DISCUSSION
ASM, death, post‐stroke epilepsy, intracerebral hemorrhage, seizures, epilepsy, stroke, seizure, Stroke, cortical syndrome, cortical ischemic stroke, antiseizure, Epilepsy, lobar hemorrhage
MIDDLE CEREBRAL ARTERY INFARCT, STROKE, INTRACEREBRAL HEMORRHAGE, EPILEPSY, STROKE, EVENT, RECRUITMENT, SECONDARY, EPILEPSY, LACUNAR INFARCT, ACUTE STROKE
The development of preventative or disease‐modifying treatments for post‐stroke epilepsy is urgently needed in view of the high incidence of stroke, and the negative impact epilepsy has on recovery from stroke. Following stroke, epilepsy develops over days to years. This would allow treatment to prevent or modify post‐stroke epilepsy, but no such treatment exists. Only low‐level evidence is available to guide the clinical management of post‐stroke epilepsy, and current guidelines provide weak recommendations on prevention of post‐stroke seizures.A previous study of valproic acid in patients with non‐traumatic, non‐aneurysmatic spontaneous intracerebral hemorrhage used the same treatment duration as our study (30 days), but initiated treatment within 4 hours of the index event, and evaluated seizure rate and neurological function (assessed using the NIHSS) over 1 year (Table The Early Treatment with Levetiracetam After Stroke for the prevention of late seizures (ETLAS) study was a multicenter, randomized, placebo‐controlled, double‐blind study in which stroke patients with a cortical syndrome and a modified Rankin score ≥3 or NIHSS ≥6 were treated with levetiracetam 1500 mg/d or placebo for 12 weeks following stroke and followed up over 1 year (Table The Early GABA‐ergic Activation Study In Stroke (EGASIS) was a randomized, double‐blind, placebo‐controlled study in which patients were treated with diazepam or placebo within 3–12 hours of acute stroke, with treatment continued for 3 days (Table A Phase II, randomized, double‐blind, placebo‐controlled study has been designed to evaluate the efficacy and safety of perampanel as an antiepileptogenic treatment in up to 328 patients with cortical ischemic stroke or lobar hemorrhage (Table A further study has been designed to assess whether early primary prophylactic treatment with low‐dose levetiracetam or perampanel, in comparison with placebo, can prevent the development of post‐stroke epilepsy in up to 180 patients with moderate to severe middle cerebral artery infarct (NIHSS >8), confirmed by brain magnetic resonance imaging studies (excluding lacunar infarct) during hospital admission (Table Comparative summary of Study BIA‐2093‐213 and other antiepileptogenic studies of ASMs following stroke.CompletedNo difference between valproic acid and placebo in risk of post‐stroke seizures (risk ratio, 0.88) or death (risk ratio, 1.20)Levetiracetam(ETLAS)US rate(12 mo)CompletedToo few participants recruited to draw conclusionsDiazepam(EGASIS)CompletedNo statistically significant difference in seizure occurrence between patients treated with diazepam versus placebo (risk ratio, 0.47)No statistically significant difference in mortality between patients treated with diazepam versus placebo at 2 wk (risk ratio, 0.84) and 3 mo (risk ratio, 0.95)Primary prophylaxis with diazepam was associated with a reduced risk of post‐stroke seizures in patients with anterior circulation cortical infarcts (risk ratio, 0.21)Perampanel(PEPSTEP)PerampanelLevetiracetam
NCT04858841Abbreviations: ASM, antiseizure medication; h, hours; IIS, investigator‐initiated study; RCT, randomized controlled trial; US, unprovoked seizure.Time to start of dosing after randomization was 14 ± 4 h in the valproic acid group and 16 ± 5 h in the placebo group.Occurrence of seizures was registered prospectively as one of the prespecified secondary outcomes (primary endpoint was independence [modified Rankin score < 3] at 3 mo).Preferably within 3 h but at most within 12 h.This was an exploratory antiepileptogenesis substudy of the EGASIS Trial, for which a planned sample size was not prespecified; 784 patients were included in the substudy (diazepam, n = 389; placebo, n = 395).What are the key requirements for a potential antiepileptogenic drug?Firstly, preclinical findings must provide a strong rationale for investigating the potential antiepileptogenic effects of an ASM in the clinical setting. In animal models of acquired epilepsy, several medications in clinical use for diverse indications have been shown to have an antiepileptogenic effect, including medications with excellent side‐effect profiles.Secondly, an antiepileptogenic drug taken prophylactically must be well tolerated, with minimal side‐effects and few interactions with other medications. An oral route of administration and once‐daily dose regimen are also important factors, since the average age of the stroke population is relatively high and patients are more likely to be burdened with polypharmacy, particularly with medications that are initiated for stroke risk reduction (statins, antihypertensives, anticoagulants, etc). Moreover, due to brain injury resulting from stroke, patients are at risk of alterations in cognition, with up to 75% experiencing executive dysfunctionThese preclinical findings and considerations regarding the key requirements of an antiepileptogenic drug provide a strong rationale for investigating the potential antiepileptogenic effects of ESL in the clinical setting. However, there are key obstacles when designing such an antiepileptogenic study.Firstly, a study with an unselected population of stroke patients would require a large sample size. This makes a study with a potentially antiepileptogenic compound difficult to operationalize and costly, as post‐stroke epilepsy does not develop in more than 15% of patients.Secondly, an operational challenge when conducting an antiepileptogenic study is the question of when to initiate ASM therapy. Although it might be considered rational to initiate treatment as soon as possible after the stroke event, there are practical considerations regarding the patient reaching a medical facility as soon as possible to receive acute treatment for the stroke event, and the logistics of subsequently obtaining informed consent for study participation prior to initiation of prophylactic ASM therapy. Antiepileptogenic studies have historically adopted a range of time frames for ASM initiation, ranging from ≤12 hours to up to 7 days following the stroke event (Table Thirdly, a study with a potential antiepileptogenic and disease‐modifying compound would require a long follow‐up period. Epilepsy can manifest more than 5 years after the epileptogenic stroke,In summary, the design of Study BIA‐2093‐213 differs from other previous and ongoing studies of ASMs in the post‐stroke antiepileptogenic setting, in terms of time frame for treatment initiation, length of treatment, duration of follow‐up, recruitment duration, and number of patients required to allow robust statistical analysis (Table Given the current lack of prophylactic therapies for individuals at risk of epileptogenesis, and the lack of evidence to support the use of ASMs for the primary or secondary prevention of seizures following stroke,