Understanding mechanisms of drug resistance in epilepsy and strategies for overcoming it

Introduction The present evidence indicates that approximately 70% of patients with epilepsy can be successfully treated with antiepileptic drugs (AEDs). A significant proportion of patients are not under sufficient control, and pharmacoresistant epilepsy is clearly associated with poor quality of life and increased morbidity and mortality. There is a great need for newer therapeutic options able to reduce the percentage of drug-resistant patients. Areas covered A number of hypotheses trying to explain the development of pharmacoresistance have been put forward. These include: target hypothesis (altered AED targets), transporter (overexpression of brain efflux transporters), pharmacokinetic (overexpression of peripheral efflux transporters in the intestine or kidneys), intrinsic severity (initial high seizure frequency), neural network (aberrant networks), and gene variant hypothesis (genetic polymorphisms). Expert opinion A continuous search for newer AEDs or among non-AEDs (blockers of efflux transporters, interleukin antagonists, cyclooxygenase inhibitors, mTOR inhibitors, angiotensin II receptor antagonists) may provide efficacious drugs for the management of drug-resistant epilepsy. Also, combinations of AEDs exerting synergy in preclinical and clinical studies (for instance, lamotrigine + valproate, levetiracetam + valproate, topiramate + carbamazepine) might be of importance in this respect. Preclinically antagonistic combinations must be avoided (lamotrigine + carbamazepine, lamotrigine + oxcarbazepine).