LAUSR

BACKGROUND Radiologically Isolated Syndrome (RIS) likely represents the earliest detectable form of multiple sclerosis (MS). There are recognized risk factors for conversion of RIS to clinically definite central nervous system (CNS) demyelinating disease. We aim to characterize a new clinical cohort with RIS and to analyze previously established risk factors for conversion to clinically definite disease. METHODS A medical records search was performed for patients who were diagnosed with RIS by their treating neurologist at our institution in Boston, USA, from January 2005 to April 2020. Demographic data, clinical outcomes, and treatment courses were analyzed. The time to first clinical event representing a demyelinating disease attack or last follow up without clinically definite disease was calculated for each person. Hazard ratios (HRs) for known risk factors for the conversion of RIS to clinically definite disease were calculated using Cox proportional hazards models. RESULTS Of 89 patients, the median age at RIS diagnosis was 41.0 years (76% female, 8% with a family history of MS and 16% of any autoimmune disorder, 66% never smokers, 40% BMI >30 kg/m2, 45% with spinal cord MRI lesions). Clinically definite disease was observed in 16 patients (18%) during follow-up (median time to first event 3.4 years; median follow-up duration of full cohort 3.8 years). Median EDSS for those who developed clinically definite disease was 1.25 (range: 0-4) at most recent follow up. Of 84 patients with longitudinal brain imaging, 42 (50%) had new demyelinating lesions. Gadolinium-enhancing lesions were seen in 36 patients (43%) at either baseline (n=24) or follow-up (n=12). Most patients had at least one T1-hypointense lesion (n=70, 83%). Five patients underwent ultra-high field MRI (7 Tesla); all were positive for central vein sign, two demonstrated leptomeningeal enhancement, and one was found to have cortical lesions. Out of 30 patients with susceptibility-weighted imaging acquired during routine clinical care, 8 had at least one paramagnetic rim positive lesion. Previously reported risk factors for conversion to MS were not significant: age ≤37 years HR 1.3 (95% confidence interval (CI), 0.47-3.5), male sex 1.5 (95% CI, 0.41-5.2), and spinal cord lesions 1.3 (0.47-3.4). Nearly one-third of RIS patients (n=26) took a disease modifying therapy (DMT) for MS (median total treatment duration on any DMT=2.7 years). The sub-cohort treated with a DMT had a statistically significantly greater number of recognized risk factors for conversion to clinically definite disease compared with the untreated group (p=0.028). Most patients took a DMT for MRI changes demonstrating new demyelinating disease activity (n=16). Dimethyl fumarate (n=9) and glatiramer acetate (n=7) were the most frequently prescribed DMTs. A second-line DMT was started in 10 patients. CONCLUSION We characterize a new cohort of RIS patients, demonstrating time to clinically evident demyelinating disease from RIS diagnosis of approximately 3.4 years. Our data suggest that early use of a DMT in RIS may mitigate the impact of recognized risk factors on the occurrence of clinically evident disease and reduce the likelihood of conversion to clinically definite CNS demyelinating disease in high-risk individuals.