To Delay or Not to Delay: The Role Cenobamate Plays in the Presurgical Evaluation

Abstract

Delayed and deferred surgery associated with cenobamate use in people with drug-resistant focal epilepsy

Pellinen J, Sillau S, Bui A, Danciutiu A, Kaye L, Sood A, Ferrari L, Rosenfeld WE, Elder C. Delayed and deferred surgery associated with cenobamate use in people with drug-resistant focal epilepsy. Epilepsia. 2026 Jul;67(7):3410-3419. doi:10.1002/epi.70215. Epub 2026 Mar 26. PMID: 41885758; PMCID: PMC13361065. Objective: Cenobamate has been shown to be an effective antiseizure medication for some patients with drug-resistant focal epilepsy being considered for epilepsy surgery. This retrospective single-center study evaluated whether surgery was obtained within 12 months for patients who received cenobamate as a treatment during the presurgical evaluation and those who did not, comparing across years before and after cenobamate approval. Methods: Patients undergoing surgical evaluation for drug-resistant focal epilepsy at the University of Colorado during 2018 and 2023 who had 12 months of follow-up data were analyzed. Comparison years were also chosen to avoid the confounding effect of the COVID-19 pandemic on surgical volume (2020-2021). This allowed for comparison times before and after cenobamate's US Food and Drug Administration approval. The primary outcome (surgery within 12 months) was modeled with potential explanatory variables using multiple logistic regression. A P-value of <.05 was considered significant. Results: After controlling for potentially confounding clinical and demographic variables, cenobamate use during the presurgical evaluation period was associated with .13 lower odds of surgery within 12 months compared to not being prescribed this medication (95% confidence interval [CI] = .04-.42, P < .001). Being Hispanic or Latino was significantly associated with .23 lower odds of surgery within 12 months compared to patients who did not report being Hispanic or Latino (95% CI = .09-.61, P = .003). Year of evaluation (2023 vs 2018), education level, age, and sex did not have significant associations with undergoing surgery within 12 months. Significance: Patients with drug-resistant focal epilepsy undergoing evaluation for epilepsy surgery may benefit from cenobamate. In this study, patients who received cenobamate during the presurgical evaluation were less likely to undergo surgery within 12 months. The delay to surgery identified among Hispanic and Latino patients suggests potential barriers to care in this patient population warranting further investigation.

Commentary

Cenobamate is a third generation anti-seizure medication (ASM), approved for adjunctive treatment of focal epilepsy in adults by the FDA in November 2019. Cenobamate is marketed under the brand name XCOPRI® by SK Life Science, a division of SK Pharmaceuticals (SK), and by license to Angelini pharma in Europe under the brand name ONTOZRY®, and is currently available in North America, Europe, Israel, UAE, and China.

The post-trial literature on cenobamate is glowing, with impressive responses to treating seizures matching and even improving on clinical trial figures of up to 33.3% seizure free, and 71.9% improvement in seizure severity, with high tolerability and retention rates. ¹ The open-label extension studies demonstrated seizure freedom in 16.4% of patients at 36-48 months. ²

The good response even in multi-medication-resistant patients has led to a common comment in our epilepsy surgery review meetings “has cenobamate been tried yet?”.

Some authors even suggest changing the definition of ASM resistance to include failure of the most efficacious drug, i.e., cenobamate. ³

We welcome additional options to treat our medication-resistant patients, including cenobamate, but has this changed our practice of surgical epileptology? Pellinen and colleagues retrospectively examined the University of Colorado epilepsy surgery database for patients referred for a presurgical evaluation in the calendar year 2018 (pre-cenobamate) and 2023 (the cenobamate era) who were discussed at their multidisciplinary epilepsy surgery conference and had 12 months of follow-up from the initiation of surgical assessment. ⁴

The primary outcome was whether these patients had epilepsy surgery within 12 months of the initial referral as documented in a clinic note by the referring neurologist. Assumptions were made that standard care was completion of surgery within 12 months of the initial referral, at least in a U.S. tertiary referral center (unless of course a patient is not deemed to be a surgical candidate or declines surgery). 360 patients in total were screened and 168 excluded due to lack of a focal epilepsy diagnosis, not meeting drug-resistance criteria or inadequate follow-up without more detail provided.

Data available and examined by univariate analysis with purposeful variable selection (avoiding multiple comparisons) also included type of surgery, age, sex, education, ethnicity, insurance, monthly seizure frequency, and number of ASM.

Patient demographics were similar in both groups, with mean age in the 30s, over 80% white, over 60% with higher education, and an even split of private insurance, Medicare, or Medicaid.

Of course, all 118 patients in the 2018 group did not have a cenobamate trial.

47 of 74 patients in the 2023 group had a cenobamate trial. The reasons for not trialing cenobamate in the other 27 patients are not given.

