Cognitive deficits in anti-LGI1 encephalitis are linked to immunotherapy-resistant white matter network changes

BACKGROUND AND OBJECTIVES: Cognitive deficits represent a major long-term complication of anti–leucine-rich, glioma-inactivated 1 encephalitis (LGI1-E). Although severely affecting patient outcomes, the structural brain changes underlying these deficits remain poorly understood. In this study, we hypothesized a link between white matter (WM) networks and cognitive outcomes in LGI1-E. METHODS: In this cross-sectional study, we combined clinical assessments, comprehensive neuropsychological testing, diffusion tensor MRI, probabilistic WM tractography, and computational network analysis in patients with LGI1-E referred to Charité-Universitätsmedizin Berlin. Healthy individuals were recruited as control participants and matched to patients for age and sex with logistic regression propensity scores. RESULTS: Twenty-five patients with LGI1-E (mean age = 63 ± 12 years, 76% male) and 25 healthy controls were enrolled. Eighty-eight percent of patients presented persistent cognitive symptoms at postacute follow-up (median: 12 months from onset, interquartile range: 6–23 months)—despite treatment with immunotherapy and good overall recovery (modified Rankin Scale [mRS] score at peak illness vs postacute: z = −4.1, p < 0.001, median mRS score at postacute visit: 1). Neuroimaging revealed that WM networks in LGI1-E are characterized by (1) a systematic reduction in whole-brain connectivity (t = −2.16, p = 0.036, d = −0.61), (2) a cortico-subcortical hypoconnectivity cluster affecting both limbic and extralimbic brain systems, and (3) a “topological reorganization” marked by a bidirectional shift in the relative importance of individual brain regions in the WM network. The extent of this WM reorganization was strongly associated with long-term deficits of verbal memory (r = −0.56), attention (r = −0.55), and executive functions (r = −0.60, all pFDR = 0.017). DISCUSSION: Although traditionally viewed as a form of limbic encephalitis, our study characterizes LGI1-E as a “network disorder” that affects the whole brain. Structural reorganization of WM networks was linked to long-term and multidomain cognitive impairment, which was not prevented by immunotherapy. These findings highlight the need for closer monitoring and improved treatment strategies to mitigate long-term cognitive impairment in LGI1-E.