Glymphatic system dysfunction in anti-NMDAR encephalitis: a comparative DTI-ALPS study with healthy controls and epilepsy patients

Anti–N-methyl-D-aspartate receptor (NMDAR) encephalitis is characterized by pathogenic autoantibody–mediated synaptic dysfunction, yet the mechanisms facilitating antibody access to the brain parenchyma remain incompletely understood. The glymphatic system, which supports cerebrospinal fluid–interstitial fluid exchange along perivascular spaces, has been implicated in immune surveillance and waste clearance; however, its involvement in anti-NMDAR encephalitis has not been fully investigated in vivo. Glymphatic system–related function was assessed using diffusion tensor imaging along the perivascular space (DTI-ALPS) in 15 patients with anti-NMDAR encephalitis, 17 patients with epilepsy, and 18 healthy controls. Group differences in ALPS-index values were analyzed with adjustment for age and sex. Associations between ALPS-indexes, clinical severity, and regional brain volumes were further examined. ALPS-index values were significantly reduced in both anti-NMDAR encephalitis and epilepsy compared with healthy controls. Across all groups, ALPS-indexes demonstrated strong bilateral correlations, with consistently lower values in the right hemisphere. In anti-NMDAR encephalitis, lower ALPS-index values were associated with longer hospitalization and higher modified Rankin Scale scores, whereas no associations were observed with cerebrospinal fluid anti-NMDAR antibody titers. In epilepsy, ALPS-indexes showed a distinct pattern of clinical and structural correlations, including associations with regional brain volumes that were absent in the NMDAR group. Receiver operating characteristic analysis indicated moderate-to-good discriminative performance of ALPS-indexes for both disease groups. DTI-ALPS reveals altered perivascular water diffusivity in anti-NMDAR encephalitis, which correlates with clinical severity independently of antibody titers. These findings suggest glymphatic-related dysfunction in anti-NMDAR encephalitis, and indicate that the ALPS-index captures disease-relevant pathophysiological processes beyond antibody burden, with potential utility as a noninvasive imaging marker for clinical assessment and prognosis in immune-mediated encephalitis.