Drug-Resistant Epilepsy: Molecular Mechanisms, Emerging Therapeutic Strategies, and Future Perspectives

Abstract

Drug-resistant epilepsy (DRE), the condition where an individual fail to achieve sustained seizure freedom despite appropriate trials of two tolerated antiseizure medications (ASMs) individually or in combination, is one of the most challenging neurological disorders encountered, affecting nearly one-third of individuals with epilepsy. Uncontrolled seizures remain a primary contributor to global morbidity, mortality, psychosocial dysfunction, cognitive decline and healthcare costs. The pathogenesis of DRE is multifactorial and includes a combination of genetic predisposition, abnormalities of drug targets, up-regulation of multi-drug efflux transporters, inflammation, oxidative stress, breakdown of blood-brain barrier and aberrant network plasticity. Progress in molecular neuroscience and neuroimaging has expanded our understanding of mechanisms of pharmacoresistance and has facilitated the development of newer therapeutic strategies such as neuromodulation, surgery, precision medicine, gene therapy and stem cell therapy. In this review, we will provide an overview of the burden and epidemiology, classification and underlying pathophysiology and consequences of DRE and examine the emerging molecular targets and novel therapeutic modalities for the improvement of clinical outcomes in patients with pharmacoresistant epilepsy, as well as outline the future directions concerning personalized medicine and disease-modifying therapies.