roche; and speaker honoraria from AstraZaneca, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Horizon Therapeutics Italy, Merck Serono SpA, Novartis, Roche, Sanofi and Teva. She receives research support from the MS Society of Canada, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla. She is Associate Editor for Multiple Sclerosis and Related Disorders. P.I. has served on scientific advisory boards for Biogen Idec, Bayer, Teva, Roche, Merck Serono, Novartis, and Genzyme and has received funding for travel and/or speaker honoraria from Sanofi Aventis, Genzyme, Biogen Idec, Teva, Merck Serono, and Novartis. M.F. is 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, Merck, Novartis, Roche, Sanofi; speaking activities from Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and TEVA; participation in Advisory Boards for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, Takeda; scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, Sanofi-Genzyme; he receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, the Italian Ministry of Health, the Italian Ministry of University and Research, and Fondazione Italiana Sclerosi Multipla. M.P.A. served on scientific advisory boards for and has received speaker honoraria and research support from Biogen Idec, Merck Serono, Bayer Schering Pharma, and Sanofi Aventis and serves on the editorial board of Multiple Sclerosis Journal and BMC Neurology., (© 2024. Fondazione Società Italiana di Neurologia.)

Background: Multiple sclerosis (MS) is a chronic inflammatory disorder affecting the brain and spinal cord, characterized by immune-mediated myelin damage. Early intervention and detection programs have emerged as promising strategies to improve patient outcomes by identifying and treating MS in its earliest stages., Objective: This systematic literature review aims to provide an overview of the preferences, attitudes, and opinions of both patients and healthcare professionals regarding early intervention or early detection programs for MS., Methods: A comprehensive search strategy was employed in March 2023 across multiple databases (MEDLINE, Scopus, PsyInfo, PubMed), from 1990 to 2023. A total of 38 articles were selected for analysis based on predefined inclusion and exclusion criteria., Results: The majority of articles were published in recent years and represented different methods from case reports to randomized controlled trials, with fewer systematic literature reviews. Data collection approaches included patients, healthcare workers, or mixed samples with varying age ranges and gender ratios, frequently preferring women. These samples represented different preference study methods. The included studies were primarily conducted in the USA and the UK. Thematic analysis revealed several key themes : 1) differences emerged between healthcare professionals' and patients' perspectives 2) interventions for MS outside Disease-Modifying Therapies (DMTs) 3) severe side effects 4) communication, information, and knowledge 5) psychological and emotional aspects., Conclusions: Understanding these diverse factors and subgroups within the MS population can inform more effective, personalized approaches to MS prevention and treatment., Competing Interests: Declaration of competing interest The Authors declare having no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: To compare Expanded Disability Status Scale (EDSS) trajectories over time between Multiple Sclerosis (MS) groups with pediatric (POMS), adult (AOMS) and late (LOMS) onset, and between patients with and without progression independent of relapse activity (PIRA)., Methods: Patients with a first visit within 1 year from onset, ≥ 5-year follow-up and ≥ 1 visit every 6 months were selected from the Italian MS Register. Adjusted disability trajectories were assessed by longitudinal models for repeated measures. Comparisons between groups and between patients with and without PIRA in subgroups were performed by evaluating the yearly differences of mean EDSS score changes versus baseline (delta-EDSS). A first CDA event was defined as a 6-months confirmed disability increase from study baseline, measured by EDSS (increase ≥ 1.5 points with baseline EDSS = 0; ≥ 1.0 with baseline EDSS score ≤ 5.0 and ≥ 0.5 point with baseline EDSS > 5.5). PIRA was defined as a CDA event occurring more than 90 days after and more than 30 days before the onset of a relapse., Results: 3777 MS patients (268 POMS, 3282 AOMS, 227 LOMS) were included. The slope of disability trajectories significantly diverged in AOMS vs POMS starting from the second year of follow-up (Year 2: delta2-EDSS 0.18 (0.05; 0.31), p = 0.0054) and then mean delta2-EDSS gradually increased up to 0.23 (0.07; 0.39, p = 0.004) at year 5. Patients with PIRA had significant (p < 0.0001) steeper increase in EDSS scores than those without PIRA in all groups, although in POMS, the disability trajectories began to diverge later and at a lesser extent with delta-EDSS score of 0.48 vs 0.83 in AOMS and 1.57 in LOMS, at 3 years after the first PIRA., Conclusions: Age is relevant in determining disability progression in MS. POMS shows a less steep increase in EDSS scores over time than older patients. The effect of PIRA in accelerating EDSS progression is less pronounced in POMS than in AOMS and LOMS., (© 2024. The Author(s).)

Background: Pediatric-onset Multiple Sclerosis (POMS) patients show more inflammatory disease compared with adult-onset MS. However, highly effective treatments are limited with only fingolimod being approved in Italy and natalizumab prescribed as off-label treatment., Objectives: to compare the efficacy of natalizumab versus fingolimod in POMS., Methods: This is an observational longitudinal multicentre study including natalizumab- and fingolimod-treated POMS patients (N-POMS and F-POMS, respectively). We collected Annual Relapse Rate (ARR), Expanded Disability Status Scale (EDSS), Symbol Digit Modality Test (SDMT), and MRI activity at baseline (T0), 12-18 months (T1), and last available observation (T2)., Results: We enrolled 57 N-POMS and 27 F-POMS patients from six Italian MS Centres. At T0, N-POMS patients showed higher ARR (p = 0.03), higher EDSS (p = 0.003) and lower SDMT (p = 0.04) at baseline compared with F-POMS. Between T 0 and T 1 ARR improved for both N-POMS and F-POMS (p < 0.001), while EDSS (p < 0.001) and SDMT (p = 0.03) improved only for N-POMS. At T 2 (66.1 ± 55.4 months) we collected data from 42 out of 57 N-POMS patients showing no further ARR decrease., Conclusion: Both natalizumab and fingolimod showed high and sustained efficacy in controlling relapses and natalizumab also associated to a disability decrease in POMS. This latter effect might be partly mediated by the high inflammatory activity at baseline in N-POMS., (© 2024. The Author(s).)

