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Background: Disability progression is a key milestone in the disease evolution of people with multiple sclerosis (PwMS). Prediction models of the probability of disability progression have not yet reached the level of trust needed to be adopted in the clinic. A common benchmark to assess model development in multiple sclerosis is also currently lacking., Methods: Data of adult PwMS with a follow-up of at least three years from 146 MS centers, spread over 40 countries and collected by the MSBase consortium was used. With basic inclusion criteria for quality requirements, it represents a total of 15, 240 PwMS. External validation was performed and repeated five times to assess the significance of the results. Transparent Reporting for Individual Prognosis Or Diagnosis (TRIPOD) guidelines were followed. Confirmed disability progression after two years was predicted, with a confirmation window of six months. Only routinely collected variables were used such as the expanded disability status scale, treatment, relapse information, and MS course. To learn the probability of disability progression, state-of-the-art machine learning models were investigated. The discrimination performance of the models is evaluated with the area under the receiver operator curve (ROC-AUC) and under the precision recall curve (AUC-PR), and their calibration via the Brier score and the expected calibration error. All our preprocessing and model code are available at https://gitlab.com/edebrouwer/ms_benchmark, making this task an ideal benchmark for predicting disability progression in MS., Findings: Machine learning models achieved a ROC-AUC of 0⋅71 ± 0⋅01, an AUC-PR of 0⋅26 ± 0⋅02, a Brier score of 0⋅1 ± 0⋅01 and an expected calibration error of 0⋅07 ± 0⋅04. The history of disability progression was identified as being more predictive for future disability progression than the treatment or relapses history., Conclusions: Good discrimination and calibration performance on an external validation set is achieved, using only routinely collected variables. This suggests machine-learning models can reliably inform clinicians about the future occurrence of progression and are mature for a clinical impact study., Competing Interests: The authors declare no competing non-financial interests but the following competing financial interests: - Dana Horakova received speaker honoraria and consulting fees from Biogen, Merck, Teva, Roche, Sanofi Genzyme, and Novartis, as well as support for research activities from Biogen and Czech Minsitry of Education [project Progres Q27/LF1]. - Francesco Patti received speaker honoraria and advisory board fees from Almirall, Bayer, Biogen, Celgene, Merck, Novartis, Roche, Sanofi-Genzyme and TEVA. He received research funding from Biogen, Merck, FISM (Fondazione Italiana Sclerosi Multipla), Reload Onlus Association and University of Catania. - Guillermo Izquierdo received speaking honoraria from Biogen, Novartis, Sanofi, Merck, Roche, Almirall and Teva. - Sara Eichau received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche and Teva. - Marc Girard received consulting fees from Teva Canada Innovation, Biogen, Novartis and Genzyme Sanofi; lecture payments from Teva Canada Innovation, Novartis and EMD. He has also received a research grant from Canadian Institutes of Health Research. - Alessandra Lugaresi has served as a Biogen, Bristol Myers Squibb, Merck Serono, Novartis, Roche, Sanofi/ Genzyme and Teva Advisory Board Member. She received congress and travel/accommodation expense compensations or speaker honoraria from Biogen, Merck, Mylan, Novartis, Roche, Sanofi/Genzyme, Teva and Fondazione Italiana Sclerosi Multipla (FISM). Her institutions received research grants from Novartis and Sanofi Genzyme. - Pierre Grammond has served in advisory boards for Novartis, EMD Serono, Roche, Biogen idec, Sanofi Genzyme, Pendopharm and has received grant support from Genzyme and Roche, has received research grants for his institution from Biogen idec, Sanofi Genzyme, EMD Serono. - Tomas Kalincik served on scientific advisory boards for BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Merck and Biogen, steering committee for Brain Atrophy Initiative