Search

Purpose: The last updates to diagnostic criteria for multiple sclerosis (MS) included a diagnostic category of 'possible MS'. However, no recent data is available to assess how much this distinction helps predict MS after isolated optic neuritis (ON). This study aimed to assess the global risk of developing MS one year after a first ON episode, and the specific risk according to the initial diagnosis of isolated ON or ON with possible MS., Methods: One-year follow-up of a multicentric prospective cohort of adult patients with acute ON., Results: This study included 55 patients with acute ON of no known etiological diagnosis. Overall, the final diagnosis at one year was MS (23, 42 %), MOGAD (7, 13 %), NMOSD (1, 2 %), CRION (3, 5 %), possible MS (6, 11 %), secondary ON (3, 5 %), and strictly isolated ON (12, 22 %). Three of the 17 (18 %) patients with strictly isolated ON and 2/8 (25 %) with possible MS at baseline progressed to MS. All secondary MS diagnosis were made through radiological monitoring., Conclusion: One year after the first ON episode, we observed a similar conversion rate to MS for patients with strictly isolated ON and possible MS, with a higher prevalence of MS than found by the ONTT., Competing Interests: Declaration of competing interest All the authors declare no competing interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Neurosarcoidosis (NS) is a systemic inflammatory granulomatous disease affecting of patients with sarcoidosis. Its diagnosis is difficult as there is no specific test for it. Because of its rarity, the management of NS has so far only been described in case series and short retrospective cohorts. The objective of this study is description of the clinical, paraclinical presentation and the therapeutic management of central nervous system (CNS) involvement in NS patients in France., Methods: This multicenter, retrospective, observational study involved patients hospitalized between 2010 and 2019 with a diagnosis of sarcoidosis and CNS involvement., Results: We included 118 patients (38 with isolated NS, 80 with NS associated with systemic sarcoidosis). NS was the initial presentation in 78% of patients, with cranial nerve involvement (36%), medullary symptoms (23%), and seizures (21%). Twenty-one percent of the patients had already been diagnosed with systemic sarcoidosis. The most frequent biological abnormality was lymphopenia (62.5%), while angiotensin-converting enzyme was increased in 21%. Meningitis was present in 45% and hyperproteinorachia in 69.5% of cases. MRI mainly revealed white matter abnormalities and leptomeningeal enhancement (34%). Corticosteroids were the most useful treatment, and immunosuppressive agents were used in steroid-resistant patients and to limit side effects. Methotrexate, cyclophosphamide, and anti-TNFα were also used, exhibiting good efficacy., Conclusions: This cohort contributes to a better understanding of the clinical phenotype and associated imaging and biological abnormalities. Sharing of clinical, biological, and imaging data, as well as the therapeutic responses, of patients with NS helps to better understand and manage this disease that affects a small number of patients per center. A database project could be implemented in the future to enable this., (© 2024 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Importance: Understanding the association between clinically defined relapses and radiological activity in multiple sclerosis (MS) is essential for patient treatment and therapeutic development., Objective: To investigate clinical events identified as relapses but not associated with new T2 lesions or gadolinium-enhanced T1 lesions on brain and spinal cord magnetic resonance imaging (MRI)., Design, Setting, and Participants: This multicenter observational cohort study was conducted between January 2015 and June 2023. Data were extracted on June 8, 2023, from the French MS registry. All clinical events reported as relapses in patients with relapsing-remitting MS were included if brain and spinal cord MRI was performed within 12 and 24 months before the event, respectively, and 50 days thereafter with gadolinium injection., Exposures: Events were classified as relapses with active MRI (RAM) if a new T2 lesion or gadolinium-enhanced T1 lesion appeared on brain or spinal cord MRI or as acute clinical events with stable MRI (ACES) otherwise., Main Outcomes and Measures: Factors associated with ACES were investigated; patients with ACES and RAM were compared regarding Expanded Disability Status Scale (EDSS) course, relapse rate, confirmed disability accrual (CDA), relapse-associated worsening (RAW), progression independent of relapse activity (PIRA), and transition to secondary progressive (SP) MS, and ACES and RAM rates under each disease-modifying therapy (DMT) were estimated., Results: Among 31 885 clinical events, 637 in 608 patients (493 [77.4%] female; mean [SD] age, 35.8 [10.7] years) were included. ACES accounted for 166 (26.1%) events and were more likely in patients receiving highly effective DMTs, those with longer disease duration (odds ratio [OR], 1.04; 95% CI, 1.01-1.07), or those presenting with fatigue (OR, 2.14; 95% CI, 1.15-3.96). ACES were associated with significant EDSS score increases, lower than those found for RAM. Before the index event, patients with ACES experienced significantly higher rates of relapse (relative rate [RR], 1.21; 95% CI, 1.01-1.46), CDA (hazard ratio [HR], 1.54; 95% CI, 1.13-2.11), and RAW (HR, 1.72; 95% CI, 1.20-2.45). Patients with ACES were at significantly greater risk of SP transition (HR, 2.58; 95% CI, 1.02-6.51). Although RAM rate decreased with DMTs according to their expected efficacy, ACES rate was stable across DMTs., Conclusions and Relevance: The findings in this study introduce the concept of ACES in MS, which accounted for one-fourth of clinical events identified as relapses.