Multiple sclerosis is a chronic, inflammatory, and neurodegenerative disease of the central nervous system and a major cause of neurological disability in young adults. Its prevalence and incidence are increasing, and it has been estimated at over 2.8 million cases worldwide, in addition to recent trends towards a shift in MS prevalence to older ages, with peak prevalence estimates in the sixth decade of life. Although historically the relapsing and progressive phases of the disease have been considered separate clinical entities, recent evidence of progression independent of relapse activity (PIRA) has led to a reconsideration of multiple sclerosis as a continuum, in which relapsing and progressive features variably coexist from the earliest stages of the disease, challenging the traditional view of the disease course. In this Series article, we provide an overview of how the traditional description of the clinical course of MS and epidemiological trends in Europe have evolved. For this purpose, we focus on the concept of PIRA, discussing its potential as the main mechanism by which patients acquire disability, how its definition varies between studies, and ongoing research in this field. We emphasise the importance of incorporating the assessment of hidden clinical manifestations into patient management to help uncover and quantify the PIRA phenomenon and the possible implications for future changes in the clinical classification of the disease. At the same time, we provide insights into overcoming the challenges of identifying and defining PIRA and adopting a new understanding of the clinical course of MS., Competing Interests: E. Portaccio received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, participation on a Data Safety Monitoring Board or Advisory Board and support for attending meetings and/or travel from Biogen, Merck Serono, Sanofi, Teva, Roche, BMS Cellgene, Janssen and Novartis. M. Magyari received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Biogen, Merck, Novartis, Roche, Sanofi, Bristol Myers Squibb and for participation on a Data Safety Monitoring Board or Advisory Board from Sanofi, Novartis, Merck, Moderna. E.K. Havrdova received grants or contracts from Czech Ministry of Education—project Cooperatio LF1, research area Neuroscience and the project National Institute for Neurological Research (Programme EXCELES, ID project No LX22NPO5107), payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Actelion (Janssen/J&J), Biogen, Celgene (BMS), Merck, Novartis, Roche, Sanofi and Teva and for participation on a Data Safety Monitoring Board or Advisory Board from Actelion (Janssen/J&J), Biogen, Celgene (BMS), Merck, Novartis, Roche and Sanofi. A. Ruet received grants or contracts from BMS Celgene, Roche, Biogen, Sanofi Genzyme, Merck, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Biogen, Merck, Sanofi Genzyme and support for attending meetings and/or travel from Alexion, Biogen, Novartis. B Brochet received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events and support for attending meetings and/or travel from BMS Celgene, Merck Serono, Roche and for participation on a Data Safety Monitoring Board or Advisory Board from BMS Celgene, Merck Serono, Novartis, Roche and Sanofi. A. Scalfari reports no disclosures relevant to this manuscript. M. Di Filippo received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, participation on a Data Safety Monitoring Board or Advisory Board and support for attending meetings and/or travel from Alexion, BMS, Bayer, Biogen Idec, Genzyme, Horizon, Janssen, Merck, Mylan, Novartis, Roche, Siemens Healthineers, Teva and Viatris. Carmen Tur received grants or contract from Junior Leader La Caixa Fellowship (fellowship code is LCF/BQ/PI20/11760008), awarded by “la Caixa” Foundation (ID 100010434), Miguel Servet Contract (CP23/00117), awarded by Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation and FORTALECE grant (FORT23/00034), awarded by Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche, Novartis, Bristol Myers Squibb, Johnson and Johnson, Immunic AG, and Merck; support for attending meetings and/or travel, participation on a Data Safety Monitoring Board or Advisory Board from Roche, Novartis, Bristol Myers Squibb, and Merck. X. Montalban received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, participation on a Data Safety Monitoring Board or Advisory Board and support for attending meetings and/or travel from AbbVie, Actelion, Alexion, Biogen, BMS/Celgene, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Genzyme, Hoffmann-La Roche, Immunic, Janssen Pharmaceuticals, MedDay, Merck, Mylan, NervGen, Novartis, Sandoz, Sanofi-Genzyme, Teva Pharmaceutical, TG Therapeutics, EXCEMED, MSIF and NMSS. M.P. Amato received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, participation on a Data Safety Monitoring Board or Advisory Board and support for attending meetings and/or travel from Biogen Idec, Merck Serono, Bayer Schering Pharma, and Sanofi Aventis., (© 2024 The Author(s).)

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., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objectives: We investigated the occurrence and relative contribution of relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA) to confirmed disability accrual (CDA) and transition to secondary progression (SP) in relapsing multiple sclerosis (MS)., Methods: Relapsing-onset MS patients with follow-up > / = 5 years (16,130) were extracted from the Italian MS Registry. CDA was a 6-month confirmed increase in Expanded Disability Status Scale (EDSS) score. Sustained disability accumulation (SDA) was a CDA with no EDSS improvement in all subsequent visits. Predictors of PIRA and RAW and the association between final EDSS score and type of CDA were assessed using logistic multivariable regression and multivariable ordinal regression models, respectively., Results: Over 11.8 ± 5.4 years, 16,731 CDA events occurred in 8998 (55.8%) patients. PIRA (12,175) accounted for 72.3% of CDA. SDA occurred in 8912 (73.2%) PIRA and 2583 (56.7%) RAW (p < 0.001). 4453 (27.6%) patients transitioned to SPMS, 4010 (73.2%) out of 5476 patients with sustained PIRA and 443 (24.8%) out of 1790 patients with non-sustained PIRA. In the multivariable ordinal regression analysis, higher final EDSS score was associated with PIRA (estimated coefficient 0.349, 95% CI 0.120-0.577, p = 0.003)., Discussion: In this real-world relapsing-onset MS cohort, PIRA was the main driver of disability accumulation and was associated with higher disability in the long term. Sustained PIRA was linked to transition to SP and could represent a more accurate PIRA definition and a criterion to mark the putative onset of the progressive phase., (© 2024. The Author(s).)

Background: There is limited information on interpretation of cognitive changes over time in multiple sclerosis (MS)., Objective: This study aimed to provide normative data for the assessment of statistically meaningful change in all tests of the Minimal Assessment of Cognitive Function in MS (MACFIMS)., Methods: We applied the reliable change methodology to a healthy Italian cohort, assessed with two alternate versions of the MACFIMS 1 year apart. We calculated confidence intervals of retest score variance using the reliable change index (RCI). Moreover, multivariable linear regression models adjusted for age, sex, education, and baseline score were built to calculate the regression-based change index (RB-CI)., Results: Overall, 200 healthy individuals were enrolled. Thresholds for interpreting change in each test were calculated. In the multivariable models, baseline score was associated with retest score in all tests ( B from 0.439 to 0.760; p < 0.001). RB-CI can be calculated with data of the multivariable models., Conclusion: We provide normative data for reliable cognitive change evaluation for all the tests of the MACFIMS, which includes the Symbol Digit Modalities Test and Brief International Cognitive Assessment in MS, two widely used tools for screening and monitoring cognition in MS. Our findings can significantly improve the interpretation of cognitive changes in MS., 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: E.P. received compensation for travel grants, participation in advisory board and speaking activities from Biogen, Merck Serono, Sanofi, Teva, Roche, BMS Celgene, Janssen, and Novartis, and served on the editorial board of Frontiers in Neurology and Brain Sciences. M.P.A. served on scientific advisory boards for and has received speaker honoraria and research support from Biogen Idec, Merck Serono, Bayer Schering Pharma, and Sanofi Aventis, and serves on the editorial board of Multiple Sclerosis Journal and BMC Neurology. P.G., F.B., V.B., S.C., M.F., B.G., C.N., E.P., and R.G.V. declare that there is no conflict of interest.

