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Background and Purpose: The European Academy of Neurology (EAN) was a merger from two parent societies: the European Neurological Association (ENS, founded in 1986) and the European Federation of Neurological Societies (EFNS, founded in 1987)., Methods: This article was written by nine former presidents, three of whom were also founders of the ENS, and is based on recollections and documents. It follows up on a review of the ENS history stored in the EAN archive., Results: The first European society (ENS) was founded by eight individual European academic clinician-neuroscientists aiming at joining with other qualified European neuroscientists on an individual membership basis. After 1990 members were also invited from behind the former Iron Curtain. A principal goal was holding neurology meetings (700 participants in 1988 and over 3000 in 2010), promoting collaborative research projects with exchange of junior neuroscientists, and providing teaching and education independent from nationality. Health politics were not part of the agenda. The executive boards (4-year term) were staffed with academic scientists from all subspecialties of neurology. Numerous bursaries and fellowships were established for junior neurologists. The impact of ENS members on research activities of young investigators was appreciated by academia at large. After years of negotiations ENS and EFNS joint efforts resulted in forming the EAN covering all fields of neurology and neuroscience under one roof., Conclusion: The basic principles of the ENS were successfully integrated into the new EAN in particular documented by the number of individual members rising to over 4000 in 2024., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Patients with multiple sclerosis (PwMS) have an increased risk of infections., Objectives: To characterize incidence, clinical characteristics, outcomes and risk factors of infections, and serious infections (SIs) in ocrelizumab (OCR)-treated PwMS., Design: Post-hoc analysis of pooled data from 6155 patients in 13 clinical trials., Methods: Descriptive analyses of clinical characteristics and outcomes were reported over ⩽14 years. A Poisson Generalized Estimating Equation model was constructed to examine risk factors in a subgroup of patients with longer exposure to OCR ( n  = 2092)., Results: Over a median (max) treatment period of 3.7 (13.9) years, 420/6155 patients (6.8%) experienced 583 SIs, excluding coronavirus disease 2019. Incidence rates in relapsing multiple sclerosis (RMS; 1.50 per 100 patient years [95% confidence interval (CI): 1.34-1.68]) and progressive multiple sclerosis (PMS; 3.70 [95% CI: 3.27-4.17]) remained stable over this period. Lower respiratory tract, urinary tract, abdominal and gastrointestinal, and skin infections were the most commonly reported SIs. Most SIs (~90%) resolved, and treatment with OCR was continued in >80% of cases. The presence of 1 or ⩾2 comorbidities (rate ratio = 1.66, 2.73, respectively), recent relapse activity (2.06), and Expanded Disability Status Scale (EDSS) score ⩾6.0 (2.02) were significant risk factors for SIs in patients with RMS treated over a median (max) period of 8.3 (11.2) years. In patients with primary PMS treated over a median (max) period of 7.1 (11.8) years, an EDSS score ⩾6.0 was associated with the greatest risk of SIs, a 4-fold increase (rate ratio, 4.31), followed by abnormal immunoglobulin (Ig)M levels (1.89), the presence of ⩾2 comorbidities (1.80), and having overweight/obesity (1.46). Time on OCR and abnormal IgG levels were not significantly associated with an increased SI risk., Conclusion: Continuous long-term treatment with OCR is associated with a manageable infection risk profile. Optimal disease control and addressing modifiable risk factors may reduce the risk of infections., (© The Author(s), 2024.)

Introduction: Multiple sclerosis (MS) is an inflammatory and degenerative autoimmune condition, resulting frequently in a disabling condition. Significant improvements of long-term prognosis have been recently achieved with an early and more aggressive use of disease modifying therapies (DMTs). Addressing the complexity of managing its progressive forms remains a significant challenge., Areas Covered: This review provides an update on DMTs for relapsing-remitting MS (RRMS) and progressive MS and their efficacy, safety, and mechanism of action, emphasizing the critical role of biomarkers in optimizing treatment decisions. Moreover, some key information on drugs used to manage symptoms such as pain, fatigue, spasticity and urinary problems will be provided. The literature search was conducted using PubMed, Embase, and Cochrane Library databases covering the period from January 2000 to January 2024., Expert Opinion: Major advances have been achieved in the treatment of RRMS. Treatment should start immediately as soon as the neurologist is confident with the diagnosis and its choice should be based on the prognostic profile and on the patient's propensity to accept drug-related risks. The therapeutic landscape for progressive MS is quite disappointing and necessitates further innovation. Personalized medicine, leveraging biomarker insights, holds promise for refining treatment efficacy and patient outcomes.

Progressive multiple sclerosis poses a considerable challenge in the evaluation of disease progression and treatment response owing to its multifaceted pathophysiology. Traditional clinical measures such as the Expanded Disability Status Scale are limited in capturing the full scope of disease and treatment effects. Advanced imaging techniques, including MRI and PET scans, have emerged as valuable tools for the assessment of neurodegenerative processes, including the respective role of adaptive and innate immunity, detailed insights into brain and spinal cord atrophy, lesion dynamics and grey matter damage. The potential of cerebrospinal fluid and blood biomarkers is increasingly recognized, with neurofilament light chain levels being a notable indicator of neuro-axonal damage. Moreover, patient-reported outcomes are crucial for reflecting the subjective experience of disease progression and treatment efficacy, covering aspects such as fatigue, cognitive function and overall quality of life. The future incorporation of digital technologies and wearable devices in research and clinical practice promises to enhance our understanding of functional impairments and disease progression. This Review offers a comprehensive examination of these diverse evaluation tools, highlighting their combined use in accurately assessing disease progression and treatment efficacy in progressive multiple sclerosis, thereby guiding more effective therapeutic strategies., (© 2024. Springer Nature Limited.)

Multiple sclerosis (MS) is a neurological disorder characterized by immune dysregulation. It begins with a first clinical manifestation, a clinically isolated syndrome (CIS), which evolves to definite MS in case of further clinical and/or neuroradiological episodes. Here we evaluated the diagnostic value of transcriptional alterations in MS and CIS blood by machine learning (ML). Deep sequencing of more than 200 blood RNA samples comprising CIS, MS and healthy subjects, generated transcriptomes that were analyzed by the binary classification workflow to distinguish MS from healthy subjects and the Time-To-Event pipeline to predict CIS conversion to MS along time. To identify optimal classifiers, we performed algorithm benchmarking by nested cross-validation with the train set in both pipelines and then tested models generated with the train set on an independent dataset for final validation. The binary classification model identified a blood transcriptional signature classifying definite MS from healthy subjects with 97% accuracy, indicating that MS is associated with a clear predictive transcriptional signature in blood cells. When analyzing CIS data with ML survival models, prediction power of CIS conversion to MS was about 72% when using paraclinical data and 74.3% when using blood transcriptomes, indicating that blood-based classifiers obtained at the first clinical event can efficiently predict risk of developing MS. Coupling blood transcriptomics with ML approaches enables retrieval of predictive signatures of CIS conversion and MS state, thus introducing early non-invasive approaches to MS diagnosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: While John Cunningham virus (JCV) is known to cause neuronal damage in progressive multifocal leukoencephalopathy (PML) among natalizumab-treated MS patients, its association with axonal loss in non-PML conditions remains unclear., Methods: In a cohort of 128 natalizumab-treated MS patients, serum neurofilament (sNfL) levels and JCV antibody titres were measured., Results: Among 128 patients (mean age = 38.4 years, 71.9% female), 51 (40%) were JCV positive. NfL levels increased by 15.3% for JCV index <0.7 (95% confidence interval [CI] = 0.963-1.381), by 18.6% for index 0.7-1.5 (95% CI = 1.009-1.394) and by 21.1% for index >1.5 (95% CI = 1.040-1.409) compared to JCV negative patients., Conclusion: These findings indicate a potential link between JCV burden and neuroaxonal degeneration in natalizumab-treated MS patients., 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: G.D.C., M.P., T.C., F.S., B.C., A.H., and R.G. report no disclosures. VM has received honoraria for activities with Biogen, Merck, Bayer, TEVA and Sanofi-Genzyme as a speaker. L.M. has received honoraria for speaking in scientific meetings and for advisory board from Biogen TEVA, Sanofi-Genzyme, and Merck. R.F. has received honoraria for speaker activities from Biogen, Merck, Novartis, Roche and Teva. L.L. has received honoraria for consulting services and/or speaking activity from Biogen, Novartis and Excemed. G.C. has received personal compensation for consulting services and/or speaking activities from Novartis, Teva, Sanofi, Sanofi-Genzyme, Merck, Biogen, Excemed, Serono Symposia International Foundation, Roche, Almirall, Receptos, Celgene and Forward Pharma.

