Antiepileptogenic agents - How close are we?

Epilepsy is a common neurological condition, affecting about 4% of individu als over their lifetime. Epilepsy can be idiopathic, secondary to an underl ying genetic abnormality or unknown causes, or acquired. Known potential ca uses account for about one third of epilepsy. Control of epilepsy has prima rily focused on suppressing seizure activity after epilepsy has developed. An intriguing possibility is to control acquired epilepsy by preventing epi leptogenesis, the process by which the brain becomes epileptic. Many labora tory models simulate human epilepsy as well as provide a system for studyin g epileptogenesis. The kindling model involves repeated application of subc onvulsive electrical stimulation to the brain. leading to spontaneous seizu res. Other models include the cortical or systemic injection of various che micals. These models suggest that many antiepileptic drugs, from phenobarbi tal and valproate (valproic acid) to levetiracetam and tiagabine, have anti epileptogenic potential. Some promising other possibilities include N-methy l-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 e xtent, diazepam have been evaluated in clinical trials to test whether they actually prevent epileptogenesis in humans. Results have been very disappo inting. Meta-analyses of 12 different drug-condition combinations show none with significantly lower unprovoked seizure rates among those receiving th e active drug. In 4 of the 12, the observed rate was actually slightly high er among treated individuals. None of the newer drugs have been evaluated i n antiepileptogenesis trials. Until some drugs demonstrate a clear antiepil eptogenic effect in clinical trials, the best course to reduce the incidenc e of epilepsy is primary prevention of the risk-increasing events - for exa mple, wearing helmets, using seat belts, or decreasing the risk of stroke b y reducing smoking.