Background: Predicting disease progression in patients with the first clinical episode suggestive of multiple sclerosis (MS) is crucial for personalized therapeutic approaches. This study aimed to develop the EUMUS score for accurately estimating the risk of early evidence of disease activity and progression (EDA)., Methods: Retrospective analysis was conducted on data from 221 patients with a first clinical MS episode collected from four Italian MS centers. Various variables including socio-demographics, clinical features, cerebrospinal fluid analysis, evoked potentials, and brain MRI were considered. A prognostic multivariate regression model was identified to develop the EUMUS score. The optimal cutoff for predicting the transition from no evidence of disease activity (NEDA3) to EDA was determined. The accuracy of the prognostic model and score were tested in a separate UK MS cohort., Results: After 12 months, 61.54% of patients experienced relapses and/or new MRI lesions. Younger age (OR 0.96, CI 0.93-0.99; p = 0.005), MRI infratentorial lesion(s) at baseline (OR 2.21, CI 1.27-3.87; p = 0.005), positive oligoclonal bands (OR 2.89, CI 1.47-5.69; p = 0.002), and abnormal lower limb somatosensory-evoked potentials (OR 2.77, CI 1.41-5.42; p = 0.003) were significantly associated with increased risk of EDA. The EUMUS score demonstrated good specificity (72%) and correctly classified 80% of patients with EDA in the independent UK cohort., Conclusions: The EUMUS score is a simple and useful tool for predicting MS evolution within 12 months of the first clinical episode. It has the potential to guide personalized therapeutic approaches and aid in clinical decision-making., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

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., Competing Interests: Declaration of interests SS has received research support from the MSBase Foundation and MS Australia. IR served on scientific advisory boards and received conference travel support or speaker honoraria from Roche, Novartis, Merck, and Biogen. CBM has received conference travel support from Merck, Novartis, and Biogen, and research support from the National Health and Medical Research Council Australia, MS Australia, The University of Melbourne, The Royal Melbourne Hospital Neuroscience Foundation, and Dementia Australia. PI has served on scientific advisory boards for Biogen Idec, Bayer, Bristol Myers Squibb (BMS), Teva, Roche, Merck Serono, Novartis, and Genzyme, and has received funding for travel or speaker honoraria from Sanofi Aventis, Genzyme, Roche, Biogen Idec, Teva, Merck Serono, Alexion, BMS, and Novartis. MF received compensation for consulting services or speaking activities from Almiral, Alexion, Bayer, Biogen, Celgene, Eli Lilly, Genzyme, Merck-Serono, Novartis, Roche, Sanofi, Takeda, and Teva Pharmaceutical Industries, and receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). EKH received honoraria or research support from Biogen, Merck Serono, Novartis, Roche, and Teva; has been member of advisory boards for Actelion, Biogen, Celgene, Merck Serono, Novartis, and Sanofi Genzyme; and has been supported by the Czech Ministry of Education (project Cooperatio LF1) and the National Institute for Neurological Research of the Czech Republic (programme EXCELES, project number LX22NPO5107) funded by the Next Generation EU. VBM received compensation for public speaking or consultancy from Merck, Novartis, Biogen, Genzyme, Teva, and Alrmirall. RA received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche, and Sanofi-Genzyme. MZ received travel support and fees for lecturing or participating in advisory boards from Almirall, Biogen, Merck, Novartis, and Sanofi-Genzyme. FP received personal compensation for serving on advisory boards by Almirall, Alexion, Biogen, BMS, Janssen, Merck, Novartis, and Roche, and research grants from Alexion, Almirall, Biogen, BMS, Merck, Novartis, Roche, Fondazione Italiana Sclerosi Multipla, Reload Association (Onlus), Italian Health Minister, and University of Catania. SE received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche, and Teva. GS received grants and honoraria from Roche, Sanofi, Merck, Biogen, and Novartis. ADS received speaker honoraria and consultant fees from Biogen, Novartis, Merck, Roche, Alexion, and Sanofi. EP received compensation for travel grants, participation in advisory boards, or speaking activities from Biogen, Merck Serono, Sanofi, Teva, and Novartis, and serves on the editorial boards of Frontiers in Neurology and Brain Sciences. MT has served on scientific advisory boards for Biogen, Novartis, Roche, Merck, and Genzyme; received speaker honoraria from Biogen, Roche, Sanofi, Merck, Genzyme, and Novartis; and received research grants for her institution from Biogen, Merck, and Novartis. MPA served on scientific advisory boards for and has received speaker honoraria and research support from Biogen Idec, Merck Serono, Bayer Schering Pharma, Novartis, Roche, BMS Celgene, and Sanofi Aventis, and is Editor of Multiple Sclerosis Journal. TK served on scientific advisory boards for MS International Federation and WHO, BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Merck, and Biogen, and the steering committee for Brain Atrophy Initiative by Sanofi Genzyme; received conference travel support or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Roche, Sanofi-Genzyme, Teva, BioCSL, and Merck; and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene, and Merck. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: In the general population, maternal COVID-19 is associated with worse maternal and fetal outcomes. Two previous studies have assessed COVID-19 clinical outcomes in pregnant women with multiple sclerosis (MS), but there are no data about maternal and fetal outcomes., Objectives: In this multicenter study, we aimed to assess maternal and fetal outcomes in pregnant women with MS and COVID-19 infection., Methods: We recruited pregnant patients with MS who contracted COVID-19 and were followed up in Italian and Turkish Centers, during 2020-2022. A control group was extracted from a previous Italian cohort. Associations between group (COVID-19 or healthy patients) and clinical outcomes (maternal complications, fetal malformations, and spontaneous abortion) were investigated with a weighted logistic regression where propensity score-based inverse probability of treatment weighting (IPTW) approach was applied for adjusting for difference in baseline confounders., Results: In the multivariable analysis, COVID-19 during pregnancy was associated with a higher risk of maternal complications (odd ratio (OR) = 2.12; 95% confidence interval (CI) = 1.32-3.48; p = 0.002), while it was not associated with higher risk of spontaneous abortion and fetal malformations., Conclusion: Our data indicate that COVID-19 during pregnancy increases the risk of maternal complications, while it seems to have no significant impact on fetal outcomes., 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: S.S. has received honoraria or consultancy fees for participating to advisory boards, giving educational lectures and/or travel and registration coverage for attending scientific congresses or symposia from F. Hoffmann-La Roche Ltd, Sanofi-Genzyme, Merck Serono, Novartis, Teva, and Biogen Idec/Gen Pharma. R.K. has received honoraria for giving educational lectures, consultancy fees for participating advisory boards, and travel grants for attending scientific congresses or symposia from Roche, Sanofi-Genzyme, Merck Serono, Novartis, Teva, Biogen Idec/Gen Pharma of Turkey, Abdi İbrahim İlac, Deva, and ARIS. A.S. has received honoraria or consultancy fees for participating to advisory boards, giving educational lectures and/or travel and registration coverage for attending scientific congresses or symposia from F. Hoffmann-La Roche Ltd, Sanofi-Genzyme, Merck Serono, Novartis, Teva, Biogen Idec/Gen Pharma of Turkey, and Abdi İbrahim İlac. E.P. received compensation for travel grants, participation in advisory board and/or speaking activities from Biogen, Merck Serono, Sanofi, Teva, and Novartis and serves on the editorial board of Frontiers in Neurology and Brain Sciences. M.P.A. served on scientific advisory boards for and has received speaker honoraria and research support from Biogen Idec, Merck Serono, Bayer Schering Pharma, and Sanofi Aventis and serves on the editorial board of Multiple Sclerosis Journal and BMC Neurology. M.P.S. received consulting fees from Roche, Biogen, Merck, Novartis, Sanofi, Celgene, Immunic, Geneuro, GSK, and MedDay; received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Roche, Biogen Merck, Novartis, Sanofi, and Celgene; and participated on a Data Safety Monitoring Board or Advisory Board for Roche, Sanofi, Novartis, and Merck. I.S. received consulting fees from Hippocrates Research, NovaNeuro, Sakura Italia, ADL Farmaceutici, and Associazione Commissione Difesa Vista Onlus. C.C. received grants or contracts from Roche, Novartis, Merck Serono, Biogen, and Celgene and received consulting fees from Biogen. L.M. received compensation for consulting services, travel grants, and/or speaking activities from Biogen, Serono, Sanofi, Teva, Roche, and Novartis. E.S. received personal compensation from Almirall, Biogen, Sanofi, Novartis, Roche, Horizon, Alexion, Merck, Mylan, and Teva for traveling and advisory boards. S.D.B. received personal compensation from Alexion, Almirall, Biogen, Merck Novartis, Roche, and Sanofi for traveling and advisory boards. M.B. received honoraria for speaking, advisory board, consulting from Teva, Genzyme, Biogen, Bristol MS, Merck, and Novartis. M.C. received personal compensations from Novartis, Genzyme, and Teva and consulting fees from Zambon. R.F. received honoraria for advisory boards and consulting from Bristol MS, Roche, Merck, and Novartis. P.C. received honoraria as speaker or travel grants to attend national and international conferences or consultation for advisory boards from Alexion, Almirall, Bayer Schering, Biogen, Cellgene-BMS, Janssen, Merck Serono, Teva, Roche, Novartis, Sandoz, and Sanofi-Genzyme. S.T. received travel grants or personal compensations from Biogen, Novartis, Sanofi-Genzyme, Roche, Janssen, Teva, and Almirall. The remaining authors have nothing to report.

