Anti-epileptic drugs for preventing seizures following acute traumatic brain injury

Abstract

Background: Seizure activity in the early post-traumatic period following head injury may cause secondary brain damage as a result of increased metabolic demands, raised intracranial pressure and excess neurotransmitter release.

Objectives: To determine the effects of prophylactic anti-epileptic agents for acute traumatic head injury.

Search strategy: We searched the Cochrane Injuries Group specialised register, Medline and the registers of the Cochrane Stroke Group and Cochrane Epilepsy Group. We contacted pharmaceutical companies who manufacture anti-epileptic agents, the National Institute of Neurological Disorders and Stroke, Epilepsy Division, and the National Institute of Health, United States.

Selection criteria: All randomised trials of anti-epileptic agents, in which study participants had a clinically defined acute traumatic head injury of any severity. Trials in which the intervention was started more than eight weeks after injury were excluded.

Data collection and analysis: Two reviewers independently extracted data and assessed the trial quality. Relative risks and 95% confidence intervals were calculated for each trial on an intention to treat basis, which included pre-drug loading exclusions. As long as statistical heterogeneity did not exist, for dichotomous data, summary relative risks and 95% confidence intervals were calculated using a fixed effects model. Where the source of heterogeneity could obviously be related to allocation concealment, drug type, or drug dose, we stratified the analyses on that dimension.

Main results: We identified 10 eligible randomised controlled trials, including 2036 participants, but data was unavailable for four unpublished trials, representing 631 participants and they were excluded. For the remaining six trials, the pooled relative risk (RR) for early seizure prevention was 0.34 (95% confidence interval 0.21 to 0.54); based on this estimate, for every 100 patients treated, 10 would be kept seizure free in the first week. Seizure control in the acute phase was not accompanied by a reduction in mortality (RR=1.15; 95% confidence interval 0.89 to 1.51), a reduction in death and neurological disability (RR = 1.49; 95% confidence interval 1.06 to 2.08 for carbamazepine and RR= 0.96; 95% confidence interval 0.72 to 1.26 for phenytoin) or a reduction in late seizures (pooled RR =1.28; 95% confidence interval 0.90 to 1.81). The pooled relative risk for skin rashes was 1.57 (95% confidence interval 0.57 to 39.88).

Reviewer's conclusions: Prophylactic anti-epileptics are effective in reducing early seizures, but there is no evidence that treatment with prophylactic anti-epileptics reduces the occurrence of late seizures, or has any effect on death and neurological disability. Insufficient evidence is available to establish the net benefit of prophylactic treatment at any time after injury.