Introduction: The Unmet Need in Post-Stroke Care
Post-stroke epilepsy (PSE) remains one of the most debilitating long-term complications of both ischemic and hemorrhagic strokes. While acute symptomatic seizures occur within the first week of a vascular event, the development of chronic epilepsy involves a complex biological process known as antiepileptogenesis. Currently, clinical guidelines do not recommend the prophylactic use of antiseizure medications (ASMs) to prevent epilepsy, primarily due to a lack of evidence that current drugs can alter the underlying disease course rather than merely suppressing symptoms.
Eslicarbazepine acetate (ESL), a once-daily, voltage-gated sodium channel blocker that targets the inactivated state of the channel, has shown promise in preclinical models for its potential neuroprotective and antiepileptogenic properties. The BIA-2093-213 trial represents a significant step in determining whether early intervention with ESL can modify the risk of unprovoked seizures in high-risk patients.
Highlights of the Study
– The Phase 2a trial successfully utilized validated risk scores (SeLECT and CAVE) to identify patients at high risk of post-stroke epilepsy.
– There was no statistically significant difference in the primary composite endpoint (seizure, death, or discontinuation) between the eslicarbazepine acetate and placebo groups at 6 months.
– The study was significantly underpowered due to slow recruitment and the global impact of the COVID-19 pandemic, resulting in wide confidence intervals.
– Safety data confirmed that eslicarbazepine acetate was generally well-tolerated, though clinicians should monitor for hyponatremia.
Background and Disease Burden
Post-stroke epilepsy affects approximately 5% to 15% of all stroke survivors, with the risk rising significantly in patients with large cortical lesions, intracerebral hemorrhage (ICH), or early acute seizures. The clinical burden is substantial, as PSE is associated with poorer functional recovery, increased mortality, and reduced quality of life.
The search for a truly “antiepileptogenic” agent—one that prevents the development of the epileptic focus rather than just treating the resulting seizures—has been a holy grail in neurology. Preclinical evidence suggested that ESL might interfere with the molecular cascades triggered by stroke that lead to hyperexcitability, making it a prime candidate for this proof-of-concept trial.
Study Design and Methodology
Study BIA-2093-213 was an exploratory, proof-of-concept, Phase 2a, double-blind, randomized, placebo-controlled trial. It targeted a specific high-risk cohort of adults who had recently suffered an acute ischemic stroke or intracerebral hemorrhage.
Patient Selection and Risk Stratification
Participants were recruited based on specific clinical markers of high risk:
– Ischemic Stroke: A SeLECT score of 5 or greater (considering Severity of stroke, Large artery atherosclerosis, Early seizure, Cortical involvement, and Territory of the MCA).
– Intracerebral Hemorrhage: A CAVE score of 2 or greater (considering Cortical involvement, Age, Volume of hemorrhage, and Early seizure).
Intervention and Follow-up
Patients were randomized 1:1 to receive either 800 mg/day of eslicarbazepine acetate or a matching placebo for a 30-day treatment period. Randomization occurred within 96 to 120 hours of stroke onset. Following the treatment phase, patients were monitored for an additional 17 months to track the development of unprovoked seizures.
Endpoints
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 post-randomization.
Key Findings and Results
A total of 125 patients were randomized (62 to ESL, 63 to placebo) across 19 university hospitals in Europe and Israel.
Efficacy Outcomes
At the 6-month mark, the primary endpoint occurred in 17 (28%) of 61 patients in the eslicarbazepine acetate group compared to 23 (37%) of 62 patients in the placebo group. While the ESL group showed a numerically lower rate of events, the difference was not statistically significant (Odds Ratio [OR] 0.66; 95% CI 0.31–1.40; p=0.37). The wide confidence intervals reflect the limited sample size and the study’s lack of statistical power to detect a definitive preventative effect.
Safety and Tolerability
Treatment-emergent adverse events (TEAEs) were reported in 82% of both groups. However, specific side effects showed variation:
– Hyponatremia: Reported in 8% of the ESL group versus 2% of the placebo group, a known side effect of sodium channel blockers.
– Dizziness: Occurred in 5% of the ESL group compared to none in the placebo group.
– Serious TEAEs: Reported in 20% of the ESL group and 21% of the placebo group. Notably, five deaths occurred in the ESL group, but none were determined by investigators to be related to the study medication.
Expert Commentary: Interpreting the Data
The failure of this trial to reach statistical significance should be viewed through the lens of its feasibility and the extraordinary circumstances of its execution. The COVID-19 pandemic severely hampered recruitment, leading to a trial that was ultimately underpowered.
From a mechanistic perspective, the 30-day treatment window may be a critical variable. The process of epileptogenesis after a stroke can span months or even years. While the trial aimed to intervene during the acute “priming” phase, it remains an open question whether a longer duration of therapy or a larger sample size would have yielded a different result.
However, the trial’s use of the SeLECT and CAVE scores is a major achievement. It demonstrates that we can successfully identify a “high-risk” population, which is essential for making future antiepileptogenesis trials economically and scientifically viable. Without such stratification, the number of patients required to see a treatment effect would be prohibitively large.
Conclusion: A Foundation for Future Research
While the BIA-2093-213 trial did not provide definitive evidence that eslicarbazepine acetate prevents post-stroke epilepsy, it provides the neurological community with a roadmap. It confirms that antiepileptogenesis studies in the acute stroke setting are feasible and that risk-scoring tools are effective for patient selection.
Future research should focus on larger, adequately powered cohorts and perhaps explore varying durations of treatment. For now, clinical practice remains unchanged, but the door has been opened wider for the next generation of preventative epilepsy trials.
Funding and Clinical Registration
This study was funded by BIAL. It is registered on the EudraCT database under the number EudraCT 2018-002747-29.
References
1. 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. The Lancet Neurology. 2026;25(3):256-267. PMID: 41722592.
2. Galovic M, et al. The SeLECT score: Predicting seizures after ischemic stroke. JAMA Neurology. 2018;75(12):1456-1463.
3. Haapaniemi E, et al. Risk of epilepsy after intracerebral hemorrhage. Stroke. 2014;45(6):1747-1751.