A Pre-symptomatic phase of Tumefactive multiple sclerosis mirrors radiologically isolated syndrome

Abstract

Tumefactive multiple sclerosis (TMS) is characterized by large brain demyelinating lesions, often with severe, disabling attacks. While MS can be preceded by a radiologically isolated syndrome (RIS), a pre-symptomatic phase in TMS is not well described. Aim To characterize pre-symptomatic TMS and compare its frequency and symptomatic evolution to a non-tumefactive MS (nTMS) cohort. Methods Adults (≥18 years) with ≥1 tumefactive demyelinating lesion (TDL; ≥2 cm), fulfilling 2024 McDonald Criteria were included. Pre-symptomatic TMS was defined as an incidental TDL fulfilling the 2024 pre-symptomatic MS criteria. The frequency of pre-symptomatic disease and symptomatic MS evolution were compared to a nTMS cohort matched on age at onset, sex, and disease duration, using Fisher’s exact test. Among patients with pre-symptomatic MS, time to symptomatic MS conversion was compared using Kaplan-Meier (KM) analysis with log-rank testing. Results Among 202 TMS patients, seven (4%) were pre-symptomatic with a median age of 51 (IQR 46, 53.5) years. Over 92 (IQR 16.5, 129.5) months, four developed new MRI lesions and one developed symptomatic MS. Four initiated disease-modifying therapy within 13.5 (IQR 1.8, 28.8) months. After matching, the frequency of pre-symptomatic disease was 3.1% (4/129; median age 38 years) in TMS compared to 5.4% (7/129; median age 38 years) in nTMS (p = 0.54). One pre-symptomatic TMS patient (25%) and one (14%) pre-symptomatic nTMS patient evolved to symptomatic MS (p = 1.0). A time-to-event analysis of symptomatic MS evolution across pre-symptomatic TMS and nTMS cohorts yielded a log-rank p = 0.67, although the overall number of observed events were limited. Discussion A pre-symptomatic phase of TMS mirroring RIS may be underrecognized, warranting consideration when evaluating incidental tumefactive brain lesions. Larger studies are needed to determine whether the temporal pattern of symptomatic evolution differs between presymptomatic TMS and nTMS.