Glymphatic System Dysfunction in Epilepsy: Clinical and Translational Perspectives.

Epilepsy has traditionally been viewed as a disorder involving neuronal hyperexcitability and brain network dysfunction. However, growing evidence indicates that recurrent seizures are associated with widespread disturbances in brain homeostasis, including metabolic stress, neuroinflammation, vascular dysregulation, and sleep disruption. These processes extend beyond neurons and involve brain-wide clearance mechanisms that have received limited attention in epilepsy research. The glymphatic system is a specialized pathway that facilitates cerebrospinal fluid-interstitial fluid exchange and promotes the clearance of metabolic waste and neurotoxic solutes from the brain. Glymphatic transport depends on astrocytic aquaporin-4 channels and is strongly modulated by sleep-wake state, which is highly relevant to epilepsy given the close bidirectional relationship between seizures and sleep disturbances. Impaired glymphatic clearance has been linked to protein accumulation, neuroinflammation, and cognitive decline during aging and in neurodegenerative diseases, suggesting that similar mechanisms may contribute to epilepsy-related disease progression. In this review, we summarize current knowledge of glymphatic anatomy and physiology, focusing on advances in neuroimaging. We then synthesize emerging evidence demonstrating glymphatic dysfunction across multiple epilepsy syndromes. We discuss the clinical implications of impaired cerebral waste clearance for disease burden, treatment outcomes, and cognitive dysfunction and highlight potential therapeutic strategies aimed at modulating glymphatic function. Finally, we address the ongoing debates regarding glymphatic mechanisms, imaging biomarkers, and causal relationships in epilepsy. Collectively, the available data suggest that glymphatic system dysfunction represents a system-level abnormality in epilepsy, offering a complementary framework that integrates the metabolic, vascular, and sleep-related aspects of epileptic brain dysfunction.