Introduction
Impaired motor function is a major cause of disability in multiple sclerosis (MS), involving various neuroplasticity processes typically assessed by neuroimaging. This study aimed to ...determine whether navigated transcranial magnetic stimulation (nTMS) could also provide biomarkers of motor cortex plasticity in patients with MS (pwMS).
Methods
nTMS motor mapping was performed for hand and leg muscles bilaterally. nTMS variables included the amplitude and latency of motor evoked potentials (MEPs), corticospinal excitability measures, and the size of cortical motor maps (CMMs). Clinical assessment included disability (Expanded Disability Status Scale, EDSS), strength (MRC scale, pinch and grip), and dexterity (9-hole Pegboard Test).
Results
nTMS motor mapping was performed in 68 pwMS. PwMS with high disability (EDSS ≥ 3) had enlarged CMMs with less dense distribution of MEPs and various MEP parameter changes compared to pwMS with low disability (EDSS < 3). Patients with progressive MS had also various MEP parameter changes compared to pwMS with relapsing remitting form. MRC score correlated positively with MEP amplitude and negatively with MEP latency, pinch strength correlated negatively with CMM volume and dexterity with MEP latency.
Conclusions
This is the first study to perform 4-limb cortical motor mapping in pwMS using a dedicated nTMS procedure. By quantifying the cortical surface representation of a given muscle and the variability of MEP within this representation, nTMS can provide new biomarkers of motor function impairment in pwMS. Our study opens perspectives for the use of nTMS as an objective method for assessing pwMS disability in clinical practice.
Les traitements de la sclérose en plaques (SEP), en particulier des biothérapies, sont complexes à organiser et nécessitent une rigueur dans la planification et le suivi.
Créer un outil informatique ...d’aide à l’organisation et la planification en vue d’améliorer la qualité et la sécurité des biothérapies de la sclérose en plaques.
Création de l’outil informatique sur la base des résumés des caractéristiques des produits et des recommandations des sociétés savantes pour le natalizumab, l’ocrelizumab et le rituximab : bilans préthérapeutiques, modalités du suivi intercure et précure, recommandations de suivi clinique, biologique, radiologique, formule de risque de LEMP. Développement d’une base de données : choix des tables, des champs, création de requêtes, de formulaires, d’états, de nomenclature. Choix de l’outil. Tests puis validation.
ClickSEP permet la création de fiche patients incluant choix du médicament, date de début, adaptation des dates de rendez-vous et de cures, dénomination des médecins, planification automatique ou personnalisée des délais entre examens/consultations/IRM ; création d’alertes et de seuils d’alertes ; calcul automatique des risques de LEMP et infectieux selon le taux d’immunoglobulines ; automatisme des rappels par emails, courriers types. Paramétrage complet générique et par patient. Adaptable à tout nouveau traitement.
Les rappels de ClickSEP au prescripteur et au patient des examens recommandés limitent les oublis ; les alertes spécifiques (LEMP) améliorent la sécurité de prescription. Ils permettent d’assurer la qualité et la sécurité des traitements avec une actualisation aisée par un référent pour le non-spécialiste. Outil de coordination, ClickSEP ne se substitue pas au dossier médical ni au planning hospitalier.
ClickSEP est le premier outil de coordination du parcours patient traité par biothérapie au cours de la sclérose en plaques visant la qualité et la sécurité du suivi.
SARS-CoV-2 seroconversion rate after COVID-19 may be influenced by disease-modifying therapies (DMTs) in patients with multiple sclerosis (MS) or neuromyelitis optica spectrum disorders (NMO-SD).
To ...investigate the seroprevalence and the quantity of SARS-CoV-2 antibodies in a cohort of patients with MS or NMO-SD.
Blood samples were collected in patients diagnosed with COVID-19 between 19 February 2020 and 26 February 2021. SARS-CoV-2 antibody positivity rates and Ig levels (anti-S IgG titre, anti-S IgA index, anti-N IgG index) were compared between DMTs groups. Multivariate logistic and linear regression models were used to estimate the influence of DMTs and other confounding variables on SARS-CoV-2 serological outcomes.
