One in three people with epilepsy never gain control over the frequency and intensity of their seizures, even with modern treatment. For these patients, diagnosed with drug-resistant epilepsy, clinicians face a difficult sequence of choices: more antiseizure medications, resective brain surgery, or implanted neuromodulation devices. A new commentary published in the journal Drugs in R&D by a group of Italian epilepsy specialists argues that a relatively recent drug, cenobamate, deserves a defined place at several points along that surgical and neuromodulation pathway, and the authors lay out exactly where and when they believe it should be considered.
Cenobamate entered the armamentarium of antiseizure medications in 2020. It is an oral, third-generation drug approved for focal seizures, and for focal seizures that spread to become bilateral tonic-clonic seizures, in adults whose epilepsy remains uncontrolled despite at least two prior medications. The commentary’s authors, led by Giancarlo Di Gennaro and including senior epilepsy researchers from centers across Italy, describe the drug’s efficacy and safety profile as the reason it began improving treatment for patients with drug-resistant disease shortly after its approval.
The clinical trial data behind that reputation are specific. In phase II clinical trials, cenobamate reduced focal-onset seizures with a tolerability profile the authors describe as satisfactory, regardless of suspected, predicted, or known pharmacodynamic and pharmacokinetic interactions with other drugs. In those trials, 21 percent of patients taking 400 milligrams per day achieved seizure freedom during the 12-week maintenance phase, compared with 1 percent on placebo, while 11 percent of those on 200 milligrams per day became seizure free. In an open-label extension study, 18.4 percent of patients achieved 100 percent seizure reduction for any consecutive period of at least 12 months.
Longer-term and post-hoc analyses extend the picture. Among a subset of patients from a long-term, phase III, open-label safety study assessed post-hoc for efficacy, 36.3 percent, or 87 of 240 patients, attained complete seizure reduction for at least 12 consecutive months at some point during the study. Cenobamate has also demonstrated the ability to reduce the overall load of antiseizure medications over one to two years in people with uncontrolled focal seizures, with long-lasting retention of the drug and good tolerability. Real-world studies back these figures: a retrospective analysis of 236 subjects from 21 Italian centers found seizure freedom rates of 9.8, 12.2, 16.3, and 14.0 percent at 3, 6, 9, and 12 months respectively, and another real-world study of 154 patients with high-frequency baseline seizures reported 15.6 percent seizure free over the three months before a 12-month follow-up visit, with 17 to 56 percent of those with focal to bilateral tonic-clonic seizures achieving at least 12 months of freedom.
Against this pharmacological backdrop, the commentary weighs the surgical option, which the authors call the most effective choice in well-selected patients. A landmark estimate by De Tisi and colleagues found that 52 percent of patients remained seizure free, apart from focal aware seizures, five years after surgery, and 47 percent at ten years. Surgery has shown superiority over continuing attempts with other medications in improving both seizure control and quality of life in the short and long term. Yet it consistently emerges as underutilized. The authors attribute part of the reluctance to perceived risks of the operation itself, and to the natural tendency to emphasize immediate surgical dangers over the tardive risks of uncontrolled epilepsy, including sudden unexpected death in epilepsy. They call for greater educational efforts directed at physicians and patients to improve awareness and utilization of epilepsy surgery.
The commentary’s central practical argument concerns timing. Randomized clinical trials specifically investigating cenobamate before surgery are currently lacking, so the authors are explicit that their recommendations rest on clinical experience rather than prospective trial evidence. In their view, the drug should not delay imminent surgery in cases where the epilepsy is clearly surgically remediable. However, they argue that a trial with cenobamate may be considered after the failure of two appropriately selected medications in selected patients, particularly when surgical candidacy is uncertain, when invasive investigations are still pending, or when waiting times are expected to be prolonged. In the most severe and surgically complex cases, where seizure frequency dominates a patient’s daily life, they suggest the drug may improve seizure control and quality of life during the evaluation period. If a patient becomes seizure free during the pre-surgical phase, they write, the decision to proceed with surgery must be reconsidered in accordance with the patient’s preferences.
The authors also flag a subtle diagnostic trade-off. Cenobamate has a long elimination half-life, and while seizure reduction during the presurgical waiting period may improve quality of life and reduce seizure-related risks, it may also decrease the probability of capturing habitual seizures during video-electroencephalogram monitoring. The benefits of seizure control, they conclude, should be balanced against diagnostic requirements, and medication management during presurgical investigations should be individualized according to patient characteristics and local protocols. They further recommend that, before invasive monitoring, patients be told that they may ultimately not qualify for resective surgery if the epileptogenic zone cannot be precisely defined or if the risk-benefit ratio is unfavorable.