Background: Computerized cognitive tests may extend the reach of cognitive screening and monitoring to those with mobility issues or living in remote areas. Moreover, it could enable frequent and autonomous remote cognitive assessments in people with multiple sclerosis (pwMS) on account of its reduced economic and organizational costs. This may further improve our understanding of longitudinal trends and significantly improve the standard of care for pwMS living in remote areas or with mobility limitations. We aimed to evaluate the psychometric properties of an electronic Symbol-Digit Modalities Test (eSDMT) designed to allow pwMS to perform a rapid cognitive assessment independently from home using their own PC/laptop., Methods: Sixty-two participants underwent a neuropsychological evaluation, and then performed the eSDMT in the clinic. Forty-two participants also repeated the eSDMT at home. We assessed concurrent validity (eSDMT vs. oral SDMT), test-retest reliability (in the clinic vs. at home), discriminant validity (pwMS with/without cognitive impairment), and other psychometric characteristics of the eSDMT (effect of age, sex, and education on test scores)., Results: We observed good-to-excellent concurrent validity (r ≥ 0.84, all p < 0.0001) and test-retest reliability (intraclass correlation coefficients [ICCs]>0.87, all p < 0.0001). Discriminant validity was excellent (area under the curves [AUCs] >0.84, all p < 0.0001). eSDMT scores were only slightly influenced by demographic characteristics (all R 2  < 0.200)., Conclusions: We provided evidence which supports the use of our eSDMT as a feasible, valid, and reliable remote assessment of cognitive function in pwMS. Future studies will investigate long-term reliability and predictive power., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Aims: Non-invasive neuromodulation by transcranial direct current stimulation (tDCS), owing to its reported beneficial effects on neuronal plasticity, has been proposed as a treatment to promote functional recovery in several neurological conditions, including demyelinating diseases like multiple sclerosis. Less information is available on the effects of tDCS in major pathological mechanisms of multiple sclerosis, such as demyelination and inflammation. To learn more about the latter effects, we applied multi-session anodal tDCS in mice exposed to long-term cuprizone (CPZ) diet, known to induce chronic demyelination., Methods: Visual evoked potentials (VEP) and motor performance (beam test) were employed for longitudinal monitoring of visual and motor pathways in 28 mice undergoing CPZ diet, compared with 12 control (H) mice. After randomization, anodal tDCS was applied for 5 days in awake, freely-moving surviving animals: 12 CPZ-anodal, 10 CPZ-sham, 5H-anodal, 5 h-sham. At the end of the experiment, histological analysis was performed on the optic nerves and corpus callosum for myelin, axons and microglia/macrophages., Key Findings: CPZ diet was associated with significantly delayed VEPs starting at 4 weeks compared with their baseline, significant compared with controls at 8 weeks. After 5-day tDCS, VEPs latency significantly recovered in the active group compared with the sham group. Similar findings were observed in the time to cross on the beam test Optic nerve histology revealed higher myelin content and lower microglia/macrophage counts in the CPZ-Anodal group compared with CPZ-Sham., Significance: Multiple sessions of anodal transcranial direct current stimulation (tDCS) in freely moving mice induced recovery of visual nervous conduction and significant beneficial effects in myelin content and inflammatory cells in the cuprizone model of demyelination. Altogether, these promising findings prompt further exploration of tDCS as a potential therapeutic approach for remyelination., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest related to the present work., (Copyright © 2024. Published by Elsevier Inc.)

Multiple sclerosis (MS) is a devastating immune-mediated disorder of the central nervous system resulting in progressive disability accumulation. As there is no cure available yet for MS, the primary therapeutic objective is to reduce relapses and to slow down disability progression as early as possible during the disease to maintain and/or improve health-related quality of life. However, optimizing treatment for people with MS (pwMS) is complex and challenging due to the many factors involved and in particular, the high degree of clinical and sub-clinical heterogeneity in disease progression among pwMS. In this paper, we discuss these many different challenges complicating treatment optimization for pwMS as well as how a shift towards a more pro-active, data-driven and personalized medicine approach could potentially improve patient outcomes for pwMS. We describe how the 'Clinical Impact through AI-assisted MS Care' (CLAIMS) project serves as a recent example of how to realize such a shift towards personalized treatment optimization for pwMS through the development of a platform that offers a holistic view of all relevant patient data and biomarkers, and then using this data to enable AI-supported prognostic modelling., Competing Interests: JP is a shareholder of icometrix NV. AR is a shareholder of icometrix NV. DS is a shareholder of icometrix NV. MS has no relevant or material financial interests that relate to the research described in this paper. However, she is employed as Operational Director of The European Charcot Foundation. TZ reports scientific advisory board and/or consulting for Biogen, Roche, Novartis, Celgene, and Merck; compensation for serving on speaker’s bureaus for Roche, Novartis, Merck, Sanofi, Celgene, and Biogen; and research support from Biogen, Novartis, Merck, and Sanofi. VZ is a shareholder of F. Hoffmann-La Roche Ltd PV reports honorarium, contributions to meeting from Biogen, Sanofi-Genzyme, Novartis, Teva, Merck, Roche, Imcyse, AB Science, Janssen, Ad Scientiam and BMS-Celgene. Research support from Novartis, Sanofi-Genzyme and Merck. EK is a shareholder of Nocturne GmbH. DH received compensation for travel, speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche, and Teva, as well as support for research activities from Biogen Idec. JR is a shareholder of Imcyse SA. GC has received consulting and speaking fees from Novartis, Sanofi, Janssen, Bristol Myers Squibb, Roche and Rewind. FP provided research support to Neurosciences Clinical Research Center, German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Einstein Foundation, Guthy Jackson Charitable Foundation, EU FP7 Framework Program, Biogen, Genzyme, Merck Serono, Novartis, Bayer, Roche, Parexel and Almirall, received honoraria for lectures, presentations, speakers from Guthy Jackson Foundation, Bayer, Biogen, Merck Serono, Sanofi Genzyme, Novartis, Viela Bio, Roche, UCB, Mitsubishi Tanabe and Celgene, in addition, received compensation for serving on a scientific advisory board of Celgene, Roche, UCB and Merck, and is an Academic Editor of PLos One and Associate Editor of Neurology® Neuroimmunology & Neuroinflammation, all unrelated to this work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Praet, Anderhalten, Comi, Horakova, Ziemssen, Vermersch, Lukas, van Leemput, Steppe, Aguilera, Kadas, Bertrand, van Rampelbergh, de Boer, Zingler, Smeets, Ribbens and Paul.)

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: Although trigeminal nerve involvement is a characteristic of multiple sclerosis (MS), its prevalence across studies varies greatly due to MRI resolution and cohort selection bias. The mechanism behind the site specificity of trigeminal nerve injury is still unclear. We aim to determine the prevalence of trigeminal nerve involvement in patients with MS in a consecutive 7T brain MRI cohort., Methods: This observational cohort originates from an ongoing China National Registry of Neuro-Inflammatory Diseases. Inclusion criteria were the following: age 18 years or older, diagnosis of MS according to the 2017 McDonald criteria and no clinical relapse within the preceding 3 months. Each participant underwent 7T MAGNETOM Terra scanner (Siemens, Erlangen, Germany), using a 32-channel phased array coil at Beijing Tiantan Hospital. T1-weighted magnetisation-prepared rapid acquisition gradient echoes, fluid-attenuated inversion recovery (FLAIR) and fluid and white matter suppression images were used to identify lesions. FLAIR* and T2* weighted images were used to identify central vein sign (CVS) within the trigeminal lesions., Results: 120 patients underwent 7T MRI scans between December 2021 and May 2023. 19/120 (15.8%) patients had a total of 45 trigeminal lesions, of which 11/19 (57.9%) were bilateral. The linear lesions extended along the trigeminal nerve, from the root entry zone (REZ) (57.8%, 26/45) to the pontine-medullary nucleus (42.2%, 19/45). 26.9% (7/26) of the lesions in REZ showed a typical central venous sign., Conclusion: In this 7T MRI cohort, the prevalence of trigeminal nerve involvement was 15.8%. Characteristic CVS was detected in 26.9% of lesions in REZ. This suggests an inflammatory demyelination mechanism of trigeminal nerve involvement in MS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Significant advancements have been achieved in delineating the progress of the Global PROMS (PROMS) Initiative. The PROMS Initiative, a collaborative endeavor by the European Charcot Foundation and the Multiple Sclerosis International Federation, strives to amplify the influence of patient input on MS care and establish a cohesive perspective on Patient-Reported Outcomes (PROs) for diverse stakeholders. This initiative has established an expansive, participatory governance framework launching four dedicated working groups that have made substantive contributions to research, clinical management, eHealth, and healthcare system reform. The initiative prioritizes the global integration of patient (For the purposes of the Global PROMS Initiative, the term "patient" refers to the people with the disease (aka People with Multiple Sclerosis - pwMS): any individual with lived experience of the disease. People affected by the disease/Multiple Sclerosis: any individual or group that is affected by the disease: E.g., family members, caregivers will be also engaged as the other stakeholders in the initiative). insights into the management of MS care. It merges subjective PROs with objective clinical metrics, thereby addressing the complex variability of disease presentation and progression. Following the completion of its second phase, the initiative aims to help increasing the uptake of eHealth tools and passive PROs within research and clinical settings, affirming its unwavering dedication to the progressive refinement of MS care. Looking forward, the initiative is poised to continue enhancing global surveys, rethinking to the relevant statistical approaches in clinical trials, and cultivating a unified stance among 'industry', regulatory bodies and health policy making regarding the application of PROs in MS healthcare strategies., Competing Interests: LuC was employed by Hoffmann-La Roche. LoC was employed by Ad Scientiam. PK was employed by Merck KGaA. ACV has received reimbursement for developing educational presentations, educational and research grants, consultation fees, and/or travel stipends from Biogen Colombia, Genzyme Colombia, Merck Colombia, Roche Colombia, Novartis Colombia. CB has received travel support and/or research grants and/or lecture fees and/or advisory services by Novartis, Merck, Genesis, Sanofi, Teva, Roche, Biogen, Mylan, Tikun Europe ECC has received reimbursement for developing educational presentations, educational and research grants, consultation fees, and/or travel stipends from Biogen Argentina and LATAM, Genzyme Argentina, Merck Argentina and LATAM, Roche Argentina and LATAM, Raffo, Novartis Argentina, AstraZeneca Argentina, Horizon therapeutics, LACTRIMS, Harvard Medical School MP has received reimbursement for developing educational presentations from Biogen and Merck. SG has received reimbursement for developing educational presentations, research grants, consultation fees, and/or travel stipends from Roche, Merck and the Sumaira Foundation. VC received a grant from the European Charcot Foundation, received support for scientific meetings from Biogen, Janssen, Novartis, BMS, Roche and speaking honoraria from Novartis and Alexion. VR reports fees for traveling from Novartis, Merck, Biogen and Roche, speaker’s honoraria from Novartis, Sandoz, Merck, Biogen, consulting fees from Biogen, Merck, Novartis, Janssen, M3 Global Research and Atheneum Partners, all outside of the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. H-PH declared that he was an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Zaratin, Samadzadeh, Seferoğlu, Ricigliano, dos Santos Silva, Tunc, Brichetto, Coetzee, Helme, Khan, McBurney, Peryer, Weiland, Baneke, Battaglia, Block, Capezzuto, Carment, Cortesi, Cutter, Leocani, Hartung, Hillert, Hobart, Immonen, Kamudoni, Middleton, Moghames, Montalban, Peeters, Sormani, van Tonder, White, Comi and Vermersch.)

