There are insufficient data to support a Level I recommendation for this topic.

Prophylactic use of phenytoin or valproate is not recommended for preventing late posttraumatic seizures (PTS).

Anticonvulsants are indicated to decrease the incidence of early PTS (within 7 days of injury). However, early PTS is not associated with worse outcomes.

PTSs are classified as early, occurring within 7 days of injury, or late, occurring after 7 days following injury. It is desirable to prevent both early and late PTS. However, it is also desirable to avoid neurobehavioral and other side effects of medications, particularly if they are ineffective in preventing seizures.

Prophylaxis for PTS refers to the practice of administering anticonvulsants to patients following traumatic brain injury (TBI) to prevent the occurrence of seizures. The rationale for routine seizure prophylaxis is that there is a relatively high incidence of PTS in TBI patients, and there are potential benefits to preventing seizures following TBI.

The incidence of seizures following penetrating injuries is about 50% in patients followed for 15 years. In civilian TBI studies that followed high-risk patients up to 36 months, the incidence of early PTS varied between 4% and 25%, and the incidence of late PTS varied between 9% and 42% in untreated patients. In the acute period, seizures may precipitate adverse events in the injured brain because of elevations in intracranial pressure (ICP), blood pressure changes, changes in oxygen delivery, and also excess neurotransmitter release. The occurrence of seizures may also be associated with accidental injury, psychological effects, and loss of driving privileges. There has been a belief that prevention of early seizures may prevent the development of chronic epilepsy. Experimental studies have supported the idea that initial seizures may initiate kindling, which then may generate a permanent seizure focus.

Early retrospective studies indicated that phenytoin was effective for the prevention of PTS. A practice survey among U.S. neurosurgeons in 1973 indicated that 60% used seizure prophylaxis for TBI patients. On the other hand, anticonvulsants have been associated with adverse side effects including rashes, Stevens-Johnson syndrome, hematologic abnormalities, ataxia, and neurobehavioral side effects. Certain risk factors have been identified that place TBI patients at increased risk for developing PTS. These risk factors include the following:

Glasgow Coma Scale (GCS) Score < 10
Cortical contusion
Depressed skull fracture
Subdural hematoma
Epidural hematoma
Intracerebral hematoma
Penetrating head wound
Seizure within 24 h of injury

It is therefore important to evaluate the efficacy and overall benefit, as well as potential harms, of anticonvulsants used for the prevention of PTS.

For this update, Medline was searched from 1996 through April of 2006 (see Appendix B for search strategy), and results were supplemented with literature recommended by peers or identified from reference lists. Of 10 potentially relevant studies, one was added to the existing table and used as evidence for this question (Evidence Table I).

Temkin et al. reported the results of a large randomized, double-blind, placebo-controlled trial of 404 patients evaluating the effect of phenytoin on early and late PTS. This trial was unique in that serum levels were independently monitored and dosages were adjusted so that therapeutic levels were maintained in at least 70% of the patients. Moreover, three quarters of the patients who had levels monitored on the day of their first late seizure had therapeutic levels. There was a significant reduction in the incidence of early PTS in the treated group from 14.2% to 3.6% (p < 0.001). There was no significant reduction in the incidence of late PTS in the treated group. The survival curves for the placebo and active treatment groups showed no significant difference.

A secondary analysis was performed on the data from this trial to determine if treatment for early PTS was associated with significant drug related adverse side effects. The occurrence of adverse drug effects during the first 2 weeks of treatment was low and not significantly different between the treated and placebo groups. Hypersensitivity reactions occurred in 0.6% of the phenytoin group versus 0% of the placebo group (p = 1.0) during week 1, and 2.5% of the phenytoin group versus 0% of the placebo group (p = 0.12) for the first 2 weeks of treatment. Mortality was also similar in both groups. The results of the study indicate that the incidence of early posttraumatic seizures can be effectively reduced by prophylactic administration of phenytoin for 1 or 2 weeks without a significant increase in serious drug related side effects.

In another secondary analysis of the same trial, Dikmen et al. found significantly impaired performance on neuropsychologic tests at 1 month after injury in severe TBI patients maintained on phenytoin. However, the difference was not apparent at 1 year following injury.

An additional randomized, double-blind study evaluated the effect of valproate to reduce the incidence of early and late posttraumatic seizures.7 The trial compared phenytoin to valproate for the prevention of early PTS, and valproate to placebo for the prevention of late PTS. The incidence of early PTS was similar in patients treated with either valproate or phenytoin. The incidence of late PTS was similar in patients treated with phenytoin for 1 week and then placebo, or patients treated with valproate for either 1 month then placebo, or with valproate for 6 months. There was a trend toward higher mortality in patients treated with valproate.

Young et al. conducted a randomized, double-blind study of 244 TBI patients and reported that phenytoin was not effective in preventing early or late PTS. The incidence of early PTS was low in the placebo and treatment groups, however, which may have influenced the lack of protective effect of treatment on early PTS. No patient with a phenytoin plasma concentration of 12 mcg/ml or higher had a seizure however, and therefore, the possibility remained that higher levels may have been more effective in preventing late PTS. Methodological flaws in this study render the evidence Class III and limit inferences.

Manaka conducted a randomized, double-blind study of 126 patients receiving placebo or phenobarbital for the prevention of late PTS. There was no significant reduction in late PTS in the active treatment group. This study provided Class III evidence.

The studies that form the evidence base for this topic indicate that anticonvulsants administered prophylactically reduce the incidence of early PTS but do not significantly reduce the incidence of late PTS. All of these studies classified seizures based on clinically recognized episodes. Currently there is no evidence on outcome in patients with non-convulsive seizures with or without prophylaxis. In addition, the available evidence does not indicate that prevention of PTS improves outcome.

The majority of studies do not support the use of the prophylactic anticonvulsants evaluated thus far for the prevention of late PTS. Routine seizure prophylaxis later than 1 week following TBI is, therefore, not recommended. If late PTS occurs, patients should be managed in accordance with standard approaches to patients with new onset seizures. Phenytoin has been shown to reduce the incidence of early PTS. Valproate may also have a comparable effect to phenytoin on reducing early PTS but may also be associated with a higher mortality.

Additional studies are needed to determine if reduction in early PTS has an effect on outcome. Such studies should utilize continuous EEG monitoring to identify seizures. Future trials should investigate incidence of PTS in patients treated with neuroprotective agents that have antiepileptic activity, such as magnesium sulphate and other NMDA receptor antagonists.