Glymphatic system in temporal lobe epilepsy associated with encephalocele

OBJECTIVES: Temporal lobe encephaloceles (ENCs) are underdiagnosed causes of drug-resistant temporal lobe epilepsy (TLE), frequently associated with idiopathic intracranial hypertension (IIH). Emerging evidence suggests glymphatic system dysfunction in both IIH and TLE. We investigated glymphatic markers in TLE associated with ENC compared with seizure-free postoperative TLE controls of different etiology. METHODS: Surgical specimens from 13 patients with TLE-ENC and 12 TLE-control patients were analyzed. Histological glymphatic markers included aquaporin-4 (AQP4), glial fibrillary acidic protein (GFAP), podoplanin, perivascular space (PVS) enlargement, and vessel density. High-resolution magnetic resonance imaging (MRI) was used to assess a global PVS score. RESULTS: Compared with specimens TLE controls, TLE-ENC specimens showed increased white matter AQP4 expression and AQP4/GFAP ratio, whereas the AQP4/GFAP ratio was reduced in gray matter. Podoplanin expression was significantly elevated in both gray and white matter in TLE-ENC cases. MRI demonstrated greater supratentorial PVS enlargement in ENC patients. Radiological features suggestive of IIH were identified in 46.1% of TLE-ENC patients. Compared with controls, TLE-ENC patients had shorter disease duration and lacked association with previous febrile seizures. Surgical treatment achieved seizure freedom in 70% of ENC patients at a median follow-up of 32 months. SIGNIFICANCE: This study provides the first characterization of glymphatic-associated pathways in TLE-ENC-related epilepsy. Dysregulation of AQP4 and podoplanin, together with increased PVS burden, suggests a distinct alteration of perivascular and astroglial homeostasis in TLE-ENC, supporting a potential pathophysiological link among ENC formation, IIH, and epileptogenesis.