Multiple Sclerosis (MS) management in individuals aged 55 and above presents unique challenges due to the complex interaction between aging, comorbidities, immunosenescence, and MS pathophysiology. This comprehensive review explores the evolving landscape of MS in older adults, including the increased incidence and prevalence of MS in this age group, the shift in disease phenotypes from relapsing-remitting to progressive forms, and the presence of multimorbidity and polypharmacy. We aim to provide an updated review of the available evidence of disease-modifying treatments (DMTs) in older patients, including the efficacy and safety of existing therapies, emerging treatments such as Bruton tyrosine kinase (BTKs) inhibitors and those targeting remyelination and neuroprotection, and the critical decisions surrounding the initiation, de-escalation, and discontinuation of DMTs. Non-pharmacologic approaches, including physical therapy, neuromodulation therapies, cognitive rehabilitation, and psychotherapy, are also examined for their role in holistic care. The importance of MS Care Units and advance care planning are explored as a cornerstone in providing patient-centric care, ensuring alignment with patient preferences in the disease trajectory. Finally, the review emphasizes the need for personalized management and continuous monitoring of MS patients, alongside advocating for inclusive study designs in clinical research to improve the management of this growing patient demographic., Competing Interests: Author OF received speaking and/or consulting fees from Allergan, Almirall, Bayer Schering, Biogen, Merck Serono, Novartis, Sanofi, and Teva; compensation for serving as a journal editor, associate editor, or member of an editorial advisory board Revista Española de Esclerosis Múltiple; and research support from Hospital Foundation FIMABIS. Author GC received consulting fees from Actelion, Bayer Schering, Merck Serono, Novartis, Sanofi, and Teva and lecture fees from Bayer Schering, Biogen Dompé, Merck Serono, Novartis, Sanofi, Serono, Symposia International Foundation, and Teva. Author PV has received honoraria and contributions for attending meetings from Biogen, Sanofi-Genzyme, Novartis, Teva, Merck, Roche, Imcyse, AB Science, Janssen, and BMS-Celgene. The author’s research has been supported by grants from Novartis, Sanofi-Genzyme, and Merck. Author H-PH received honoraria for serving on steering, data monitoring or scientific advisory boards from Aurinia Pharma, BMS Celgene, Boehringer Ingelheim, Horizon Therapeutics, Merck, Novartis, Roche, TG Therapeutics. Author BVW has received advisory board and/or speaking fees from Almirall, Biogen, Merck, Novartis, Roche, and Sanofi; research support from Biogen, Merck, Novartis, and Sanofi, and contracted research from Biogen, Merck, Sanofi, Novartis, and Roche. Author PS has received personal compensation for consultations, serving on scientific advisory boards, steering committees, independent data monitoring committees or has received honoraria as speaker from Biogen, Merck, Novartis, TEVA, GlaxoSmithKline, SanofiAventis/Genzyme, and BMS/Celgene. Author TB has participated in meetings sponsored by and received honoraria lectures, advisory boards, consultations from pharmaceutical companies marketing treatments for multiple sclerosis: Almirall, Bayer, Biogen, Biologix, Bionorica, Bristol-Myers-Squibb, Eisai, GW Pharma, Horizon, Janssen-Cilag, MedDay, Merck, Novartis, Octapharma, Roche, Sandoz, Sanofi/Genzyme, TG Pharmaceuticals, TEVA-ratiopharm and UCB. His institution has received financial support in the last 12 months by unrestricted research grants Biogen, Bayer, Bristol-Myers-Squibb, Merck, Novartis, Roche, Sanofi/Genzyme, and TEVA ratiopharm and for participation in clinical trials in multiple sclerosis sponsored by Alexion, Bayer, Biogen, Bristol-Myers-Squibb, Merck, Novartis, Octapharma, Roche, Sanofi/Genzyme, and TEVA. Author CO-G has received speaking and consulting honoraria from Biogen, BMS, Merck, Novartis, Sanofi, Janssen, and Roche. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decisions., (Copyright © 2024 Fernández, Sörensen, Comi, Vermersch, Hartung, Leocani, Berger, Van Wijmeersch and Oreja-Guevara.)

Background: In REFLEX, subcutaneous interferon beta-1a (sc IFN β-1a) delayed the onset of multiple sclerosis (MS) in patients with a first clinical demyelinating event (FCDE)., Objectives: This post hoc analysis aimed to determine whether baseline serum neurofilament light (sNfL) chain can predict conversion to MS and whether correlations exist between baseline sNfL and magnetic resonance imaging (MRI) metrics., Methods: sNfL was measured for 494 patients who received sc IFN β-1a 44 μg once weekly (qw; n  = 168), three times weekly (tiw; n  = 161), or placebo ( n  = 165) over 24 months. Median baseline sNfL (26.1 pg/mL) was used to define high/low sNfL subgroups. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox's proportional hazard model to determine factors influencing the risk of conversion to MS. Kaplan-Meier estimates calculated median time-to-conversion to MS (McDonald 2005 criteria) or clinically definite MS (CDMS; Poser criteria). Correlations between sNfL and MRI findings were assessed using Spearman's rank correlation coefficient ( r )., Results: Multivariable models indicated that high baseline sNfL was associated with the likelihood of converting to MS and inversely to time-to-conversion (HR = 1.3, 95% CI: 1.03-1.64; p  = 0.024). Significant additional factors affecting conversion to McDonald MS were on-study treatment (sc IFN β-1a/placebo; qw: HR = 0.59, 95% CI: 0.46-0.76; tiw: HR = 0.45, 95% CI: 0.34-0.59), classification of FCDE (monofocal/multifocal; HR = 0.69, 95% CI: 0.55-0.85), and most baseline imaging findings (T2 and T1 gadolinium-enhancing [Gd+] lesions; HR = 1.02, 95% CI: 1.01-1.03 and HR = 1.07, 95% CI: 1.03-1.11); all p  ⩽ 0.001. Conversion to CDMS showed similar results. At month 24, sNfL was strongly correlated with a mean number of combined unique active ( r  = 0.71), new T2 ( r  = 0.72), and new T1 Gd+ ( r  = 0.60) lesions; weak correlations were observed between sNfL and clinical outcomes for all treatment groups., Conclusion: Higher baseline sNfL was associated with an increased risk of MS conversion, a risk that was mitigated by treatment with sc IFN β-1a tiw., Trial Registration: ClinicalTrials.gov identifier: NCT00404352. Date registered: 28 November 2006., (© The Author(s), 2024.)

Cognitive impairment affects 34-65% of People with Multiple Sclerosis (PwMS), significantly impacting their quality of life. Clinicians routinely address cognitive deficits with in-clinic neuro-behavioural interventions, but accessibility issues exist. Given these challenges, coupled with the lifelong need for continuous assistance in PwMS, researchers have underscored the advantageous role of telerehabilitation in addressing these requirements. Nonetheless, the feasibility and efficacy of home-based cognitive remediation remain to be firmly established. In this narrative review, we aimed to investigate the feasibility and efficacy of digital telerehabilitation for cognition in PwMS. Thirteen relevant studies were identified and carefully assessed. Regarding the feasibility of cognitive telerehabilitation, evidence shows adherence rates are generally good, although, surprisingly, not all studies reported measures of compliance with the cognitive training explored. Considering the efficacy of rehabilitative techniques on cognitive performance in PwMS, findings are generally inconsistent, with only one study reporting uniformly positive results. A range of methodological limitations are reported as potential factors contributing to the variable results. Future research must address these challenges, as more rigorous studies are required to draw definitive conclusions regarding the efficacy of home-based cognitive remediation in PwMS. Researchers must prioritise identifying optimal intervention approaches and exploring the long-term effects of telerehabilitation.

Background: As of September 2022, there was no globally recommended set of core data elements for use in multiple sclerosis (MS) healthcare and research. As a result, data harmonisation across observational data sources and scientific collaboration is limited., Objectives: To define and agree upon a core dataset for real-world data (RWD) in MS from observational registries and cohorts., Methods: A three-phase process approach was conducted combining a landscaping exercise with dedicated discussions within a global multi-stakeholder task force consisting of 20 experts in the field of MS and its RWD to define the Core Dataset., Results: A core dataset for MS consisting of 44 variables in eight categories was translated into a data dictionary that has been published and disseminated for emerging and existing registries and cohorts to use. Categories include variables on demographics and comorbidities (patient-specific data), disease history, disease status, relapses, magnetic resonance imaging (MRI) and treatment data (disease-specific data)., Conclusion: The MS Data Alliance Core Dataset guides emerging registries in their dataset definitions and speeds up and supports harmonisation across registries and initiatives. The straight-forward, time-efficient process using a dedicated global multi-stakeholder task force has proven to be effective to define a concise core dataset., 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: T.P. has no other conflicts of interests to disclose than that she is funded by the Flemish Government under the ‘Special Research Fund (Bijzonder Onderzoeksfonds, BOF)’: BOF22OWB01. L.G. has no other conflicts of interests to disclose than that she is funded by the Flemish Government under the ‘Onderzoeksprogramma Artificiële Intelligentie Vlaanderen’. A.H. has no personal pecuniary interests to disclose, other than being an employee of the MS International Federation, which receives income from a range of corporate sponsors, recently including: Biogen, BristolMyersSquibb, Coloplast, Janssen, Merck, Viatris (formerly Mylan), Novartis, Roche and Sanofi – all of which is publicly disclosed. J.H. has received honoraria for serving on advisory boards for Biogen, Bristol-Myers-Squibb, Sanofi-Genzyme, Merck KGaA, Novartis, and Sandoz and speaker’s fees from Biogen, Novartis, Merck KGaA, Teva and Sanofi-Genzyme. He has served as P.I. for projects, or received unrestricted research support from, Biogen, Bristol-Myers-Squibb, Merck KGaA, Novartis, Roche and Sanofi-Genzyme. His MS research was funded by the Swedish Research Council and the Swedish Brain foundation. H.S. works for the Accelerated Cure Project for MS (ACP), which has received grants, collaboration funding, payments for use of assets, or in-kind contributions from the following companies: EMD Serono, Sanofi/Genzyme, Biogen, Genentech, AbbVie, Octave, GlycoMinds, Pfizer, MedDay, AstraZeneca, Teva, Mallinckrodt, MSDx, Regeneron Genetics Centre, BC Platforms, and Celgene. A.C.P. has also received funding from the Patient-Centred Outcomes Research Institute (PCORI) and the National MS Society (NMSS). A.S. is on the editorial board for Neurology and serves as a consultant for Gryphon Bio, LLC. She has received research funding from the Department of Defence, MS Society of Canada, National MS Society and the Consortium of MS Centres. A.S. works for the NARCOMS Registry which is supported by the Consortium of MS Centres (CMSC) and the Foundation of the CMSC. R.M. has received no personal funding from any sources, the UK MS Register is funded by the MS Society, and has received funding for specific projects from Novartis, Sanofi-Genzyme, and Merck KGaA. A.S. has no personal pecuniary interests to disclose, other than being the lead of the German MS-Registry, which receives funding from a range of public and corporate sponsors, recently including: The German Innovation Fund (G-BA), The German MS Trust, The German Retirement Insurance, German MS Society, Biogen, Celgene (BMS), Merck, Novartis, Roche and Sanofi. P.D. is a full-time employee and a shareholder of Biogen. E.H.M.-L. and K.P. have no conflicts of interest to disclose. The views expressed in this article are the personal views of the author(s) and may not be understood or quoted as being made on behalf of or reflecting the position of the EMA or one of its committees or working parties. 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, Alexion and Novartis. J.I.R. has received honoraria from Novartis as a scientific advisor. He has received travel grants and attended courses and conferences on behalf of Merck-Serono Argentina, Novartis, Roche, Sanofi-Genzyme, Biogen, Bayer and Teva. He receives unrestricted research funding from Novartis, Biogen, Roche, Merck and Sanofi. M.M. has served in scientific advisory board for Sanofi, Novartis, Merck, and has received honoraria for lecturing from Biogen, Merck, Novartis, Roche, Genzyme, Bristol-Myers Squibb. She received research support and support for congress participation from Biogen, Genzyme, Roche, Merck, Novartis. A.v.d.W. has received honoraria and unrestricted research funding from Novartis, Biogen, Roche, Merck and Sanofi. G.C. reports that he has received consulting and speaking fees from Novartis, Teva Pharmaceutical Industries Ltd, Teva Italia Srl, Sanofi-Genzyme Corporation, Genzyme Europe, Merck KGgA, Merck Serono SpA, Celgene Group, Biogen Idec, Biogen Italia Srl, F. Hoffman-La Roche, Roche SpA, Almirall SpA, Forward Pharma, Medday, and Excemed. L.M.P. has no conflict to report related to this work other than being the chair and the coordinator of the MSDA initiative, receiving funding from a range of corporate sponsors, including Biogen, Bristol-Myers Squibb, Janssen Pharmaceuticals, Merck, Novartis, and Roche. All other co-authors have no relevant competing interests to report. The authors declare that the funding sources did not influence the content of this work.

