Identification of RIMKLA-IgG Paraneoplastic Neurological Syndrome With Cerebellar Ataxia

Importance Autoimmune cerebellar ataxias are debilitating neurological syndromes that need early detection and intervention. Antineural antibodies are a crucial diagnostic marker, however, lack of knowledge of specific autoantibodies in seronegative patients remains a significant challenge. Objective To pair a cutting-edge, standardized, and rigorous autoantibody detection pathway with global clinical networks to identify novel autoantibody markers of autoimmune ataxia. Design, Setting, and Participants This was a multicenter case series study that included samples of patients with uncharacterized central nervous system disorders, collected between 2015 and 2020 at the University of California, San Francisco (UCSF). A comprehensive screening for additional patients was conducted using a blinded cell-based and tissue-based assay in the French reference center on paraneoplastic neurological syndrome (PNS) and autoimmune encephalitis (AE). Analysis was completed in 2026. Referred participants included those with idiopathic neurological disease with suspicion of autoimmune etiology, controls with noninflammatory disease, and patients with known paraneoplastic autoantibody associations who served as positive controls. Sera and cerebrospinal fluid were collected for autoantibody screening and validation experiments. Exposures Autoantibody screening and candidate antibody validations. Main Outcomes and Measures Detection of autoantibodies and characterization of their usefulness as biomarkers of autoimmune clinical symptoms. Results A total of 35 patients were referred, and 8 patients (median [IQR] age, 65 [47-74] years; 6 male [75%]) were identified to have IgG targeting the intracellular neural protein ribosomal modification protein RimK-like family member A (RIMKLA). Initially, cerebrospinal fluid (CSF) from a UCSF index patient with small cell lung cancer and inflammatory cerebellar ataxia showed a specific staining pattern in the deep nuclei of the cerebellum and brainstem but was seronegative on all known panels of PNS biomarkers. Subsequent screening identified 7 additional patients sharing a similar clinical profile characterized by progressive cerebellar ataxia, diplopia, cranial VI paresis, and sensory and motor abnormalities. The majority of patients (6 of 8 [75%]) had associated small cell lung cancer. All patients also exhibited inflammatory CSF and immunoglobulin synthesis. Conclusions and Relevance In this case series, novel PNS autoantibodies targeting the neural protein RIMKLA were identified in patients with small cell lung cancer and cerebellar ataxia. RIMKLA-IgG represents a new diagnostic biomarker for an intracellular-antigen PNS associated with cerebellar and hindbrain encephalitis with possible peripheral and motor involvement.