Non-invasive Assessment of Glymphatic System Function in Patients with Anti-LGI1 Encephalitis

Cognitive impairment is a core deficit in anti-LGI1 encephalitis, yet its underlying mechanisms remain incompletely understood. The glymphatic system (GS), a brain waste clearance pathway, is implicated in cognitive dysfunction in other neuroinflammatory conditions. However, its role in anti-LGI1 encephalitis is unknown. We hypothesized that GS dysfunction is a key mechanism contributing to cognitive deficits in this disease. This study aimed to investigate GS function using diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) and other MRI indices, and evaluate its association with hippocampal/amygdala volumes and cognition.

This prospective study enrolled 42 healthy controls (HCs) and 40 patients with a confirmed diagnosis of anti-LGI1 encephalitis who underwent brain MRI and neurocognitive assessment. Clinical and neuropsychological data were collected, including the Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), Modified Rankin Scale (mRS), and Clinical Assessment Scale for Autoimmune Encephalitis (CASE). Patients were stratified into three cognitive subgroups based on MoCA scores: LGI1-NCI (no cognitive impairment, MoCA ≥ 26), LGI1-MCI (mild cognitive impairment, MoCA 18-25), and LGI1-SCI (moderate-to-severe cognitive impairment, MoCA < 18). Imaging-derived biomarkers included the DTI-ALPS index, hippocampal and amygdala volumes extracted from 3D T1-weighted images, perivascular space (PVS) volume fraction, and free water fraction with in white matter (FW-WM).

Key imaging biomarkers showed significant differences between patients and HCs. Specifically, the DTI-ALPS index was significantly decreased in patients (1.483 vs. 1.671, p_FDR= 0.011), whereas the FW-WM was significantly increased (0.210 vs. 0.174, p_FDR=0.007). Subgroup analysis demonstrated a progressive decline in the DTI-ALPS index (LGI1-SCI: 1.3813 vs. HCs: 1.6706, p_FDR=0.004) and concomitant elevation in FW-WM (LGI1-SCI: 0.2258 vs. HCs: 0.1743, p_FDR=0.001) associated with increasing cognitive impairment severity. Unilateral hippocampal atrophy was also observed, with a significantly reduced volumes in the left hippocampus (2.942 vs. 3.216 cm³, p_FDR=0.049).

We observed glymphatic dysfunction and left hippocampal atrophy in anti-LGI1 encephalitis, with both features showing trends of greater severity in patients with more pronounced cognitive impairment. Longitudinal observations indicate that recovery of these pathological features lags behind clinical improvement, suggesting independent underlying mechanisms.