Background: Monoamine oxidase (MAO) inhibitors can interact with selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs). There is clinical interest surrounding use of ozanimod with SSRIs/SNRIs because the major metabolites of ozanimod are weak inhibitors of MAO-B in vitro., Objective: To evaluate the incidence of treatment-emergent adverse events (TEAEs) potentially related to serotonin accumulation (SA) during concomitant ozanimod and SSRI/SNRI use by performing analyses of data from an open-label, oral ozanimod 0.92 mg trial (DAYBREAK; NCT02576717)., Methods: SA narrow (serotonin syndrome, neuroleptic malignant syndrome, and hyperthermia malignant) and broad (terms potentially associated with SA) MedDRA v24.0 searches were performed using TEAE data from participants with relapsing multiple sclerosis who entered DAYBREAK from phase 3 studies (cutoff February 1, 2022). Incidences of TEAEs matching terms from each search were stratified by SSRI/SNRI use., Results: Of 2257 DAYBREAK participants, 274 (12.1%) used an SSRI/SNRI. No participants had TEAEs matching the SA narrow search terms. There was no significant difference in the percentage of participants with ⩾1 TEAE matching the SA broad search for those on versus off SSRIs/SNRIs (on: 12.4%, n = 34/274; off: 15.6%, n = 310/1982, nominal p = 0.1630)., Conclusion: MedDRA searches showed no increase in TEAEs potentially associated with SA with concomitant SSRI/SNRI and ozanimod use., 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: R.T.N. consulted for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Celltrion, Genentech, Genzyme, GW Therapeutics, Horizon Therapeutics, Janssen Pharmaceuticals, Lundbeck, NervGen, and TG Therapeutics. J.A.C. received personal compensation for consulting for Astoria, Bristol Myers Squibb, Convelo, EMD Serono, Find Therapeutics, INmune, and Sandoz, and serving as an editor of Multiple Sclerosis Journal. A.B.-O. received fees for advisory board participation and/or consulting from Accure, Atara Biotherapeutics, Biogen, BMS/Celgene/Receptos, GlaxoSmithKline, Gossamer Bio, Janssen/Actelion, MedImmune, Merck/EMD Serono, Novartis, Roche/Genentech, Sanofi-Genzyme and has received grant support to the University of Pennsylvania from Biogen Idec, Merck/EMD Serono, Novartis, and Roche/Genentech. G.C. reports compensation for consulting and/or speaking activities from Almirall, Biogen, Celgene, EXCEMED, Forward Pharma, Genzyme, Merck, Novartis, Roche, Sanofi, and Teva. K.W.S. reports consulting for Biogen, Celgene, Genzyme, Merck, Novartis, Ono Pharma, Roche, Synthon, and Teva. H.-P.H. reports personal fees for consulting, serving on steering committees, and speaking from Bayer Healthcare, Biogen, Celgene, GeNeuro, Genzyme, MedImmune, Merck, Novartis, Octapharma, Roche, Sanofi, and Teva. J.K.S., A.K., D.T., C.-Y.C., J.R., V.K., J.V.R., and D.S. are employees and/or shareholders of Bristol Myers Squibb. B.A.C.C. reports personal compensation for consulting for Alexion, Atara, Autobahn, Avotres, Biogen, Boston Pharma, EMD Serono, Gossamer Bio, Hexal/Sandoz, Horizon Therapeutics, Immunic AG, Neuron23, Novartis, Sanofi, Siemens, and TG Therapeutics and received research support from Genentech.

Multiple Sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system, causing increased vulnerability to infections and disability among young adults. Ever since the outbreak of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 infections, there have been concerns among people with MS (PwMS) about the potential interactions between various disease-modifying therapies and COVID-19. The COVID-19 in MS Global Data Sharing Initiative (GDSI) was initiated in 2020 with the aim of addressing these concerns. This paper focuses on the anonymisation and publicly releasing of a GDSI sub-dataset, comprising data entered by PwMS and clinicians using a fast data entry tool. The dataset includes information on demographics, comorbidities and hospital stay and COVID-19 symptoms of PwMS. The dataset can be used to perform different statistical analyses to improve our understanding of COVID-19 in MS. Furthermore, this dataset can also be used within the context of educational activities to educate different stakeholders on the complex data science topics that were used within the GDSI., (© 2024. The Author(s).)

Introduction: Multiple sclerosis (MS) is a leading cause of disability among young adults, but standard clinical scales may not accurately detect subtle changes in disability occurring between visits. This study aims to explore whether wearable device data provides more granular and objective measures of disability progression in MS., Methods: Remote Assessment of Disease and Relapse in Central Nervous System Disorders (RADAR-CNS) is a longitudinal multicenter observational study in which 400 MS patients have been recruited since June 2018 and prospectively followed up for 24 months. Monitoring of patients included standard clinical visits with assessment of disability through use of the Expanded Disability Status Scale (EDSS), 6-minute walking test (6MWT) and timed 25-foot walk (T25FW), as well as remote monitoring through the use of a Fitbit., Results: Among the 306 patients who completed the study (mean age, 45.6 years; females 67%), confirmed disability progression defined by the EDSS was observed in 74 patients, who had approximately 1392 fewer daily steps than patients without disability progression. However, the decrease in the number of steps experienced over time by patients with EDSS progression and stable patients was not significantly different. Similar results were obtained with disability progression defined by the 6MWT and the T25FW., Conclusion: The use of continuous activity monitoring holds great promise as a sensitive and ecologically valid measure of disability progression 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: S.V. and V.N. are employees of Janssen Research & Development LLC and may own equity in the company.

Direct oral anticoagulants (DOACs) represent the cornerstone therapy for cardioembolic events prevention in patients with nonvalvular atrial fibrillation (NVAF). In practice, the choice of one DOAC over another is guided by the decision-making process of the physician, which considers specific patient and drug characteristics. This study aimed to evaluate the clinical features and long-term outcomes of a real-world population treated with DOACs, where the use of the 4 different DOACs is quite equal. We conducted a retrospective observational, single-center, multidisciplinary study enrolling consecutive NVAF patients treated with one of the 4 DOACs. From an initial number of 753 patients, we excluded 72 patients because of loss to follow-up, at the end we enrolled 681:174 (23%) treated with dabigatran, 175 (23%) with apixaban, 190 (25%) with rivaroxaban, and 214 (29%) with edoxaban. Patients treated with apixaban were significantly older, more women represented (p <0.001), and with a higher cardioembolic and bleeding risk (p <0.001). Dabigatran was preferred in patients with liver failure (p = 0.008), whereas Apixaban and Edoxaban were chosen in chronic kidney disease (p = 0.002). At 3-year follow-up, 20 patients (2.7%) experienced a systemic thromboembolic event without significant differences in the 4 DOACs. In the same period, an International Society of Thrombosis and Hemostasis classification major bleeding event occurred in 26 patients (3.6%), more statistically correlated to edoxaban (6.1%) (p = 0.038). Thromboembolic events or major bleeding were higher in the edoxaban group (10%) compared with the others (p = 0.014). In our single-center real-world experience, the choice of the DOAC for a patient with NVAF was tailored to specific clinical features and drug pharmacokinetics of the patient. As a result, a small number of adverse events were observed., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Over the years, disease registers have been increasingly considered a source of reliable and valuable population studies. However, the validity and reliability of data from registers may be limited by missing data, selection bias or data quality not adequately evaluated or checked. This study reports the analysis of the consistency and completeness of the data in the Italian Multiple Sclerosis and Related Disorders Register., Methods: The Register collects, through a standardized Web-based Application, unique patients. Data are exported bimonthly and evaluated to assess the updating and completeness, and to check the quality and consistency. Eight clinical indicators are evaluated., Results: The Register counts 77,628 patients registered by 126 centres. The number of centres has increased over time, as their capacity to collect patients. The percentages of updated patients (with at least one visit in the last 24 months) have increased from 33% (enrolment period 2000-2015) to 60% (enrolment period 2016-2022). In the cohort of patients registered after 2016, there were ≥ 75% updated patients in 30% of the small centres (33), in 9% of the medium centres (11), and in all the large centres (2). Clinical indicators show significant improvement for the active patients, expanded disability status scale every 6 months or once every 12 months, visits every 6 months, first visit within 1 year and MRI every 12 months., Conclusions: Data from disease registers provide guidance for evidence-based health policies and research, so methods and strategies ensuring their quality and reliability are crucial and have several potential applications., (© 2023. The Author(s).)

