Perampanel for Early Seizure Prophylaxis After Severe Traumatic Brain Injury: A Retrospective Comparative Study with Levetiracetam

Early post-traumatic seizures (EPTS) after severe traumatic brain injury (TBI) are linked to poor neurological outcomes. While levetiracetam (LEV) is commonly used for seizure prophylaxis, perampanel (PER), an AMPA receptor antagonist, is gaining interest due to its potential neuroprotective effects. This retrospective cohort study included adults (≥18 years) admitted to a tertiary trauma center between 2018 and 2025 who received LEV or PER within 12 h post-injury (<i>N</i> = 200; LEV, <i>n</i> = 145; PER, <i>n</i> = 55). Monotherapy was initiated with either drug. The primary outcome was EPTS incidence within 7 days. Secondary outcomes included mechanical ventilation duration, hospital stay, and Glasgow Outcome Scale (GOS) score. Analyses included Firth's logistic regression and inverse probability of treatment weighting (IPTW) adjusted for key clinical confounders. EPTS occurred at 15.9% (LEV) versus 1.8% (PER). PER significantly reduced seizure risk (Firth-adjusted OR = 0.158; 95% CI, 0.017-0.644; <i>p</i> = 0.007), which was confirmed by IPTW (OR = 0.112; 95% CI, 0.014-0.873; <i>p</i> = 0.037). PER also shortened ventilation duration (IRR = 0.515; 95% CI, 0.303-0.907; <i>p</i> = 0.015). GOS and hospital stay did not differ significantly. No adverse events occurred in either group. PER significantly reduced EPTS and mechanical ventilation duration compared with LEV. The safety and utility of PER in acute care suggest it might be a valuable alternative for seizure prophylaxis in patients with severe TBI.