Real-world use of Cenobamate in pediatric drug-resistant epilepsy: A European multicenter retrospective study

Pediatric drug-resistant epilepsy (DRE) remains a significant clinical challenge, with few effective pharmacological options. This European multicenter retrospective study assessed the real-world efficacy, tolerability, and retention of off-label cenobamate (CNB) in 108 children and adolescents with DRE (median age: 13.83 years, range 3.9-19.8). Overall, 57/108 patients (52.8%) achieved a ≥50% seizure reduction, including 20/108 (18.5%) who were seizure-free during the documented interval between visits. The median monthly seizure frequency declined from 30 to 9. Median follow-up was 581.5 days (IQR 340,8; range 27-1160); 5 patients had follow-up ≤90 days and 10 had follow-up <180 days. In sensitivity analyses excluding patients with follow-up ≤90 days and <180 days, ≥50% responder rates were 54.4% and 56.1%, respectively. Concomitant ASM dose reductions and discontinuations occurred in 44% and 51% of patients, respectively, with the median ASM count declining from 3 to 2. Adverse events were documented in 57.4%, most frequently fatigue, vertigo, and behavioral symptoms. No cases of DRESS were reported. CNB retention at 12 months was 86.8% and was higher in patients without adverse events (93.5% vs. 81.6%, p = 0.0076). The initiation dose was most commonly 12.5 mg (0.25 mg/kg/day, IQR 0.12), with titration to a median maintenance dose of 3.57 mg/kg/day (IQR 1.95; range 0.3-10). These findings suggest that CNB is a generally well-tolerated and clinically effective adjunctive treatment in pediatric DRE, with the potential to reduce polypharmacy and support long-term adherence. Controlled prospective studies are needed to confirm these results and to establish safe, evidence-based use of CNB in children. PLAIN LANGUAGE SUMMARY: Many children and adolescents with drug-resistant epilepsy do not respond to available medications. In this European multicenter study, we evaluated cenobamate, used off label, in 108 young patients with severe epilepsy. More than half had their seizures reduced by at least 50%, and nearly one in five became seizure-free. Seizure frequency dropped markedly, and many patients could reduce other anti-seizure medications. Side effects were common but usually mild, and most patients continued treatment long term. These results suggest cenobamate may be a useful option in pediatric drug-resistant epilepsy, but prospective studies are needed to confirm safety and effectiveness.