Optimizing Drug-Resistant Epilepsy Management: Cenobamate’s role in the Surgery/Neuromodulation Pathway

Despite the advancement in management, one third of patients with epilepsy experience failure in controlling the frequency and intensity of seizures [1, 2]. Drug-resistant epilepsy (DRE) is characterized by an intrinsic complexity and multi-factorial etiology, embodying a spectrum of different clinical conditions that require a multi-dimensional approach and still represent an everyday clinical challenge [3, 4].

Considering this complex framework, from 2020, cenobamate (CNB) entered the armamentarium of antiseizure medications (ASMs) and, thanks to its efficacy and safety profile, it started improving the treatment of patients with DRE. CNB is a third-generation oral ASM approved for the treatment of focal seizures or focal to bilateral tonic-clonic seizures in adults with epilepsy not controlled with at least two ASMs [5].

In phase II clinical trials, CNB showed a reduction in focal-onset seizures with a satisfactory tolerability profile, regardless of suspected, predicted, or known pharmacodynamic and pharmacokinetic interactions [6–8]. The proportion of patients achieving seizure freedom was 21% with CNB 400 mg/day (vs 1% placebo) and 11% for CNB 200 mg/day during their 12-week maintenance phases [7]. In the long-term, during an open-label extension, 18.4% achieved 100% seizure reduction for any consecutive period ≥ 12 months [9].

Among a subset of patients from a long-term, phase III, open-label safety study who were assessed post-hoc for efficacy, 100% seizure reduction was attained by 36.3% (87/240) for ≥ 12 consecutive months at any time during the study [8]. CNB demonstrated efficacy in long-term (1–2 years) reduction of ASM load, in subjects with uncontrolled focal seizures, with a long-lasting retention and good tolerability [10].

In real-world studies, CNB was shown to significantly reduce seizure frequency in patients with drug-resistant focal epilepsy [11–13]. In particular, a retrospective study on 236 subjects from 21 Italian centers showed that patients treated with CNB experienced a seizure freedom rate of 9.8%, 12.2%, 16.3%, and 14.0% at 3, 6, 9, and 12 months, respectively [11]. In another recently published real-world study on 154 patients affected by focal epilepsy with high-frequency baseline seizures, 15.6% of patients were seizure free during the 3-month period preceding the 12-month follow-up visit, for all types of seizures [13]. Among patients with focal to bilateral tonic-clonic seizures, 17–56% had ≥ 12 months of seizure freedom [13].

Moreover, CNB treatment has been correlated to a reduction in symptom severity of the anxiety score [14]. These advantages have led to an increased use of CNB by patients with DRE. As the likelihood of response to CNB is higher than to other agents, as demonstrated in clinical evidence [6–8], we support the rationale of conducting an attempt with CNB after two ASM failures.

For patients with DRE, different options are available today, including resective surgery and neuromodulation. The aim of this commentary is to depict the role of CNB in the path of patients with DRE who are candidates for resective surgery or neuromodulation.

Surgical Approach in Patients with DRE

The surgical option remains the most effective choice in well-selected patients, owing to its widely proven efficacy in achieving seizure freedom or significant seizure reduction [2, 15]. De Tisi and colleagues estimated that 52% of patients remained seizure free (apart from focal aware seizures) at 5 years after surgery, and 47% at 10 years [16]. In particular, surgery has shown superiority in comparison to continuing attempts with other ASMs in improving seizure control and quality of life (QoL) in the short term, and in the long term [1, 16, 17]. Nevertheless, it consistently emerges that surgery is an underutilized treatment [18–20]. The reluctance towards surgery can be, in part, related to the perceived risks of the surgical procedure and the natural tendency to emphasize immediate surgical risks versus tardive risks related to uncontrolled epilepsy, including sudden unexpected death in epilepsy [19]. In this setting, greater educational efforts directed at both physicians and patients may improve awareness and utilization of epilepsy surgery, including pathologic substrates and molecular mechanisms in non-lesional focal epilepsy, to improve patient selection and surgery outcomes [18, 21].

