Anti‐Glutamic Acid Decarboxylase 65 (GAD65) Antibodies and Neurological Syndromes

ABSTRACT Various neurological disorders have been linked to the presence of serum antibodies targeting glutamic acid decarboxylase (GAD), a key enzyme in the production of γ‐aminobutyric acid (GABA). Associated conditions include stiff‐person syndrome (SPS) (classic and variant forms), cerebellar ataxia, limbic or extra‐limbic encephalitis, nystagmus issues, drug‐resistant epilepsy, paraneoplastic SPS, and progressive encephalopathy with rigidity and myoclonus (PERM). Although PERM and paraneoplastic SPS are mainly associated with antibodies targeting glycine receptors and amphiphysin, GAD antibodies might also be detected. Despite evidence of autoimmune activity and GABAergic dysfunction in some cases, the direct pathological role of GAD antibodies remains uncertain and debated. Diagnosis relies on clinical evaluation combined with detecting GAD antibodies in serum and cerebrospinal fluid (CSF), alongside confirmation of intrathecal antibody production. While GAD antibodies are not always required for diagnoses like SPS, they are essential for confirming cerebellar ataxia, encephalitis, or epilepsy. Treatment typically involves immunotherapy, with first‐line options including intravenous immunoglobulins, steroids, or plasma exchange to induce remission. Long‐term immunosuppression is often necessary. Symptomatic therapies (e.g., for muscle spasms, seizures, or delirium) are also recommended. The prognosis can differ, but it is typically positioned at an intermediate level between neurological syndromes associated with antibodies that target neural membrane antigens and those linked to onconeural antibodies. This review aims to further investigate the pathogenic role of these antibodies to improve predictions and select more appropriate treatment strategies.