Neuroimmune mechanisms of the cerebellum–brainstem network in autoimmune encephalitis and related neuroimmune disorders: antibody targets, selective vulnerability, and translational opportunities

Abstract

Autoimmune encephalitis (AE) comprises clinically and immunopathologically heterogeneous central nervous system disorders whose early recognition should be syndrome-based and should not depend on antibody results alone. Cerebellar and brainstem manifestations occur in selected AE and related central nervous system neuroimmune disorders, but their frequency, anatomical specificity, and mechanisms remain incompletely defined. In this narrative Review, we use the cerebellum–brainstem network as an anatomical and clinical organizing framework rather than proposing a discrete anatomical axis or a new disease entity. In selected neuronal-surface-antibody disorders, antibodies can directly alter receptor trafficking, receptor availability, protein interactions, or synaptic transmission, whereas intracellular-antigen-associated and paraneoplastic syndromes are more often linked to cytotoxic T-cell-dominant neuronal injury. To stabilize disease scope, central AE and directly relevant central nervous system autoimmune syndromes form the core evidence base; immune-mediated cerebellar ataxias, paraneoplastic syndromes, acute disseminated encephalomyelitis, and myelin oligodendrocyte glycoprotein antibody-associated disease are included only when they provide direct infratentorial evidence; and Miller Fisher syndrome and Guillain–Barré syndrome are retained solely as peripheral anatomical comparators, whereas Bickerstaff brainstem encephalitis represents a central brainstem syndrome. We present a hypothesis-generating circuit framework linking immune target engagement to cerebellar output and connected brainstem manifestations, while explicitly marking extrapolations from non-AE models as hypotheses [H]. We also distinguish a predominantly functional pattern from an established structural-injury pattern as non-sequential research constructs rather than stages, biomarker-defined transitions, treatment windows, or clinical algorithms. Current imaging studies demonstrate that infratentorial metabolic and structural abnormalities can occur, but no reproducible cerebellum–brainstem diagnostic, prognostic, or treatment-selection signature has been prospectively validated.