Risk of multiple sclerosis in individuals with infectious mononucleosis: a national population-based cohort study using hospital records in England, 2003-2023

Background: Epstein-Barr virus (EBV) is thought to be a necessary causative agent in the development of multiple sclerosis (MS). Infectious mononucleosis (IM), which occurs up to 70% of adolescents and young adults with primary EBV infection, appears to be a further risk factor but few studies have been highly powered enough to explore this association by time since IM diagnosis. Objective: The objective was to quantify the risk of MS in individuals with IM compared with the general population, with particular focus on time since IM diagnosis. Methods: In this retrospective cohort study using English national Hospital Episode Statistics from 2003 to 2023, patients with a hospital diagnosis of IM were compared with the general population for MS incidence. Results: MS incidence in patients with IM was nearly three times higher than the general population after multivariable adjustment (adjusted hazard ratio = 2.8, 95% confidence interval (CI = 2.3-3.4), driven by strong associations at long time intervals (>5 years) between IM diagnosis and subsequent MS diagnosis. Conclusion: While EBV infection may be a prerequisite for MS, the disease process of IM (i.e. the body's defective immune response to primary EBV infection) seems to be, in addition, implicated over the long term.