Juvenile myoclonic epilepsy as a spectrum disorder: mechanisms of drug resistance and precision management

Juvenile myoclonic epilepsy (JME) has traditionally been regarded as a homogeneous and pharmacoresponsive epilepsy syndrome. However, a substantial proportion of patients do not achieve sustained seizure freedom, challenging this concept of benignity. Increasing evidence suggests that JME represents a spectrum disorder characterized by clinical, electrophysiological, and neurobiological heterogeneity. In this review, we re-examine drug resistance (DR) in JME from a spectrum-based and systems-level perspective. We distinguish true DR from pseudo-resistance, highlighting the contribution of modifiable factors (e.g., misdiagnosis, inappropriate ASM selection, lifestyle influences, and poor adherence). We further synthesize multilevel determinants of treatment response, encompassing clinical features, EEG markers, genetic susceptibility, and large-scale brain network dysfunction. Based on these insights, we propose a dynamic model of treatment responsiveness and discuss its implications for individualized management. Finally, we outline future directions toward integrated, biomarker-driven, and precision medicine approaches in JME. This framework aims to refine risk stratification and support more individualized and mechanism-informed therapeutic decision-making in this common but heterogeneous epilepsy syndrome.