Prognostic Factors for Multiple Sclerosis Symptoms in Radiologically Isolated Syndrome

IMPORTANCE Understanding the risk factors for symptom development will allow clinicians to stratify people with radiologically isolated syndrome (pwRIS) more effectively and tailor their management strategies accordingly. OBJECTIVE To identify prognostic factors at radiologically isolated syndrome (RIS) diagnosis associated with the development of multiple sclerosis (MS) symptoms. DESIGN, SETTING, AND PARTICIPANTS This cohort study was performed in samples collected between July 2004 and September 2022 and included 33 MS centers. All pwRIS who meet the 2017 McDonald criteria for dissemination in space with a sample collected near the diagnostic magnetic resonance imaging were included. No patients who met eligibility criteria were excluded. The data were analyzed from July 2024 to November 2024. EXPOSURE Body fluid biomarkers and environmental factors in pwRIS. MAIN OUTCOMES AND MEASURES The main outcome was the development of MS symptoms. Analyses involved univariable and multivariable Cox proportional hazards models, including age, sex, and treatment following RIS diagnosis, as additional independent variables. RESULTS The study included 273 pwRIS (mean age, 38.6 [SD 11.6] years; 207 women [75.8%] and 66 men [24.2%]) with a median follow-up of 5.0 [IQR, 2.5-7.7] years. A total of 101 pwRIS developed MS symptoms (37.0%). The presence of immunoglobulin G oligoclonal bands (OBs) (hazard ratio [HR], 5.09; 95% CI, 2.36-10.97; P < .001), immunoglobulin M OBs (HR, 2.58; 95% CI, 1.61-4.14; P < .001), and a κ free light chain index of 6.1 or more (HR, 2.79; 95% CI, 1.37-5.67; P = .005) were associated with MS symptoms. High cerebrospinal fluid neurofilament light chain (NfL) levels (HR, 1.31; 95% CI, 1.18-1.45; P < .001) and high serum NfL z scores (HR, 1.42; 95% CI, 1.16-1.72; P = .005) were also associated with an increased risk of MS symptoms. In contrast, high anti-cytomegalovirus titers (HR, 0.59; 95% CI, 0.38-0.93; P = .02) and high ultraviolet radiation exposure in the year before (HR, 0.52; 95% CI, 0.37-0.74; P < .001) and the year after (HR, 0.54, 95% CI, 0.38-0.75; P < .001) diagnosis reduced the risk of MS symptoms. For all these prognostic factors, the multivariable analysis yielded similar results. The combination of high serum NfL z scores and positive immunoglobulin G OBs conferred a 5-year risk of clinical symptoms of 58.3% (95% CI, 45.9-67.9). This risk increased to 81.6% (95% CI, 60.9-91.4) in pwRIS who were younger and positive for immunoglobulin M OBs. CONCLUSIONS AND RELEVANCE The study elucidates the prognostic factors that significantly impact the risk of developing MS symptoms in pwRIS at diagnosis, thereby, enhancing the potential for tailored clinical interventions.