Glymphatic-meningeal lymphatic dysfunction in epilepsy: novel mechanistic insights and therapeutic avenues

Despite advances in pharmacotherapy, approximately one-third of individuals with epilepsy develop drug-resistant epilepsy (DRE), accounting for a disproportionate share of the global disease burden. Emerging evidence implicates dysfunction of the meningeal lymphatic system-a critical regulator of waste clearance and immune surveillance-in the pathogenesis of DRE. This suggests that impaired lymphatic drainage may represent a novel mechanistic pathway and therapeutic target. In this review, we systematically examine the interplay between the lymphatic drainage and neural networks in epileptogenesis. We map the neuroimmunological landscape, delineate the crosstalk between peripheral immune cells and resident glia in the central nervous system (CNS), and evaluate how blood-brain barrier disruption contributes to seizure progression. Central to our synthesis is the "lymphatic drainage-neural network" paradigm, through which we characterize dynamic alterations in the glymphatic system (GS) and meningeal lymphatic vessels (mLVs) across ictal and interictal states. We further explore how these systems drive epilepsy-associated comorbidities and assess emerging therapeutic strategies aimed at restoring lymphatic function. We conclude by highlighting the critical role of the meningeal lymphatic system, particularly the GS, in fostering epileptogenesis. While direct experimental evidence linking mLVs to epilepsy remains nascent, their established contribution of impaired immune surveillance and dysfunctional cerebral lymphatic drainage to diverse CNS disorders strongly positions mLVs-alongside the GS-as compelling therapeutic targets. We advocate for intensified investigation into the lymphatic drainage system as an active and indispensable frontier in epilepsy research.