Real-world effectiveness and safety of cenobamate in children and adolescents with drug-resistant epilepsy: a systematic review, meta-analysis, and meta-regression

Background and objectives Cenobamate is a third-generation antiseizure medication (ASM) approved for focal-onset seizures in adults; pediatric use remains off-label and supported primarily by retrospective studies. We conducted a systematic review, meta -analysis, and meta -regression to evaluate the real-world effectiveness and safety of adjunctive cenobamate in pediatric drug-resistant epilepsy (DRE). Methods We conducted a PRISMA 2020–compliant systematic review and meta -analysis (PROSPERO: CRD420261475361) of real-world studies including patients ≤18 years with DRE. Single-arm proportions were pooled using random-effects generalized linear mixed models. Heterogeneity was assessed using I 2 and τ 2 . Pre-specified random-effects meta -regression explored study-level moderators of ≥50 % seizure reduction. Risk of bias was assessed using the JBI Critical Appraisal Checklist for Case Series. Results Sixteen retrospective cohorts comprising 720 pediatric patients from 10 countries were included. The pooled proportion achieving ≥50 % seizure reduction was 59.9 % (95 % CI, 51.4 %–67.9 %; 95 % prediction interval, 30.2 %–83.8 %; I 2 = 68.2 %). Pooled estimates were 41.9 % (95 % CI, 26.4–59.2 %) for >75 % seizure reduction, 18.6 % (95 % CI, 12.3–27.1 %) for seizure freedom, and 49.9 % (95 % CI, 44.1–55.7 %) for any adverse effect. Leave-one-out analysis showed that no individual study disproportionately influenced the pooled ≥50 % seizure-response proportion (58.3–61.9 %). Visual and regression-based assessments did not detect marked funnel-plot asymmetry or an association between study size and effect estimates. No pre-specified moderator, including age, prior ASM burden, cenobamate dose, follow-up duration, focal epilepsy, clobazam exposure, or etiology, was significantly associated with response. Conclusions Approximately six in ten pediatric patients with DRE achieved ≥50 % seizure reduction with cenobamate. However, persistent unexplained heterogeneity and exclusively retrospective evidence limit subgroup-level inference. Prospective individual-patient-data registries with standardized outcome and dosing measures are needed to better define effectiveness, safety, and predictors of response in pediatric populations.