Uygunoğlu, Uğur

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

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.

Background Steps towards the development of diagnostic criteria are needed for children with the radiologically isolated syndrome to identify children at risk of clinical demyelination. Objectives To evaluate the 2005 and 2016 MAGNIMS magnetic resonance imaging criteria for dissemination in space for multiple sclerosis, both alone and with oligoclonal bands in cerebrospinal fluid added, as predictors of a first clinical event consistent with central nervous system demyelination in children with radiologically isolated syndrome. Methods We analysed an international historical cohort of 61 children with radiologically isolated syndrome (≤18 years), defined using the 2010 magnetic resonance imaging dissemination in space criteria (Ped-RIS) who were followed longitudinally (mean 4.2 ± 4.7 years). All index scans also met the 2017 magnetic resonance imaging dissemination in space criteria. Results Diagnostic indices (95% confidence intervals) for the 2005 dissemination in space criteria, with and without oligoclonal bands, were: sensitivity 66.7% (38.4–88.2%) versus 72.7% (49.8–89.3%); specificity 83.3% (58.6–96.4%) versus 53.9% (37.2–69.9%). For the 2016 MAGNIMS dissemination in space criteria diagnostic indices were: sensitivity 76.5% (50.1–93.2%) versus 100% (84.6–100%); specificity 72.7% (49.8–89.3%) versus 25.6% (13.0–42.1%). Conclusions Oligoclonal bands increased the specificity of magnetic resonance imaging criteria in children with Ped-RIS. Clinicians should consider testing cerebrospinal fluid to improve diagnostic certainty. There is rationale to include cerebrospinal fluid analysis for biomarkers including oligoclonal bands in planned prospective studies to develop optimal diagnostic criteria for radiologically isolated syndrome in children.

Objective: To evaluate the impact of age on recovery from multiple sclerosis relapses. Background: Increasing disability in multiple sclerosis is a consequence of progressive disease and incomplete relapse recovery. Methods: The first and last-ever relapse data (357 relapses in 193 patients) from the Olmsted County population-based multiple sclerosis cohort were systematically reviewed for age, fulminance, location (optic nerve, brainstem/cerebellar, spinal cord), peak deficit, and maximum recovery. Three different relapse-outcome measures were studied both as paired analyses and as an overall group effect: change from peak deficit to maximum recovery in raw functional system score related to the relapse (ΔFSS), a previously published FSS-based relapse-impact model, and change from peak deficit to maximum recovery in Extended Disability Status Scale (ΔEDSS) score. Results: Older age was linearly associated with worse recovery in the ΔFSS outcome ( p = 0.002), ΔEDSS outcome ( p < 0.001), and the FSS-based relapse-impact model ( p < 0.001). A multivariate analysis of ΔFSS outcome linked poor recovery to older age ( p = 0.015), relapse location (transverse myelitis or brainstem/cerebellar syndrome; p < 0.001), and relapse fulminance ( p = 0.004). Conclusion: Multiple sclerosis-relapse recovery declines in a linear fashion with increased age, which should be considered when making treatment decisions.

Background: Younger age, male sex and presence of spinal cord lesion(s) increase the risk of conversion from radiologically isolated syndrome (RIS) to relapsing-remitting multiple sclerosis (RRMS). Elevated cerebrospinal fluid (CSF) chitinase-3-like protein 1 (CHI3L1) levels predict conversion from clinically isolated syndrome (CIS) to RRMS. Objective: To evaluate the prognostic value of CSF CHI3L1 in RIS patients for conversion to RRMS. Methods: We compared CSF CHI3L1 concentrations in RIS, CIS, RRMS and symptomatic controls (SCs). We analysed the influence of epidemiological, radiological and CSF parameters on the risk of clinical event. Results: A total of 211 patients (71 RIS, 48 CIS, 50 RRMS and 42 SC) were included. CSF CHI3L1 levels were lower in RIS than in RRMS and higher in RIS with positive CSF versus negative CSF and SC. The presence of at least one spinal cord lesion was the only independent predictor of faster conversion to RRMS. Association of high CSF CHI3L1 levels, positive CSF (presence of oligoclonal bands and/or an elevated IgG index) or four Barkhof criteria with any spinal cord lesion showed a tendency for reduced mean conversion time. Conclusion: CSF CHI3L1 correlates with positive CSF but is not an independent predictor of the risk of conversion from RIS to RRMS.

ObjectiveTo describe the clinical and distinctive imaging features of myelopathy associated with Behçet's disease (BD).MethodsWe evaluated the records of patients meeting the following criteria: (1) fulfillment of the International Study Group criteria for BD; (2) clinically suggestive of myelopathy; (3) simultaneous spinal cord and brain magnetic resonance images (MRIs) within 1 month of acute worsening of myelopathy; and (4) follow‐up duration ≥ 1 year after initial MRI evaluation. Patients not fulfilling all inclusion criteria and having MRIs with poor quality or missing sequences were excluded.ResultsIn 11 patients (9 men, 2 women), we studied 14 MRIs during distinct myelopathy episodes and nine follow‐up MRIs. Two distinct MRI patterns of spinal cord involvement were described according to T2‐weighted (T2W) axial images: (1) “Bagel Sign” pattern: a central lesion with hypointense core and hyperintense rim with or without contrast enhancement; and (2) “Motor Neuron” pattern: a symmetric involvement of the anterior horn cells. Bagel Sign was present in 13 of 14 myelopathy episodes whereas Motor Neuron pattern was observed in 1 of 14 MRIs. Of the 13 MRIs with Bagel Sign long myelopathy (n = 9), both long and short myelopathy (n = 2) and short myelopathy (n = 2) was observed. All patterns cleared with some residual lesions after steroid use and immunomodulation with associated clinical recovery in patients.InterpretationThe signal characteristics of the Bagel Sign potentially represent venous engorgement and/or acute blood products within the spinal cord. To our knowledge, Bagel Sign has not been observed in other forms of longitudinal myelopathy outside of BD, including neuromyelitis optica. Ann Neurol 2017;82:288–298