Pre-surgical Use of cenobamate

Patients with DRE are often offered to start a pre-surgical study. Randomized clinical trials that specifically investigate the efficacy of CNB pre-surgically in patient candidates are currently lacking. In our vision, CNB use should not delay imminent surgery in surgically remediable cases; however, we agree that a trial with CNB may be considered as a parallel support in the patient’s path toward surgery. Nevertheless, after the failure of two appropriately selected ASMs, a trial with CNB may be considered before surgery in selected patients, particularly when surgical candidacy is uncertain, when invasive investigations are still pending, or when waiting times are expected to be prolonged. Conversely, in patients with a clearly defined surgically remediable epilepsy syndrome, CNB should not unnecessarily delay referral and surgical treatment. Based on our clinical experience, the use of CNB during the evaluation for surgery may help to improve seizure control and QoL, and CNB use could be considered in particular in the most severe and surgically complex cases, where seizure frequency has a major impact on a patient’s daily life. In the case where a patient becomes seizure free during the pre-surgical phase, the choice of undergoing surgery must be reconsidered in accordance with the patient’s preferences.

An additional practical consideration, during presurgical evaluation, is the long elimination half-life of CNB. While seizure reduction may improve QoL and reduce seizure-related risks during the waiting period, it may also decrease the probability of capturing habitual seizures during video-electroencephalogram monitoring. Consequently, prolonged monitoring periods may occasionally be required to adequately define the epileptogenic zone. Therefore, the benefits of seizure control should be balanced against diagnostic requirements, and ASM management during presurgical investigations should be individualized according to patient characteristics and local protocols.

Moreover, we suggest that, in the context of counseling before invasive monitoring, it is essential to inform the patient that, at the end of the monitoring process, there is a possibility of not being a candidate for resective surgery, owing to the inability to precisely define the epileptogenic zone or because of an unfavorable risk-benefit ratio, considering both the risk of neurological deficits and the low probability of achieving seizure freedom.

Cenobamate After Resective Surgical Failure

Some evidence suggested that the majority of patients who failed epilepsy surgery will probably not benefit from further attempts of pharmacologic retreatment [22]. Nonetheless, in this particular group of patients, CNB exhibited efficacy in a post-hoc analysis of a phase III open-label study: after surgery (resection/disconnection/ablation), 35% (n = 13/40) of patients treated with CNB maintained 100% seizure reduction for ≥12 months at any consecutive month interval [23].

In addition, a real-world study in adults treated with CNB, which included patients who had prior epilepsy surgery, concluded that CNB should be considered in patients who remain refractory after epilepsy surgery [24]. Overall, this evidence supports CNB as an effective opportunity in the case of a failure of surgical approach, expanding therapeutic options in surgically complicated cases. After surgery or neuromodulation, in patients taking CNB and reaching a seizure-free period, the drug could be tapered until possible suspension.

Cenobamate and Neuromodulation

While resective surgery aims to achieve seizure freedom by acting on the epileptogenic zone, neuromodulation goals are to reduce seizure frequency and improve overall QoL [25]. Moreover, neuromodulation consists of continuous treatment, and it needs to be titrated over a time frame. Thus, we recommend that patients undergoing neuromodulation be evaluated separately from subjects undergoing resective surgery within clinical trials.

Neuromodulation undergoes different procedures such as vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS) [26]. Neuromodulation is an effective treatment with a few major complications, improving outcomes over time. In particular, VNS can reduce seizure frequency by ~34.7% [25], even if some studies indicate a reduction by more than 50% [26]. Systematic literature review results, including 2869 patients across 78 studies, at the last follow-up, showed that 60.1% of individuals were responders, with 8.0% achieving seizure freedom [27]. A systematic review of RNS in DRE underscores RNS as an effective treatment, with a median reduction reaching up to 75%, and substantial improvements in responder rates. In the long term, VNS shows relatively poorer outcomes compared with RNS [2]. While DBS showed seizure frequency reduction of 56%, 65%, and 75% at 2, 5, and 7 years, respectively [25].

Specific randomized clinical trials investigating the outcome of CNB treatment in association with neuromodulation are currently lacking. Nonetheless, current data, even incomplete and with a limited number of patients, suggest a positive contribution of CNB in seizure outcomes when associated with VNS or RNS [23, 28]. In particular, the post-hoc analysis by Abou-Kalil and colleagues showed efficacy of the treatment with CNB in patients with uncontrolled focal seizures and prior neuromodulation: after VNS or RNS, 22.6% (n = 7/31) of patients treated with CNB maintained 100% seizure reduction for ≥ 12 months, at any consecutive month interval [23].

These data are also supported by real-world studies [24, 29]. Patients with prior VNS and/or resective surgery experienced meaningful seizure outcomes over a median treatment period with CNB of 11 months: 5.3% achieved seizure freedom (n = 3), 42.1% had a 75–99% seizure frequency reduction, and 28.1% showed a 50–74% seizure frequency reduction [24]. Based on this evidence, Laxer and colleagues recently published recommendations concerning the use of CNB in adults referred for surgery, recommending a trial with CNB before neuromodulation [28]. A recent real-world study in 54 patients treated with prolonged VNS therapy indicates that the addition of CNB could be beneficial: 44.4% of patients had a significant improvement in seizure control after 10 months of CNB, and 11% of them achieved seizure freedom [29].

