Drug-Resistant Epilepsy: Multiple Hypotheses, Few Answers

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.

Lamotrigine‐resistant corneal‐kindled mice: A model of pharmacoresistant partial epilepsy for moderate‐throughput drug discovery

“…Nearly 30% of the over 65 million patients worldwide with epilepsy have, or will develop, resistance to available antiseizure drugs (ASDs) . The precise mechanisms that contribute to pharmacoresistance remain unclear and the subject of scientific investigation . Pharmacoresistant epilepsy contributes to greater economic burden, more severe comorbidities, and increased risk of sudden unexpected death in epilepsy (SUDEP) .…”

Comprehensive Circular RNA Profiling Reveals the Regulatory Role of the CircRNA-0067835/miR-155 Pathway in Temporal Lobe Epilepsy

“…Currently, antiepileptic drugs (AEDs) merely provide symptomatic control of seizures. Resistance to AEDs has been an important clinical challenge in refractory epilepsy therapy for neurologists [3][4]. Temporal lobe epilepsy (TLE) is the most common form of adult localization-related epilepsy that is accompanied by progressive etiopathology and high incidences of drug resistance [5][6].…”

Activation of nicotinamide adenine dinucleotide phosphate oxidase is the primary trigger of epileptic seizures in rodent models

“…2 Moreover, the proportion of those not becoming seizurefree despite treatment has not decreased substantially over the past 50 years. However, despite the availability of at least 22 antiseizure drugs, 1 about 30% of patients with epilepsy remain resistant to drug therapy and continue to have seizures.…”