Drug Resistance

Drug resistance remains to be one of the major challenges in epilepsy therapy. Identification of factors that contribute to therapeutic failure is crucial for future development of novel therapeutic strategies for difficult-to-treat epilepsies. Several clinical studies have shown that high seizure frequency before onset of therapy predicts a poor outcome of pharmacotherapy. Based on this observation the ‘intrinsic severity hypothesis’ has been proposed. This hypothesis implies that neurobiological factors which contribute to increased disease severity correlate with drug resistance. Further hypotheses propose specific mechanisms of resistance. The mechanisms discussed include alterations in drug targets as well as alterations at the blood-brain barrier including the up-regulation of efflux transporters. Respective data that render experimental support for the hypotheses, pose the question whether these constitute a basis for the development of novel treatment strategies. However, any strategy aiming to outwit one of the suggested mechanisms is challenged by paucity of convincing clinical support for the hypotheses as well as the fact that drug resistance is generally considered as a multi-factorial problem. Future studies are necessary to explore whether the mechanisms have any clinical relevance, and if so, to explore whether selected mechanisms might predominate in patient subgroups.