What happens when surgery fails? Some evidence suggests that most patients who fail epilepsy surgery will probably not benefit from further pharmacologic retreatment. Yet in a post-hoc analysis of a phase III open-label study, cenobamate showed efficacy in this very group: after resection, disconnection, or ablation, 35 percent of patients, 13 of 40, maintained complete seizure reduction for at least 12 consecutive months at some interval. A real-world study in adults treated with cenobamate, which included patients with prior epilepsy surgery, concluded that the drug should be considered in patients who remain refractory after surgery. The authors also note that after surgery or neuromodulation, in patients taking cenobamate who reach a seizure-free period, the drug could be tapered until possible suspension.
Neuromodulation, the third pillar of treatment, works differently from resection: rather than removing the epileptogenic zone, devices such as vagus nerve stimulation, deep brain stimulation, and responsive neurostimulation aim to reduce seizure frequency and improve quality of life through continuous, titrated stimulation. The evidence base is substantial. Vagus nerve stimulation can reduce seizure frequency by roughly 34.7 percent, though some studies indicate reductions exceeding 50 percent. A systematic literature review including 2,869 patients across 78 studies found that 60.1 percent were responders at last follow-up, with 8.0 percent achieving seizure freedom. A systematic review of responsive neurostimulation found median seizure reductions reaching up to 75 percent, and in the long term vagus nerve stimulation shows relatively poorer outcomes than responsive neurostimulation. Deep brain stimulation showed seizure frequency reductions of 56, 65, and 75 percent at 2, 5, and 7 years respectively. Because neuromodulation is continuous and requires titration, the authors recommend that these patients be evaluated separately from surgical candidates in clinical trials.
Specific randomized trials of cenobamate combined with neuromodulation are lacking, but the available data, though incomplete and based on limited patient numbers, suggest a positive contribution. In the same post-hoc analysis by Abou-Kalil and colleagues, after vagus nerve stimulation or responsive neurostimulation, 22.6 percent of patients, 7 of 31, treated with cenobamate maintained complete seizure reduction for at least 12 consecutive months. Real-world studies support this: among patients with prior vagus nerve stimulation and/or resective surgery followed for a median of 11 months on cenobamate, 5.3 percent achieved seizure freedom, 42.1 percent had a 75 to 99 percent reduction in seizure frequency, and 28.1 percent showed a 50 to 74 percent reduction. A recent real-world study of 54 patients on prolonged vagus nerve stimulation therapy found that adding cenobamate was beneficial for 44.4 percent of patients after 10 months, with 11 percent achieving seizure freedom. Based on such evidence, Laxer and colleagues recently recommended a trial with cenobamate before neuromodulation in adults referred for surgery.
The commentary is candid about the limits of the evidence. There are insufficient prospective data to quantify how frequently cenobamate can definitively obviate the need for surgery or neuromodulation, and evidence on the long-term durability of seizure freedom, including seizure recurrence after prolonged remission, remains limited. Decisions to postpone or cancel invasive procedures should therefore be individualized, weighing epilepsy etiology, presurgical findings, expected procedural benefit, and patient preferences. The authors call for randomized clinical trials comparing early cenobamate introduction after a diagnosis of drug-resistant epilepsy against immediate progression to neuromodulation or standard presurgical management, with seizure freedom and quality-of-life measures as primary endpoints, and reductions in medication burden, need for invasive procedures, time to intervention, and long-term retention as secondary outcomes. Until such trials are done, they conclude, cenobamate offers a new opportunity at multiple points in the drug-resistant epilepsy pathway, but each decision to add it must be made case by case.
Subject of Research: The role of the antiseizure medication cenobamate in the surgical and neuromodulation treatment pathway for drug-resistant epilepsy
Article Title: Optimizing Drug-Resistant Epilepsy Management: Cenobamate’s role in the Surgery/Neuromodulation Pathway
Article References: Di Gennaro, G., Bonanni, P., Deleo, F., Gambardella, A., Michelucci, R., Pauletto, G., Specchio, N., & D’Aniello, A. (2026). Optimizing Drug-Resistant Epilepsy Management: Cenobamate’s role in the Surgery/Neuromodulation Pathway. Drugs in R&D, 26(2), 197-201. https://doi.org/10.1007/s40268-026-00548-7
Image Credits: AI Generated
DOI: 10.1007/s40268-026-00548-7
Keywords: drug-resistant epilepsy, cenobamate, antiseizure medications, epilepsy surgery, neuromodulation, vagus nerve stimulation, deep brain stimulation, responsive neurostimulation, seizure freedom, presurgical evaluation, phase III trials, real-world evidence
News Source: Kendall Mcintyre. (October 28, 2026). Cenobamate Reshapes the Treatment Path for Drug-Resistant Epilepsy. Scienmag.