119 patients (115 MS, 4 NMO, mean age: 43.0 years) were analysed. Overall, seroconversion rate was 80.6% within 5.0 (SD 3.4) months after infection. 20/21 (95.2%) patients without DMT and 66/77 (85.7%) patients on DMTs other than anti-CD20 had at least one SARS-CoV-2 Ig positivity, while this rate decreased to only 10/21 (47.6%) for patients on anti-CD20 (p<0.001). Being on anti-CD20 was associated with a decreased odd of positive serology (OR, 0.07 (95% CI 0.01 to 0.69), p=0.02) independently from time to COVID-19, total IgG level, age, sex and COVID-19 severity. Time between last anti-CD20 infusion and COVID-19 was longer (mean (SD), 3.7 (2.0) months) in seropositive patients compared with seronegative patients (mean (SD), 1.9 (1.5) months, p=0.04).
SARS-CoV-2 antibody response was decreased in patients with MS or NMO-SD treated with anti-CD20 therapies. Monitoring long-term risk of reinfection and specific vaccination strategies in this population may be warranted.
NCT04568707.
Abstract
The radiologically isolated syndrome (RIS) was defined in 2009 as the presence of asymptomatic, incidentally identified demyelinating-appearing white matter lesions in the CNS within ...individuals lacking symptoms typical of multiple sclerosis (MS). The RIS criteria have been validated and predict the transition to symptomatic MS reliably. The performance of RIS criteria that require fewer MRI lesions is unknown.
2009-RIS subjects, by definition, fulfil three to four of four criteria for 2005 dissemination in space (DIS) and subjects fulfilling only one or two lesions in at least one 2017 DIS location were identified within 37 prospective databases. Univariate and multivariate Cox regression models were used to identify predictors of a first clinical event. Performances of different groups were calculated.
Seven hundred and forty-seven subjects (72.2% female, mean age 37.7 ± 12.3 years at the index MRI) were included. The mean clinical follow-up time was 46.8 ± 45.4 months. All subjects had focal T2 hyperintensities suggestive of inflammatory demyelination on MRI; 251 (33.6%) fulfilled one or two 2017 DIS criteria (designated as Groups 1 and 2, respectively), and 496 (66.4%) fulfilled three or four 2005 DIS criteria representing 2009-RIS subjects. Group 1 and 2 subjects were younger than the 2009-RIS group and were more likely to develop new T2 lesions over time (P < 0.001). Groups 1 and 2 were similar regarding survival distribution and risk factors for transition to MS.
At 5 years, the cumulative probability for a clinical event was 29.0% for Groups 1 and 2 compared to 38.7% for 2009-RIS (P = 0.0241). The presence of spinal cord lesions on the index scan and CSF-restricted oligoclonal bands in Groups 1–2 increased the risk of symptomatic MS evolution at 5 years to 38%, comparable to the risk of development in the 2009-RIS group. The presence of new T2 or gadolinium-enhancing lesions on follow-up scans independently increased the risk of presenting with a clinical event (P < 0.001). The 2009-RIS subjects or Groups 1 and 2 with at least two of the risk factors for a clinical event demonstrated better sensitivity (86.0%), negative predictive value (73.1%), accuracy (59.8%) and area under the curve (60.7%) compared to other criteria studied.
This large prospective cohort brings Class I evidence that subjects with fewer lesions than required in the 2009 RIS criteria evolve directly to a first clinical event at a similar rate when additional risk factors are present. Our results provide a rationale for revisions to existing RIS diagnostic criteria.
Lebrun-Frénay et al. show that individuals who do not meet the diagnostic criteria for radiologically isolated syndrome based on their number of white matter lesions nevertheless transition to symptomatic multiple sclerosis at a similar rate to individuals who do fulfil the criteria, when additional risk factors are present.
Background
Outcomes of coronavirus disease 2019 (COVID‐19) in patients with neuromyelitis optica spectrum disorders (NMOSD) or myelin oligodendrocyte glycoprotein antibody‐associated disease (MOGAD), ...often treated with immunosuppressive therapies, are still unknown.
Methods
We conducted a multicenter, retrospective, observational cohort study among all French expert centers for neuromyelitis optica and related disorders. Patients with NMOSD or MOGAD included in the study received a confirmed or highly suspected diagnosis of COVID‐19 between 1 March 2020 and 30 June 2020. Main outcome was COVID‐19 severity score assessed on a seven‐point ordinal scale ranging from 1 (not hospitalized with no limitations on activities) to 7 (death).
