226 Scopus citations

Abstract

Epilepsy is a common neurological disorder that affects over 70 million people worldwide. Despite the recent introduction of new antiseizure drugs (ASDs), about one-third of patients with epilepsy have seizures refractory to pharmacotherapy. Early identification of patients who will become refractory to ASDs could help direct such patients to appropriate non-pharmacological treatment, but the complexity in the temporal patterns of epilepsy could make such identification difficult. The target hypothesis and transporter hypothesis are the most cited theories trying to explain refractory epilepsy, but neither theory alone fully explains the neurobiological basis of pharmacoresistance. This review summarizes evidence for and against several major theories, including the pharmacokinetic hypothesis, neural network hypothesis, intrinsic severity hypothesis, gene variant hypothesis, target hypothesis, and transporter hypothesis. The discussion is mainly focused on the transporter hypothesis, where clinical and experimental data are discussed on multidrug transporter overexpression, substrate profiles of ASDs, mechanism of transporter upregulation, polymorphisms of transporters, and the use of transporter inhibitors. Finally, future perspectives are presented for the improvement of current hypotheses and the development of treatment strategies as guided by the current understanding of refractory epilepsy.

Original languageEnglish
Article number301
JournalFrontiers in Neurology
Volume8
Issue numberJUL
DOIs
StatePublished - Jul 6 2017

Bibliographical note

Funding Information:
We thank and acknowledge our team members Stephanie Edelmann and Nader El Seblani for editorial assistance, and we thank and acknowledge Tom Dolan at UK Information Technology Services for graphical assistance. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The project described was supported by grant number 1 R01NS079507 from the National Institute of Neurological Disorders and Stroke (to BB). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke or the National Institutes of Health.

Publisher Copyright:
© 2017 Tang, Hartz and Bauer.

Keywords

  • Blood-brain barrier
  • Epilepsy
  • P-glycoprotein
  • Refractory epilepsy
  • Target hypothesis
  • Transporter hypothesis
  • Transporter inhibition
  • Transporter regulation

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Fingerprint

Dive into the research topics of 'Drug-resistant epilepsy: Multiple hypotheses, few answers'. Together they form a unique fingerprint.

Cite this