Autoimmune neurological disorders associated with antibodies to glutamate decarboxylase 65 (GAD65): clinical features, comorbidity and treatment principles

Neurological disorders associated with antibodies to glutamate decarboxylase 65 (GAD65) constitute a clinically heterogeneous spectrum of conditions, including stiff-person syndrome, cerebellar ataxia, limbic encephalitis, epilepsy, overlap syndromes and rare additional phenotypes. This article presents up-to-date information on the clinical phenotypes, diagnosis and treatment of GAD65-associated diseases (GADAD). The pathogenesis is thought to involve an immune-mediated disruption of GABAergic transmission, leading to neuronal hyperexcitability. For the laboratory diagnosis of GADAD, an enzyme-linked immunosorbent assay (ELISA) is recommended, involving the analysis of paired serum and cerebrospinal fluid samples. A low concentration of anti-GAD65 antibodies is non-specific, whereas a high concentration allows a diagnosis to be made in the presence of a characteristic clinical phenotype. The frequent association of neurological GADAD with organ-specific autoimmune diseases requires vigilance regarding concomitant autoimmune pathology. The efficacy of immunotherapy is determined by the clinical phenotype and the timing of its initiation, with epilepsy and cerebellar ataxia showing a poorer response to treatment. Raising awareness of GADAD is a key priority, as timely diagnosis and early initiation of immunotherapy can improve functional outcomes by preventing the development of irreversible structural damage and permanent disability.