This study involved a secondary analysis of the FAERS database. We conducted a disproportionality analysis of FAERS between the fourth quarter of 2003 and the third quarter of 2023. MS DMTs and the Bruton tyrosine kinase inhibitor, ibrutinib, were included in the analysis. An inverse association was defined as the upper limit of the 95% confidence interval (CI) for the reporting odds ratio (ROR) being less than 1. A safety signal, per Evans criteria, was defined as ≥3 reports, proportional reporting ratio (PRR) ≥2, and chi-squared value ≥4.

We found an inverse association between the following drugs and epilepsy: ibrutinib (ROR: 0.338; 95% CI: 0.218-0.524), ocrelizumab (ROR: 0.541; 95% CI: 0.341-0.859), ofatumumab (ROR: 0.536; 95% CI: 0.311-0.924), rituximab (ROR: 0.782; 95% CI: 0.639-0.957), and teriflunomide (ROR: 0.452; 95% CI: 0.285-0.718). The strongest inverse association was seen with ibrutinib. A safety signal for epilepsy was found for fingolimod based on the Evans criteria (PRR: 2.164; 95% CI: 1.863-2.513, χ2=106.06).

Our observations suggest that agents that reduce or modulate B lymphocytes (ibrutinib and the anti-CD20 agents) or reduce the proliferation of activated T and B lymphocytes (teriflunomide) may be inversely associated with epileptic seizures. The strongest inverse association was seen with ibrutinib, which has also been shown to modulate myeloid cell subsets, including CNS microglia. Our findings suggest the possibility of considering these medications for repurposing opportunities in epilepsy and support a potential pathogenic role of leukocyte subsets in seizure perpetuation.