Dual mechanism of anti-seizure medications in controlling seizure activity

Abstract Anti-seizure medications (ASMs) can reduce seizure duration, but their precise modes of action are unclear. Specifically, it is unknown whether ASMs shorten seizures by curtailing existing seizure activity early or by selectively suppressing certain seizure activity patterns from emerging. We retrospectively analysed intracranial EEG (iEEG) recordings of 457 seizures from 28 people with epilepsy undergoing ASM tapering. Beyond measuring seizure occurrence and duration, we categorized distinct seizure propagation activity patterns (states) based on spatial and frequency power characteristics and related these to different ASM levels. We found that reducing ASM levels led to increased seizure frequency (r = 0.87, P < 0.001) and longer seizure duration (β = −0.033, P < 0.001), consistent with prior research. Further analysis revealed two distinct mechanisms in which seizures became prolonged: Emergence of new seizure propagation patterns—In ∼40% of patients, ASM tapering unmasked additional seizure activity states, and seizures containing these ‘taper-emergent states’ were substantially longer (r = 0.49, P < 0.001). Prolongation of existing seizure patterns—Even in seizures without taper-emergent states, lower ASM levels still resulted in ∼12–224% longer durations depending on the ASM dosage and tapering (β = −0.049, P < 0.001). ASMs influence seizures through two mechanisms: they (i) suppress specific seizure propagation patterns (states) in an all-or-nothing fashion and (ii) curtail the duration of other seizure patterns. These findings highlight the complex role of ASMs in seizure modulation and could inform personalized dosing strategies for epilepsy management. These findings may also have implications in understanding the effects of ASMs on cognition and mood.