Seizure risk in multiple sclerosis patients treated with disease-modifying therapy: A systematic review and network meta-analysis

Background: Multiple sclerosis patients experience 3-6 times more seizures than the general population, but observations vary among studies. Seizure risk in disease-modifying therapy recipients remains unknown. Objective: The objective of this study was to compare seizure risk in multiple sclerosis patients receiving disease-modifying therapy versus placebo. Methods: MEDLINE(OVID), Embase, CINAHL, and ClinicalTrials.gov were searched from database inception until August 2021. Phase 2-3 randomized, placebo-controlled trials reporting efficacy and safety data for disease-modifying therapies were included. Network meta-analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, using Bayesian random effects model for individual and pooled (by drug target) therapies. Main outcome was log(e) seizure risk ratios [95% credible intervals]. Sensitivity analysis included meta-analysis of non-zero-event studies. Results: A total of 1993 citations and 331 full-texts were screened. Fifty-six included studies (29,388 patients-disease-modifying therapy = 18,909; placebo = 10,479) reported 60 seizures (therapy = 41; placebo = 19). No individual therapy was associated with altered seizure risk ratio. Exceptions were daclizumab (-17.90 [-65.31; -0.65]) and rituximab (-24.86 [-82.71; -1.37]) trending toward lower risk ratio; cladribine (25.78 [0.94; 4.65]) and pegylated interferon-beta-1a (25.40 [0.78; 85.47]) trended toward higher risk ratio. Observations had wide credible intervals. Sensitivity analysis of 16 non-zero-event studies revealed no difference in risk ratio for pooled therapies (l0.32 [-0.94; 0.29]) Conclusion: No evidence of association was found between disease-modifying therapy and seizure risk-this informs seizure management in multiple sclerosis patients.