Results
Fifteen cases (mean SD age: 39.3 14.3 years, 11 female) were included. Five patients (33.3%) were hospitalized, all receiving rituximab. A 24‐year‐old patient with positive aquaporine‐4 antibody, with obesity as comorbidity, needed mechanical ventilation. Outpatients were receiving anti‐CD20 (5), mycophenolate mofetil (3) or azathioprine (3). They were younger (mean SD age: 37.0 13.4 years), with a longer disease duration (mean SD: 8.3 6.3 years) and had a lower expanded disability severity score (EDSS) score (median range EDSS: 2.5 0–4) relative to patients requiring hospitalization (mean SD age: 44.0 16.4 years, mean SD disease duration: 5.8 5.5 years, median range EDSS: 4 0–6.5).
Conclusions
COVID‐19 outcome was overall favorable in this cohort. Larger international studies are needed to identify risk factors of severe COVID‐19; however, we recommend personal protective measures to reduce risk of SARS‐CoV‐2 infection in this immunocompromised population.
We present a cohort of 15 patients with neuromyelitis optica and associated disorders who had Coronavirus disease 2019 (COVID‐19). COVID‐19 outcome was overall favorable, 5 patients, all on Rituximab, needed hospitalization, and one patient needed mechanical ventilation.
Objectives
To evaluate compliance with the available recommendations, we assessed the current clinical practice of imaging in the evaluation of multiple sclerosis (MS).
Methods
An online ...questionnaire was emailed to all members and affiliates. Information was gathered on applied MR imaging protocols, gadolinium-based contrast agents (GBCA) use and image analysis. We compared the survey results with the Magnetic Resonance Imaging in MS (MAGNIMS) recommendations considered as the reference standard.
Results
A total of 428 entries were received from 44 countries. Of these, 82% of responders were neuroradiologists. 55% performed more than ten scans per week for MS imaging. The systematic use of 3 T is rare (18%). Over 90% follow specific protocol recommendations with 3D FLAIR, T2-weighted and DWI being the most frequently used sequences. Over 50% use SWI at initial diagnosis and 3D gradient-echo T1-weighted imaging is the most used MRI sequence for pre- and post-contrast imaging. Mismatches with recommendations were identified including the use of only one sagittal T2-weighted sequence for spinal cord imaging, the systematic use of GBCA at follow-up (over 30% of institutions), a delay time shorter than 5 min after GBCA administration (25%) and an inadequate follow-up duration in pediatric acute disseminated encephalomyelitis (80%). There is scarce use of automated software to compare images or to assess atrophy (13% and 7%). The proportions do not differ significantly between academic and non-academic institutions.
Conclusions
While current practice in MS imaging is rather homogeneous across Europe, our survey suggests that recommendations are only partially followed.
Clinical relevance statement
Hurdles were identified, mainly in the areas of GBCA use, spinal cord imaging, underuse of specific MRI sequences and monitoring strategies. This work will help radiologists to identify the mismatches between their own practices and the recommendations and act upon them.
Key Points
• While current practice in MS imaging is rather homogeneous across Europe, our survey suggests that available recommendations are only partially followed.
• Several hurdles have been identified through the survey that mainly lies in the areas of GBCA use, spinal cord imaging, underuse of specific MRI sequences and monitoring strategies.
Moderately effective therapies (METs) have been the main treatment in pediatric-onset multiple sclerosis (POMS) for years. Despite the expanding use of highly effective therapies (HETs), treatment ...strategies for POMS still lack consensus.
To assess the real-world association of HET as an index treatment compared with MET with disease activity.
This was a retrospective cohort study conducted from January 1, 2010, to December 8, 2022, until the last recorded visit. The median follow-up was 5.8 years. A total of 36 French MS centers participated in the Observatoire Français de la Sclérose en Plaques (OFSEP) cohort. Of the total participants in OFSEP, only treatment-naive children with relapsing-remitting POMS who received a first HET or MET before adulthood and at least 1 follow-up clinical visit were included in the study. All eligible participants were included in the study, and none declined to participate.
HET or MET at treatment initiation.
The primary outcome was the time to first relapse after treatment. Secondary outcomes were annualized relapse rate (ARR), magnetic resonance imaging (MRI) activity, time to Expanded Disability Status Scale (EDSS) progression, tertiary education attainment, and treatment safety/tolerability. An adapted statistical method was used to model the logarithm of event rate by penalized splines of time, allowing adjustment for effects of covariates that is sensitive to nonlinearity and interactions.