Thrombotic microangiopathy (TMA) has been observed in some patients receiving interferon beta (IFNβ) therapy for relapsing-remitting multiple sclerosis, but little is known about its clinical features and outcomes. We searched the literature to identify cases with IFNβ-related TMA and assessed their pattern of organ involvement, the presence of prodromal manifestations, the treatments used, and the outcomes. Thirty-five articles met the inclusion criteria, and data of 67 patients were collected. The median duration of IFNβ therapy before the diagnosis of TMA was 8 years, and 56/67 (84%) presented with acute kidney injury (AKI), of which 33 required acute dialysis. All but three patients had manifestations during the four weeks before TMA onset, including flu-like symptoms, headache, and worsening blood pressure control. In only two patients, ADAMTS13 activity was reduced, while 27% had low C3 levels. However, none showed causative genetic mutations associated with development of atypical hemolytic uremic syndrome. All patients discontinued IFNβ, 34 (55%) also received plasma exchange, and 12 (18%) received eculizumab. Complete renal recovery was achieved by 20 patients (30%), while 13 (20%) developed end-stage renal disease. Among those with AKI requiring dialysis, eculizumab therapy was associated with a significantly reduced risk of ESRD compared with plasma exchange. Therefore, TMA with features of aHUS mainly occurs after prolonged treatment with IFNβ and is preceded by prodromes, which may lead to an early diagnosis before life-threatening complications occur. Eculizumab appears beneficial in cases with severe kidney involvement, which supports a role of the complement system in the pathogenesis of these forms.

Background: Active relapsing-remitting (RR) and secondary progressive (SP) multiple sclerosis (MS) are currently defined as "relapsing MS" (RMS). The aim of this cross-sectional study was to assess drivers of treatment switches due to clinical relapses in a population of RMS patients collected in the Italian MS and Related Disorders Register (I-MS&RD)., Methods: RRMS and SPMS patients with at least one relapse in a time window of 2 years before of data extraction were defined as RMS. Factors associated with disease-modifying therapy (DMT) switching due to clinical activity were assessed through multivariable logistic regression models in which treatment exposure was included as the last recorded DMT and the last DMT's class [moderate-efficacy (ME), high-efficacy (HE) DMTs and anti-CD20 drugs]., Results: A cohort of 4739 RMS patients (4161 RRMS, 578 SPMS) was extracted from the I-MS&RD. A total of 2694 patients switching DMTs due to relapses were identified. Switchers were significantly (p < 0.0001) younger, less disabled, more frequently affected by an RR disease course in comparison to non-switcher patients. The multivariable logistic regression models showed that Alemtuzumab (OR 0.08, 95% CI 0.02-0.37), Natalizumab (0.48, 0.30-0.76), Ocrelizumab (0.1, 0.02-0.45) and Rituximab (0.23, 0.06-0.82) exposure was a protective factor against treatment switch due to relapses. Moreover, the use of HE DMTs (0.43, 0.31-0.59), especially anti-CD20 drugs (0.14, 0.05-0.37), resulted to be a protective factor against treatment switch due to relapses in comparison with ME DMTs., Conclusions: More than 50% of RMS switched therapy due to disease activity. HE DMTs, especially anti-CD20 drugs, significantly reduce the risk of treatment switch., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Importance: Although up to 20% of patients with multiple sclerosis (MS) experience onset before 18 years of age, it has been suggested that people with pediatric-onset MS (POMS) are protected against disability because of greater capacity for repair., Objective: To assess the incidence of and factors associated with progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW) in POMS compared with typical adult-onset MS (AOMS) and late-onset MS (LOMS)., Design, Setting, and Participants: This cohort study on prospectively acquired data from the Italian MS Register was performed from June 1, 2000, to September 30, 2021. At the time of data extraction, longitudinal data from 73 564 patients from 120 MS centers were available in the register., Main Outcomes and Measures: The main outcomes included age-related cumulative incidence and adjusted hazard ratios (HRs) for PIRA and RAW and associated factors., Exposures: Clinical and magnetic resonance imaging features, time receiving disease-modifying therapy (DMT), and time to first DMT., Results: After applying the inclusion and exclusion criteria, the study assessed 16 130 patients with MS (median [IQR] age at onset, 28.7 [22.8-36.2 years]; 68.3% female). Compared with AOMS and LOMS, patients with POMS had less disability, exhibited more active disease, and were exposed to DMT for a longer period. A first 48-week-confirmed PIRA occurred in 7176 patients (44.5%): 558 patients with POMS (40.4%), 6258 patients with AOMS (44.3%), and 360 patients with LOMS (56.8%) (P < .001). Factors associated with PIRA were older age at onset (AOMS vs POMS HR, 1.42; 95% CI, 1.30-1.55; LOMS vs POMS HR, 2.98; 95% CI, 2.60-3.41; P < .001), longer disease duration (HR, 1.04; 95% CI, 1.04-1.05; P < .001), and shorter DMT exposure (HR, 0.69; 95% CI, 0.64-0.74; P < .001). The incidence of PIRA was 1.3% at 20 years of age, but it rapidly increased approximately 7 times between 21 and 30 years of age (9.0%) and nearly doubled for each age decade from 40 to 70 years (21.6% at 40 years, 39.0% at 50 years, 61.0% at 60 years, and 78.7% at 70 years). The cumulative incidence of RAW events followed a similar trend from 20 to 60 years (0.5% at 20 years, 3.5% at 30 years, 7.8% at 40 years, 14.4% at 50 years, and 24.1% at 60 years); no further increase was found at 70 years (27.7%). Delayed DMT initiation was associated with higher risk of PIRA (HR, 1.16; 95% CI, 1.00-1.34; P = .04) and RAW (HR, 1.75; 95% CI, 1.28-2.39; P = .001)., Conclusions and Relevance: PIRA can occur at any age, and although pediatric onset is not fully protective against progression, this study's findings suggest that patients with pediatric onset are less likely to exhibit PIRA over a decade of follow-up. However, these data also reinforce the benefit for DMT initiation in patients with POMS, as treatment was associated with reduced occurrence of both PIRA and RAW regardless of age at onset.

