Imaging Features and Prognosis of Anti‑Sez6l2 Encephalitis: A Longitudinal Cohort Study and Literature Review

Anti-Seizure-Related 6 Homolog Like 2 (Sez6l2) encephalitis is a rare autoimmune disorder characterized by cerebellar ataxia and cognitive impairment. The 13 previously reported cases included in our systematic analysis focus on adults, leaving gaps in pediatric demographics, longitudinal multimodal imaging markers, and effective management of refractory cases. This study aimed to expand the clinical spectrum, evaluate multimodal imaging in localizing neuroinflammation/monitoring response, and assess the efficacy of combined first- and second-line immunotherapy. We analyzed a longitudinal cohort of five Sez6l2-antibody-positive patients (aged 15-72 years) alongside a systematic review (N = 18). Clinical severity (mRS, CASE, MMSE, MoCA), structural MRI, and 18F-DPA714 PET/MRI mapped neuroinflammation and monitored therapeutic response. Our cohort features the first documented adolescent case. All five patients presented with ataxia and cognitive deficits. While MRI revealed cerebellar atrophy in three patients, 18F-DPA714 PET/MRI detected microglial activation in the cerebellum (n = 4) and bilateral mesial temporal lobes (n = 1), mapping precisely to clinical phenotypes. Longitudinally, clinical improvement paralleled a 7%-8% reduction in cerebellar tracer uptake in Case 1. Patients receiving combined first- and second-line immunotherapy (efgartigimod, ofatumumab; n = 3) achieved pronounced cognitive and psychiatric recovery. Conversely, first-line therapy alone yielded limited efficacy in the 66-year-old patient with established atrophy, while the adolescent showed more favorable responsiveness. The systematic review (N = 18) confirmed universal ataxia (100%), frequent cognitive impairment (72%), and significant residual disability (median mRS 4). This study expands the demographic spectrum of Sez6l2 encephalitis to adolescents and provides cohort-based evidence for multimodal imaging in localizing neuroinflammation/monitoring response, highlighting combined immunosuppressants as possible new therapeutic options.