To compare the effectiveness of primary versus secondary seizure prophylaxis in acute ischemic stroke (AIS) patients at high-risk for post-stroke epilepsy (PSE).

PSE is a common complication of AIS that increases disability and mortality. Prophylactic anti-seizure medications (ASMs) are currently not recommended, but their use in high-risk patients could potentially prevent neuronal injury and reduce mortality.

A systematic search was conducted in PubMed using predefined search criteria for relevant literature from inception to September 2025. Two authors independently performed a database search, data collection, and study quality evaluation. The primary outcome was PSE.

Six studies evaluating 5000+ stroke patients were included. A short prophylactic course of diazepam after AIS was shown to decrease PSE frequency compared to placebo (1.5% vs 3.3%, p=0.11). In the subgroup analysis of patients with cortical anterior circulation stroke, the seizure rate was significantly lower in the diazepam group (0.9% vs. 4.6% p=0.02). In patients aged 65 or older with new, non-severe AIS, primary prophylaxis with an ASM increased mortality even after adjusting for confounding factors (Risk difference 131 deaths/1000 patients).

A decision analysis model evaluating primary and secondary ASM prophylaxis strategies on quality-adjusted life-years (QALYs) in patients with AIS revealed that primary prophylaxis resulted in fewer QALYs than secondary prophylaxis, which was safer and more effective. Starting ASMs promptly after PSE is identified, but continuing them only for a limited time, led to better patient outcomes than indefinite treatment.

Secondary prophylaxis was safer and more effective than primary prophylaxis. However, there is limited data to suggest that a small group of high-risk patients may benefit from early ASM use. Since there are no direct comparisons of ASM prophylaxis strategies in this patient population, we hope this study will serve as a platform for larger multi-center studies to develop targeted interventions for this high-risk group.