by Sanofi Genzyme, received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Sanofi-Genzyme, Teva, BioCSL and Merck and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck. - Raed Alroughani received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche and Sanofi-Genzyme. - Francois Grand’Maison received honoraria or research funding from Biogen, Genzyme, Novartis, Teva Neurosciences, Mitsubishi and ONO Pharmaceuticals. - Murat Terzi received travel grants from Novartis, Bayer-Schering, Merck and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. - Jeannette Lechner-Scott travel compensation from Novartis, Biogen, Roche and Merck. Her institution receives the honoraria for talks and advisory board commitment as well as research grants from Biogen, Merck, Roche, TEVA and Novartis. - Samia J. Khoury received compensation for participation in the Novartis Maestro program. - Vincent van Pesch has received travel grants from Merck, Biogen, Sanofi, Bristol Myers Squibb, Almirall and Roche; his institution receives honoraria for consultancy and lectures and research grants from Roche, Biogen, Sanofi, Merck, Bristol Myers Squibb, Janssen, Almirall and Novartis Pharma. - Radek Ampapa received conference travel support from Novartis, Teva, Biogen, Bayer and Merck and has participated in a clinical trials by Biogen, Novartis, Teva and Actelion. - Daniele Spitaleri received honoraria as a consultant on scientific advisory boards by Bayer-Schering, Novartis and Sanofi-Aventis and compensation for travel from Novartis, Biogen, Sanofi Aventis, Teva and Merck. - Claudio Solaro served on scientific advisory boards for Merck, Genzyme, Almirall, and Biogen; received honoraria and travel grants from Sanofi Aventis, Novartis, Biogen, Merck, Genzyme and Teva. - Davide Maimone served on scientific advisory boards for Bayer, Biogen, Merck, Sanofi-Genzyme, Novartis, Roche, and Almirall; received honoraria and travel grants from Sanofi Genzyme, Novartis, Biogen, Merck, and Roche. - Gerardo Iuliano (retired - no PI successor but has approved ongoing use of data) had travel/accommodations/meeting expenses funded by Bayer Schering, Biogen, Merck, Novartis, Sanofi Aventis, and Teva. - Bart Van Wijmeersch received research and travel grants, honoraria for MS-Expert advisor and Speaker fees from Bayer-Schering, Biogen, Sanofi Genzyme, Merck, Novartis, Roche and Teva. - Tamara Castillo Triviño received speaking/consulting fees and/or travel funding from Bayer, Biogen, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. - Jose Luis Sanchez-Menoyo accepted travel compensation from Novartis, Merck and Biogen, speaking honoraria from Biogen, Novartis, Sanofi, Merck, Almirall, Bayer and Teva and has participated in clinical trials by Biogen, Merck and Roche - Guy Laureys received travel and/or consultancy compensation from Sanofi-Genzyme, Roche, Teva, Merck, Novartis, Celgene, Biogen. - Anneke van der Walt served on advisory boards and receives unrestricted research grants from Novartis, Biogen, Merck and Roche She has received speaker’s honoraria and travel support from Novartis, Roche, and Merck. She receives grant support from the National Health and Medical Research Council of Australia and MS Research Australia. - Jiwon Oh has received research funding from the MS Society of Canada, National MS Society, Brain Canada, Biogen, Roche, EMD Serono (an affiliate of Merck KGaA); and personal compensation for consulting or speaking from Alexion, Biogen, Celgene (BMS), EMD Serono (an affiliate of Merck KGaA), Novartis, Roche, and Sanofi-Genzyme. - Ayse Altintas received speaker honoraria from Merck, Alexion,; received travel and registration grants from Merck, Biogen - Gen Pharma, Roche, Sanofi-Genzyme. - Yara Fragoso received honoraria as a consultant on scientific advisory boards by Novartis, Teva, Roche and Sanofi-Aventis and compensation for travel from Novartis, Biogen, Sanofi Aventis, Teva, Roche and Merck. - Tunde Csepany received speaker honoraria/ conference travel support from Bayer Schering, Biogen, Merck, Novartis, Roche, Sanofi-Aventis and Teva. - Suzanne Hodgkinson received honoraria and consulting fees from Novartis, Bayer Schering and Sanofi, and travel grants from Novartis, Biogen Idec and Bayer Schering. - Norma