Purpose: To compare the efficacy of treatment of optic neuritis (ON) with corticosteroids (CTC) alone, CTC+plasmapheresis (PLP), and CTC+intravenous immunoglobulin (IVIG)., Design: After an episode of ON, although visual recovery is usually good, some patients may have significant visual sequelae. While the efficacy of first-line CTC is now indisputable, there is no consensus on the nature of second-line treatment. To date, no systematic review has compared the efficacy of treatment of ON with CTC alone, CTC+plasmapheresis (PLP), and CTC+intravenous immunoglobulin (IVIG). A meta-analysis is needed to compare the efficacy of PLP and IVIG in steroid-resistant ON., Methods: This systematic review included all studies comparing at least two of the three treatments for steroid-resistant ON (CTC alone, CTC+PLP, and CTC+IVIG). From all articles published on PubMed between January 2000 and June 2022, two independent ophthalmologists selected studies of interest using the PRISMA method. Methodology, patient characteristics, and outcomes were identified. A network metaanalysis was then performed to compare the efficacy of the three treatments., Results: Six comparative studies were included, representing 209 patients. The percentage of significant visual recovery after CTC alone, CTC+PLP, and CTC+IVIG in the acute treatment of steroid-resistant ON was 30 %, 45 %, and 77 %, respectively. Comparison of CTC+IVIG vs CTC alone, CTC+PLP vs CTC only, and CTC+PLP vs CTC+IVIG yielded odds ratios of 12.81, 2.47, and 0.19 respectively., Conclusion: Treatment of steroid-resistant ON with CTC+PLP or CTC+IVIG is more effective than treatment with CTC alone. Although no study has directly compared the two treatments, IVIG may be more effective than PLP., Competing Interests: Declaration of competing interest None, (Copyright © 2024 Elsevier B.V. All rights reserved.)

In multiple sclerosis (MS), alterations of the gut microbiota lead to inflammation. However, the role of other microbiomes in the body in MS has not been fully elucidated. In a pilot case-controlled study, we carried out simultaneous characterization of faecal and oral microbiota and conducted an in-depth analysis of bacterial alterations associated with MS. Using 16S rRNA sequencing and metabolic inference tools, we compared the oral/faecal microbiota and bacterial metabolism pathways in French MS patients (n = 14) and healthy volunteers (HV, n = 21). A classification model based on metabolite flux balance was established and validated in an independent German cohort (MS n = 12, HV n = 38). Our analysis revealed decreases in diversity indices and oral/faecal compartmentalization, the depletion of commensal bacteria (Aggregatibacter and Streptococcus in saliva and Coprobacter and Roseburia in faeces) and enrichment of inflammation-associated bacteria in MS patients (Leptotrichia and Fusobacterium in saliva and Enterobacteriaceae and Actinomyces in faeces). Several microbial pathways were also altered (the polyamine pathway and remodelling of bacterial surface antigens and energetic metabolism) while flux balance analysis revealed associated alterations in metabolite production in MS (nitrogen and nucleoside). Based on this analysis, we identified a specific oral metabolite signature in MS patients, that could discriminate MS patients from HV and rheumatoid arthritis patients. This signature allowed us to create and validate a discrimination model on an independent cohort, which reached a specificity of 92%. Overall, the oral and faecal microbiomes were altered in MS patients. This pilot study highlights the need to study the oral microbiota and oral health implications in patients with autoimmune diseases on a larger scale and suggests that knowledge of the salivary microbiome could help guide the identification of new pathogenic mechanisms associated with the microbiota in MS patients., (© 2024. The Author(s).)

Importance: 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., Objective: To assess the real-world association of HET as an index treatment compared with MET with disease activity., Design, Setting, and Participants: 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., Exposure: HET or MET at treatment initiation., Main Outcomes and Measures: 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., Results: 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)., Conclusions and Relevance: 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.

Introduction: Patient partnership is a key component of patient-centred care. One form of partnership is individual peer support, which can improve patients' quality of life and adherence to treatment. Patient with multiple sclerosis could benefit from this type of support, but such an intervention has not been explored in the literature.We propose in this article a pilot study protocol to assess the feasibility and acceptability of healthcare-integrated individual peer support, and the feasibility of a large-scale efficacy trial., Methods and Analysis: The PAIR-SEP study is a mixed-methods pilot clinical trial combining quantitative and qualitative approaches. Sixty patients with relapsing-remitting multiple sclerosis undergoing drug therapy from the Neurology centre of Nantes University Hospital (France) will be randomised on a 1:1 ratio to receive either usual care only or usual care combined with peer support (three individual sessions at 1, 3 and 5 months with a peer helper).We will evaluate clinical outcomes in preparation of the large-scale trial: therapeutic adherence 6 months after baseline, therapeutic compliance, quality of life, anxiety and depression, social support. All dimensions will be assessed using validated health questionnaires at baseline and at 6 months.Intervention's acceptability and feasibility will be evaluated using qualitative methods: undirected interviews with patients from the intervention group and separate focus-groups with the peer helpers the healthcare team., Ethics and Dissemination: Ethical approval was obtained from the local ethics committee on 1 October 2022. This study was designed in collaboration with multiple sclerosis peer helpers.The trial findings will be published in peer-reviewed journals., Trial Registration Number: NCT05519553., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Radiologically isolated syndrome (RIS) represents the earliest detectable preclinical phase of multiple sclerosis (MS) punctuated by incidental magnetic resonance imaging (MRI) white matter anomalies within the central nervous system., Objective: To determine the time to onset of symptoms consistent with MS., Design, Setting, and Participants: From September 2017 to October 2022, this multicenter, double-blind, phase 3, randomized clinical trial investigated the efficacy of teriflunomide in delaying MS in individuals with RIS, with a 3-year follow-up. The setting included referral centers in France, Switzerland, and Turkey. Participants older than 18 years meeting 2009 RIS criteria were randomly assigned (1:1) to oral teriflunomide, 14 mg daily, or placebo up to week 96 or, optionally, to week 144., Interventions: Clinical, MRI, and patient-reported outcomes (PROs) were collected at baseline and yearly until week 96, with an optional third year in the allocated arm if no symptoms have occurred., Main Outcomes: Primary analysis was performed in the intention-to-treat population, and safety was assessed accordingly. Secondary end points included MRI outcomes and PROs., Results: Among 124 individuals assessed for eligibility, 35 were excluded for declining to participate, not meeting inclusion criteria, or loss of follow-up. Eighty-nine participants (mean [SD] age, 37.8 [12.1] years; 63 female [70.8%]) were enrolled (placebo, 45 [50.6%]; teriflunomide, 44 [49.4%]). Eighteen participants (placebo, 9 [50.0%]; teriflunomide, 9 [50.0%]) discontinued the study, resulting in a dropout rate of 20% for adverse events (3 [16.7%]), consent withdrawal (4 [22.2%]), loss to follow-up (5 [27.8%]), voluntary withdrawal (4 [22.2%]), pregnancy (1 [5.6%]), and study termination (1 [5.6%]). The time to the first clinical event was significantly extended in the teriflunomide arm compared with placebo, in both the unadjusted (hazard ratio [HR], 0.37; 95% CI, 0.16-0.84; P = .02) and adjusted (HR, 0.28; 95% CI, 0.11-0.71; P = .007) analysis. Secondary imaging end point outcomes including the comparison of the cumulative number of new or newly enlarging T2 lesions (rate ratio [RR], 0.57; 95% CI, 0.27-1.20; P = .14), new gadolinium-enhancing lesions (RR, 0.33; 95% CI, 0.09-1.17; P = .09), and the proportion of participants with new lesions (odds ratio, 0.72; 95% CI, 0.25-2.06; P = .54) were not significant., Conclusion and Relevance: Treatment with teriflunomide resulted in an unadjusted risk reduction of 63% and an adjusted risk reduction of 72%, relative to placebo, in preventing a first clinical demyelinating event. These data suggest a benefit to early treatment in the MS disease spectrum., Trial Registration: ClinicalTrials.gov Identifier: NCT03122652.