Background: Cognitive impairment (CI) is a prevalent and debilitating manifestation of multiple sclerosis (MS); however, it is not included in the widely used concept of No Evidence of Disease Activity (NEDA-3). We expanded the NEDA-3 concept to NEDA-3 + by encompassing CI assessed through the Symbol Digit Modality Test (SDMT) and evaluated the effect of teriflunomide on NEDA3 + in patients treated in a real-world setting. The value of NEDA-3 + in predicting disability progression was also assessed., Methods: This 96-weeks observational study enrolled patients already on treatment with teriflunomide for ≥ 24 weeks. The predictiveness of NEDA-3 and NEDA-3 + at 48 weeks on the change in motor disability at 96 weeks was compared through a two-sided McNemar test., Results: The full analysis set (n = 128; 38% treatment naïve) featured relatively low level of disability (baseline EDSS = 1.97 ± 1.33). NEDA-3 and NEDA-3 + statuses were achieved by 82.8% and 64.8% of patients, respectively at 48 weeks vs. baseline, and by 57.0% and 49.2% of patients, respectively at 96 weeks vs. baseline. All patients except one were free of disability progression at Week 96, and NEDA-3 and NEDA-3 + were equally predictive. Most patients were free of relapse (87.5%), disability progression (94.5%) and new MRI activity (67.2%) comparing 96 weeks with baseline. SDMT scores were stable in patients with baseline score ˃35 and improved significantly in those with baseline score ≤ 35. Treatment persistence was high (81.0% at Week 96)., Conclusion: Teriflunomide confirmed its real-world efficacy and was found to have a potentially beneficial effect on cognition., (© 2023. The Author(s).)

Background: In the general population, maternal SARS-CoV-2 infection during pregnancy is associated with worse maternal outcomes; however, only one study so far has evaluated COVID-19 clinical outcomes in pregnant and postpartum women with multiple sclerosis, showing no higher risk for poor COVID-19 outcomes in these patients., Objective: In this multicenter study, we aimed to evaluate COVID-19 clinical outcomes in pregnant patients with multiple sclerosis., Methods: We recruited 85 pregnant patients with multiple sclerosis who contracted COVID-19 after conception and were prospectively followed-up in Italian and Turkish Centers, in the period 2020-2022. A control group of 1354 women was extracted from the database of the Multiple Sclerosis and COVID-19 (MuSC-19). Univariate and subsequent logistic regression models were fitted to search for risk factors associated with severe COVID-19 course (at least one outcome among hospitalization, intensive care unit [ICU] admission and death)., Results: In the multivariable analysis, independent predictors of severe COVID-19 were age, body mass index ⩾ 30, treatment with anti-CD20 and recent use of methylprednisolone. Vaccination before infection was a protective factor. Vaccination before infection was a protective factor. Pregnancy was not a risk nor a protective factor for severe COVID-19 course., Conclusion: Our data show no significant increase of severe COVID-19 outcomes in patients with multiple sclerosis who contracted the infection during pregnancy.

Introduction: Cognitive impairment (CI) is a core feature of Multiple Sclerosis (MS), being detectable in up to 65% of subjects. Treatment of CI can be considered of paramount importance. However, no standardized strategies are available to date to define the best treatment approach, especially for the pharmacological management., Areas Covered: In this narrative review, the authors outline the latest advances in pharmacological management of CI in MS, including Disease Modifying Treatments (DMTs) which indirectly may or may not influence CI and symptomatic drugs. Selected publications were restricted to those written in English, reporting on an adult relapsing-remitting MS or progressive MS sample, assessing the effects of (at least) 1 DMT or treatment in a longitudinal design, reporting data on (at least) one standardized cognitive test performed at baseline and follow-up, and published between January 2018 and May 2022., Expert Opinion: Recent data can be considered encouraging and inspiring for future studies. Overall, there is preliminary evidence of a beneficial effect of DMTs on cognition, particularly for high-efficacy DMTs. As for symptomatic treatments, dalfampridine appears to be the only medication with robust evidence of a positive effect on cognition. However, the definition of clinically meaningful change/improvement in cognitive functions remains an unmet need. Future studies should assess the role of other patient-related factors that can be associated with a better cognitive response to treatments and investigate the possible positive effect of multimodal interventions on cognition.

Cognitive impairment (CI) is a core feature of multiple sclerosis (MS) and affects up to 65% of patients in every phase of the disease, having a deep impact on all aspects of patients' lives. Cognitive functions most frequently involved include information processing speed, learning and memory, visuospatial abilities, and executive function. The precise pathogenetic mechanisms underpinning CI in MS are still largely unknown, but are deemed to be mainly related to pathological changes in lesioned and normal-appearing white matter, specific neuronal grey matter structures, and immunological alterations, with particular impact on synaptic transmission and plasticity. Moreover, much research is needed on therapeutic strategies. Small to moderate efficacy has been reported for disease-modifying therapies, particularly high-efficacy drugs, and symptomatic therapies (dalfampridine), while the strongest benefit emerged after cognitive training. The present narrative review provides a concise, updated overview of more recent evidence on the prevalence, profile, pathogenetic mechanisms, and treatment of CI in people with MS. CI should be screened on a regular basis as part of routine clinical assessments, and brief tools are now widely available (such as the Symbol Digit Modalities Test). The main goal of cognitive assessment in MS is the prompt implementation of preventive and treatment interventions., Competing Interests: Conflicts of InterestEP received compensation for travel grants, participation in advisory board and/or speaking activities from Biogen, Merck Serono, Sanofi, Teva, and Novartis; serves on the editorial board of Frontiers in Neurology and Brain Sciences. MPA served on scientific advisory boards and has received speaker honoraria and research support from Biogen Idec, Merck Serono, Bayer Schering Pharma, and Sanofi Aventis, and serves on the editorial board of Multiple Sclerosis Journal and BMC Neurology., (© 2022 by the authors.)