Deri received funding from Bayer, Merck, Biogen, Genzyme and Novartis. - Bruce Taylor received funding for travel and speaker honoraria from Bayer Schering Pharma, CSL Australia, Biogen and Novartis, and has served on advisory boards for Biogen, Novartis, Roche and CSL Australia. - Fraser Moore participated in clinical trials sponsored by EMD Serono and Novartis. - Orla Gray received honoraria as consultant on scientific advisory boards for Genzyme, Biogen, Merck, Roche and Novartis; has received travel grants from Biogen, Merck, Roche and Novartis; has participated in clinical trials by Biogen and Merck. - Csilla Rozsa received speaker honoraria from Bayer Schering, Novartis and Biogen, congress and travel expense compensations from Biogen, Teva, Merck and Bayer Schering. - Allan Kermode received speaker honoraria and scientific advisory board fees from Bayer, BioCSL, Biogen, Genzyme, Innate Immunotherapeutics, Merck, Novartis, Sanofi, Sanofi-Aventis, and Teva. - Magdolna Simo received speaker honoraria from Novartis, Biogen, Bayer Schering; congress/travel compensation from Teva, Biogen, Merck, Bayer Schering. - Todd Hardy has received speaking fees or received honoraria for serving on advisory boards for Biogen, Merck, Teva, Novartis, Roche, Bristol-Myers Squibb and Sanofi-Genzyme, is Co-Editor of Advances in Clinical Neurosciences and Rehabilitation, and serves on the editorial board of Journal of Neuroimmunology and Frontiers in Neurology. - Nikolaos Grigoriadis received honoraria, consultancy/lecture fees, travel support and research grants from Biogen Idec, Biologix, Novartis, TEVA, Bayer, Merck Serono, Genesis Pharma, Sanofi – Genzyme, ROCHE, Cellgene, ELPEN and research grants from Hellenic Ministry of Development., (Copyright: © 2024 De Brouwer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Access to, standardization and reimbursement of multidisciplinary care for people with MS (PwMS) is lacking in many countries. Therefore, this study aims to describe the current multidisciplinary care for people with MS (PwMS) in Belgium and identify benefits, needs and future perspectives METHODS: A survey for PwMS questioned various aspects of MS and viewpoints on care. For MS nurses (MSN) and neurologists, employment, education, job-content, care organization and perspectives were inquired. Descriptive and univariate statistics were performed RESULTS: The PwMS survey comprised 916 respondents with a mean age of 46±12.7 years and 75,4 % of the respondents being female. The majority of the participants had relapsing remitting MS (60.8 %) and the mean patient determined disease steps (PDDS) was 2.0 (IQR=3). 65.3 % and 60.4 % of the PwMS reported having access to a multidisciplinary team (MDT) or MSN. Access to an MSN was associated with more frequent disease modifying treatment (p=.015), spasticity (p=.042) and gait treatment (p=.035), but also more physiotherapy (p=.004), driver's license adjustment (p<.001) and a higher employment rate (p=.004). MDT access was associated with more frequent symptomatic bladder treatment (p=.047), higher physiotherapy rate (p<.001), higher work- (p=.002), insurance- (p<.001) and home support measures (p=.019). PwMS without an available MDT more often indicated that MS care needs improvement (p<.001). MSN's (n = 22) were mainly funded through various budgets, including hospital and neurology practice budgets. Finally, 69 % and 75 % neurologists (n = 62) working without an MSN or MDT stated a need of such support and 61 % agreed that MDT's should be organized at hospital-network level CONCLUSION: MDT and MSN availability may enhance medical and socio-economic support for PwMS. Guidelines, alignment and reimbursement are needed., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest to report., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Geographical variations in the incidence and prevalence of multiple sclerosis have been reported globally. Latitude as a surrogate for exposure to ultraviolet radiation but also other lifestyle and environmental factors are regarded as drivers of this variation. No previous studies evaluated geographical variation in the risk of secondary progressive multiple sclerosis, an advanced form of multiple sclerosis that is