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

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).

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.

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.

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.