Structural Brain Changes Are Linked to Clinical and Cognitive Outcomes in Anti-LGI1 Encephalitis

BACKGROUND AND OBJECTIVES: Anti-leucine-rich glioma-inactivated 1 encephalitis (LGI1E) is traditionally considered as limbic encephalitis, but emerging evidence characterizes LGI1E as a whole-brain disorder. Furthermore, most neuroimaging studies have relied on cross-sectional designs and purely volumetric measures. Here, we integrate volume and fractal dimensionality (FD), a novel measure of structural complexity, to investigate cross-sectional and longitudinal brain changes in LGI1E and their associations with clinical and cognitive outcomes. METHODS: This observational study included 3T MRI, clinical evaluations, and comprehensive cognitive assessments at Charité - Universitätsmedizin Berlin. Patients with LGI1E underwent up to 3 study visits at median disease durations of 10, 46, and 58 months. Disease severity was rated using the modified Rankin Scale (mRS) and the Clinical Assessment Scale in Autoimmune Encephalitis (CASE). T1-weighted MRI was processed using FreeSurfer to extract volumetric data, alongside fractal analysis to estimate FD. Dominance analysis determined the relative importance of FD and volume. Longitudinal changes were examined using linear mixed-effects models in relation to age at onset, disease duration, and relapses. RESULTS: We studied 34 patients with LGI1E (median age: 67 years; 29% female; 52 study visits) and 34 age-matched and sex-matched healthy controls. Patients showed clinical improvement in both mRS and CASE scores from peak illness to first study visit. Morphological analyses revealed reduced FD in fronto-temporo-parietal cortices and reduced FD and volume in subcortical areas, with FD more frequently emerging as the more important measure in affected areas. Furthermore, reduced FD in the pallidum at the first study visit was associated with less mRS improvement since peak illness, while reduced accumbens volume was linked to less CASE improvement. Reductions in both FD and volume in frontotemporal cortices and subcortical areas were associated with impaired overall cognition, with FD more frequently emerging as the dominant measure in brain-cognition associations. Finally, longer disease duration and relapses were associated with longitudinal reductions in FD and volume in subcortical areas. DISCUSSION: LGI1E is characterized by widespread morphological brain alterations beyond the limbic system, with meaningful associations to clinical outcomes, cognitive function, and longitudinal disease course. FD emerged as the more comprehensive imaging marker, capturing unique morphological brain characteristics undetected by volumetry analyses.