Antibodies against GAD65 (glutamic-acid-decarboxylase 65) are associated with several neurologic syndromes, including stiff person syndrome, cerebellar ataxia, and limbic encephalitis (LE). GAD65 is a crucial enzyme involved in the production of a neurotransmitter named GABA (Gamma-Aminobutyric Acid). GABA is the major inhibitory neurotransmitter in the CNS. It is widely distributed in the brain and plays a principal role in reducing neuronal excitability throughout the CNS. There still is a lot unknown as to the role GAD65 antibodies play in neuroinflammation and their pathogenic role remains controversial; in addition, T-cell mediated immune response seem to be important in the pathogenesis of GAD65 LE.

Women are more frequently affected than men, and the median age of symptom onset is 30 years (range, 5–80 years). Patients with neurological disorders associated with GAD65 antibodies typically have a personal or familial history of autoimmunity, including Type 1 Diabetes Mellitus, thyroiditis, pernicious anemia, or vitiligo; which are found in nearly half of the patients and indicate a genetic predisposition.

GAD65-associated LE is characterized by the subacute onset of seizures and amnesia. While virtually all patients will experience seizures at some point, which moreover are usually refractory to antiepileptic treatment, status epilepticus is rarely reported. Psychiatric symptoms, such as anxiety, depressive symptoms, apathy and behavioral changes, are less frequent than for other antibodies.

CSF analysis can display inflammatory findings, with a moderate pleocytosis (-increased cell count, 6–36%) and a mild elevation in protein levels. CSF-specific oligoclonal bands (63%–100%) and intrathecal synthesis of GAD Ab’s are commonly found. The EEG and MRI show temporal abnormalities in about two-thirds of patients.

GAD autoantibodies are generally not associated with cancer. However, thymoma, small-lung carcinoma and other neuroendocrine tumors have been found in a few patients.

The first-line treatment of this type of autoimmune encephalitis relies on the administration of IVIG, high-dose intravenous corticosteroids, or Plasma Exchange, alone or in combination, followed by a rapid switch to rituximab or cyclophosphamide in absence of satisfactory clinical response. Improvement rates after immunotherapy administration are usually modest and most patients continue experiencing seizures and cognitive impairment.

In a study of patients with LE, only 18% of patients with GAD Ab were seizure free after receiving immunotherapy compared to 55% of patients with paraneoplastic LE and other antibodies suggesting that GAD-related epilepsy is particularly difficult to control. This was in line with another study that found active seizures in 80% of the patients and cognitive disturbances in 69%.

• Muñoz-Lopetegi et al., Neurologic syndromes related to anti-GAD65, Clinical and serologic response to treatment. Neurol. Neuroimmunol. Neuroinflamm., 2020
• Vrillon et al., Psychiatric symptoms in anti glutamic acid decarboxylase associated limbic encephalitis in adults: a systematic review, Neurosci Biobehav Rev,2020
• Husari and Dubey, Autoimmune Epilepsy, Neurotherapeutics, 2019
• Dade et al., Neurological Syndromes Associated with Anti-GAD Antibodies, Int J Mol Sci. 2020
• Muñiz-Castrillo et al, Primary DQ effect in the association between HLA and neurological syndromes with anti-GAD65 antibodies, J Neurol 2020
• Bastien Joubert et al, Long-term outcomes in temporal lobe epilepsy with glutamate decarboxylase antibodies, J Neurol 2020

Sergio Muñiz-Castrillo MD, PhD, French Reference Center for Paraneoplastic Neurological Syndromes, Hospital for Neurology and Neurosurgery

Pierre Wertheimer, Lyon, France