Etiology and management of refractory epilepsies

The epilepsies are an important, common and diverse group of symptom complexes characterized by recurrent spontaneous seizures. Although many patients with epilepsy have their seizures controlled effectively by antiepileptic drugs (AEDs), about one-third of patients continue to have seizures, despite trying a range of AEDs. Such patients bear the heaviest burden of epilepsy, with increased morbidity and risk of premature mortality. Our current understanding of the refractory epilepsies--the most common of which are focal--is limited; even their definition is problematic. Standard treatments for refractory epilepsies include optimization of existing AED regimens, trials of further AEDs, and, for some patients, therapeutic resective neurosurgery. Recent basic research has explored possible underlying causes of refractory epilepsy, and two main hypotheses have emerged to account for the failure of AED treatment. According to one hypothesis, AEDs might fail because of alterations in the properties of their usual targets. Alternatively, they might fail because multidrug transporter mechanisms limit concentrations of the drugs at their targets. The refractory epilepsies can be viewed as offering remarkable insights into biological processes in the epilepsies, and their effective treatment remains an important aim; treatment would potentially bring much-needed relief to hundreds of thousands of patients across the world.