Background: To characterise the response to treatment of inaugural optic neuritis (ON) in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD)., Methods: We searched the French MOGAD database for adults with inaugural ON with a detailed report of acute treatment modalities and measures of high-contrast best-corrected visual acuity (BCVA) at nadir and after 3 months. Predictors of visual outcomes were assessed by multivariable analysis., Results: Among 245 patients with at least one episode of ON, 82 fulfilled all criteria, and data on the peripapillary retinal nerve fibre layer (pRNFL) were available for 44. All patients received methylprednisolone (MP), combined with plasma exchange in 18. After 3 months, 75 of 82 (91%) patients retained full BCVA recovery, and median (range) pRNFL of the affected eye was 72 µm (40-102). Failure to regain 0.0 logarithmic minimum angle of resolution vision (Snellen 20/20) at 3 months was associated with time to first MP treatment ≥10 days (OR 16, 95% CI 1.14 to 213, p=0.01). pRNFL thickness after 3 months was related to better BCVA at nadir and time to first MP treatment <10 days (r2=19%, p=0.004 and r2=11%, p=0.03, respectively)., Conclusions: Time to MP affects functional but also structural visual outcomes of ON in MOGAD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Multiple sclerosis is an autoimmune disease of the central nervous system. Yet, the autoimmune targets are still undefined. The extracellular e1 sequence of KCNJ10, the inwardly rectifying potassium channel 4.1, has been subject to fierce debate for its role as a candidate autoantigen in multiple sclerosis. Inwardly rectifying potassium channel 4.1 is expressed in the central nervous system but also in peripheral tissues, raising concerns about the central nervous system-specificity of such autoreactivity. Immunization of C57Bl6/J female mice with the e1 peptide (amino acids 83-120 of Kir4.1) induced anti-e1 immunoglobulin G- and T-cell responses and promoted demyelinating encephalomyelitis with B cell central nervous system enrichment in leptomeninges and T cells/macrophages in central nervous system parenchyma from forebrain to spinal cord, mostly in the white matter. Within our cohort of multiple sclerosis patients ( n = 252), 6% exhibited high anti-e1 immunoglobulin G levels in serum as compared to 0.7% in the control cohort ( n = 127; P = 0.015). Immunolabelling of inwardly rectifying potassium channel 4.1-expressing white matter glia with the anti-e1 serum from immunized mice increased during murine autoimmune neuroinflammation and in multiple sclerosis white matter as compared with controls. Strikingly, the mouse and human anti-e1 sera labelled astrocytoma cells when N -glycosylation was blocked with tunicamycin. Western blot confirmed that neuroinflammation induces Kir4.1 expression, including its shorter aglycosylated form in murine experimental autoencephalomyelitis and multiple sclerosis. In addition, recognition of inwardly rectifying potassium channel 4.1 using mouse anti-e1 serum in Western blot experiments under unreduced conditions or in cells transfected with the N -glycosylation defective N104Q mutant as compared to the wild type further suggests that autoantibodies target an e1 conformational epitope in its aglycosylated form. These data highlight the e1 sequence of inwardly rectifying potassium channel 4.1 as a valid central nervous system autoantigen with a disease/tissue-specific post-translational antigen modification as potential contributor to autoimmunity in some multiple sclerosis patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background and Objectives: Ocrelizumab (OCR), a humanized anti-CD20 monoclonal antibody, is highly efficient in patients with relapsing-remitting multiple sclerosis (RR-MS). We assessed early cellular immune profiles and their association with disease activity at treatment start and under therapy, which may provide new clues on the mechanisms of action of OCR and on the disease pathophysiology., Methods: A first group of 42 patients with an early RR-MS, never exposed to disease-modifying therapy, was included in 11 centers participating to an ancillary study of the ENSEMBLE trial (NCT03085810) to evaluate the effectiveness and safety of OCR. The phenotypic immune profile was comprehensively assessed by multiparametric spectral flow cytometry at baseline and after 24 and 48 weeks of OCR treatment on cryopreserved peripheral blood mononuclear cells and analyzed in relation to disease clinical activity. A second group of 13 untreated patients with RR-MS was included for comparative analysis of peripheral blood and CSF. The transcriptomic profile was assessed by single-cell qPCRs of 96 genes of immunologic interest., Results: Using an unbiased analysis, we found that OCR as an effect on 4 clusters of CD4 + T cells: one corresponding to naive CD4 + T cells was increased, the other clusters corresponded to effector memory (EM) CD4 + CCR6 - T cells expressing homing and migration markers, 2 of them also expressing CCR5 and were decreased by the treatment. Of interest, one CD8 + T-cell cluster was decreased by OCR corresponding to EM CCR5-expressing T cells with high expression of the brain homing markers CD49d and CD11a and correlated with the time elapsed since the last relapse. These EM CD8 + CCR5 + T cells were enriched in the CSF of patients with RR-MS and corresponded to activated and cytotoxic cells., Discussion: Our study provides novel insights into the mode of action of anti-CD20, pointing toward the role of EM T cells, particularly a subset of CD8 T cells expressing CCR5., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: In relapsing-remitting multiple sclerosis (RRMS), early identification of suboptimal responders can prevent disability progression., Objective: We aimed to develop and validate a dynamic score to guide the early decision to switch from first- to second-line therapy., Methods: Using time-dependent propensity scores (PS) from a French cohort of 12,823 patients with RRMS, we constructed one training and two validation PS-matched cohorts to compare the switched patients to second-line treatment and the maintained patients. We used a frailty Cox model for predicting individual hazard ratios (iHRs)., Results: From the validation PS-matched cohort of 348 independent patients with iHR ⩽ 0.69, we reported the 5-year relapse-free survival at 0.14 (95% confidence interval (CI) 0.09-0.22) for the waiting group and 0.40 (95% CI 0.32-0.51) for the switched group. From the validation PS-matched cohort of 518 independent patients with iHR > 0.69, these values were 0.37 (95% CI 0.30-0.46) and 0.44 (95% CI 0.37-0.52), respectively., Conclusions: By using the proposed dynamic score, we estimated that at least one-third of patients could benefit from an earlier switch to prevent relapse.

