Glutamic acid decarboxylase autoimmunity with brainstem, extrapyramidal, and spinal cord dysfunction

OBJECTIVE: To describe novel neurological manifestations associated with glutamic acid decarboxylase (GAD65) autoimmunity. PATIENTS AND METHODS: This retrospective study (1987-2003) describes 62 patients incidentally found to have a serum autoantibody that bound selectively to synapse-rich central nervous system tissues. The immunostaining pattern was determined to be GAD65-specific by radioimmunoprecipitation assay. These cases were identified among samples submitted for paraneoplastic autoantibody evaluation using indirect immunofluorescence. In no case had GAD65 or any other islet cell antibody testing been requested. RESULTS: In most cases, the patients' presentations were initially considered neurodegenerative or inflammatory (multiple sclerosis or paraneoplastic). Median age at onset was 50 years, and 77% were women. Of the 44 patients seen at the Mayo Clinic, 23% were African American; in contrast, less than 10% of Mayo Clinic's neurology patients are African American. Median follow-up was 24 months. The radioimmunoprecipitation assay values for GAD65 antibody were extremely high (median, 1429 nmol/L; interquartile range, 643-3078 nmol/L) and correlated significantly with immunofluorescence titers (median, 3840; interquartile range, 1920-15,360; r=0.81; P<.001). Neurological manifestations were multifocal in 41 patients and included cerebellar ataxia (63%), brainstem involvement (29%), seizures (27%), stiff-man phenomena (26%), extrapyramidal signs (16%), and myelopathy (8%). One third of the patients had type 1 diabetes mellitus, 53% had thyroid autoantibodies, and 16% had vitiligo. Eleven of 20 patients identified as African American had brainstem involvement. Some patients appeared to benefit from short-term immunosuppression (none received long-term therapy). CONCLUSIONS: The neurological spectrum of GAD65 autoimmunity includes brainstem, extrapyramidal, and spinal cord syndromes. In our experience, African American patients were disproportionately affected. A patient with a presumed neurodegenerative disorder of new onset, with high levels of GAD65 antibody (>20 nmol/L), merits consideration of immunotherapy.