To Örebro University

If Epstein-Barr virus is essential for multiple sclerosis (MS) pathogenesis, there may be differences in MS risk for auxiliary exposures that occur before or after Epstein-Barr virus infection. Infectious mononucleosis (IM) during adolescence typically represents the primary Epstein-Barr virus infection, so can be used as a proxy marker, while concussion in adolescence is considered a separate non-essential risk factor for MS. The objective here was to examine if concussion before or after IM during adolescence is differently associated with MS risk. Using national Swedish health registers, among those born from 1980 with follow-up to 2023, we identified a cohort with IM between ages 11 and 20 years among people without a demyelinating disease diagnosis by age 20 years (n = 37 432), among whom 174 had a subsequent MS diagnosis. The median age (and interquartile range) at IM was 17.00 (15.52-18.59) years among those without MS and 16.66 (15.15-18.29) years among those with MS. In this cohort, between ages 11 and 20 years, there were 1474 episodes of concussion before IM and 1171 occurring afterwards. Associations between concussion and MS risk were estimated using Cox regression, with age as the underlying timescale and adjustment for age at IM, year of birth (both modelled as continuous measures using restricted cubic splines), sex and county. Notably, only concussion occurring before, but not after, IM was associated with increased MS risk producing adjusted hazard ratios (with 95% confidence intervals) of 2.23 (1.24-4.03; P = 0.008) for concussion before IM and 0.85 (0.35-2.09; P = 0.726) for concussion after IM. However, there is no statistically significant effect modification for MS with an interaction for concussion before and after IM of 1.60 (0.16-15.60; P = 0.685). Our findings suggest that changes in the environment of the CNS caused by concussion facilitate development of MS if present before primary Epstein-Barr virus infection.