Paraneoplastic Cerebellar Degeneration With P/Q-VGCC vs Yo Autoantibodies

Abstract

Background and ObjectivesParaneoplastic cerebellar degeneration (PCD) is characterized by a widespread loss of Purkinje cells (PCs) and may be associated with autoantibodies against intracellular antigens such as Yo or cell surface neuronal antigens such as the P/Q-type voltage-gated calcium channel (P/Q-VGCC). Although the intracellular location of the target antigen in anti–Yo-PCD supports a T cell–mediated pathology, the immune mechanisms in anti–P/Q-VGCC-PCD remain unclear. In this study, we compare neuropathologic characteristics of PCD with anti–P/Q-VGCC and anti-Yo autoantibodies in an archival autopsy cohort.MethodsWe performed neuropathology, immunohistochemistry, and multiplex immunofluorescence on formalin-fixed and paraffin-embedded brain tissue of 1 anti–P/Q-VGCC, 2 anti–Yo-PCD autopsy cases and controls.ResultsAnti–Yo-PCD revealed a diffuse and widespread PC loss together with microglial nodules with pSTAT1+ and CD8+granzymeB+ T cells and neuronal upregulation of major histocompatibility complex (MHC) Class I molecules. Some neurons showed a cytoplasmic immunoglobulin G (IgG) staining. In contrast, PC loss in anti–P/Q-VGCC-PCD was focal and predominantly affected the upper vermis, whereas caudal regions and lateral hemispheres were spared. Inflammation was characterized by scattered CD8+ T cells, single CD20+/CD79a+ B/plasma cells, and an IgG staining of the neuropil in the molecular layer of the cerebellar cortex and neuronal cytoplasms. No complement deposition or MHC-I upregulation was detected. Moreover, synaptophysin was reduced, and neuronal P/Q-VGCC was downregulated. In affected areas, axonal spheroids and the accumulation of amyloid precursor protein and glucose-regulated protein 78 in PCs indicate endoplasmatic reticulum stress and impairment of axonal transport. In both PCD types, calbindin expression was reduced or lost in the remaining PCs.DiscussionAnti–Yo-PCD showed characteristic features of a T cell–mediated pathology, whereas this was not observed in 1 case of anti–P/Q-VGCC-PCD. Our findings support a pathogenic role of anti–P/Q-VGCC autoantibodies in causing neuronal dysfunction, probably due to altered synaptic transmission resulting in calcium dysregulation and subsequent PC death. Because disease progression may lead to irreversible PC loss, anti–P/Q-VGCC-PCD patients could benefit from early oncologic and immunologic therapies.