Neurodegeneration is the main contributor to disability accumulation in multiple sclerosis. Previous studies in neuro-ophthalmology have revealed that neurodegeneration in multiple sclerosis also affects the neuro-retina. Optical coherence tomography has been used to measure thinning of retinal layers, which correlates with several other markers for axonal/neuronal loss in multiple sclerosis. However, the existing analytical tools have limitations in terms of sensitivity and do not provide topographical information. In this study, we aim to evaluate whether voxel-based morphometry can increase sensitivity in detecting neuroaxonal degeneration in the retina and offer topographical information. A total of 131 people with multiple sclerosis (41 clinically isolated syndrome, 53 relapsing-remitting and 37 progressive multiple sclerosis) and 50 healthy subjects were included. Only eyes with normal global peripapillary retinal nerve fibre layer thickness and no history of optic neuritis were considered. Voxel-based morphometry and voxel-wise statistical comparisons were performed on the following: (i) patients at different disease stages and 2) patients who experienced the first demyelination attack without subclinical optic neuritis, assessed by visual evoked potentials. Standard parameters failed to discern any differences; however, voxel-based morphometry-optical coherence tomography successfully detected focal macular atrophy of retinal nerve fibre layer and ganglion cell/inner plexiform layer, along with thickening of inner nuclear layer in patients who experienced the first demyelination attack (disease duration = 4.2 months). Notably, the atrophy pattern of the ganglion cell/inner plexiform layer was comparable across disease phenotypes. In contrast, the retinal nerve fibre layer atrophy spread from the optic nerve head to the fovea as the disease evolved towards the progressive phase. Furthermore, for patients who experienced the first neurological episode, the severity of retinal nerve fibre layer atrophy at entry could predict a second attack. Our results demonstrate that voxel-based morphometry-optical coherence tomography exhibits greater sensitivity than standard parameters in detecting focal retinal atrophy, even at clinical presentation, in eyes with no history of optic neuritis and with normal latency of visual evoked potentials. Thinning of the ganglion cell/inner plexiform layer primarily concentrated in nasal perifovea in all disease phenotypes, indicating selective vulnerability of retinal ganglion cells and their perifoveal axons. Conversely, the degree of retinal nerve fibre layer thinning seems to be related to the clinical course of multiple sclerosis. The findings suggest bidirectional neurodegeneration in the visual pathway. Voxel-based morphometry-optical coherence tomography shows potential as a valuable tool for monitoring neurodegeneration on a patient level and evaluating the efficacy of novel neuroprotective treatments., Competing Interests: The authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Objectives: Alemtuzumab demonstrated superior efficacy versus subcutaneous interferon (IFN) beta-1a in participants with relapsing-remitting multiple sclerosis in the 2-year CARE-MS I and II trials. Efficacy was maintained in the 4-year CARE-MS extension, during which alemtuzumab-treated participants ('alemtuzumab-only') could receive additional courses upon disease activity, and IFN-treated participants switched to alemtuzumab ('IFN-alemtuzumab'). Participants who completed the CARE-MS extension could enroll in the open-label TOPAZ study which assessed safety and efficacy for 5-7 years (11-13 years after alemtuzumab/IFN initiation)., Methods: Participants received additional alemtuzumab courses as needed. Assessments included adverse events (AEs; primary outcome), annualized relapse rate (ARR), 6-month confirmed disability worsening [CDW; ⩾1.0-point Expanded Disability Status Scale (EDSS) score increase or ⩾1.5 if baseline EDSS = 0], and 6-month confirmed disease improvement [CDI; >1.0-point EDSS decrease (baseline score ⩾2.0)]., Results: 43.5% of alemtuzumab-only participants from CARE-MS II and 54.2% from CARE-MS I received no additional alemtuzumab courses; 30.0% and 20.9%, respectively, received one additional course (the median). Incidences of AEs, including thyroid AEs and infections, declined over time. The safety profile of alemtuzumab was similar for participants who received zero, one, or two additional courses. For CARE-MS II participants, who had inadequate response to previous treatment, ARR remained low during Years 3-13 for the alemtuzumab-only [0.17; 95% confidence interval (CI) 0.15-0.20] and IFN-alemtuzumab (0.14; 0.11-0.17) groups. At Year 11, the proportions of participants who were either free from CDW or who had CDI were higher in the alemtuzumab-only group (58% and 49%, respectively) than in the IFN-alemtuzumab group (51% and 37%). For CARE-MS I participants, who were previously treatment-naïve, clinical outcomes remained improved, and no between-group differences were apparent., Conclusion: Safety risks associated with alemtuzumab treatment declined over time. Clinical benefits were maintained up to 11-13 years, and most participants did not require more than one additional course., Clinicaltrialsgov Identifiers: NCT00530348; NCT00548405; NCT00930553; NCT02255656., Competing Interests: AJC reports consulting fees, lecture fees, and institutional grant support from Sanofi up to September 2017. AA reports research and travel grants, honoraria for MS-expert advice and consulting, and/or speaking fees (Biogen, Merck Serono, Novartis, Roche, and Sanofi). AT reports consulting and/or speaking fees and grant/research support (Biogen, EMD Serono, Novartis, Roche, and Sanofi). BAS reports research grant support from AbbVie, Biogen, Bristol Myers Squibb, Greenwich Biosciences, Novartis, and Sanofi; and consulting and/or speaking fees from AbbVie, Alexion, Biogen, Bristol Myers Squibb, Cigna, EMD Serono, Janssen, Genentech, Greenwich Biosciences, Horizon, Novartis, Octave Bioscience, Roche, Sanofi, and TG Therapeutics. CP reports consulting and/or speaking fees, research, and travel grants (Actelion, Almirall, Biogen, Merck, Novartis, Roche, Sanofi, and Teva). COG reports speaking and/or consultancy fees (Bayer, Biogen, Merck Serono, Novartis, Roche, Sanofi, and Teva). GG reports compensation for serving as a consultant or speaker for or has received research support from AbbVie, Aslan, Atara Bio, Biogen, BMS-Celgene, GlaxoSmithKline, GW Pharma, Janssen/J&J, Japanese Tobacco, Jazz Pharmaceuticals, LifNano, Merck & Co, Merck KGaA/EMD Serono, Moderna, Novartis, Sanofi, Roche/Genentech, and Teva in the past 5 years. GC reports consulting fees (Actelion, Bayer Schering, Merck Serono, Novartis, Sanofi, and Teva) and lecture fees (Bayer Schering, Biogen Dompé, Merck Serono, Novartis, Sanofi, Serono, Symposia International Foundation, and Teva). MS Freedman reports honoraria/consulting fees (Alexion/AstraZeneca, Atara Biotherapeutics, Bayer HealthCare, Beigene, BMS/Celgene, EMD Inc., Hoffman La-Roche, Janssen/J&J, Merck Serono, Quanterix, Novartis, Sanofi, and Teva Canada Innovation); serving as a member of an advisory board, board of directors, or other similar group (Alexion, Atara Biotherapeutics, Bayer HealthCare, Beigene, BMS/Celgene, Celestra, Hoffman La-Roche, Janssen/J&J, McKesson, Merck Serono, Novartis and Sanofi); participation in the speakers bureau (EMD Serono and Sanofi); and grant/research support (Sanofi). TZ reports consulting and/or speaking fees (Almirall, Bayer, Biogen, BMS, Celgene, Merck, Novartis, Roche, Sanofi, Viatris and Teva) and grant/research support (Biogen, BMS, Novartis, Roche, Sanofi, and Teva). DS, AMR, ATW, and MC are employees of Sanofi and may hold shares and/or stock options in the company. XM reports speaking honoraria and travel expenses for scientific meetings, being a steering committee member of clinical trials, or participating in advisory boards of clinical trials in the past 3 years (Actelion, Alexion, Bayer, Biogen, Celgene, EMD Serono, EXCEMED, MedDay, Merck, MSIF, NervGen, NMSS, Novartis, Roche, Sanofi, Teva Pharmaceutical, and TG Therapeutics)., (© The Author(s), 2023.)

Objectives: Neurofilament light chain (NfL) has emerged as a promising biomarker for detecting and monitoring axonal injury. Until recently, NfL could only be reliably measured in cerebrospinal fluid, but digital single molecule array (Simoa) technology has enabled its precise measurement in blood samples where it is typically 50-100 times less abundant. We report development and multi-center validation of a novel fully automated digital immunoassay for NfL in serum for informing axonal injury status., Methods: A 45-min immunoassay for serum NfL was developed for use on an automated digital analyzer based on Simoa technology. The analytical performance (sensitivity, precision, reproducibility, linearity, sample type) was characterized and then cross validated across 17 laboratories in 10 countries. Analytical performance for clinical NfL measurement was examined in individual patients with relapsing remitting multiple sclerosis (RRMS) after 3 months of disease modifying treatment (DMT) with fingolimod., Results: The assay exhibited a lower limit of detection (LLoD) of 0.05 ng/L, a lower limit of quantification (LLoQ) of 0.8 ng/L, and between-laboratory imprecision <10 % across 17 validation sites. All tested samples had measurable NfL concentrations well above the LLoQ. In matched pre-post treatment samples, decreases in NfL were observed in 26/29 RRMS patients three months after DMT start, with significant decreases detected in a majority of patients., Conclusions: The sensitivity characteristics and reproducible performance across laboratories combined with full automation make this assay suitable for clinical use for NfL assessment, monitoring in individual patients, and cross-comparisons of results across multiple sites., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

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.

