Cenobamate in Focal-Onset Refractory and Super-Refractory Status Epilepticus

Background and Objectives Cenobamate (CNB) is an antiseizure medication (ASM) with demonstrated efficacy in drug-resistant focal epilepsy, but its role in status epilepticus (SE) remains unclear. Emerging evidence suggests that it may achieve early clinically meaningful seizure control at relatively low doses, with an acceptable safety profile, supporting its potential utility as an urgent adjunctive therapy in severe refractory epilepsy. We aimed to evaluate the effectiveness and safety of CNB for the treatment of focal-onset refractory SE (RSE) and super-refractory SE (SRSE) in real-world clinical practice. Methods We conducted a multicenter retrospective cohort study using a prospectively maintained registry including adult patients with focal RSE and SRSE treated between January 2022 and October 2025. Clinical, EEG, and treatment data were collected. The primary outcome was sustained SE termination (>24 hours) with electroclinical resolution attributable to CNB. A secondary propensity score-matched analysis (1:2) compared CNB-exposed patients with matched nonexposed controls from the same registry (2011–2025), using target trial emulation principles. Results Thirty-one patients received CNB (mean age 61 ± 21 years; 54.8% male); 45.2% met criteria for SRSE. CNB was initiated a median of 4 days (interquartile range [IQR] 2–12) after SE onset after failure of 5 ASMs (IQR 4–5), at a median starting dose of 50 mg/d (IQR 25–50). Sustained SE resolution occurred in 26 patients (83.9%), including all patients with RSE (17/17) and 64.3% with SRSE. Response occurred after a median of 2 days (IQR 1–6). In the matched cohort analysis (28 CNB exposed vs 56 controls), SE resolution was higher in CNB-treated patients (82.1% vs 57.1%; p = 0.02). In multivariable analysis, CNB exposure was independently associated with SE resolution (adjusted odds ratio 5.9, 95% CI 1.2–30, p = 0.03). No serious CNB-related adverse events occurred. Mild adverse events were observed in 51.6%, most commonly somnolence. In-hospital mortality was 22.6% with no deaths attributed to CNB. Discussion In this multicenter real-world cohort, CNB was associated with high rates of sustained SE termination in RSE and SRSE and improved outcomes compared with matched controls, without serious safety signals. These findings support CNB as a potential adjunctive therapeutic option in refractory focal SE. Classification of Evidence This study provides Class IV evidence that CNB is effective as an adjunctive therapy for the control of focal-onset RSE and SRSE in adult patients.