Treatment of epilepsy: Existing therapies and future developments

Epilepsy is a major public health issue, not least because of the aging pop ulation in many developed nations and the known increase in the frequency o f epilepsy and seizures in later life. Despite the massive scale of the pro blem and much research, epilepsy remains poorly understood. Despite more th an 20 approved drugs in the developed nations and several non-pharmacologic al options, up to 30% of patients are still refractory to treatment. Despit e over a century of pharmacotherapy and neuroscience research, rational des ign of anti-epileptic drugs (AEDs) is only now starting to yield results, b ecause of the heterogeneity of the disease and our still limited understand ing of it. Discovery and development of AEDs has been especially difficult, because of the regulatory issues of satisfactorily proving safety and effi cacy, ethical constraints on placebo-controlled trial designs, the fact tha t seizures are typically widely spaced in time, and the fact that the perso n undergoing the seizure is typically in no state to remember, let alone as sess, what happened. Several non-pharmacological therapies have been develo ped: brain surgery was first used more than a century ago; the ketogenic di et was first developed 80 years ago; and the vagus nerve stimulator was int roduced recently. Pharmacotherapy remains the mainstay of treatment and is effective in most patients. AEDs can be roughly divided according to their time on the market. The first generation extends from the bromides and the barbiturates (the first of which was phenobarbital), to sodium valproate an d carbamazepine. The second generation begins with felbamate and includes d rugs approved from 1993 to 2000. "Next generation" drugs are still in clini cal development and may reach the marketplace in the near future. Intensive research is being conducted both by pharmaceutical and biotech companies a nd by academic scientists and clinicians; our understanding of the conditio n is advancing rapidly but many challenges remain in discovering and develo ping better AEDs.