Hepatocyte nuclear factor 4 α (HNF4α), a transcription factor (TF) essential for embryonic development, has been recently shown to regulate the expression of inflammatory genes. To characterize HNF4a function in immunity, we measured the effect of HNF4α antagonists on immune cell responses in vitro and in vivo. HNF4α blockade reduced immune activation in vitro and disease severity in the experimental model of multiple sclerosis (MS). Network biology studies of human immune transcriptomes unraveled HNF4α together with SP1 and c-myc as master TF regulating differential expression at all MS stages. TF expression was boosted by immune cell activation, regulated by environmental MS risk factors and higher in MS immune cells compared to controls. Administration of compounds targeting TF expression or function demonstrated non-synergic, interdependent transcriptional control of CNS autoimmunity in vitro and in vivo. Collectively, we identified a coregulatory transcriptional network sustaining neuroinflammation and representing an attractive therapeutic target for MS and other inflammatory disorders., Competing Interests: Declaration of competing interest The authors declare no competing interests related to the manuscript., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system. Monoclonal antibodies (mAbs) have shown efficacy in reducing MS relapse rates, disease progression, and brain lesion activity., Areas Covered: This article reviews the literature on the use of mAbs for the treatment of MS, including their mechanisms of action, clinical trial data, safety profiles, and long-term outcomes. The review focuses on the three main categories of mAbs used in MS: alemtuzumab, natalizumab, and anti-CD20 drugs. A literature search was conducted using relevant keywords and guidelines and reports from regulatory agencies were reviewed. The search covered studies published from inception to 31 December 202231 December 2022. The article also discusses the potential risks and benefits of these therapies, including their effects on infection rates, malignancies, and vaccination efficacy., Expert Opinion: Monoclonal antibodies have revolutionized the treatment of MS, but safety concerns must be considered, particularly with regards to infection rates, malignancy risk, and vaccination efficacy. Clinicians must weigh the potential benefits and risks of mAbs on an individual patient basis, taking into account factors such as age, disease severity, and comorbidities. Ongoing monitoring and surveillance are essential to ensure the long-term safety and effectiveness of monoclonal antibody therapies in MS.

Introduction: Different disease-modifying therapies (DMTs) have been developed to slow down the progression of pediatric multiple sclerosis (MS). Teriflunomide is one such DMT that has recently been approved for use in pediatric MS in the European Union., Areas Covered: The article provides an introduction to the mechanism of action of teriflunomide, reviews the clinical trials conducted on the safety and efficacy of the drug, and the optimal dosing and monitoring strategies., Expert Opinion: Teriflunomide is an oral medication that has shown promise in improving outcomes for pediatric MS patients, including reduced relapse rates and improved quality of life. However, more research is needed to determine its long-term safety in pediatric patients. As MS often presents with an aggressive course in children, the choice of disease-modifying treatment should be carefully evaluated, with a preference for second-line therapy. Despite the potential benefits of teriflunomide, changes in clinical practice may be hindered by factors such as cost and physician familiarity with alternative treatments. Longer-term studies and biomarker identification are areas for improvement, but the future of research in this area holds promise for the continued development and refinement of disease-modifying therapies and more personalized, targeted treatments for pediatric MS patients.

The aim of this study was to investigate the feasibility of automatically assessing the 2-Minute Walk Distance (2MWD) for monitoring people with multiple sclerosis (pwMS). For 154 pwMS, MS-related clinical outcomes as well as the 2MWDs as evaluated by clinicians and derived from accelerometer data were collected from a total of 323 periodic clinical visits. Accelerometer data from a wearable device during 100 home-based 2MWD assessments were also acquired. The error in estimating the 2MWD was validated for walk tests performed at hospital, and then the correlation (r) between clinical outcomes and home-based 2MWD assessments was evaluated. Robust performance in estimating the 2MWD from the wearable device was obtained, yielding an error of less than 10% in about two-thirds of clinical visits. Correlation analysis showed that there is a strong association between the actual and the estimated 2MWD obtained either at hospital (r = 0.71) or at home (r = 0.58). Furthermore, the estimated 2MWD exhibits moderate-to-strong correlation with various MS-related clinical outcomes, including disability and fatigue severity scores. Automatic assessment of the 2MWD in pwMS is feasible with the usage of a consumer-friendly wearable device in clinical and non-clinical settings. Wearable devices can also enhance the assessment of MS-related clinical outcomes.

Aging accounts for increased risk and dismal outcome of ischemic stroke. Here, we investigated the impact of age-related changes in the immune system on stroke. Upon experimental stroke, compared with young mice, aged mice had increased neutrophil clogging of the ischemic brain microcirculation, leading to worse no-reflow and outcomes. Aged mice showed an enhanced granulopoietic response to stroke that led to the accumulation of CD101 + CD62L lo mature and CD177 hi CD101 lo CD62L lo and CD177 lo CD101 lo CD62L hi immature atypical neutrophils in the blood, endowed with increased oxidative stress, phagocytosis and procoagulant features. Production of CXCL3 by CD62L lo neutrophils of the aged had a key role in the development and pathogenicity of aging-associated neutrophils. Hematopoietic stem cell rejuvenation reverted aging-associated neutropoiesis and improved stroke outcome. In elderly patients with ischemic stroke, single-cell proteome profile of blood leukocytes identified CD62L lo neutrophil subsets associated with worse reperfusion and outcome. Our results unveil how stroke in aging leads to a dysregulated emergency granulopoiesis impacting neurological outcome., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Introduction: Visual evoked potentials (VEPs) are a non-invasive technique routinely used in clinical and preclinical practice. Discussion about inclusion of VEPs in McDonald criteria, used for Multiple Sclerosis (MS) diagnosis, increased the importance of VEP in MS preclinical models. While the interpretation of the N1 peak is recognized, less is known about the first and second positive VEP peaks, P1 and P2, and the implicit time of the different segments. Our hypothesis is that P2 latency delay describes intracortical neurophysiological dysfunction from the visual cortex to the other cortical areas., Methods: In this work, we analyzed VEP traces that were included in our two recently published papers on Experimental Autoimmune Encephalomyelitis (EAE) mouse model. Compared with these previous publications other VEP peaks, P1 and P2, and the implicit time of components P1-N1, N1-P2 and P1-P2, were analyzed in blind., Results: Latencies of P2, P1-P2, P1-N1 and N1-P2 were increased in all EAE mice, including group without N1 latency change delay at early time points. In particular, at 7 dpi the P2 latency delay change was significantly higher compared with N1 latency change delay. Moreover, new analysis of these VEP components under the influence of neurostimulation revealed a decrease in P2 delay in stimulated animals., Discussion: P2 latency delay, P1-P2, P1-N1, and N1-P2 latency changes which reflect intracortical dysfunction, were consistently detected across all EAE groups before N1 change. Results underline the importance of analyzing all VEP components for a complete overview of the neurophysiological visual pathway dysfunction and treatment efficacy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Marenna, Rossi, Huang, Castoldi, Comi and Leocani.)

Objective: The aim of this study was to evaluate the association between changes in the autonomic control of cardiorespiratory system induced by walk tests and outcome measures in people with Multiple Sclerosis (pwMS). Methods: Electrocardiogram (ECG) recordings of 148 people with Relapsing-Remitting MS (RRMS) and 58 with Secondary Progressive MS (SPMS) were acquired using a wearable device before, during, and after walk test performance from a total of 386 periodical clinical visits. A subset of 90 participants repeated a walk test at home. Various MS-related symptoms, including fatigue, disability, and walking capacity were evaluated at each clinical visit, while heart rate variability (HRV) and ECG-derived respiration (EDR) were analyzed to assess autonomic nervous system (ANS) function. Statistical tests were conducted to assess differences in ANS control between pwMS grouped based on the phenotype or the severity of MS-related symptoms. Furthermore, correlation coefficients ( r ) were calculated to assess the association between the most significant ANS parameters and MS-outcome measures. Results: People with SPMS, compared to RRMS, reached higher mean heart rate (HRM) values during walk test, and larger sympathovagal balance after test performance. Furthermore, pwMS who were able to adjust their HRM and ventilatory values, such as respiratory rate and standard deviation of the ECG-derived respiration, were associated with better clinical outcomes. Correlation analyses showed weak associations between ANS parameters and clinical outcomes when the Multiple Sclerosis phenotype is not taken into account. Blunted autonomic response, in particular HRM reactivity, was related with worse walking capacity, yielding r = 0.36 r = 0.29 (RRMS) and r > 0.5 (SPMS). A positive strong correlation r > 0.7 r > 0.65 between cardiorespiratory parameters derived at hospital and at home was also found. Conclusion: Autonomic function, as measured by HRV, differs according to MS phenotype. Autonomic response to walk tests may be useful for assessing clinical outcomes, mainly in the progressive stage of MS. Participants with larger changes in HRM are able to walk longer distance, while reduced ventilatory function during and after walk test performance is associated with higher fatigue and disability severity scores. Monitoring of disorder severity could also be feasible using ECG-derived cardiac and respiratory parameters recorded with a wearable device at home., Competing Interests: MB has received speaker honoraria from Novartis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kontaxis, Laporta, Garcia, Guerrero, Zabalza, Matteo, Lucia, Simblett, Weyer, Hotopf, Narayan, Rashid, Folarin, Dobson, Buron, Leocani, Cummins, Vairavan, Costa, Magyari, Sørensen, Nos, Bailón, Comi and the RADAR-CNS Consortium.)

Background: Sleep disorders are common in patients with multiple sclerosis and have a bidirectional interplay with fatigue and depression., Objective: To evaluate the effect of treatment with oral dimethyl fumarate on the quality of sleep in relapsing-remitting multiple sclerosis., Methods: This was a multicentre observational study with 223 relapsing-remitting multiple sclerosis subjects starting treatment with dimethyl fumarate ( n =177) or beta interferon ( n =46). All patients underwent subjective (Pittsburgh Sleep Quality Index) and objective (wearable tracker) measurements of quality of sleep. Fatigue, depression, and quality of life were also investigated and physical activity was monitored., Results: Patients treated with dimethyl fumarate had significant improvement in the quality of sleep as measured with the Pittsburgh Sleep Quality Index ( p <0.001). At all-time points, no significant changes in Pittsburgh Sleep Quality Index score were observed in the interferon group. Total and deep sleep measured by wearable tracker decreased at week 12 with both treatments, then remained stable for the total study duration. Depression significantly improved in patients treated with dimethyl fumarate. No significant changes were observed in mobility, fatigue and quality of life., Conclusion: In patients with relapsing-remitting multiple sclerosis, the treatment with dimethyl fumarate was associated with improvements in patient-reported quality of sleep. Further randomised clinical trials are needed to confirm the benefits of long-term treatment with dimethyl fumarate., (© The Author(s), 2023.)

