OBJECTIVE: This study was undertaken to investigate the regional burden of enlarged perivascular spaces (EPVSs) in patients with temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) and explore its prognostic relevance. METHODS: In this retrospective observational study, EPVSs in the temporal lobe (T-EPVS), centrum semiovale (CS-EPVS), basal ganglia (BG-EPVS), midbrain, and hippocampus were visually rated in 68 treatment-naïve patients with TLE-HS. Regional EPVS burden was dichotomized into high and low degrees (cutoff: >
10 for BG-EPVS/T-EPVS
>
20 for CS-EPVS). Cox proportional hazards models were used to determine the potential predictors of seizure freedom (SF
no seizure for >
1 year) and delayed SF (SF achieved >
6 months after initiating antiseizure medication [ASM]). Multivariate logistic regression using stepwise variable selection based on the Akaike information criterion was performed to investigate whether EPVS burden was associated with medical refractoriness (never achieving SF). RESULTS: Of the 68 patients, 20 were classified into the refractory group (29.4%). The high T-EPVS group had an older epilepsy onset (37.3 ± 12.3 vs. 26.5 ± 13.0 years, p = .005), higher pretreatment seizure density (median = 12.0, interquartile range [IQR] = 5.0-20.0 vs. 4.0, IQR = 2.0-10.5, p = .008), and lower focal to bilateral tonic-clonic seizure prevalence (13.3% vs. 73.6%, p <
.001) than the low T-EPVS group. High T-EPVS burden (odds ratio [OR] = 10.908, 95% confidence interval [CI] = 1.895-62.789) was an independent predictor of medial refractoriness, along with female sex (OR = 12.906, 95% CI = 2.214-75.220) and ASM treatment duration (OR = .985, 95% CI = .971-.999). The low T-EPVS group had higher probability of achieving delayed SF than the high T-EPVS group (p SIGNIFICANCE: Increased T-EPVS burden may serve as an imaging marker of unfavorable prognosis in patients with TLE-HS, underscoring the potential role of perivascular dysfunction in diminished ASM response.