Abstract
Onconeural antibodies are associated with cancer and paraneoplastic encephalitis. While their pathogenic role is still largely unknown, their high diagnostic value is undisputed. In this study we describe the discovery of a novel target of autoimmunity in an index case of paraneoplastic encephalitis associated with urogenital cancer.A 75-year-old man with a history of invasive bladder carcinoma 6 years ago with multiple recurrences and a newly discovered renal cell carcinoma presented with seizures and progressive cognitive decline followed by super-refractory status epilepticus. Clinical and ancillary findings including brain biopsy suggested paraneoplastic encephalitis. Immunohistochemistry of the brain biopsy was used to characterize the inflammatory response. Indirect immunofluorescence assay (IFA) was used for autoantibody screening. The autoantigen was identified by histo-immunoprecipitation and mass spectrometry and was validated by expressing the recombinant antigen in HEK293 cells and neutralization tests. Sera from 125 control patients were screened using IFA to test for the novel autoantibodies.IFA analysis of serum revealed a novel autoantibody against brain tissue. An intracellular enzyme, Rho-associated protein kinase 2 (ROCK2), was identified as target-antigen. ROCK2 was expressed in affected brain tissue and archival bladder tumor samples of this patient. Brain histopathology revealed appositions of cytotoxic CD8+ T cells on ROCK2-positive neurons. ROCK2 antibodies were not found in the sera of 20 patients with bladder cancer and 17 with renal cancer, both without neurological symptoms, 49 healthy controls, and 39 patients with other antineuronal autoantibodies. In conclusion, novel onconeural antibodies targeting ROCK2 are associated with paraneoplastic encephalitis and should be screened for when paraneoplastic neurological syndromes, especially in patients with urogenital cancers, occur.
Highlights
Paraneoplastic encephalitis is a rare disease that commonly presents with seizures, cognitive and psychiatric disturbances and is secondary to various tumors [9]
Patients The index patient was treated for symptomatic epilepsy and later refractory status epilepticus due to paraneoplastic encephalitis at the Ruhr-University of Bochum, Germany
Six cases of paraneoplastic limbic encephalitis associated with renal cancer have been described so far [5, 7, 10, 17, 20, 22, 33]
Summary
Paraneoplastic encephalitis is a rare disease that commonly presents with seizures, cognitive and psychiatric disturbances and is secondary to various tumors [9]. It usually affects limbic areas, but may involve extralimbic structures. Paraneoplastic encephalitis is associated with neural antibodies targeting intracellular antigens or cell-surface proteins [6]. The former presumably are not pathogenic themselves, but are considered an epiphenomenon of the T cell-mediated immunoreaction against the antigen. We report a unique case of biopsyconfirmed encephalitis associated with antineuronal autoantibodies against a hitherto unknown antigen in a patient with bladder and kidney tumors
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