Hippocampal atrophy and functional plasticity underlie cognitive outcome in anti‐leucine‐rich glioma‐inactivated protein 1 encephalitis and their clinical correlates

OBJECTIVE: Patients with anti-leucine-rich glioma-inactivated protein 1 (LGI1) encephalitis frequently exhibit long-term cognitive impairment despite immunotherapy. In this study, we aimed to delineate hippocampal structural and functional alterations that underlie these deficits and examined their clinical correlates. METHODS: We recruited 34 patients with anti-LGI1 encephalitis in the post-acute phase and 34 matched healthy controls. All participants underwent neuropsychological testing, high-resolution T1-weighted magnetic resonance imaging (MRI), and resting-state functional MRI. We assessed group differences in hippocampal volume and its whole-brain functional connectivity (FC) using a seed-based approach. Partial correlation, multivariable linear regression, and mediation analyses were employed to relate imaging metrics to cognitive scores and clinical features. RESULTS: Patients exhibited significant cognitive impairment, predominantly in verbal memory. This was paralleled by bilateral hippocampal atrophy, which strongly correlated with poorer performance across multiple cognitive domains. In contrast, patients demonstrated significantly increased FC between the left hippocampus and medial orbitofrontal cortex (mOFC). The enhanced connectivity was associated with better memory performance, suggesting a compensatory mechanism. Mediation analyses revealed that ipsilateral hippocampal volume mediated the relationship between acute medial temporal T2/fluid-attenuated inversion recovery (FLAIR) hyperintensity and memory scores. In addition, early immunotherapy was associated with an increase in left hippocampus-mOFC connectivity, contributing to improved cognitive performance. SIGNIFICANCE: Our findings reveal a dual neural mechanism underlying cognitive outcome in anti-LGI1 encephalitis: the hippocampal atrophy correlates with cognitive deficits, whereas enhanced left hippocampal-mOFC connectivity represents a compensatory plastic response. Early immunotherapy may promote this beneficial plasticity, highlighting these structural and functional signatures as potential biomarkers for stratifying patients and monitoring therapeutic efficacy.