Background and Purpose: There has been scant research on the consequences of discontinuing second-line disease-modifying treatment (DMT) in middle-aged patients with multiple sclerosis (MS). The objective was therefore to examine the occurrence of focal inflammatory activity after the discontinuation of second versus first-line DMT in patients over 45 years., Methods: Patients who had been treated for at least 6 months with second (natalizumab, fingolimod, anti CD20) or first-line DMT and who stopped their DMT were retrospectively included. Kaplan-Meier survival curves were used to study the occurrence of relapse and MRI activity according to the type of DMT stopped. Proportional hazard Cox models were calculated to identify factors associated with focal inflammatory activity. The annualized relapse rate was calculated under treatment and for every 3 months after DMT discontinuation., Results: We included 232 patients (median age: 52.8 years), 49 of whom stopped second-line DMT. The probability of having a relapse within the year following discontinuation was 6% for first-line DMT, 9% for fingolimod and 43% for natalizumab. In multivariate analysis, the probability of relapse after DMT discontinuation was significantly increased with natalizumab compared to first-line DMT (HR = 3.24; 95% CI [1.52; 6.90]). A peak of relapse was observed at 0-3 months after stopping natalizumab or fingolimod., Conclusion: Our study suggests that the risk of inflammatory activity is greater after discontinuation of natalizumab compared to other DMT even in middle-aged patients. As for younger patients, natalizumab discontinuation should only be considered if there is an adequate substitution of a different therapy. ., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: In Multiple Sclerosis (MS) women, therapeutic management for pregnancy planning and during pregnancy still represents a challenge regarding timing of disease-modifying therapies (DMT) stop, risk of disease reactivation and potential fetal toxicity. The objective of this study was to describe disease activity during pregnancy and postpartum depending on treatment status before conception in women with MS., Methods: 339 MS patients who have achieved a pregnancy between 2007 and 2017 were included. Women were classified according to their exposure to DMT in the 18 months period prior to pregnancy (untreated / first- / second/third-line treatment)., Results: 122 women were not exposed to DMT prior to conception, whereas 147 were exposed to first-line DMT and 70 to second/third line DMT (73% to natalizumab and 23% to fingolimod) before conception. In the first-line group, the ARR decreased from 0.39 during the year before conception to 0.21 during pregnancy, whereas it increased in the second/third-line group from 0.59 to 0.78. 47.1% of the second/third-line group faced at least one relapse during pregnancy and the time from conception to first relapse was significantly shorter in this group (p < 10 -4 ). The risk of relapse during pregnancy and postpartum was associated with occurrence of pre-conception relapses and second/third line DMT exposure before pregnancy., Conclusion: Careful consideration should be given to natalizumab and fingolimod exposed patients before conception as they are at higher risk of reactivation of MS during pregnancy., (Copyright © 2022. Published by Elsevier B.V.)