Conclusions

CNB offers a new opportunity in the management of patients with DRE who are candidates for resective surgery or neuromodulation. CNB may be taken into consideration in different phases: before invasive monitoring, while waiting for surgery, and before and after the neuromodulation implant. Before surgery, CNB could be beneficial in surgically complex cases, waiting for invasive monitoring. After the failure of resective surgery or neuromodulation, CNB can represent a viable option in the continuum of patients with DRE management. In the view of personalized therapy, the decision to add CNB should be made on a case-by-case basis, taking into consideration seizure etiology, patients’ preferences, potential surgical risks, and the likely surgical outcome [27].

At present, there are insufficient prospective data to quantify how frequently CNB can definitively obviate the need for epilepsy surgery or neuromodulation. However, available clinical and real-world evidence suggests that a subset of patients may achieve sustained seizure freedom or substantial seizure reduction, warranting re-evaluation of the indication for invasive procedures on an individual basis.

An unresolved issue concerns the long-term durability of seizure freedom achieved with CNB. Currently, evidence regarding seizure recurrence after prolonged remission remains limited. Therefore, in patients who achieve sustained seizure freedom during the presurgical pathway, decisions regarding postponement or cancellation of surgery or neuromodulation should be individualized and based on the overall clinical context, including epilepsy etiology, presurgical findings, expected procedural benefit, and patient preferences.

Further investigations through randomized clinical trials are needed to deepen the efficacy and safety of CNB in the different treatment groups of patients: pre- and post-resective surgery, and pre- and post-neuromodulation. Future randomized controlled trials could evaluate a strategy of early CNB introduction after the diagnosis of DRE versus immediate progression to neuromodulation or standard presurgical management. Primary endpoints may include seizure freedom and quality-of-life measures, while secondary outcomes could assess reduction in ASM burden, need for invasive procedures, time to surgery or neuromodulation, and long-term retention. Such studies may clarify whether CNB can alter the therapeutic pathway and reduce the need for invasive interventions in selected patients. These clinical studies will provide solid evidence about the role of CNB in terms of control of disease and quality of life in patients with DRE.

Funding

This publication was supported by an unrestricted grant from Angelini-Pharma.

Declarations

Conflicts of Interest

GDG has received speaker honoraria from Eisai, UCB Pharma, LivaNova, Lusofarmaco, and GW Pharmaceuticals; and has served on advisory boards for Arvelle Therapeutics, Neuraxpharma, Angelini Pharma, LivaNova, and UCB Pharma. PB has received speaker honoraria and has served on advisory boards for Angelini, LivaNova, Eisai, UCB, Jazz, Biocodex, Ethypharme, and Neuraxapharm. He was supported by the Italian Ministry of Health with Current Research Funds. FD has received travel support from Angelini Pharma and has served as a Principal Investigator for a Roche-sponsored trial. AG has received speaker honoraria and has served on advisory boards for Eisai, Angelini Pharma, and UCB. RM has received speaker honoraria from Angelini Pharma and Eisai. GP has received speaker fees from LivaNova, Eisai, UCB, Lusofarmaco, and Angelini Pharma and has served on advisory boards for UCB, Eisai, and Angelini Pharma. NS has served on scientific advisory boards for GW Pharma, BioMarin, Arvelle, Marinus, and Takeda; has received speaker honoraria from Eisai, Biomarin, LivaNova, and Sanofi; and has served as an investigator for Zogenix, Marinus, Biomarin, UCB, and Roche. He was supported by the Italian Ministry of Health with Current Research Funds. ADA has participated in pharmaceutical industry-sponsored clinical trials for UCB Pharma and Angelini Pharma; received speaker honoraria from Eisai, UCB, Angelini Pharma, and Neuraxpharm; and has served on advisory boards for Angelini Pharma.

Ethics Approval

This article is a commentary based on previously published studies and does not contain any studies involving human participants or animals performed by any of the authors. Therefore, ethics committee approval was not required.

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Not applicable. This article does not involve human participants enrolled by the authors.

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Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

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Authors’ Contributions

All authors contributed to the conceptual development of the article, critically revised the manuscript for important intellectual content, approved the final version, and agree to be accountable for all aspects of the work.