Glymphatic dysfunction in drug-resistant epilepsy and its association with vagus nerve stimulation outcomes: a DTI-ALPS study

Background: The glymphatic system (GS) is critical for interstitial fluid clearance and has been implicated in various neurological disorders. However, its role in drug-resistant epilepsy (DRE) and response to vagus nerve stimulation (VNS) remains unclear. Objectives: This study aimed to assess GS function in patients with DRE using diffusion tensor image analysis along the perivascular space (DTI-ALPS) and to explore its association with VNS outcomes. Design: Data from patients with DRE who underwent VNS were retrospectively analyzed at a single center. Methods: Forty patients with DRE and 30 healthy controls were enrolled. ALPS indices were calculated for the left (ALPS-L), right (ALPS-R), and bilateral (ALPS-B) hemispheres. The clinical outcomes after VNS were classified using McHugh outcome classification. Statistical comparisons and logistic regression were used to examine group differences and the predictive value of ALPS indices. Results: Compared to controls, patients with DRE exhibited significantly reduced ALPS-L ( p < 0.001) and ALPS-B ( p = 0.005) indices. Among patients with DRE, responders to VNS had significantly higher ALPS-R ( p = 0.021) and ALPS-B ( p = 0.027) indices than nonresponders. ALPS-L exhibited a positive trend ( p = 0.073). In logistic regression analyses, ALPS-R and ALPS-B were significantly associated with favorable VNS outcomes in univariate and multivariate models. After adjusting for age, sex, and disease duration, ALPS-L ( p = 0.028, odds ratio (OR) = 2.739), ALPS-R ( p = 0.020, OR = 2.802), and ALPS-B ( p = 0.020, OR = 3.241) all emerged as independent predictors of VNS response. Conclusion: Glymphatic dysfunction is present in DRE and may influence responsiveness to VNS. Higher ALPS indices predicted better treatment outcomes, supporting ALPS potential as a noninvasive imaging biomarker for presurgical stratification in epilepsy.