Real-world effectiveness of cenobamate in drug-resistant and ultra-refractory epilepsy: A multicenter study

To evaluate the real-world effectiveness, safety, and treatment retention of cenobamate (CNB) in patients with drug-resistant epilepsy (DRE), including ultra-refractory epilepsy (URE), high seizure burden, and extensive prior treatment history.

We conducted a retrospective, multicenter study of 500 adults with DRE (focal or combined epilepsy) who were treated with CNB at three Czech tertiary epilepsy centers. Among these patients, 83.4% met criteria for URE. Seizure outcomes, treatment retention, and adverse events were analyzed, with stratification by treatment duration and cumulative ASM exposure (number of previous and concomitant anti-seizure medications). Primary outcomes were ≥ 50% responder rate and seizure freedom at 12 months.

Among 436 patients with evaluable seizure data after ≥ 3 months of CNB treatment, 55.7% achieved ≥ 50% seizure reduction and 16.5% became seizure-free. At 12 months (n = 331), ≥ 50% response was achieved in 61.6%, and 18.1% became seizure-free. Among patients with focal to bilateral tonic-clonic seizures or bilateral tonic-clonic seizures, 46.1% achieved seizure freedom at 12 months. CNB efficacy persisted across high cumulative ASM burden, with seizure freedom in 22.7%, 20.2%, and 10.4% of patients with ≤ 5, 6-10, and > 10 ASMs, respectively. Multivariable analyses identified high baseline seizure burden, greater cumulative ASM exposure (> 10 ASMs), and concomitant use of sodium channel blockers as independent negative predictors of treatment response. Treatment retention at 12 months was 83.0%.

CNB was effective and well-tolerated in a highly treatment-resistant population. Although seizure freedom rates declined with increasing cumulative ASM burden, CNB retained clinically meaningful efficacy even in highly refractory patients.

The study examined the effectiveness of cenobamate in routine clinical practice in adults with highly treatment-resistant epilepsy. In a large multicenter cohort, many patients achieved substantial seizure reduction, including complete seizure freedom, despite extensive prior treatment. Most patients remained on cenobamate during follow-up, consistent with good effectiveness and tolerability in routine clinical practice. These findings indicate that cenobamate can offer meaningful benefits even in very difficult-to-treat epilepsy and may inform treatment decisions in clinical practice.