Background and Objectives: Tertiary lymphoid structures and aggregates are reported in the meninges of patients with multiple sclerosis (MS), especially at the progressive stage, and are strongly associated with cortical lesions and disability. Besides B cells, these structures comprise follicular helper T (Tfh) cells that are crucial to support B-cell differentiation. Tfh cells play a pivotal role in amplifying autoreactive B cells and promoting autoantibody production in several autoimmune diseases, but very few are known in MS. In this study, we examined the phenotype, frequency, and transcriptome of circulating cTfh cells in the blood and CSF of patients with relapsing-remitting MS (RRMS)., Methods: The phenotype and frequency of cTfh cells were analyzed in the blood of 39 healthy controls and 41 untreated patients with RRMS and in the CSF and paired blood of 10 patients with drug-naive RRMS at diagnosis by flow cytometry. Using an in vitro model of blood-brain barrier, we assessed the transendothelial migratory abilities of the different cTfh-cell subsets. Finally, we performed an RNA sequencing analysis of paired CSF cTfh cells and blood cTfh cells in 8 patients sampled at their first demyelinating event., Results: The blood phenotype and frequency of cTfh cells were not significantly modified in patients with RRMS. In the CSF, we found an important infiltration of Tfh1 cells, with a high proportion of activated PD1 + cells. We demonstrated that the specific subset of Tfh1 cells presents increased migration abilities to cross an in vitro model of blood-brain barrier. Of interest, even at the first demyelinating event, cTfh cells in the CSF display specific characteristics with upregulation of EOMES gene and proinflammatory/cytotoxic transcriptomic signature able to efficiently distinguish cTfh cells from the CSF and blood. Finally, interactome analysis revealed potential strong cross talk between pathogenic B cells and CSF cTfh cells, pointing out the CSF as opportune supportive compartment and highlighting the very early implication of B-cell helper T cells in MS pathogenesis., Discussion: Overall, CSF enrichment in activated Tfh1 as soon as disease diagnosis, associated with high expression of EOMES, and a predicted high propensity to interact with CSF B cells suggest that these cells probably contribute to disease onset and/or activity., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: No specific treatment has demonstrated its effectiveness to prevent post-partum relapses for multiple sclerosis (MS) women., Objective: To assess the effectiveness of preventive high-dose corticosteroids in the post-partum period by comparing two strategies: (1) no preventive treatment and (2) standardized preventive treatment., Methods: We selected five French Multiple Sclerosis centers using the same post-partum strategy for their patients-either high-dose steroids (treating centers TC) or no treatment (non-treating centers NTC). We included relapsing-remitting multiple sclerosis women who delivered between January 2007 and January 2017. Our primary outcomes were the time from delivery to first relapse, EDSS progression and MRI activity between patients of treating centers and non-treating centers, after propensity-score weighting., Results: 350 patients were included (116 from treating centers, 234 from non-treating centers). For both groups, the annualized relapse rate decreased during pregnancy (0.28 in treating centers and 0.34 in non-treating centers during the third trimester) and increased during the first post-partum trimester (0.45 and 0.69, respectively) with 11% and 14% (NS) of patients facing at least one relapse, respectively. Our primary outcomes were not statistically different between both groups., Conclusion: This study provides class III evidence that systematic high-dose corticosteroids are not associated with a reduced inflammatory activity during the post-partum period in multiple sclerosis patients., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Introduction: Assessing the quality of care management for patients with a chronic disease such as multiple sclerosis (MS) is a major challenge for healthcare systems around the world. It needs to be carried out using tools that are recognized by professionals and patients alike, and should concern practices, systems, and scientific data. No such tools are currently available in Europe. The purpose of the present study was to develop indicators to contribute to assess the quality of care management for patients with MS in France., Methods: An expert panel comprising 25 professionals from well known teams across France selected the indicators on the basis of consensus. In accordance with the Rand/UCLA Appropriateness Method, each expert had to agree with the recommendations, and there had to be agreement among the experts., Results: The expert panel selected 48 indicators representing seven domains of care management for patients with MS: physical and rehabilitation medicine, disease progression, access to care, magnetic resonance imaging (MRI) management, relapse management, management of disease-modifying treatments, and management of the symptoms of disability progression. Some of these quality indicators (notably pertaining to MRI management) had not previously been identified in the literature., Conclusion: These indicators may allow professionals to comprehensively assess and compare their practices and cooperation, thereby contributing to improve the quality of care management for patients with MS in France., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Introduction: Evaluating the quality of the care pathway for patients with chronic diseases, such as multiple sclerosis (MS), is an important issue. Process indicators are a recognized method for evaluating professional practices. However, these tools have been little developed in the field of MS, and few data are available. The aim of this study was to describe, retrospectively, with validated indicators, the quality of the care pathway in a population-based cohort of 700 patients with the first manifestations of the disease occurring between January 1, 2000 and December 31, 2001 and during the first 10 years of disease., Method: This assessment was based on 48 indicators specific to MS. The information required for the calculation of each indicator was collected from the source files of the 700 patients of the cohort., Results: Data for the 10 years of follow-up were collected for 80% of the patients. In total, 36 indicators were calculated. These results reveal that there is room for improvement, particularly in terms of the initial assessment, access to ophthalmological evaluation, employment, obtaining an evaluation of the need for rehabilitation and access to such care., Conclusion: The results of this survey provide access to unprecedented new data in France, that professionals and patients can appropriate to improve the targeting of actions, to improve the quality of care further for patients with MS in France. We propose to continue this process by submitting, for discussion, a targeted list of updated indicators relating to changes in guidelines, and in issues concerning the quality of patient management., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Background: Studies have shown that oral high-dose methylprednisolone (MP) is non-inferior to intravenous MP in treating multiple sclerosis relapses in terms of effectiveness and tolerance. In order to assist with resource allocation and decision-making, its cost-effectiveness must also be assessed. Our objective was to evaluate the cost-utility of per os high-dose MP as well as the cost-savings associated with implementing the strategy., Methods: A cost-utility analysis at 28 days was carried out using data from the French COPOUSEP multicenter, double-blind randomized controlled non-inferiority trial and the statutory health insurance reimbursement database. Costs were calculated using a societal perspective, including both direct and indirect costs. An incremental cost-effectiveness ratio was calculated and bootstrapping methods assessed the uncertainty surrounding the results. An alternative scenario analysis in which MP was administered at home was also carried out. A budgetary impact analysis was carried at five years., Results: In the conditions of the trial (hospitalized patients), there was no significant difference in utilities and costs at 28 days. The incremental cost-effectiveness ratio was €15,360 per quality-adjusted life-year gained. If multiple sclerosis relapses were treated at home, oral MP would be more effective, less costly and associated with annual savings up to 25 million euros for the French healthcare system., Conclusions: Oral MP is cost-effective in the treatment of multiple sclerosis relapses and associated with major savings., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

