RT Journal Article
SR Electronic
T1 Paraneoplastic Cerebellar Degeneration With P/Q-VGCC vs Yo Autoantibodies
JF Neurology - Neuroimmunology Neuroinflammation
JO Neurol Neuroimmunol Neuroinflamm
FD Lippincott Williams & Wilkins
SP e200006
DO 10.1212/NXI.0000000000200006
VO 9
IS 4
A1 Michael Winklehner
A1 Jan Bauer
A1 Verena Endmayr
A1 Carmen Schwaiger
A1 Gerda Ricken
A1 Masakatsu Motomura
A1 Shunsuke Yoshimura
A1 Hiroshi Shintaku
A1 Kinya Ishikawa
A1 Yukio Tsuura
A1 Takahiro Iizuka
A1 Takanori Yokota
A1 Takashi Irioka
A1 Romana Höftberger
YR 2022
UL http://nn.neurology.org/content/9/4/e200006.abstract
AB Background and Objectives Paraneoplastic 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.Methods We 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.Results Anti–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.Discussion Anti–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.APP=amyloid precursor protein; CTL=cytotoxic T cell; cWM=cerebellar white matter; FFPE=formalin-fixed and paraffin-embedded; GRP78=glucose-regulated protein 78; HLA=human leukocyte antigen; IFN=interferon; IgG=immunoglobulin G; IHC=immunohistochemistry; IVIG=IV immunoglobulin; LEMS=Lambert-Eaton myasthenic syndrome; MHC=major histocompatibility complex; mRS=modified Rankin Scale; PC=Purkinje cell; PCD=paraneoplastic cerebellar degeneration; PLEX=plasma exchange; P/Q-VGCC=P/Q-type voltage-gated calcium channel