Levetiracetam for Seizure Prophylaxis after Traumatic Brain Injury: A Severity‐Stratified Cohort Study of 51,000 Patients

OBJECTIVES: The objective of this study was to evaluate the effectiveness and adverse effect profile of prophylactic levetiracetam in preventing epilepsy after traumatic brain injury (TBI). METHODS: This retrospective cohort study used the TriNetX Research Network, encompassing >150 million patients. Adults (≥18 years) with a first TBI and Glasgow Coma Scale (GCS) score recorded were included. Patients with pre-existing epilepsy, seizures on the day of injury, or prior levetiracetam exposure were excluded. The cohort (n = 51,263) was stratified into mild (GCS 13-15; n = 33,625) and severe (GCS 3-8; n = 10,805) TBI. The risk of early (<7 days) and late (<1 year) epilepsy was assessed using Cox proportional hazards models adjusted for known predictors. Adverse events were evaluated for up to 5 years. RESULTS: Levetiracetam was administered to 14,630 patients (30%). After adjustment, levetiracetam reduced early epilepsy in severe TBI (hazard ratio [HR] = 0.55, 95% confidence interval [CI] = 0.31-0.97, p = 0.04) but not in mild TBI (HR = 0.85, 95% CI = 0.45-1.61, p = 0.61). Levetiracetam did not reduce late epilepsy in either mild (HR = 1.00, 95% CI = 0.79-1.15, p = 0.997) or severe (HR = 0.90, 95% CI = 0.68-1.19, p = 0.45) TBI. Older age, cerebral edema, and subdural hemorrhage were consistent risk factors. Adverse outcomes included impaired memory and awareness, metabolic disorders, and psychiatric symptoms. INTERPRETATION: Levetiracetam prophylaxis reduced early epilepsy only in severe TBI and conferred no long-term protection. Given its adverse effect burden, routine prophylaxis should be limited to severe TBI or high-risk patients. These findings support re-evaluation of current seizure prophylaxis guidelines, which are based on older antiseizure medications and predate large-scale real-world data. ANN NEUROL 2026;100:416-425.