Antiepileptogenic agents: how close are we?

Epilepsy is a common neurological condition, affecting about 4% of individuals over their lifetime. Epilepsy can be idiopathic, secondary to an underlying genetic abnormality or unknown causes, or acquired. Known potential causes account for about one third of epilepsy. Control of epilepsy has primarily focused on suppressing seizure activity after epilepsy has developed. An intriguing possibility is to control acquired epilepsy by preventing epileptogenesis, the process by which the brain becomes epileptic. Many laboratory models simulate human epilepsy as well as provide a system for studying epileptogenesis. The kindling model involves repeated application of subconvulsive electrical stimulation to the brain, leading to spontaneous seizures. Other models include the cortical or systemic injection of various chemicals. These models suggest that many antiepileptic drugs, from phenobarbital and valproate (valproic acid) to levetiracetam and tiagabine, have antiepileptogenic potential. Some promising other possibilities include N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) antagonists as well as the neurotrophins and their receptors. Phenobarbital, phenytoin, valproate, carbamazepine and, to a very limited extent, diazepam have been evaluated in clinical trials to test whether they actually prevent epileptogenesis in humans. Results have been very disappointing. Meta-analyses of 12 different drug-condition combinations show none with significantly lower unprovoked seizure rates among those receiving the active drug. In 4 of the 12, the observed rate was actually slightly higher among treated individuals. None of the newer drugs have been evaluated in antiepileptogenesis trials. Until some drugs demonstrate a clear antiepileptogenic effect in clinical trials, the best course to reduce the incidence of epilepsy is primary prevention of the risk-increasing events--for example, wearing helmets, using seat belts, or decreasing the risk of stroke by reducing smoking.