In France, two therapeutic strategies can be offered after fingolimod (FNG) withdrawal to highly active relapsing-remitting multiple sclerosis (RRMS) patients: natalizumab (NTZ) or anti-CD20. We compared the effectiveness of these two strategies as a switch for FNG within the OFSEP database. The primary endpoint was the time to first relapse. Other outcomes were the relapse rates over 3-month periods, time to worsening the EDSS score, proportion of patients with worsened 24-month MRI, time to treatment discontinuation, and incidence rates of serious adverse events. The dynamics of event rates over time were modeled using multidimensional penalized splines, allowing the possibility to model the effects of covariates in a flexible way, considering non-linearity and interactions. A total of 740 patients were included (337 under anti-CD20 and 403 under NTZ). There was no difference between the two treatments regarding the dynamic of the first occurrence of relapse, with a monthly probability of 5.0% at initiation and 1.0% after 6 months. The rate of EDSS worsening increased in both groups until 6 months and then decreased. No difference in the proportion of patients with new T2 lesions at 24 months was observed. After 18 months of follow-up, a greater risk of NTZ discontinuation was found compared to anti-CD20. This study showed no difference between NTZ and anti-CD20 after the FNG switch regarding the clinical and radiological activity. The effect of these treatments was optimal after 6 months and there was more frequent discontinuation of NTZ after 18 months, probably mainly related to JC virus seroconversions., (© 2022. The American Society for Experimental NeuroTherapeutics, Inc.)

Background and Objectives: Inhibition of de novo pyrimidine synthesis in proliferating T and B lymphocytes by teriflunomide, a pharmacological inhibitor of dihydroorotate dehydrogenase (DHODH), has been shown to be an effective therapy to treat patients with MS in placebo-controlled phase 3 trials. Nevertheless, the underlying mechanism contributing to the efficacy of DHODH inhibition has been only partially elucidated. Here, we aimed to determine the impact of teriflunomide on the immune compartment in a longitudinal high-dimensional follow-up of patients with relapse-remitting MS (RRMS) treated with teriflunomide., Methods: High-dimensional spectral flow cytometry was used to analyze the phenotype and the function of innate and adaptive immune system of patients with RRMS before and 12 months after teriflunomide treatment. In addition, we assessed the impact of teriflunomide on the migration of memory CD8 T cells in patients with RRMS, and we defined patient immune metabolic profiles., Results: We found that 12 months of treatment with teriflunomide in patients with RRMS does not affect the B cell or CD4 T cell compartments, including regulatory T REG follicular helper T FH cell and helper T H cell subsets. In contrast, we observed a specific impact of teriflunomide on the CD8 T cell compartment, which was characterized by decreased homeostatic proliferation and reduced production of TNFα and IFNγ. Furthermore, we showed that DHODH inhibition also had a negative impact on the migratory velocity of memory CD8 T cells in patients with RRMS. Finally, we showed that the susceptibility of memory CD8 T cells to DHODH inhibition was not related to impaired metabolism., Discussion: Overall, these findings demonstrate that the clinical efficacy of teriflunomide results partially in the specific susceptibility of memory CD8 T cells to DHODH inhibition in patients with RRMS and strengthens active roles for these T cells in the pathophysiological process of MS., Competing Interests: DL has received consulting and lecturing fees, travel grants and unconditional research support from Biogen, Genzyme, Novartis, Merck, Roche, Sanofi, Medday, Teva Pharma and BMS. SW has received speaking honoraria and travel expense reimbursement for participation in scientific meetings and has participated in advisory boards in the past years with Alexion, Biogen, Merck, Novartis, Roche, Sanofi and Teva. 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 © 2021 Tilly, Cadoux, Garcia, Morille, Wiertlewski, Pecqueur, Brouard, Laplaud and Degauque.)

Background: Long-term effectiveness of treatment remains a key question in multiple sclerosis (MS) and the cumulative effects of past treatment have not been investigated so far., Objective: Explore the relationship between treatment exposure and disability risk in patients with relapsing-remitting multiple sclerosis (RRMS)., Methods: A total of 2285 adult patients from the French nationwide cohort were included. Outcomes were irreversible EDSS4, and conversion to secondary progression of multiple sclerosis (SPMS). Associations between treatments and risk of disability were assessed using a novel weighted cumulative exposure model, assuming a 3-year lag to account for reverse causality. This flexible approach accounts for past exposure in a multivariate Cox proportional hazards model by computing a weight function., Results: At baseline, mean ± standard deviation age of patients was 33.4 ± 8.9 years and 75.0% were women. A 15-year continuous treatment starting 20 years ago was associated with a decrease in risk of 26% for irreversible EDSS4, and 34% for SPMS compared to a 5-year treatment starting 10 years ago. The risk of disability decreased with increasing duration of exposure to disease-modifying treatment (DMT)., Conclusion: Long-term use of treatments in RRMS has a stronger beneficial cumulative impact than only early uses and delays the occurrence of moderate disability and conversion to SPMS.

Background: There are few head-to-head studies to compare highly active treatments in multiple sclerosis (MS)., Objective: The aim of this study was to compare the effectiveness between natalizumab (NTZ) and fingolimod (FTY) in active relapsing-remitting MS., Method: Best Escalation STrategy in Multiple Sclerosis (BEST-MS) is a multicentric, prospective study with a 12-month follow-up including patients with active MS. Treatment choice was at the discretion of physician. Clinical and magnetic resonance imaging (MRI) data were collected at baseline and at 12 months. The primary outcome was the proportion of patients reaching no evidence of disease activity (NEDA) at 12 months. Secondary outcomes included annualized relapse rate and MRI activity., Results: A total of 223 patients were included (NTZ: 109 and FTY: 114). Treatment groups were well balanced at baseline. Proportion of NEDA patients was 47.8% in NTZ group versus 30.4% in FTY group ( p  = 0.015). This superiority was driven by annualized relapse rate and MRI activity. In the multivariate analysis, treatment group was the only factor associated with NEDA at 12 months with a lower probability in FTY group (odds ratio (OR) = 0.49, p  = 0.029)., Conclusion: BEST-MS is a prospective study that compared head-to-head the effectiveness of NTZ and FTY in active relapsing-remitting MS. Our results suggest a superiority of NTZ over FTY.