Of the 3841 children (5.2% of 74 367 total participants in OFSEP), 530 patients (mean SD age, 16.0 1.8 years; 364 female 68.7%) were included in the study. In study patients, both treatment strategies were associated with a reduced risk of first relapse within the first 2 years. HET dampened disease activity with a 54% reduction in first relapse risk (adjusted hazard ratio HR, 0.46; 95% CI, 0.31-0.67; P < .001) sustained over 5 years, confirmed on MRI activity (adjusted odds ratio OR, 0.34; 95% CI, 0.18-0.66; P = .001), and with a better tolerability pattern than MET. The risk of discontinuation at 2 years was 6 times higher with MET (HR, 5.97; 95% CI, 2.92-12.20). The primary reasons for treatment discontinuation were lack of efficacy and intolerance. Index treatment was not associated with EDSS progression or tertiary education attainment (adjusted OR, 0.51; 95% CI, 0.24-1.10; P = .09).
Results of this cohort study suggest that compared with MET, initial HET in POMS was associated with a reduction in the risk of first relapse with an optimal outcome within the first 2 years and was associated with a lower rate of treatment switching and a better midterm tolerance in children. These findings suggest prioritizing initial HET in POMS, although long-term safety studies are needed.
The question of the long-term safety of pregnancy is a major concern in patients with multiple sclerosis (MS), but its study is biased by reverse causation (women with higher disability are less ...likely to experience pregnancy). Using a causal inference approach, we aimed to estimate the unbiased long-term effects of pregnancy on disability and relapse risk in patients with MS and secondarily the short-term effects (during the perpartum and postpartum years) and delayed effects (occurring beyond 1 year after delivery).
We conducted an observational cohort study with data from patients with MS followed in the Observatoire Français de la Sclérose en Plaques registry between 1990 and 2020. We included female patients with MS aged 18-45 years at MS onset, clinically followed up for more than 2 years, and with ≥3 Expanded Disease Status Scale (EDSS) measurements. Outcomes were the mean EDSS score at the end of follow-up and the annual probability of relapse during follow-up. Counterfactual outcomes were predicted using the longitudinal targeted maximum likelihood estimator in the entire study population. The patients exposed to at least 1 pregnancy during their follow-up were compared with the counterfactual situation in which, contrary to what was observed, they would not have been exposed to any pregnancy. Short-term and delayed effects were analyzed from the first pregnancy of early-exposed patients (who experienced it during their first 3 years of follow-up).
We included 9,100 patients, with a median follow-up duration of 7.8 years, of whom 2,125 (23.4%) patients were exposed to at least 1 pregnancy. Pregnancy had no significant long-term causal effect on the mean EDSS score at 9 years (causal mean difference 95% CI = 0.00 -0.16 to 0.15) or on the annual probability of relapse (causal risk ratio 95% CI = 0.95 0.93-1.38). For the 1,253 early-exposed patients, pregnancy significantly decreased the probability of relapse during the perpartum year and significantly increased it during the postpartum year, but no significant delayed effect was found on the EDSS and relapse rate.
Using a causal inference approach, we found no evidence of significantly deleterious or beneficial long-term effects of pregnancy on disability. The beneficial effects found in other studies were probably related to a reverse causation bias.
In this study, we compared the effectiveness of teriflunomide (TRF) and dimethyl fumarate (DMF) on both clinical and MRI outcomes in patients followed prospectively in the Observatoire Français de la ...Sclérose en Plaques.
A total of 1,770 patients with relapsing-remitting multiple sclerosis (RRMS) (713 on TRF and 1,057 on DMF) with an available baseline brain MRI were included in intention to treat. The 1- and 2-year postinitiation outcomes were relapses, increase of T2 lesions, increase in Expanded Disability Status Scale score, and reason for treatment discontinuation. Propensity scores (inverse probability weighting) and logistic regressions were estimated.
The confounder-adjusted proportions of patients were similar in TRF- compared to DMF-treated patients for relapses and disability progression after 1 and 2 years. However, the adjusted proportion of patients with at least one new T2 lesion after 2 years was lower in DMF compared to TRF (60.8% vs 72.2%, odds ratio OR 0.60,
< 0.001). Analyses of reasons for treatment withdrawal showed that lack of effectiveness was reported for 8.5% of DMF-treated patients vs 14.5% of TRF-treated patients (OR 0.54,
< 0.001), while adverse events accounted for 16% of TRF-treated patients and 21% of DMF-treated patients after 2 years (OR 1.39,
< 0.001).
After 2 years of treatment, we found similar effectiveness of DMF and TRF in terms of clinical outcomes, but with better MRI-based outcomes for DMF-treated patients, resulting in a lower rate of treatment discontinuation due to lack of effectiveness.
This study provides Class III evidence that for patients with RRMS, TRF and DMF have similar clinical effectiveness after 2 years of treatment.
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