characterized by steady accrual of irreversible disability. We evaluated differences in the risk of secondary progressive multiple sclerosis in relation to latitude and country of residence, modified by high-to-moderate efficacy immunotherapy in a geographically diverse cohort of patients with relapsing-remitting multiple sclerosis. The study included relapsing-remitting multiple sclerosis patients from the global MSBase registry with at least one recorded assessment of disability. Secondary progressive multiple sclerosis was identified as per clinician diagnosis. Sensitivity analyses used the operationalized definition of secondary progressive multiple sclerosis and the Swedish decision tree algorithm. A proportional hazards model was used to estimate the cumulative risk of secondary progressive multiple sclerosis by country of residence (latitude), adjusted for sex, age at disease onset, time from onset to relapsing-remitting phase, disability (Multiple Sclerosis Severity Score) and relapse activity at study inclusion, national multiple sclerosis prevalence, government health expenditure, and proportion of time treated with high-to-moderate efficacy disease-modifying therapy. Geographical variation in time from relapsing-remitting phase to secondary progressive phase of multiple sclerosis was modelled through a proportional hazards model with spatially correlated frailties. We included 51 126 patients (72% female) from 27 countries. The median survival time from relapsing-remitting phase to secondary progressive multiple sclerosis among all patients was 39 (95% confidence interval: 37 to 43) years. Higher latitude [median hazard ratio = 1.21, 95% credible interval (1.16, 1.26)], higher national multiple sclerosis prevalence [1.07 (1.03, 1.11)], male sex [1.30 (1.22, 1.39)], older age at onset [1.35 (1.30, 1.39)], higher disability [2.40 (2.34, 2.47)] and frequent relapses [1.18 (1.15, 1.21)] at inclusion were associated with increased hazard of secondary progressive multiple sclerosis. Higher proportion of time on high-to-moderate efficacy therapy substantially reduced the hazard of secondary progressive multiple sclerosis [0.76 (0.73, 0.79)] and reduced the effect of latitude [interaction: 0.95 (0.92, 0.99)]. At the country-level, patients in Oman, Tunisia, Iran and Canada had higher risks of secondary progressive multiple sclerosis relative to the other studied regions. Higher latitude of residence is associated with a higher probability of developing secondary progressive multiple sclerosis. High-to-moderate efficacy immunotherapy can mitigate some of this geographically co-determined risk., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: The prognostic significance of non-disabling relapses in people with relapsing-remitting multiple sclerosis (RRMS) is unclear., Objective: To determine whether early non-disabling relapses predict disability accumulation in RRMS., Methods: We redefined mild relapses in MSBase as 'non-disabling', and moderate or severe relapses as 'disabling'. We used mixed-effects Cox models to compare 90-day confirmed disability accumulation events in people with exclusively non-disabling relapses within 2 years of RRMS diagnosis to those with no early relapses; and any early disabling relapses. Analyses were stratified by disease-modifying therapy (DMT) efficacy during follow-up., Results: People who experienced non-disabling relapses within 2 years of RRMS diagnosis accumulated more disability than those with no early relapses if they were untreated ( n  = 285 vs 4717; hazard ratio (HR) = 1.29, 95% confidence interval (CI) = 1.00-1.68) or given platform DMTs ( n  = 1074 vs 7262; HR = 1.33, 95% CI = 1.15-1.54), but not if given high-efficacy DMTs ( n  = 572 vs 3534; HR = 0.90, 95% CI = 0.71-1.13) during follow-up. Differences in disability accumulation between those with early non-disabling relapses and those with early disabling relapses were not confirmed statistically., Conclusion: This study suggests that early non-disabling relapses are associated with a higher risk of disability accumulation than no early relapses in RRMS. This risk may be mitigated by high-efficacy DMTs. Therefore, non-disabling relapses should be considered when making treatment decisions.

