Introduction: The Challenge of Post-Stroke Epilepsy
Post-stroke epilepsy (PSE) is one of the most common causes of acquired epilepsy in adults, significantly complicating the recovery process for survivors of both ischemic and hemorrhagic strokes. Despite the high incidence of seizures following cerebrovascular events, current medical practice remains reactive rather than proactive. Physicians typically wait for the occurrence of unprovoked seizures before initiating antiseizure medications (ASMs). The concept of antiepileptogenesis—intervening during the latent period to prevent the development of epilepsy—remains a ‘holy grail’ in clinical neurology. Eslicarbazepine acetate (ESL), a voltage-gated sodium channel blocker that preferentially targets the inactivated state of the channel, has demonstrated potential antiepileptogenic properties in preclinical models, prompting the investigation of its efficacy in a clinical setting.
The BIA-2093-213 Trial: Study Design and Population
The Study BIA-2093-213 was a phase 2a, double-blind, randomised, placebo-controlled, proof-of-concept trial designed to evaluate whether early intervention with ESL could reduce the risk of unprovoked seizures in high-risk stroke patients. The trial was conducted across 19 university hospitals in eight countries, including Austria, Germany, Italy, Israel, Portugal, Spain, Sweden, and the UK.
Risk Stratification and Inclusion Criteria
A critical component of this trial was the use of validated risk-stratification tools to identify patients most likely to develop PSE. Patients were eligible if they had a SeLECT score of 5 or greater (for ischemic stroke) or a CAVE score of 2 or greater (for intracerebral hemorrhage). The SeLECT score incorporates stroke severity, large artery atherosclerosis, early seizures, cortical involvement, and middle cerebral artery territory involvement. The CAVE score considers cortical involvement, age, hemorrhage volume, and early seizures. Participants were randomized within 96 to 120 hours of stroke onset to receive either ESL 800 mg/day or a placebo for a 30-day treatment period, followed by a 17-month observation phase.
Key Findings: Efficacy and Safety
Between May 2019 and February 2022, 125 patients were randomized (62 to ESL and 63 to placebo). The primary endpoint was a composite of the proportion of patients who experienced a first unprovoked seizure, died, or discontinued the study for any reason within the first 6 months after randomization.
Primary Endpoint Results
The analysis showed that 28% (17 of 61) of the ESL group met the primary endpoint compared to 37% (23 of 62) of the placebo group. While the numerical trend favored ESL, the difference was not statistically significant, with an odds ratio (OR) of 0.66 (95% CI 0.31–1.40; p=0.37). The wide confidence intervals reflect the study’s primary limitation: it was significantly underpowered due to slow recruitment and the disruptions caused by the COVID-19 pandemic.
Safety and Tolerability Profile
Treatment-emergent adverse events (TEAEs) occurred with equal frequency in both groups (82%). However, specific adverse events were more common in the ESL group, most notably hyponatraemia (8% vs. 2% in placebo) and dizziness (5% vs. 0%). Serious TEAEs were reported in 20% of the ESL group and 21% of the placebo group. Notably, three serious adverse events in the ESL group were deemed related to the study drug: one case each of nodal arrhythmia, hepatic failure, and hyponatraemia. Although five deaths occurred in the ESL group, independent review determined they were unrelated or unlikely to be related to the study drug, often stemming from the underlying severity of the initial stroke.
Expert Commentary: Interpreting the Data
The BIA-2093-213 trial, while not achieving statistical significance for its primary endpoint, provides invaluable data for the field of epileptology. The use of the SeLECT and CAVE scores allowed researchers to enrich the study population with high-risk individuals, which is essential for testing antiepileptogenic interventions. The trend toward a lower incidence of the composite endpoint in the ESL group (OR 0.66) suggests that a larger, adequately powered phase 3 trial might yield different results.
Methodological Insights
One major takeaway is the feasibility of the trial design. Identifying and enrolling patients in the acute phase of a stroke for an antiepileptogenesis study is logistically demanding. This trial demonstrated that such studies can be conducted across multiple international centers, even under the duress of a global pandemic. However, the use of a composite endpoint (seizure, death, or discontinuation) complicates the interpretation of ‘pure’ antiepileptogenic efficacy. Future studies may need to separate these outcomes or utilize longer treatment durations if the window of epileptogenesis extends beyond the initial 30 days post-stroke.
Clinical Implications and Future Directions
For clinicians, the results do not currently support the routine prophylactic use of eslicarbazepine acetate following an acute stroke. However, the safety data confirms that ESL is generally well-tolerated in this fragile population, provided that sodium levels and liver function are monitored. The trial underscores the necessity of continued research into the molecular mechanisms of post-stroke neuroinflammation and circuit remodeling that lead to epilepsy.
Conclusion
The BIA-2093-213 trial represents a sophisticated attempt to address a major unmet need in stroke care. Although the primary endpoint did not reach statistical significance, the study serves as a successful proof-of-concept for the recruitment and risk-stratification of patients at high risk for post-stroke epilepsy. It paves the way for future, larger-scale trials that could eventually transform the management of stroke survivors from reactive seizure control to proactive epilepsy prevention.
Funding and Registration
The study was funded by BIAL. It is registered on the EudraCT database under the number 2018-002747-29.
References
Koepp MJ, Trinka E, Mah YH, et al. Safety and efficacy of eslicarbazepine acetate for seizure prevention in patients with stroke at high risk of developing post-stroke epilepsy: a proof-of-concept, phase 2a, randomised, double-blind, placebo-controlled antiepileptogenesis trial. Lancet Neurol. 2026 Mar;25(3):256-267. doi: 10.1016/S1474-4422(25)00491-0.