Objectives: To assess the impact of timing of natalizumab cessation/redosing on long-term maternal and infant outcomes in 72 out of the original 74 pregnancies of the Italian Pregnancy Dataset in multiple sclerosis (MS)., Methods: Maternal outcomes in patients who received natalizumab until conception and restarted the drug within 1 month after delivery ("treatment approach," (TA)) and patients who stopped natalizumab before conception and/or restarted the drug later than 1 month after delivery ("conservative approach," (CA)) were compared through multivariable Cox regression analyses. Pediatric outcomes were assessed through a semi-structured questionnaire., Results: After a mean follow-up of 6.1 years, CA (hazard ratio (HR) = 4.1, 95% CI 1.6-10.6, p  = 0.003) was the only predictor of relapse occurrence. Worsening on the Expanded Disability Status Scale (EDSS) was associated with higher annualized relapse-rate during the follow-up (HR = 3.3, 95% CI 1.4-7.9 p  = 0.007). We found no major development abnormalities in children., Discussion: Our data confirm that TA reduces the risk of disease activity; we did not observe an increase in major development abnormalities in the child.

Background: COVID-19 vaccination is highly recommended to multiple sclerosis (MS) patients. Little is known about the role of patients' clinical and demographic characteristics in determining antibody response., Methods: We evaluated safety and efficacy of anti-SARS-CoV-2 vaccines on 143 included MS patients. Then, we analyzed antibody titer in a subgroup, assessing clinical and demographic variables associated with protection and antibody titer., Results: After completing the vaccination cycle, the rate of local adverse events was similar after the first and second dose. A higher proportion of systemic AEs was reported after the second dose (65.7% vs 24.5% after the first dose). Antibody response was evaluated in 97 patients. Higher EDSS (OR 0.6, 95% CI 0.4-0.9, p = 0.006) and treatment with antiCD20 (OR 0.02, 95% CI 0.003-0.098, p 0.001) were associated with a lower chance of having an efficacious response. Higher weight was associated with higher Ab titer (β = 15.2, 95% CI 2.8-27.6, p = 0.017), while treatment with antiCD20 with lower titers (β =  - 1092.3, 95% CI - 1477.4 to - 702.2, p < 0.001). In patients treated with antiCD20, hypogammaglobulinemia (β - 543, 95% CI - 1047.6 to - 39.1, p = 0.036) and treatment duration (β - 182, 95% CI - 341.4 to - 24.3, p = 0.027) were associated with lower Ab titer., Conclusion: Our study confirms that COVID-19 vaccination in MS patient is safe and effective in preventing symptomatic COVID-19 and should be recommended to all patients. Moreover, we suggest a possible role of hypogammaglobulinemia in reducing Ab response in patients treated with antiCD20 therapies., (© 2022. Fondazione Società Italiana di Neurologia.)

