Cytotoxic CD8+ T cells and CD138+ plasma cells prevail in cerebrospinal fluid in non-paraneoplastic cerebellar ataxia with contactin-associated protein-2 antibodies

Abstract

Objective: The purpose of this paper is to report a patient with otherwise unexplained cerebellar ataxia with serum antibodies against contactin-associated protein-2 (CASPR-2) and provide a detailed description of the composition of cellular infiltrates in the cerebrospinal fluid (CSF) compared to the peripheral blood (PB). CASPR-2 antibodies strongly labeling axons of cerebellar granule neurons have recently been identified in sera from nine patients with otherwise unexplained progressive cerebellar ataxia with mild to severe cerebellar atrophy.

Design: This is a report of a single case.

Methods: The study methods used were neurologic examination, magnetic resonance imaging, fluorodeoxyglucose positron emisson tomography, lumbar puncture and multicolor flow-cytometry.

Results: A 23-year-old Caucasian male presented with a two-year history of a progressive cerebellar and brainstem syndrome. Magnetic resonance imaging (MRI) showed pronounced cerebellar atrophy, especially of the medial parts of the hemispheres and the vermis. Cerebral fluorodeoxyglucose positron emission tomography (FDG-PET) showed pronounced hypometabolism of the whole cerebellum. CASPR-2 antibodies were detected in the serum but not the CSF, and none of the staging and laboratory assessments revealed other causes of progressive cerebellar degeneration. Interestingly, flow-cytometry of the CSF as compared to the PB showed increased fractions of CD138+ plasma cells as well as human leukocyte antigen (HLA)-DR+ CD8+ T cells suggesting that both B cells and CD8+ T cells were preferentially recruited to and activated within the CSF- (and putatively central nervous system (CNS)-) compartment.

Conclusion: We confirm the association of CASPR-2 serum antibodies with cerebellar ataxia and provide the first evidence for a combined humoral and cellular immune response in this novel antibody-associated inflammatory CNS disease.

Figure 1

Humoral and cellular immune response within the CSF- (and putatively central nervous system (CNS)-) compartment. The initial cerebral MRI about half a year after symptom onset was unremarkable (A, FLAIR-weighted images, C, T2 weighted images). Two years after symptom onset a pronounced cerebellar atrophy, especially of the medial parts of the hemispheres and the vermis, was evident (B, FLAIR-weighted images, D, T2 weighted images), and cerebral FDG-PET showed pronounced hypometabolism of the whole cerebellum (E, arrow). A computed tomography (CT)-scan of the chest showed a nodular lesion of the apical thymus (F, arrow). Flow-cytometry of the cerebrospinal fluid (G, lower panels; H, open red circles; CSF) as compared to the peripheral blood (G, upper panels; H, filled red circles; PB) and to a total of 17 healthy controls (H, filled and empty black circles) showed a low CD4/CD8 ratio together with increased fractions of activated HLA-DR⁺ CD4⁺ T cells and especially HLA-DR⁺ CD8⁺ T cells as well as CD19⁺ B cells and CD138⁺ plasma cells suggesting that both B cells and CD8⁺ T cells were preferentially recruited to and activated within the cerebrospinal fluid-compartment.