Background: The Multiple Sclerosis Severity Score (MSSS) is a widely used measure of the disability progression rate. However, the global MSSS may not be the best basis for comparison between all patient groups., Objective: We evaluated sex-specific and onset phenotype-specific MSSS matrices to determine if they were more effective than the global MSSS as a basis for comparison within these subsets., Methods: Using a large international dataset of multiple sclerosis (MS) patient records and the original MSSS algorithm, we constructed global, sex-specific and onset phenotype-specific MSSS matrices. We compared matrices using permutation analysis., Results: Our final dataset included 30,203 MS cases, with 28.9% males and 6.5% progressive-onset cases. Our global MSSS matrix did not differ from previously published data ( p  > 0.05). The progressive-onset-specific matrix differed significantly from the relapsing-onset-specific matrix ( p  < 0.001), with lower MSSS attributed to cases with the same Expanded Disability Status Score (EDSS) and disease duration. When evaluated with a simulation, using an onset-specific MSSS improved statistical power in mixed cohorts. There were no significant differences by sex., Conclusion: The differences in the disability accrual rate between progressive- and relapsing-onset MS have a significant effect on MSSS. An onset-specific MSSS should be used when comparing the rate of disability progression among progressive-onset cases and for mixed cohorts.

Background: Fatigue is a frequently occurring, often disabling symptom in MS with no single effective treatment. In current fatigue management interventions, personalized, real-time follow-up is often lacking. The objective of the study is to assess the feasibility of the MS TeleCoach, a novel intervention offering telemonitoring of fatigue and telecoaching of physical activity and energy management in persons with MS (pwMS) over a 12-week period. The goal of the MS TeleCoach, conceived as a combination of monitoring, self-management and motivational messages, is to enhance levels of physical activity thereby improving fatigue in pwMS in an accessible and interactive way, reinforcing self-management of patients., Methods: We conducted a prospective, open-label feasibility study of the MS TeleCoach in pwMS with Expanded Disability Status Scale ≤ 4 and moderate to severe fatigue as measured by the Fatigue Scale for Motor and Cognitive Functions (FSMC). Following a 2-week run-in period to assess the baseline activity level per patient, the target number of activity counts was gradually increased over the 12-week period through telecoaching. The primary efficacy outcome was change in FSMC total score from baseline to study end. A subset of patients was asked to fill in D-QUEST 2.0, a usability questionnaire, to evaluate the satisfaction with the MS TeleCoach device and the experienced service., Results: Seventy-five patients were recruited from 16 centres in Belgium, of which 57 patients (76%) completed the study. FSMC total score (p = 0.009) and motor and cognitive subscores (p = 0.007 and p = 0.02 respectively) decreased from baseline to week 12, indicating an improvement in fatigue. One third of participants with severe fatigue changed to a lower FSMC category for both FSMC total score and subscores. The post-study evaluation of patient satisfaction showed that the intervention was well accepted and that patients were very satisfied with the quality of the professional services., Conclusion: Using MS TeleCoach as a self-management tool in pwMS suffering from mild disability and moderate to severe fatigue appeared to be feasible, both technically and from a content perspective. Its use was associated with improved fatigue levels in the participants who completed the study. The MS Telecoach seems to meet the need for a low-cost, accessible and interactive self-management tool in MS., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Poor treatment adherence is common among patients with multiple sclerosis (MS). This survey evaluated neurologists' perception of treatment adherence among MS patients., Materials and Methods: This questionnaire-based survey of Belgian neurologists treating MS patients was conducted between June and July 2014. Face-to-face interviews with the neurologists were based on a semistructured questionnaire containing questions regarding the perception of the treatment-adherence level., Results: A total of 41 neurologists participated in the survey. Of these, 88% indicated frequent discussions about treatment adherence as beneficial for treatment efficacy. The mean time spent on the treatment-adherence discussion during the initial consultation was 11 minutes, with 24% of doctors spending 5 minutes and 24% of doctors spending 10 minutes discussing this issue. The majority of neurologists (56%) perceived the adherence level in MS as good, and 12% perceived it as excellent. The majority of neurologists (64%) indicated intolerance as a main cause of poor adherence, and all neurologists reported insufficient efficacy as a consequence of nonadherence. The importance of adherence in the neurologists' practice was evaluated on a scale of 1-10, with 1= "not very important" and 10= "very important": 44% of doctors indicated a score of 10, and the mean score was 9.0., Conclusion: Belgian neurologists consider treatment adherence in MS as essential for the benefits of therapies. However, although neurologists are aware of the consequences of nonadherence, they generally spend limited time discussing the importance of treatment adherence with their patients.