Optic neuritis (ON) can be associated with inflammatory disease of the central nervous system or can be isolated, with or without relapse. It can also be associated with infectious or systemic disease. These multiple associations based on a variety of clinical, radiological, and biological criteria that have changed over time have led to overlapping phenotypes: a single ON case can be classified in several ways simultaneously or over time. As early, intensive treatment is often required, its diagnosis should be rapid and precise. In this review, we present the current state of knowledge about diagnostic criteria for ON aetiologies in adults and children, we discuss overlapping phenotypes, and we propose a homogeneous classification scheme. Even if distinctions between typical and atypical ON are relevant, their phenotypes are largely overlapping, and clinical criteria are neither sensitive enough, nor specific enough, to assure a diagnosis. For initial cases of ON, clinicians should perform contrast enhanced MRI of the brain and orbits, cerebral spinal fluid analysis, and biological analyses to exclude secondary infectious or inflammatory ON. Systematic screening for MOG-IgG and AQP4-IgG IgG is recommended in children but is still a matter of debate in adults. Early recognition of neuromyelitis optica spectrum disorder, MOG-IgG-associated disorder , and chronic relapsing idiopathic optic neuritis is required, as these diagnoses require therapies for relapse prevention that are different from those used to treat multiple sclerosis.

Background and Purpose: Patients with a chronic illness, such as multiple sclerosis (MS), and their natural caregivers have a specific experience of healthcare and health services. These experiences need to be assessed to evaluate the quality of care. Our objective was to develop a French-language questionnaire to evaluate the quality of care as experienced by MS patients and their natural caregivers., Methods: Eligible patients had been diagnosed with MS according to the McDonald criteria. Eligible caregivers were individuals designated by the patients. The MusiCare questionnaire was developed in two standard phases: (i) item generation, based on interviews with patients and caregivers; and (ii) validation, consisting of validity, reliability, external validity, reproducibility, and responsiveness measures., Results: In total, 1088 patients (n = 660) and caregivers (n = 488) were recruited. The initial 64-item version of MusiCare was administered to a random subsample (n = 748). The validation process generated a 35-item questionnaire. Internal consistency and scalability were satisfactory. Testing of the external validity revealed expected associations between MusiCare scores and sociodemographic and clinical data. The questionnaire showed good reproducibility and responsiveness., Conclusions: The availability of a reliable and validated French-language self-report questionnaire probing the experience of the quality of care for MS will allow the feedback of patients and caregivers to be incorporated into a continuous healthcare quality-improvement strategy., (© 2020 European Academy of Neurology.)

Background: In relapsing-remitting multiple sclerosis (RRMS), relapse severity and residual disability are difficult to predict. Nevertheless, this information is crucial both for guiding relapse treatment strategies and for informing patients., Objective: We, therefore, developed and validated a clinical-based model for predicting the risk of residual disability at 6 months post-relapse in MS., Methods: We used the data of 186 patients with RRMS collected during the COPOUSEP multicentre trial. The outcome was an increase of ≥ 1 EDSS point 6 months post-relapse treatment. We used logistic regression with LASSO penalization to construct the model, and bootstrap cross-validation to internally validate it. The model was externally validated with an independent retrospective French single-centre cohort of 175 patients., Results: The predictive factors contained in the model were age > 40 years, shorter disease duration, EDSS increase ≥ 1.5 points at time of relapse, EDSS = 0 before relapse, proprioceptive ataxia, and absence of subjective sensory disorders. Discriminative accuracy was acceptable in both the internal (AUC 0.82, 95% CI [0.73, 0.91]) and external (AUC 0.71, 95% CI [0.62, 0.80]) validations., Conclusion: The predictive model we developed should prove useful for adapting therapeutic strategy of relapse and follow-up to individual patients.

Background: A recent controlled trial suggested that high-dose biotin supplementation reverses disability progression in patients with progressive multiple sclerosis., Objective: To analyze the impact of high-dose biotin in routine clinical practice on disability progression at 12 months., Methods: Progressive multiple sclerosis patients who started high-dose biotin at Nantes or Rennes Hospital between 3 June 2015 and 15 September 2017 were included in this prospective study. Disability outcome measures, patient-reported outcome measures, relapses, magnetic resonance imaging (MRI) data, and adverse events were collected at baseline, 6, and 12 months., Results: A total of 178 patients were included. At baseline, patients were 52.0 ± 9.4 years old, mean Expanded Disability Status Scale (EDSS) score was 6.1 ± 1.3, mean disease duration was 16.9 ± 9.5 years. At 12 months, 3.8% of the patients had an improved EDSS score. Regarding the other disability scales, scores either remained stable or increased significantly. In total, 47.4% of the patients described stability, 27.6% felt an improvement, and 25% described a worsening. Four patients (2.2%) had a relapse. Of the 74 patients (41.6%) who underwent an MRI, 20 (27.0%) had new T2 lesions, 8 (10.8%) had gadolinium-enhancing lesions. Twenty-five (14%) reported adverse event., Conclusion: In this study, high-dose biotin did not seem to be associated with a clear improvement in disability.

