SALT LAKE CITY—The incidence of epilepsy among soldiers who have experienced head trauma in the Iraq War is expected to increase, with no clearly effective strategy available to treat or prevent it, according to Daniel H. Lowenstein, MD. Although traumatic brain injury (TBI)-induced epilepsy has been a well-documented phenomenon after combat, the rate is expected to be particularly high in veterans of the Iraq conflict due to the nature of the weaponry, with explosive devices being a key source of injury.
“Brain trauma has been the signature injury of the Iraq War,” said Dr. Lowenstein, Professor and Vice Chairman of the Department of Neurology at the University of California, San Francisco (UCSF). Although the rate of thoracic injuries has been much lower among American soldiers in Iraq than that observed in previous conflicts, including Vietnam and World War II, concussive explosions are a common phenomenon, he reported at the 133rd Annual Meeting of the American Neurological Association.
No Clear Evidence for Preventive Measures
Seizures can usually be controlled in those who experience them immediately (within the first week) after TBI, noted Dr. Lowenstein, who is also Director of the UCSF Epilepsy Center and Director of Physician-Scientist and Education Training Programs for the UCSF School of Medicine. However, it is estimated that between 25% and 50% of individuals who have a severe brain injury will eventually develop epilepsy. Although more than half will develop seizures within the first year of the injury, a substantial number will not experience their first seizure for years or as much as a decade later. Various studies have looked at prophylaxis, usually with conventional antiepileptic drugs, but there is no clear evidence of protection.
Dr. Lowenstein characterized results of the four placebo-controlled trials that have been conducted thus far as “quite sobering.” Not only was there no clear-cut preventive effect with such drugs as phenytoin, but “the more troubling result was that in the two most carefully controlled studies, there was a suggestion that the intervention was actually increasing the relative risk of epilepsy after TBI.” Although some noncontrolled studies have associated antiepileptic agents with potential protection from trauma-induced seizures, a meta-analysis of the placebo-controlled trials also indicated an absence of preventive effect.
When stratifying head injuries by mild (loss of consciousness for less than 30 minutes and no fracture), moderate (loss of consciousness from 30 minutes to 24 hours with concussion), and severe (loss of consciousness for longer than 24 hours with hematoma and/or fracture), there is at least a trend for a dose response, whether the trauma was sustained during combat or elsewhere. According to Dr. Lowenstein, TBI is one of the most common etiologies of acquired epilepsy. In general, individuals with TBI have about 30 times the risk for epilepsy compared with the healthy population, but the risk may be far greater regarding severe TBI acquired in combat. Data from the Vietnam War suggested that the relative risk was more than 500-fold greater in the first year after injury and 25 times greater 10 to 15 years after injury.
Imaging tools, such as EEG, CT, and MRI, have not been effective for predicting which patients with TBI will progress to epilepsy. Clonic and partial seizures are particularly common after TBI, but Dr. Lowenstein noted that essentially all forms of epilepsy are represented.
Mechanism of Epilepsy After TBI Is Uncertain
There are a number of theories regarding the mechanism of epilepsy after TBI, but the precise mechanism or mechanisms have not been isolated, Dr. Lowenstein explained. One theory is that changes in iron metabolism and deposition increase free radical damage and an excessive release of glutamine that alters electrical activity. In animal models, even brief trauma to the dura mater results in selective loss in neuronal populations, including those considered to be important to inhibition of electrical signaling. In addition, surviving neurons often undergo a change in architecture that includes increases in axon length and the number of axon collaterals. This can also contribute to enhanced excitability.
“This is an area that is ripe for translational research,” said Dr. Lowenstein, who indicated that this step is likely to be critical in the effort to develop targets for prophylaxis. The need for prophylaxis is especially acute. For soldiers, an increasing incidence of epilepsy is predicted by the higher rate of survival after head injury in the Iraq War. Wounded soldiers are reaching hospitals in Germany or the United States within two or three days, versus two or more weeks in the Vietnam War, Dr. Lowenstein pointed out. Of the 30,200 soldiers wounded in Iraq, more than 2,000 have had significant TBI. The long-term care costs of these injuries are expected to be substantial.