Glymphatic system dysfunction and its impact on seizure severity, cognitive function, and affective symptoms in...

Generalized tonic-clonic seizures alone (GTCS alone) represent a distinct idiopathic epilepsy syndrome. Glymphatic system (GS) dysfunction-a brain-wide perivascular clearance pathway-has been proposed as a contributing mechanism in epilepsy and its related comorbidities.

To assess GS function in patients with GTCS alone using the Analysis Along the Perivascular Space (ALPS) index derived from diffusion spectrum imaging (DSI), and to explore its associations with clinical, cognitive, and emotional measures.

A total of 101 patients with GTCS alone and 76 demographically matched healthy controls underwent DSI. The ALPS index was calculated and correlated with scores from standardized assessments, including the National Hospital Seizure Severity Scale (NHS3), Epileptic Discharge Index (EDI), Montreal Cognitive Assessment (MoCA), Kilifi Stigma Scale for Epilepsy (KSSE), and Hamilton Depression Rating Scale (HAMD).

Patients with GTCS alone had lower ALPS indices compared to healthy controls (1.43 vs. 1.52, p < 0.01). Among patients, the ALPS index positively correlated with MoCA scores (r = 0.30, p = 0.002) and negatively correlated with age (r = -0.22, p = 0.030), NHS3 (r = -0.27, p = 0.007), KSSE (r = -0.21, p = 0.038), and HAMD (r = -0.20, p = 0.042). The ALPS index was lower in patients with higher antiseizure medication loads (1.36 vs. 1.44, p = 0.042) and elevated EDI values (1.39 vs. 1.45, p = 0.039).

Glymphatic function is impaired in patients with GTCS alone, as indicated by reduced ALPS indices. These indices are associated with seizure severity, cognitive impairment, depressive symptoms, and perceived stigma. The ALPS index may serve as a noninvasive imaging biomarker of disease burden and a novel tool for understanding pathophysiological mechanisms in GTCS alone.