Cohen, Mikaël

ABSTRACT Objectives We aimed to determine the frequency of subclinical optic nerve (ON) lesions using MRI, optical coherence tomography (OCT), and visual evoked potentials (VEP) in radiologically isolated syndrome (RIS), and to assess their diagnostic and prognostic significance. Methods We conducted a retrospective, multicenter study of 179 RIS individuals followed in clinical practice who met the 2023 RISC criteria. The diagnostic performance of the 2024 McDonald criteria, with and without optic nerve assessment, was evaluated and compared with that of the 2017 criteria. Associations with clinical conversion, comorbidities, and MRI disease activity were analyzed using multivariate models. Results Silent ON lesions appeared in 107/179 (59.8%) individuals, mainly detected by VEP (100/164; 61.0%) and OCT (69/118; 58.5%), with routine MRI identifying 31/166 (18.7%). During follow‐up, 71 (39.7%) had a first clinical event. The presence, laterality, or number of silent ON lesions did not correlate with clinical conversion, event type, or MRI activity. Younger age and the absence of comorbidities associated with other MRI lesions, rather than with ON lesions, were associated with clinical conversion. Including ON in the 2024 McDonald criteria increased sensitivity but decreased specificity, with 17/179 (9.5%) meeting dissemination‐in‐space criteria solely due to ON lesions. Interpretation Subclinical ON lesions are common in RIS and are mainly found by OCT and VEP, not routine MRI. Including ON increases sensitivity but does not predict clinical conversion and may lower specificity. These findings suggest cautious interpretation of ON and support a multimodal assessment approach in RIS.

Background: Previous studies have shown that people with multiple sclerosis (MS) had frequent healthcare visits up to 10 years before being diagnosed but with no information from magnetic resonance imaging (MRI) scans of the connection with the radiologically isolated syndrome (RIS). Objective: To analyze healthcare use 3 years before the RIS diagnosis. Methods: We examined healthcare usage before the first scan in RIS cases from 2010 to 2019. RIS subjects were identified from the French National MS observatory and compared to the general population (matched 10:1) and MS patients (matched 4:1). Results: Among 482 RIS individuals, 223 (46.3%) were not linked to the healthcare resources database. The remaining RIS individuals (53.7%) had higher healthcare usage before their RIS diagnosis for issues related to neurology visits, headaches (odds ratio (OR): 3.34, confidence interval (CI): [2.00–5.57], p < 0.0001), and the use of anti-migraine drugs (OR: 2.61, CI: [1.37–4.99], p = 0.004) compared to MS. Conclusion: Only about half of RIS patients had MS-selected healthcare resources, which allowed for data linkage. Those who did seek care before their RIS diagnosis were most commonly known for other neurological comorbidities. These findings do not support the idea of a systemic prodrome before RIS diagnosis.

AbstractObjectiveThe radiologically isolated syndrome (RIS) represents the earliest detectable preclinical phase of multiple sclerosis (MS). Increasing evidence suggests that the central vein sign (CVS) enhances lesion specificity, allowing for greater MS diagnostic accuracy. This study evaluated the diagnostic performance of the CVS in RIS.MethodsPatients were prospectively recruited in a single tertiary center for MS care. Participants with RIS were included and compared to a control group of sex and age‐matched subjects. All participants underwent 3 Tesla magnetic resonance imaging, including postcontrast susceptibility‐based sequences, and the presence of CVS was analyzed. Sensitivity and specificity were assessed for different CVS lesion criteria, defined by proportions of lesions positive for CVS (CVS+) or by the absolute number of CVS+ lesions.Results180 participants (45 RIS, 45 MS, 90 non‐MS) were included, representing 5285 white matter lesions. Among them, 4608 were eligible for the CVS assessment (970 in RIS, 1378 in MS, and 2260 in non‐MS). According to independent ROC comparisons, the proportion of CVS+ lesions performed similarly in diagnosing RIS from non‐MS than MS from non‐MS (p = 0.837). When a 6‐lesion CVS+ threshold was applied, RIS lesions could be diagnosed with an accuracy of 87%. MS could be diagnosed with a sensitivity of 98% and a specificity of 83%. Adding OCBs or Kappa index to CVS biomarker increased the specificity to 100% for RIS diagnosis.InterpretationThis study shows evidence that CVS is an effective imaging biomarker in differentiating RIS from non‐MS, with similar performances to those in MS.

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: Vaccination in patients with multiple sclerosis (MS) treated with immunosuppressive drugs is highly recommended. Regarding COVID-19 vaccination, no specific concern has been raised. Objectives: We aimed to evaluate if COVID-19 vaccination or infection increased the risk of disease activity, either radiological or clinical, with conversion to MS in a cohort of people with a radiologically isolated syndrome (RIS). Methods: This multicentric observational study analyzed patients in the RIS Consortium cohort during the pandemic between January 2020 and December 2022. We compared the occurrence of disease activity in patients according to their vaccination status. The same analysis was conducted by comparing patients’ history of COVID-19 infection. Results: No difference was found concerning clinical conversion to MS in the vaccinated versus unvaccinated group (6.7% vs 8.5%, p > 0.9). The rate of disease activity was not statistically different (13.6% and 7.4%, respectively, p = 0.54). The clinical conversion rate to MS was not significantly different in patients with a documented COVID-19 infection versus non-infected patients. Conclusion: Our study suggests that COVID-19 infection or immunization in RIS individuals does not increase the risk of disease activity. Our results support that COVID-19 vaccination can be safely proposed and repeated for these subjects.

Objective We have previously identified male sex, younger age, and the presence of spinal cord lesions as independent factors that increase the 5‐year risk for evolution from radiologically isolated syndrome (RIS) to multiple sclerosis. Here, we investigate risk factors for the development of a clinical event using a 10‐year, multinational, retrospectively identified RIS dataset. Methods RIS subjects were identified according to 2009 RIS criteria and followed longitudinally as part of a worldwide cohort study. We analyzed data from 21 individual databases from 5 different countries. Associations between clinical and magnetic resonance imaging (MRI) characteristics and the risk of developing a first clinical event were determined using multivariate Cox regression models. Results Additional follow‐up data were available in 277 of 451 RIS subjects (86% female). The mean age at RIS diagnosis was 37.2 years (range, 11–74 years), with a median clinical follow‐up of 6.7 years. The cumulative probability of a first clinical event at 10 years was 51.2%. Age, positive cerebrospinal fluid for oligoclonal bands, infratentorial lesions on MRI, and spinal cord lesions, were baseline independent predictors associated with a subsequent clinical event. The presence of gadolinium‐enhanced lesions during follow‐up was also associated with the risk of a seminal event. The reason for MRI and gadolinium‐enhancing lesions at baseline did not influence the risk of a subsequent clinical event. Interpretation Approximately half of all individuals with RIS experience a first clinical event within 10 years of the index MRI. The identification of independent predictors of risk for symptom onset may guide education and clinical management of individuals with RIS. ANN NEUROL 2020;88:407–417.