Paramagnetic Rim Lesions and Development of Clinical MS in Radiologically Isolated Syndrome

Importance: Most people with radiologically isolated syndrome (RIS) have high proportions of white matter lesions (WMLs) demonstrating the central vein sign (ie, central vein sign-positive lesion CVS+L) and at least 1 paramagnetic rim lesion (PRL), representing perivenular lesion development and chronic active demyelination, respectively. Whether these imaging measures predict developing clinical multiple sclerosis (MS) in people with RIS is not yet known. Objective: To determine the prognostic value of various magnetic resonance imaging (MRI) measures, particularly PRLs and CVS+L, in predicting clinical MS in people with RIS. Design, Setting, and Participants: This was a multicenter prospective cohort study conducted from 2011 and 2024. Participants older than 18 years and fulfilling published RIS criteria were consecutively recruited from 3 large academic MS centers. Exposures: Participants underwent 3-T MRI including brain and spinal cord (SC) sequences and longitudinal clinical assessments. MRIs were evaluated for the total WML, PRL, and SC lesion (SCL) counts as well as the proportion of CVS+L. Main Outcomes and Measures: The primary outcome was the development of clinical symptoms of MS. Time-varying Cox regression assessed the association between PRLs and symptom onset. Elastic net regression identified key predictors, incorporating PRLs, age, sex, and SCL. Results: A total of 79 eligible people with RIS were included (36 46% in the discovery cohort DC, 43 54% in the validation cohort VC). Of the initial 46 DC participants, 10 withdrew or were lost to follow-up, whereas all VC participants completed follow-up. In the DC (median IQR age, 40 31-51 years; 25 female 70%; median IQR follow-up, 6.4 5.0-9.1 years), 9 of 36 people with RIS (25%) developed MS (median IQR time, 5.2 5.0-6.8 years). In the VC (median IQR age, 43 36-51 years; 23 female 53%; median IQR follow-up, 4.4 2.5-7.9 years), 9 of 43 people with RIS (21%) developed MS (median IQR time, 4.4 2.5-4.7 years). Higher PRL count was associated with earlier symptom onset between 5 and 30 years after initial RIS diagnosis (hazard ratio HR, 1.15; 95% CI, 1.05-1.26; P = .004) in the DC, replicated in the VC (HR, 1.51; 95% CI, 1.00-2.27; P = .04). In the DC, having 4 or more PRLs (odds ratio OR, 14.64; 95% CI, 2.00-207.23; P = .02) and higher PRL count (OR, 1.15; 95% CI, 1.03-1.32; P = .02) predicted clinical MS. In the VC, having any PRL was significantly associated with developing clinical MS (OR, 20.90; 95% CI, 2.35-533.30; P = .02). Conclusions and Relevance: Study findings suggest that accrual of nonresolving chronic inflammation in WML portends development of clinical MS in people with RIS, which may have clinical utility in guiding treatment decisions across the MS spectrum and strengthens the case for including asymptomatic MS in the diagnostic criteria. There is growing recognition that early detection of most chronic neurological diseases is critical to prevent or diminish future disability, and these findings are a specific example of how this principle might operate in practice.