Listening Across Frequencies: Capturing Seizures of all Patients to Advance Antiseizure Medication Development

Seizure frequency has traditionally been the primary measure of treatment effectiveness in epilepsy clinical trials and remains a key requirement for enrollment. Most trials require at least four seizures per month, a threshold chosen to ensure enough seizure events are captured to provide adequate statistical power. However, as antiseizure medications have improved, fewer patients meet this criterion. For example, only 42% of adults with treatment-resistant focal epilepsy and 25% of individuals with Dravet syndrome experience four or more countable seizures within a 4-week period. This suggests that current eligibility criteria may exclude a substantial proportion of patients despite ongoing disease burden.

Some researchers have proposed placing greater emphasis on cognitive and developmental outcomes, particularly in developmental and epileptic encephalopathies (DEEs), where developmental impairment is a core feature of the disease. The growing development of disease-modifying therapies, including gene therapies, has increased interest in these outcomes. However, seizure control remains critically important, as patients who continue to experience generalized tonic–clonic seizures remain at risk of sudden unexpected death in epilepsy (SUDEP).

Alternative trial designs may help evaluate antiseizure efficacy without relying on the traditional four-seizures-per-month threshold. One increasingly validated approach is the time-to-event design, which uses individualized endpoints based on the occurrence of a predefined number of seizures rather than a fixed maintenance period. This allows patients with lower baseline seizure frequencies to participate while maintaining statistical rigor and reducing prolonged exposure to placebo. Future epilepsy trials should better integrate both seizure and developmental outcomes, supporting continued advances in antiseizure medications while also evaluating therapies that may improve long-term developmental trajectories.

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