Symptomatic internal carotid artery occlusion by atherosclerosis and by cervical dissection are distinct conditions with different long-term prognoses. The purpose of the present study is to investigate if regional cerebral blood flow and oxygen metabolism, after onset of stroke, differ between both conditions. Seventeen patients with symptomatic unilateral atherosclerotic internal carotid occlusion and 10 patients with symptomatic internal carotid occlusion due to cervical dissection were submitted to a positron emission tomographic (PET) study between 1 and 2 months after stroke onset. The steady state technique with 15O was used in order to determine regional cerebral blood flow, regional oxygen extraction fraction, and regional cerebral metabolic rate for oxygen in the infarct area, the peri-infarct zone, the remaining homolateral hemisphere, and the contralateral hemisphere. The results were compared between both patient's populations. The patients with cervical dissection were on average much younger than those with atherosclerotic occlusion, but neurological impairment on admission and disability at 3 months were comparable. Between both patient populations, no differences in rCBF, rOEF, and rCMRO2 could be demonstrated in the different regions of interest when the results were age-adjusted. Except for age-related changes, no differences in PET findings could be demonstrated between patients with symptomatic internal carotid occlusion caused by either atherosclerosis or cervical dissection.

Serotonin (5-HT) and more specifically the 5-HT(2A) receptor is involved in cognitive and non-cognitive behavior and plays an important role in Alzheimer's disease (AD). The objective was to assess the 5-HT(2A) binding potential (BP) in healthy volunteers and AD with SPECT and 123I-5-I-R91150, a selective radio-iodinated 5-HT(2A) receptor antagonist. Twenty-six controls and nine AD patients were included. A semiquantitive analysis with normalization on cerebellar uptake provided estimates of BP for 26 cortical regions of interest. An age-related decline of neocortical BP was found (11.6% per decade). Compared to age-matched controls, a generally decreased neocortical BP in AD was found with a significant regional reduction in the orbitofrontal, prefrontal, lateral frontal, cingulate, sensorimotor, parietal inferior, and occipital region. These results are in line with previous postmortem, in vitro, and PET findings. The age-related decline highlights the necessity for matched advanced age study samples. The fact that the 5-HT(2A) receptor is differentially affected in AD patients has implications for both the etiological basis and therapeutic management of AD.

Objectives: Inflammation contributes to degeneration in Alzheimer's disease (AD), not simply as a secondary phenomenon, but primarily as a significant source of pathology. [(123)I]iodo-PK11195 is a single photon emission computed tomography (SPECT) ligand for the peripheral benzodiazepine receptor, the latter being expressed on microglia (brain resident macrophages) and upregulated under inflammatory circumstances. The objectives were to assess AD inflammation by detecting [(123)I]iodo-PK11195 uptake changes and investigate how uptake values relate with perfusion SPECT and neuropsychological findings., Methods: Ten AD and 9 control subjects were included. [(123)I]iodo-PK11195 SPECT images were realigned into stereotactic space where binding indices, normalized on cerebellar uptake, were calculated., Results: The mean [(123)I]iodo-PK11195 uptake was increased in AD patients compared with controls in nearly all neocortical regions; however, statistical significance was only reached in the frontal and right mesotemporal regions. Significant correlations were found between regional increased [(123)I]iodo-PK11195 uptake and cognitive deficits., Conclusions: [(123)I]iodo-PK11195 is a cellular disease activity marker and allows in vivo assessment of microglial inflammation in AD., (Copyright 2003 S. Karger AG, Basel)