Objective: Assessing the risk of clinical and radiological reactivation during pregnancy and post partum in women with multiple sclerosis (MS) treated with natalizumab (NTZ) throughout pregnancy (LONG&#95;EXP) compared with women interrupting treatment before (NO&#95;EXP) and within >-30 days and ≤90 days from conception (SHORT&#95;EXP), and describing newborns' outcomes., Methods: Maternal clinical and radiological outcomes and obstetric and fetal outcomes were retrospectively collected and compared among groups (NO&#95;EXP, SHORT&#95;EXP, LONG&#95;EXP). Predictors of clinical and radiological reactivation were investigated through univariable and multivariable analysis., Results: 170 eligible pregnancies from 163 women referring to 29 Italian MS centres were included. Annualised relapse rate (ARR) was significantly lower in LONG&#95;EXP (n=66, 0.02 (0.001-0.09)) compared with NO&#95;EXP (n=31, 0.43 (0.21-0.75), p=0.002) and SHORT&#95;EXP (n=73, 0.46 (0.30-0.66), p=0.0004) during pregnancy, and in LONG&#95;EXP (0.12 (0.05-0.24)) compared with SHORT&#95;EXP (0.30 (0.17-0.50), p=0.008) during post partum. Gadolinium-enhancing (Gd+) lesions were less frequent in LONG&#95;EXP (n=6/50, 2.00%) compared with NO&#95;EXP (n=9/21, 42.86%) and SHORT&#95;EXP after delivery (n=17/49, 34.69%, p=0.010).Delaying NTZ resumption after delivery significantly increased the risk of relapses (OR=1.29 (95% CI 1.07 to 1.57), p=0.009) and Gd+ lesions (OR=1.49 (95% CI 1.17 to 1.89, p=0.001). Newborns' weight, length, head circumference and gestational age did not differ among groups after adjusting for confounders. Anaemia was tracked in 4/69 LONG&#95;EXP newborns. Congenital anomaly rate was within the expected range for the untreated MS population., Conclusions: Our findings indicate that in women with MS treated with NTZ before conception, continuation of NTZ throughout pregnancy and its early resumption after delivery mitigate the risk of clinical and radiological reactivation. This approach has no major impact on newborns' outcomes., Competing Interests: Competing interests: DL received travel funding from Biogen, Merck-Serono, Sanofi-Genzyme, Teva, speaking or consultations fees from Sanofi-Genzyme, Merck-Serono, Teva, Biogen, Roche; FB received teaching honoraria from Novartis; AGr reports no disclosures relevant to the manuscript; PA received travel support, compensation for serving on scientific advisory boards and speaker's fees from Almirall, Biogen, Celgene, Merck-Serono, Mylan, Novartis, Sanofi-Genzyme and Teva; ABe reports no disclosures relevant to the manuscript; ABi reports no disclosures relevant to the manuscript; GB received honoraria for speaking or consultation fee from Almirall, Biogen, Merck, Novartis, Sanofi, Teva, Roche; VB received fees for consultancies or public speaking from Merck, Novartis, Biogen, Roche, Genzyme and Biogen; SB has been founded for advisory board, academic purposes and speech honoraria by Genzyme, Roche, Biogen, Merck-Serono, Novartis and Almirall; MCB has advisory board membership and honoraria for speaking from Teva, Novartis, Sanofi, Merck-Serono and Biogen; FC received honoraria for advisory board and/or for public speaking, and/or travel grant, from Biogen, Merck, Teva, Sanofi-Genzyme, Roche; RCa received lecture fees and/or travel grants from Novartis, Biogen, Roche, Celgene and Merck; DC is an Advisory Board member of Almirall, Bayer-Schering, Biogen, GW Pharmaceutical, Merck-Serono, Novartis, Roche, Sanofi-Genzyme and Teva and received honoraria for speaking or consultation fee from Almirall, Bayer-Schering, Biogen, GW Pharmaceuticals, Merck-Serono, Novartis, Roche, Sanofi-Genzyme and Teva. He is also the principal investigator in clinical trials for Bayer-Schering, Biogen, Merck-Serono, Novartis, Roche, Sanofi-Genzyme; RCe has received funding for travel and/or speaker honoraria from Sanofy, Biogen Idec, Merck-Serono and Roche; CGC received grants for congress participation from Almirall, Biogen, Merck-Serono, Novartis, Roche, Sanofi-Genzyme and Teva; MCa received personal compensation for speaking/advising/consulting from Merck, Sanofi-Genzyme, Biogen, Novartis, Roche, Teva, EMF Serono; was supported in travelling expenses for congresses from Merck, Sanofi-Genzyme, Biogen, Novartis, Roche, Teva, Almirall; received research grants from Italian MS Foundation (FISM), Italian Ministry of Research, Merck, Sanofi-Genzyme, Biogen, Novartis; ECo received travel grant, speaker fee and consultancy from Biogen Idec, Teva, Genzyme, Merck-Serono, Novartis, Roche and Admirall; CC received personal compensation for advisory board and speaking from: Biogen, Roche, Novartis, Almirall, Merck-Serono; ECu received fees for advisory boards and speaking honoraria from Merck-Serono, Novartis and Biogen, travel funding from Biogen, Sanofi-Genzyme, Merck-Serono, Roche, Novartis and Teva; AD reports no disclosures relevant to the manuscript; EDA received speaking honoraria from Biogen, Merck-Serono, Novartis, Sanofi-Genzyme, Bayer-Schering; GDL served on scientific advisory boards for Merck, Sanofi-Genzyme and Roche, and has received travel and/or speaker honoraria from Merck, Roche, Teva, Biogen, Novartis and Sanofi-Genzyme; MDF participated on advisory boards for and received speaker or writing honoraria and funding for travelling from Bayer, Biogen Idec, Genzyme, Merck, Mylan, Novartis, Roche and Teva; DF has received travel grants, speaker honoraria and/or research support to her institution by Merck-Serono, Biogen, Roche, Genzyme, Novartis, Teva and Binding Site; AGa received speaker and consulting fees from Actelion, Biogen, Coloplast, Merck-Serono, Mylan, Roche, Sanofi-Genzyme, Teva; CG received fee as speaker or advisory board from Merck, Biogen, Teva, Bayer, Roche, Sanofi, Almirall; FG received research funding from Sanofi-Genzyme and Biogen, fees for advisory boards and speaking honoraria from Biogen, Novartis, Sanofi-Genzyme, Merck-Serono and Roche, travel funding from Biogen, Sanofi-Genzyme, Merck-Serono and Roche; MI received grants from NIH, NMSS, FISM; received fees for consultation from Roche, Genzyme, Merck, Biogen and Novartis; RL received fees for consultancies or public speaking from Merck, Novartis, Biogen, Roche, Genzyme and Biogen; LL received travel grant, speaker fee and consultancy from Biogen Idec, Teva, Genzyme, Merck-Serono, Novartis, Roche and Admirall; GL received speaker honoraria and/or consultancy from Biogen, Teva, Genzyme, Merck, Novartis, Almirall, Roche; MM received personal fees from Sanofi-Genzyme, Merck-Serono, Novartis and Almirall; MM has scientific advisory board membership of Bayer-Schering, Biogen, Sanofi-Genzyme, Merck, Novartis, Teva; consulting and/or speaking fees, research support or travel grants from Almirall, Bayer-Schering, Biogen, CSL, Sanofi-Genzyme, Merck, Novartis, Teva, Roche, Ultragenix; principal investigator in clinical trials for Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, Teva, Ultragenix, CSL Behring; LM received honoraria for speaking activity at scientific meetings and/or advisory boards from Biogen Idec, Merck-Serono, Sanofi-Genzyme, Novartis, Roche; CGN received travel funding from Almirall, Biogen, Novartis and Sanofi-Genzyme, Merck-Serono; VN has received consulting fees from Novartis, Roche, Mylan, Biogen Idec, Merk and Bayer; speaker and writing honoraria from Mylan, Teva, Biogen Idec, Bayer, Sanofi-Genzyme and Merk; travel grants from Teva, Biogen Idec, Sanofi-Genzyme, Roche and Novartis; FPa received honoraria for speaking activities by Almirall, Bayer-Schering, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi-Genzyme and Teva; he also served as advisory board member the following companies: Bayer-Schering, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi-Genzyme and Teva; he was also funded by Pfizer and FISM for epidemiological studies; he received grants for congress participation from Almirall, Bayer Shering, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi-Genzyme and Teva; EP received compensation for travel grants, participation in advisory board and/or speaking activities from Biogen, Merck-Serono, Sanofi, Teva and Novartis; serves on the editorial board of Frontiers in Neurology and Brain Sciences; CP received honoraria for speaking or consultation fee from Almirall, Biogen, Merck, Novartis, Sanofi, Teva, Roche; PR received travel expenses or honoraria for speaking or participating to advisory board by: Biogen, Merck, Sanofi-Genzyme, Novartis, Teva, Roche; GS received travel expenses or honoraria for speaking or participating to advisory board by: Biogen idec, Sanofi-Genzyme, Novartis, Roche; ESi received speaker honoraria and/or consultancy from Biogen, Teva, Genzyme, Merck, Novartis, Almirall, Roche; FV has received travel grants and/or speaker honoraria by Merck-Serono, Biogen, Roche, Genzyme, Novartis and Teva; RT has served on advisory boards and/or received honoraria for speaking or consultation fees from Almirall, Biogen, Laborest, Merck-Serono, Novartis, Roche, Sanofi-Genzyme and Teva; MPS received personal fees from Biogen, Merck, Teva, Novartis, Sanofi-Genzyme, Roche, GeNeuro and Medday, outside the submitted work; MPA received research grants and honoraria as a speaker and member of advisory boards by: Bayer, Biogen, Merck, Novartis, Sanofi-Genzyme, Teva, Almirall, Celgene and Roche; GAM received speaking or consultation fees from Almirall, Bayer-Schering, Biogen, Genzyme, Merck-Serono, Novartis, Teva, Sanofi-Genzyme., (© Author(s) (or their employer(s)) 2022. 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Importance: Except for ocrelizumab, treatment options in primary progressive multiple sclerosis (PPMS) are lacking., Objective: To investigate the effectiveness of DMTs on the risk of becoming wheelchair dependent in a real-world population of patients with PPMS., Design, Setting, and Participants: This was a multicenter, observational, retrospective, comparative effectiveness research study. Data were extracted on November 28, 2018, from the Italian multiple sclerosis register and analyzed from June to December 2021. Mean study follow-up was 11 years. Included in the study cohort were patients with a diagnosis of PPMS and at least 3 years of Expanded Disability Status Scale (EDSS) evaluations and 3 years of follow-up., Main Outcomes and Measures: The risk of reaching an EDSS score of 7.0 was assessed through multivariable Cox regression models., Exposures: Patients who received DMT before the outcome were considered treated. DMT was assessed as a time-dependent variable and by class of DMT (moderately and highly effective)., Results: From a total of 3298 patients with PPMS, 2633 were excluded because they did not meet the entry criteria for the phase 3, multicenter, randomized, parallel-group, double-blind, placebo-controlled study to evaluate the efficacy and safety of ocrelizumab in adults with PPMS (ORATORIO) trial. Among the remaining 665 patients (mean [SD] age, 43.0 [10.7] years; 366 female patients [55.0%]), 409 were further selected for propensity score matching (288 treated and 121 untreated patients). In the matched cohort, during the study follow-up, 37% of patients (152 of 409) reached an EDSS score of 7.0 after a mean (SD) follow-up of 10.6 (5.6) years. A higher EDSS score at baseline (adjusted hazard ratio [aHR], 1.32; 95% CI, 1.13-1.55; P < .001), superimposed relapses (aHR, 2.37; 95% CI, 1.24-4.54; P = .009), and DMT exposure (aHR, 1.75; 95% CI, 1.04-2.94; P = .03) were associated with a higher risk of an EDSS score of 7.0, whereas the interaction term between DMT and superimposed relapses was associated with a reduced risk of EDSS score of 7.0 (aHR, 0.33; 95% CI, 0.16-0.71; P = .004). Similar findings were obtained when treatment according to DMT class was considered and when DMT was included as a time-dependent covariate. These results were confirmed in the subgroup of patients with available magnetic resonance imaging data., Conclusions and Relevance: Results of this comparative effectiveness research study suggest that inflammation also occurs in patients with PPMS, may contribute to long-term disability, and may be associated with a reduced risk of becoming wheelchair dependent by current licensed DMTs.

