Prophylactic levetiracetam is associated with reduced risk for early epilepsy after severe traumatic brain injury (TBI) but not with reduced risk for long-term epilepsy, according to study results published in the Annals of Neurology. Patients with TBI are often prescribed ASMs to prevent post-traumatic epilepsy. However, current recommendations are largely based on older phenytoin and valproate trials and do not incorporate large-scale evidence evaluating levetiracetam, the current agent of choice.

Researchers used data from the TriNetX Research Network to examine the effectiveness and safety of prophylactic levetiracetam for preventing post-traumatic epilepsy after TBI. Patients (N=51,263) were assessed on the basis of whether they received levetiracetam (n=14,630) or no ASMs (n=34,226). Mild TBI was defined as a Glasgow Coma Scale (GCS) score of 13 to 15, moderate TBI as a GCS score of 9 to 12, severe TBI as a GCS score of 3 to 8, early epilepsy as onset within 7 days of injury, and late epilepsy as onset between day 7 and 1 year after injury. Our findings challenge widespread use of levetiracetam and suggest that prophylaxis should not be offered indiscriminately.

The levetiracetam and no ASM cohorts comprised 31.0% and 35.8% women (P <.0001), had a mean (SD) age of 53.9 (20.5) and 47.9 (20.5) years (P <.0001), included 28.9% and 31.2% non-White patients (P <.0001), and included 34.7% and 17.9% of patients with severe TBI, respectively (P <.0001).

Overall, epilepsy occurred in 6.7% of participants, and 14.1% died within 1 year of injury. Epilepsy within 1 year of injury was more frequent among patients with moderate (12.1%) and severe (11.3%) TBI than among those with mild TBI (4.8%; P <.001). Similarly, mortality was higher among patients with severe (39.0%) and moderate (15.7%) TBI than among those with mild TBI (4.7%; P <.001).

After adjustment for potential confounders, levetiracetam was associated with reduced risk for early epilepsy among patients with severe TBI (hazard ratio [HR], 0.545; 95% CI, 0.306-0.969; P =.039). Independent predictors of early epilepsy in this cohort included traumatic subdural hemorrhage, left cerebral contusion or laceration, craniectomy or craniotomy, and routine electroencephalography (EEG).

The researchers observed no significant association between prophylactic levetiracetam and late epilepsy overall or among patients with mild or severe TBI (HR range, 0.897-1.001). Levetiracetam was associated with lower risk for mortality through 1 year in the overall cohort (HR, 0.826; 95% CI, 0.787-0.867; P <.001) and among individuals who survived longer than 7 days after injury (HR, 0.881; 95% CI, 0.815-0.952; P =.001). However, in a sensitivity analysis limited to patients who survived longer than 7 days after injury, levetiracetam was not associated with a reduced risk for early epilepsy, including among patients with severe TBI.

Across 5 years of follow-up, patients who received levetiracetam had higher rates of mortality (difference, 2.2%; P <.0001), impaired memory or awareness (difference, 5.4%; P <.0001), migraine and headache (difference, 4.3%; P <.0001), metabolic disorders (difference, 2.6%; P <.0001), and malaise and fatigue (difference, 2.0%; P <.0001), among other adverse outcomes.

Study limitations include the inability of the TriNetX dataset to determine the sequence of events on the day of injury, preventing investigators from establishing whether levetiracetam was administered before seizure onset.

The researchers concluded, “In this large, severity-stratified cohort study, prophylactic levetiracetam reduced the risk of early seizures only in patients with severe TBI, without preventing late posttraumatic epilepsy and while conferring a substantial burden of adverse outcomes.” They continued, “Our findings challenge widespread use of levetiracetam and suggest that prophylaxis should not be offered indiscriminately.”