Of all patients who did not have a cenobamate trial, 92% had surgery with a mean time to surgery of 6.6 months.

Of patients on cenobamate, 60% had surgery with a mean time to surgery of 12 months.

Cenobamate use during the presurgical evaluation was associated with 0.13 lower odds of surgery within 12 months.

Sixteen patients (34%) became seizure free on cenobamate at last follow-up with duration of use or dose not provided. 33 patients (70%) on cenobamate had >50% seizure reduction at 6 months.

Only 36 patients in total had resective epilepsy surgery, 4 in the cenobamate trial group, and 32 in those not given cenobamate. Other surgeries included were laser ablation, DBS/RNS, or VNS with one callosotomy.

Individual data on the type of epilepsies, etiologies, or MRI/EEG findings in terms of suitability for surgery were not available, nor specific reasoning on who went on cenobamate instead. The numbers of individual types of surgeries are small limiting interpretation. Given that many patients had palliative procedures or no surgery, a significant proportion may have been poor surgical candidates to begin with.

The authors found coincidentally that being Hispanic or Latino was associated with an even lower odds of surgery within 12 months independent of other factors.

For full disclosure, several of the authors have received consultancy or speakers fees from SK, one author is an SK vice-president of medical affairs, and the study was funded by SK. The author of the commentary in the same edition of Epilepsia discloses paid consultancy fees from SK. ⁵

The authors note that for cenobamate responders, “deferred surgery was a positive outcome”, although is this really the case? A substantial proportion still went on to have surgery later. The best case long-term data available on sustained cenobamate seizure freedom is 21% at 30 months. ⁶ At the risk of coming across ‘glass half empty’ (or actually 79% empty), the follow-up in this study is too short to make meaningful comparisons between long-term benefits of cenobamate over surgery. ASM are symptomatic treatments, whereas with surgery, there is an opportunity long term (or even life-long) to alter the trajectory of the epilepsy.

How does this play out in clinical practice? I will use an example of a patient I saw last month in our epilepsy monitoring unit; a woman in her 30s with left mesial temporal sclerosis, who had previously turned down epilepsy surgery. Now she was willing to move forward. Her seizures were left temporal, but there were now rhythmic delta and rare sharp waves in the right temporal region. She has not tried cenobamate. Based on published data discussed here, initiating cenobamate could delay her surgery—is this positive or negative?

An expert panel (a 1-day virtual conference of neurologists invited by SK) recommended resective surgery should proceed if “iminent.” ⁷ Cenobamate initiation is slow, with standard titration to 200 mg daily taking a minimum of 10 weeks, and say at least a 3-month trial period, and follow-up sometime after that. What will happen to her right hippocampus in the next 6+ months, particularly if cenobamate is not fully effective. Given the superiority of resective epilepsy surgery in good surgical candidates, delaying surgery in some patients may be dangerous, exposing them to risks of SUDEP, epilepsy progression, or other seizure-related risks. The authors in no way suggest that cenobamate is as effective as successful resective surgery, but we would not want to leave any impression of this with the wider epilepsy community.

The authors also comment that cenobamate use during the presurgical evaluation might reduce costs and complications from epilepsy surgery, although there is no data yet to support this. Epilepsy surgery has clearly been shown to be cost-effective in the right surgical candidates, ⁸ with better outcomes when performed earlier. ⁹ Long-term outcomes of those with delayed or obviated surgery are unknown.

For a balanced view, when weighing whether to delay the surgical procedure in place of cenobamate, the potential effects of cenobamate on the patient's care need to be considered, as well as who might benefit the most. The more refractory patients have a less impressive cenobamate response.^1,10 There is significant potential for dose-dependent cognitive-sedative side effects, particularly at doses over 200 mg (the dose recommended by the expert group in place of surgery). ¹⁰ There may be elevated liver function tests which require monitoring and can limit dosing; in Europe, there is a recent European Medicines Agency warning on liver dysfunction. ¹¹ There are complex drug-drug interactions ¹² (for which the company has recently produced a useful brochure). Lipids may be elevated with associated unclear increased vascular risks with longer term use. Cenobamate is potentially teratogenic for women of childbearing age and interacts with hormonal contraception. Cenobamate is still out of reach for many patients due to coverage, cost or availability in their country. Patents will not expire until beyond 2032 due to settlements SK has made with generic manufacturers. I have seen excellent initial responses to cenobamate, fading to tolerance and return of seizures over time.

A cenobamate trial may be more beneficial for poor or palliative surgical candidates, or in less refractory epilepsy. However, long-term outcomes of potential surgical patients moved to cenobamate are still unknown and need to be studied further, as the authors themselves suggest. Ultimately, the decision for surgery depends on many different factors and should be individualized for the patient, but potentially curative epilepsy surgery should not be delayed. Much effort has been invested to reduce delays to epilepsy surgery, not increase them.