Background and Purpose: Fifteen percent of patients with myasthenia gravis (MG) are refractory to conventional treatment. Case reports and a few studies show probable benefit of rituximab in these cases. Our objective was to assess the efficacy and the safety of rituximab in patients with MG, in a multicentric real-life study., Method: Inclusion criteria were: age > 18 years; MG with anti-acetylcholine receptor (AChR) antibodies, anti-muscle-specific kinase (MuSk) antibodies or significant decrement after repetitive nerve stimulation; Myasthenia Gravis Foundation of America (MGFA) class >II; refractory or steroid-dependent MG; and treatment with rituximab. Efficacy was assessed at 6 months using the MGFA-post-intervention status (PIS) score, the myasthenic muscle score (MMS) and the number of patients receiving steroids <10 mg/day. Data on adverse events were collected., Results: Twenty-nine patients were included: 20 with anti-AChR MG, five with anti-MuSK MG and four with seronegative MG. MGFA-PIS score was improved or better (improved, minimal manifestations or remission) in 86.2% of patients after 6 months of treatment (P < 0.0001). The mean MMS increased from 68.8 to 83.1 (P < 0.0001). A decrease in steroid dosage (<10 mg/day) was effective in 57.9% of treated patients. In all, 42.8% of patients experienced adverse events: infections (21.4% of patients); infusion reaction (7%); bradycardia (3.7%); and cytopenia (7%)., Conclusion: The present study demonstrates the efficacy and safety of rituximab in patients with MG. Additional studies remain necessary to determine the role of rituximab in the pharmacopeia of MG treatment and to establish precise recommendations for the infusion protocol., (© 2020 European Academy of Neurology.)

Importance: Risk factors associated with the severity of coronavirus disease 2019 (COVID-19) in patients with multiple sclerosis (MS) are unknown. Disease-modifying therapies (DMTs) may modify the risk of developing a severe COVID-19 infection, beside identified risk factors such as age and comorbidities., Objective: To describe the clinical characteristics and outcomes in patients with MS and COVID-19 and identify factors associated with COVID-19 severity., Design, Setting, and Participants: The Covisep registry is a multicenter, retrospective, observational cohort study conducted in MS expert centers and general hospitals and with neurologists collaborating with MS expert centers and members of the Société Francophone de la Sclérose en Plaques. The study included patients with MS presenting with a confirmed or highly suspected diagnosis of COVID-19 between March 1, 2020, and May 21, 2020., Exposures: COVID-19 diagnosed with a polymerase chain reaction test on a nasopharyngeal swab, thoracic computed tomography, or typical symptoms., Main Outcomes and Measures: The main outcome was COVID-19 severity assessed on a 7-point ordinal scale (ranging from 1 [not hospitalized with no limitations on activities] to 7 [death]) with a cutoff at 3 (hospitalized and not requiring supplemental oxygen). We collected demographics, neurological history, Expanded Disability Severity Scale score (EDSS; ranging from 0 to 10, with cutoffs at 3 and 6), comorbidities, COVID-19 characteristics, and outcomes. Univariate and multivariate logistic regression models were used to estimate the association of collected variables with COVID-19 outcomes., Results: A total of 347 patients (mean [SD] age, 44.6 [12.8] years, 249 women; mean [SD] disease duration, 13.5 [10.0] years) were analyzed. Seventy-three patients (21.0%) had a COVID-19 severity score of 3 or more, and 12 patients (3.5%) died of COVID-19. The median EDSS was 2.0 (range, 0-9.5), and 284 patients (81.8%) were receiving DMT. There was a higher proportion of patients with a COVID-19 severity score of 3 or more among patients with no DMT relative to patients receiving DMTs (46.0% vs 15.5%; P < .001). Multivariate logistic regression models determined that age (odds ratio per 10 years: 1.9 [95% CI, 1.4-2.5]), EDSS (OR for EDSS ≥6, 6.3 [95% CI. 2.8-14.4]), and obesity (OR, 3.0 [95% CI, 1.0-8.7]) were independent risk factors for a COVID-19 severity score of 3 or more (indicating hospitalization or higher severity). The EDSS was associated with the highest variability of COVID-19 severe outcome (R2, 0.2), followed by age (R2, 0.06) and obesity (R2, 0.01)., Conclusions and Relevance: In this registry-based cohort study of patients with MS, age, EDSS, and obesity were independent risk factors for severe COVID-19; there was no association found between DMTs exposure and COVID-19 severity. The identification of these risk factors should provide the rationale for an individual strategy regarding clinical management of patients with MS during the COVID-19 pandemic.

Objective: What is the proportion of antibodies to myelin oligodendrocyte glycoprotein (MOG-Ab) in optic neuritis (ON) in adults and what would be the ON presentation for which MOG-Ab should be tested?, Methods: Multicentric prospective study conducted during 1 year on all patients diagnosed with acute ON in all ophthalmological units in hospitals in a region in western France., Results: Sixty-five patients were included. MOG-Ab prevalence was 14% (9/65) during an acute ON and 13% (7/55) after exclusion of patients already diagnosed with multiple sclerosis (MS) (8) or MOG+ON (2). Compared with MS and clinically isolated syndrome, MOG+ON had no female preponderance (67% of men in case of MOG+ON and 22% of men in case of MS and clinically isolated syndrome, p<0.05) were more often bilateral (44% vs 3%, p < 0.005) and associated with optic disc swelling (ODS) (78% vs 14%, p < 0.001). To predict MOG+ON, the positive predictive values (PPVs) of male sex, ODS and bilateral involvement were 29% (95% CI 9% to 48%), 41% (95% CI 18% to 65%) and 40% (95% CI 10% to 70%), respectively, while the negative predictive values (NPV) were 93% (95% CI 86% to 100%), 96% (95% CI 90% to 100%) and 91% (95% CI 83% to 99%), respectively. The combined factor 'ODS or bilateral or recurrent ON' was the best compromise between PPV (31% (95% CI 14% to 48%)) and NPV (100% (95% CI 100% to 100%))., Conclusion: Among ON episodes, MOG-Ab were found in 14% of cases. MOG+ON occurred without female preponderance and was significantly associated with ODS and/or bilateral ON. Testing MOG-Ab only in patients presenting with ODS or bilateral or recurrent ON would limit MOG-Ab tests to fewer than half of all patients without the risk of missing any MOG+ON cases., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)