A personalized approach is strongly advocated for treatment selection in Multiple Sclerosis patients due to the high number of available drugs. Machine learning methods proved to be valuable tools in the context of precision medicine. In the present work, we applied machine learning methods to identify a combined clinical and genetic signature of response to fingolimod that could support the prediction of drug response. Two cohorts of fingolimod-treated patients from Italy and France were enrolled and divided into training, validation, and test set. Random forest training and robust feature selection were performed in the first two sets respectively, and the independent test set was used to evaluate model performance. A genetic-only model and a combined clinical-genetic model were obtained. Overall, 381 patients were classified according to the NEDA-3 criterion at 2 years; we identified a genetic model, including 123 SNPs, that was able to predict fingolimod response with an AUROC= 0.65 in the independent test set. When combining clinical data, the model accuracy increased to an AUROC= 0.71. Integrating clinical and genetic data by means of machine learning methods can help in the prediction of response to fingolimod, even though further studies are required to definitely extend this approach to clinical applications.

Background: White matter (WM) lesions and brain atrophy are present early in multiple sclerosis (MS). However, their spatio-temporal relationship remains unclear., Methods: Yearly magnetic resonance images were analysed in 387 patients with a first clinical demyelinating event (FCDE) from the 5-year REFLEXION study. Patients received early (from baseline; N = 258; ET) or delayed treatment (from month-24; N = 129; DT) with subcutaneous interferon beta-1a. FSL-SIENA/VIENA were used to provide yearly percentage volume change of brain (PBVC) and ventricles (PVVC). Yearly total lesion volume change (TLVC) was determined by a semi-automated method. Using linear mixed models and voxel-wise analyses, we firstly investigated the overall relationship between TLVC and PBVC and between TLVC and PVVC in the same follow-up period. Analyses were then separately performed for: the untreated period of DT patients (first two years), the first year of treatment (year 1 for ET and year 3 for DT), and a period where patients had received at least 1 year of treatment (stable treatment; ET: years 2, 3, 4, and 5; DT: years 4 and 5)., Results: Whole brain: across the whole study period, lower TLVC was related to faster atrophy (PBVC: B = 0.046, SE = 0.013, p < 0.001; PVVC: B = -0.466, SE = 0.118, p < 0.001). Within the untreated period of DT patients, lower TLVC was related to faster atrophy (PBVC: B = 0.072, SE = 0.029, p = 0.013; PVVC: B = -0.917, SE = 0.306, p = 0.003). A similar relationship was found within the first year of treatment of ET patients (PBVC: B = 0.081, SE = 0.027, p = 0.003; PVVC: B = -1.08, SE = 0.284, p < 0.001), consistent with resolving oedema and pseudo-atrophy. Voxel-wise: overall, higher TLVC was related to faster ventricular enlargement. Lower TLVC was related to faster widespread atrophy in year 1 in both ET (first year of treatment) and DT (untreated) patients. In the second untreated year of DT patients and within the stable treatment period of ET patients (year 4), faster periventricular and occipital lobe atrophy was associated with higher TLVC., Conclusions: WM lesion changes and atrophy occurred simultaneously in early MS. Spatio-temporal correspondence of these two processes involved mostly the periventricular area. Within the first year of the study, in both treatment groups, faster atrophy was linked to lower lesion volume changes, consistent with higher shrinking and disappearing lesion activity. This might reflect the pseudo-atrophy phenomenon that is probably related to the therapy driven (only in ET patients, as they received treatment from baseline) and "natural" (both ET and DT patients entered the study after a FCDE) resolution of oedema. In an untreated period and later on during stable treatment, (real) atrophy was related to higher lesion volume changes, consistent with increased new and enlarging lesion activity., Competing Interests: Declaration of Competing Interest RMM has received research support from Merck. IB has received research support from Merck, Novartis, Teva, and the Dutch MS Research Foundation. BMJU reports research support and/or consultancy fees from Biogen, Merck, Novartis, Roche, Sanofi, Teva, and Immunic Therapeutics. LK's institution (University Hospital Basel) has received the following exclusively for research support: Steering committee, advisory board, and consultancy fees from Actelion (Janssen/J&J), Bayer, Biogen, BMS, Janssen (J&J), Merck, Novartis, Roche, Sanofi, Santhera, and TG Therapeutics; speaker fees from Bayer, Biogen, Merck, Novartis, Roche, and Sanofi; support of educational activities from Allergan, Bayer, Biogen, CSL Behring, Desitin, Merck, Novartis, Roche, Pfizer, Sanofi, Shire, and Teva; license fees for Neurostatus products; and grants from Bayer, Biogen, European Union, InnoSwiss, Merck, Novartis, Roche, Swiss MS Society, and Swiss National Research Foundation. MSF has received honoraria or consultation fees from Alexion, Atara Biotherapeutics, Bayer, BeiGene, BMS (Celgene), EMD Serono, Janssen (J&J), Merck, Novartis, PendoPharm, Roche, and Sanofi; has been a member of a company advisory board, board of directors, or other similar group for Alexion, Atara Biotherapeutics, Bayer, BeiGene, BMS (Celgene), Clene Nanomedicine, Janssen (J&J), McKesson, Merck, Novartis, Roche, and Sanofi; has participated in a company sponsored speaker’s bureau for EMD Serono and Sanofi; and has been in receipt of research or educational grants from Sanofi. GC has received consulting fees from Bayer, Biogen, Merck, Novartis, Receptos, Roche, Sanofi, and Teva; lecture fees from Bayer, Biogen, Merck, Novartis, Sanofi, Serono Symposia International Foundation, and Teva; and trial grant support from Bayer, Biogen, Merck, Novartis, Receptos, Roche, Sanofi, and Teva. DJ is an employee of Merck Serono Ltd, Feltham, UK (an affiliate of Merck KGaA, Darmstadt, Germany). FB is supported by the NIHR Biomedical Research Centre at UCLH and is a consultant to Biogen, Combinostics, IXICO, Merck, and Roche. NDeS is a consultant for Biogen, Merck, Novartis, Sanofi, Roche, and Teva; has grants or grants pending from FISM and Novartis, is on the speakers’ bureaus of Biogen, Merck, Novartis, Roche, Sanofi, and Teva; and has received travel funds from Merck, Novartis, Roche, Sanofi, and Teva. HV has received research support from Merck, Novartis, Pfizer, and Teva; consulting fees from Merck; and speaker honoraria from Novartis. All funds were paid to his institution. GG, RAvS, JWRT, and MB report no disclosures., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Innovative pro-regenerative treatment strategies for progressive multiple sclerosis (PMS), combining neuroprotection and immunomodulation, represent an unmet need. Neural precursor cells (NPCs) transplanted in animal models of multiple sclerosis have shown preclinical efficacy by promoting neuroprotection and remyelination by releasing molecules sustaining trophic support and neural plasticity. Here we present the results of STEMS, a prospective, therapeutic exploratory, non-randomized, open-label, single-dose-finding phase 1 clinical trial ( NCT03269071 , EudraCT 2016-002020-86), performed at San Raffaele Hospital in Milan, Italy, evaluating the feasibility, safety and tolerability of intrathecally transplanted human fetal NPCs (hfNPCs) in 12 patients with PMS (with evidence of disease progression, Expanded Disability Status Scale ≥6.5, age 18-55 years, disease duration 2-20 years, without any alternative approved therapy). The safety primary outcome was reached, with no severe adverse reactions related to hfNPCs at 2-year follow-up, clearly demonstrating that hfNPC therapy in PMS is feasible, safe and tolerable. Exploratory secondary analyses showed a lower rate of brain atrophy in patients receiving the highest dosage of hfNPCs and increased cerebrospinal fluid levels of anti-inflammatory and neuroprotective molecules. Although preliminary, these results support the rationale and value of future clinical studies with the highest dose of hfNPCs in a larger cohort of patients., (© 2023. The Author(s).)

The anterior optic pathway is one of the preferential sites of involvement in CNS inflammatory demyelinating diseases, such as multiple sclerosis and neuromyelitis optica, with optic neuritis being a common presenting symptom. What is more, optic nerve involvement in these diseases is often subclinical, with optical coherence tomography demonstrating progressive neuroretinal thinning in the absence of optic neuritis. The pathological substrate for these findings is poorly understood and requires investigation. We had access to post-mortem tissue samples of optic nerves, chiasms and tracts from 29 multiple sclerosis (mean age 59.5, range 25-84 years; 73 samples), six neuromyelitis optica spectrum disorders (mean age 56, range 18-84 years; 22 samples), six acute disseminated encephalomyelitis (mean age 25, range 10-39 years; 12 samples) cases and five non-neurological controls (mean age 55.2, range 44-64 years; 16 samples). Formalin-fixed paraffin-embedded samples were immunolabelled for myelin, inflammation (microglial/macrophage, T- and B-cells, complement), acute axonal injury and astrocytes. We assessed the extent and distribution of these markers along the anterior optic pathway for each case in all compartments (i.e. parenchymal, perivascular and meningeal), where relevant. Demyelinated plaques were classified as active based on established criteria. In multiple sclerosis, demyelination was present in 82.8% of cases, of which 75% showed activity. Microglia/macrophage and lymphocyte inflammation were frequently found both in the parenchymal and meningeal compartments in non-demyelinated regions. Acute axonal injury affected 41.4% of cases and correlated with extent of inflammatory activity in each compartment, even in cases that died at advanced age with over 20 years of disease duration. An antero-posterior gradient of anterior optic pathway involvement was observed with optic nerves being most severely affected by inflammation and acute axonal injury compared with the optic tract, where a higher proportion of remyelinated plaques were seen. In neuromyelitis optica spectrum disorder, cases with a history of optic neuritis had extensive demyelination and lost aquaporin-4 reactivity. In contrast, those without prior optic neuritis did not have demyelination but rather diffuse microglial/macrophage, T- and B-lymphocyte inflammation in both parenchymal and meningeal compartments, and acute axonal injury was present in 75% of cases. Acute demyelinating encephalomyelitis featured intense inflammation, and perivenular demyelination in 33% of cases. Our findings suggest that chronic inflammation is frequent and leads to neurodegeneration in multiple sclerosis and neuromyelitis optica, regardless of disease stage. The chronic inflammation and subsequent neurodegeneration occurring along the optic pathway broadens the plaque-centred view of these diseases and partly explains the progressive neuroretinal changes observed in optic coherence tomography studies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

While the role of common genetic variants in multiple sclerosis (MS) has been elucidated in large genome-wide association studies, the contribution of rare variants to the disease remains unclear. Herein, a whole-genome sequencing study in four affected and four healthy relatives of a consanguineous Italian family identified a novel missense c.1801T > C (p.S601P) variant in the GRAMD1B gene that is shared within MS cases and resides under a linkage peak (LOD: 2.194). Sequencing GRAMD1B in 91 familial MS cases revealed two additional rare missense and two splice-site variants, two of which (rs755488531 and rs769527838) were not found in 1000 Italian healthy controls. Functional studies demonstrated that GRAMD1B , a gene with unknown function in the central nervous system (CNS), is expressed by several cell types, including astrocytes, microglia and neurons as well as by peripheral monocytes and macrophages. Notably, GRAMD1B was downregulated in vessel-associated astrocytes of active MS lesions in autopsied brains and by inflammatory stimuli in peripheral monocytes, suggesting a possible role in the modulation of inflammatory response and disease pathophysiology.