Disability accrual in multiple sclerosis may occur as relapse-associated worsening or progression independent of relapse activity. The role of progression independent of relapse activity in early multiple sclerosis is yet to be established. The objective of this multicentre, observational, retrospective cohort study was to investigate the contribution of relapse-associated worsening and progression independent of relapse activity to confirmed disability accumulation in patients with clinically isolated syndrome and early relapsing-remitting multiple sclerosis, assessed within one year from onset and with follow-up ≥5 years (n = 5169). Data were extracted from the Italian Multiple Sclerosis Register. Confirmed disability accumulation was defined by an increase in Expanded Disability Status Scale score confirmed at 6 months, and classified per temporal association with relapses. Factors associated with progression independent of relapse activity and relapse-associated worsening were assessed using multivariable Cox regression models. Over a follow-up period of 11.5 ± 5.5 years, progression independent of relapse activity occurred in 1427 (27.6%) and relapse-associated worsening in 922 (17.8%) patients. Progression independent of relapse activity was associated with older age at baseline [hazard ratio (HR) = 1.19; 95% confidence interval (CI) 1.13-1.25, P < 0.001], having a relapsing-remitting course at baseline (HR = 1.44; 95% CI 1.28-1.61, P < 0.001), longer disease duration at baseline (HR = 1.56; 95% CI 1.28-1.90, P < 0.001), lower Expanded Disability Status Scale at baseline (HR = 0.92; 95% CI 0.88-0.96, P < 0.001) and lower number of relapses before the event (HR = 0.76; 95% CI 0.73-0.80, P < 0.001). Relapse-associated worsening was associated with younger age at baseline (HR = 0.87; 95% CI 0.81-0.93, P < 0.001), having a relapsing-remitting course at baseline (HR = 1.55; 95% CI 1.35-1.79, P < 0.001), lower Expanded Disability Status Scale at baseline (HR = 0.94; 95% CI 0.89-0.99, P = 0.017) and a higher number of relapses before the event (HR = 1.04; 95% CI 1.01-1.07, P < 0.001). Longer exposure to disease-modifying drugs was associated with a lower risk of both progression independent of relapse activity and relapse-associated worsening (P < 0.001). This study provides evidence that in an early relapsing-onset multiple sclerosis cohort, progression independent of relapse activity was an important contributor to confirmed disability accumulation. Our findings indicate that insidious progression appears even in the earliest phases of the disease, suggesting that inflammation and neurodegeneration can represent a single disease continuum, in which age is one of the main determinants of disease phenomenology., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Over the recent years, the treatment of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) has evolved very rapidly and a large number of disease-modifying treatments (DMTs) are now available. However, most DMTs are associated with adverse events, the most frequent of which being infections. Consideration of all DMT-associated risks facilitates development of risk mitigation strategies. An international focused workshop with expert-led discussions was sponsored by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and was held in April 2021 to review our current knowledge about the risk of infections associated with the use of DMTs for people with MS and NMOSD and corresponding risk mitigation strategies. The workshop addressed DMT-associated infections in specific populations, such as children and pregnant women with MS, or people with MS who have other comorbidities or live in regions with an exceptionally high infection burden. Finally, we reviewed the topic of DMT-associated infectious risks in the context of the current SARS-CoV-2 pandemic. Herein, we summarize available evidence and identify gaps in knowledge which justify further research.

Decannulation is a rehabilitation milestone in patients with Disorders of Consciousness (DoC). investigate the relationship between decannulation and improvement of responsiveness (IR) in DoC. 236 tracheostomized patients with severe Acquired Brain Injury and DoC admitted in the Intensive Rehabilitation Unit were retrospectively included. They received personalized interdisciplinary rehabilitation. At discharge, IR was evaluated. The association between IR and demographic/clinical data was investigated using a logistic regression analysis, both in the Unresponsive Wakefulness Syndrome (UWS) and Minimal Consciousness State (MCS) group, divided according to their Coma Recovery Scale-Revised score at admission. In the UWS group ( N  = 107), only decannulation was associated with IR at discharge (OR: 5.94, CI: 2.08-16.91, p  = .001). In the MCS group ( N  = 129) time post-injury (OR: 0.983, CI: 0.97-0.99, p  = .012) and decannulation were associated with IR at discharge (OR: 17.9, CI: 6.39-50.13, p  < .001). Decannulation and IR were found to be strongly related, independently from the initial clinical state. While the retrospective nature of the study could not exclude that decannulation may be a consequence of a spontaneous recovery, the obtained results may disclose its potential influence on the clinical history of patients with DoC.