What Is This Summary About?: This is a summary of an article originally published in the journal Advances in Therapy . Cladribine tablets are approved for treating people with relapsing multiple sclerosis (shortened to MS). People with MS take cladribine tablets for 2 periods of 4 to 5 days per year. This analysis looks at the results from 2 studies called the CLARITY and CLARITY Extension studies. These studies looked at what effect a 2-year course of treatment with cladribine tablets had on disability over 5 years in people with MS., How Was the Analysis Carried Out?: In this analysis, researchers measured disability worsening at regular intervals during the 2-year treatment period in the CLARITY study and thereafter in the 2-year CLARITY Extension study. As many patients had a bridging interval between CLARITY and CLARITY extension, the researchers were able to assess disability over a 5-year timeframe., What Were the Results?: When measurements were taken at Year 5 of the study, disability remained stable in more than half of participants. Over the 5-year period, 70% of participants did not experience persistent disease worsening that lasted more than 6 months., What Do the Results Mean?: Researchers concluded that a 2-year course of cladribine tablets may provide long-term benefits on disability for up to 5 years. Clinical Trial Registration : NCT00213135 (ClinicalTrials.gov) Clinical Trial Registration : NCT00641537 (ClinicalTrials.gov).

Background: Definitions for reliable identification of transition from relapsing-remitting multiple sclerosis (MS) to secondary progressive (SP)MS in clinical cohorts are not available., Objectives: To compare diagnostic performances of two different data-driven SPMS definitions., Methods: Data-driven SPMS definitions based on a version of Lorscheider's algorithm (DDA) and on the EXPAND trial inclusion criteria were compared, using the neurologist's definition (ND) as gold standard, in terms of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), Akaike information criterion (AIC) and area under the curve (AUC)., Results: A cohort of 10,240 MS patients with ⩾5 years of follow-up was extracted from the Italian MS Registry; 880 (8.5%) patients were classified as SPMS according to the neurologist definition, 1806 (17.6%) applying the DDA and 1134 (11.0%) with the EXPAND definition. The DDA showed greater discrimination power (AUC: 0.8 vs 0.6) and a higher sensitivity (77.1% vs 38.0%) than the EXPAND definition, with similar specificity (88.0% vs 91.5%). PPV and NPV were higher using the DDA than considering EXPAND definition (37.5% vs 29.5%; 97.6% vs 94.0%)., Conclusion: Data-driven definitions demonstrated greater ability to capture SP transition than neurologist's definition and the global accuracy of DDA seems to be higher than the EXPAND definition.

Background and Purpose: Clinical outcomes of multiple sclerosis (MS) patients affected by coronavirus disease 2019 (COVID-19) have been thoroughly investigated, but a further analysis on main signs and symptoms and their risk factors still needs attention. The objective of this study was to group together and describe based on similarity the most common signs and symptoms of COVID-19 in MS patients and identify all factors associated with their manifestation., Method: Logistic and linear regression models were run to recognize factors associated with each pooled group of symptoms and their total number., Results: From March 2020 to November 2021, data were collected from 1354 MS patients with confirmed infection of COVID-19. Ageusia and anosmia was less frequent in older people (odds ratio [OR] 0.98; p = 0.005) and more in smoker patients (OR 1.39; p = 0.049). Smoke was also associated with an incremental number of symptoms (OR 1.24; p = 0.031), substance abuse (drugs or alcohol), conjunctivitis and rash (OR 5.20; p = 0.042) and the presence of at least one comorbidity with shortness of breath, tachycardia or chest pain (OR 1.24; p = 0.008). Some disease-modifying therapies were associated with greater frequencies of certain COVID-19 symptoms (association between anti-CD20 therapies and increment in the number of concomitant symptoms: OR 1.29; p = 0.05). Differences in frequencies between the three waves were found for flu-like symptoms (G1, p = 0.024), joint or muscle pain (G2, p = 0.013) and ageusia and anosmia (G5, p &lt; 0.001). All cases should be referred to variants up to Delta., Conclusion: Several factors along with the choice of specific therapeutic approaches might have a different impact on the occurrence of some COVID-19 symptoms., (© 2022 European Academy of Neurology.)

Background: Changes in lifestyle, finances and work status during COVID-19 lockdowns may have led to biopsychosocial changes in people with pre-existing vulnerabilities such as Major Depressive Disorders (MDDs) and Multiple Sclerosis (MS)., Methods: Data were collected as a part of the RADAR-CNS (Remote Assessment of Disease and Relapse-Central Nervous System) program. We analyzed the following data from long-term participants in a decentralized multinational study: symptoms of depression, heart rate (HR) during the day and night; social activity; sedentary state, steps and physical activity of varying intensity. Linear mixed-effects regression analyses with repeated measures were fitted to assess the changes among three time periods (pre, during and post-lockdown) across the groups, adjusting for depression severity before the pandemic and gender., Results: Participants with MDDs (N = 255) and MS (N = 214) were included in the analyses. Overall, depressive symptoms remained stable across the three periods in both groups. A lower mean HR and HR variation were observed between pre and during lockdown during the day for MDDs and during the night for MS. HR variation during rest periods also decreased between pre- and post-lockdown in both clinical conditions. We observed a reduction in physical activity for MDDs and MS upon the introduction of lockdowns. The group with MDDs exhibited a net increase in social interaction via social network apps over the three periods., Conclusions: Behavioral responses to the lockdown measured by social activity, physical activity and HR may reflect changes in stress in people with MDDs and MS. Remote technology monitoring might promptly activate an early warning of physical and social alterations in these stressful situations. Future studies must explore how stress does or does not impact depression severity.

Background and Objectives: Multiple sclerosis (MS) is a progressive inflammatory and neurodegenerative disease of the central nervous system affecting over 2.5 million people globally. In-clinic six-minute walk test (6MWT) is a widely used objective measure to evaluate the progression of MS. Yet, it has limitations such as the need for a clinical visit and a proper walkway. The widespread use of wearable devices capable of depicting patients' activity profiles has the potential to assess the level of MS-induced disability in free-living conditions., Methods: In this work, we extracted 96 features in different temporal granularities (from minute-level to day-level) from wearable data and explored their utility in estimating 6MWT scores in a European (Italy, Spain, and Denmark) MS cohort of 337 participants over an average of 10 months' duration. We combined these features with participants' demographics using three regression models including elastic net, gradient boosted trees and random forest. In addition, we quantified the individual feature's contribution using feature importance in these regression models, linear mixed-effects models, generalized estimating equations, and correlation-based feature selection (CFS)., Results: The results showed promising estimation performance with R 2 of 0.30, which was derived using random forest after CFS. This model was able to distinguish the participants with low disability from those with high disability. Furthermore, we observed that the minute-level (≤ 8 minutes) step count, particularly those capturing the upper end of the step count distribution, had a stronger association with 6MWT. The use of a walking aid was indicative of ambulatory function measured through 6MWT., Conclusions: This study demonstrates the utility of wearables devices in assessing ambulatory impairments in people with MS in free-living conditions and provides a basis for future investigation into the clinical relevance., Competing Interests: Declaration of Competing Interest SV and VAN are employees of Janssen Research and Development LLC. MM has served in scientific advisory board for Sanofi, Novartis, Merck, and has received honoraria for lecturing from Biogen, Merck, Novartis, Roche, Genzyme, Bristol Myers Squibb., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Natalizumab (NAT) has a strong impact on disease activity of aggressive pediatric multiple sclerosis (MS), with no difference in safety profile compared to adult MS. However, available data are limited by short follow-up. Our aim was to report long-term follow-up data (up to 11 years) of a large Italian pediatric MS cohort treated with NAT., Materials and Methods: We retrospectively collected data of pediatric MS patients treated with NAT included in a previous study and prospectively followed in Italian MS centers. We compared disease activity pre, during, and post-NAT and we performed survival analyses of time to evidence of disease activity (EDA) during NAT, time to reach EDA post-NAT, and time to NAT discontinuation., Results: Ninety-two patients were included from 19 MS centers in Italy. At NAT initiation, cohort's characteristics were as follows: 55 females; 14.7 ± 2.4 (mean ± SD) years of age; 34 naïve to disease modifying therapies; 1-year pre-NAT annualized relapse rate (ARR): 2.2 ± 1.2; EDSS (median [IQR]): 2.5 [2.0-3.0]; gadolinium-enhancing lesions: 2 [1-5]; 41 JCV positives. During NAT treatment (61.9 ± 35.2 mean infusions), ARR lowered to 0.08 ± 0.23 (p < 0.001), EDSS score to 1.5 [1.0-2.5] at last infusion (p < 0.001), and 51% patients had EDA (21% after 6 months of rebaseline). No serious adverse events were reported. Forty-nine patients discontinued NAT, mainly due to PML concern; the majority (29/49) had disease reactivation in the subsequent 12 months, of which three with a clinical rebound., Conclusion: NAT treatment maintains its high efficacy for a long time in pediatric MS patients, with no new safety issues., (© 2022. Fondazione Società Italiana di Neurologia.)