Anti-GABA_A receptor encephalitis

Anti-GABA_A (gamma aminobutyric acid-A) receptor encephalitis is an autoimmune disease mediated by GABA_A -related antibodies. 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. Anti-GABA_AR encephalitis is characterized by frequent seizures and distinctive MRI abnormalities that provide an important clue to diagnosis.

GABA_AR encephalitis affects both children and adults, and men and women. In younger patients, the disorder may be confused with anti-NMDAR encephalitis due to the common presence of dyskinesias (involuntary movements).

Current findings confirm that seizures are the most frequent clinical manifestation of this disorder. Up to 88% of the patients had seizures, usually at symptom presentation, and frequently accompanied by status epilepticus. Children were more likely to have generalized seizures and movement disorders and less likely to have an underlying tumor than adults.

A study by Spatola et al., showed that symptoms included seizures (88%), alteration of cognition (67%), behavior (46%), consciousness (42%), or abnormal movements (35%).

Considering the clinical similarities among many forms of autoimmune encephalitis, an important finding is the association of anti-GABA_AR encephalitis with multifocal unilateral or bilateral cortical-subcortical T2/FLAIR MRI abnormalities.

The electroencephalograms of patients with anti-GABA_AR encephalitis may demonstrate generalized slowing suggestive of encephalopathy, multifocal ictal and interictal discharges, or status epilepticus. CSF findings are abnormal in the majority of patients, including pleocytosis, increased protein concentration, or oligoclonal bands. Distinctive to GABA_AR antibodies, the majority of patients, especially those with high antibody titers, had extensive temporal and extratemporal MRI brain abnormalities. Antibodies to the GABA_AR may be found in serum or CSF.

Studies suggest that 40% of patients with anti-GABA_AR encephalitis have tumors, mostly thymomas, and less commonly, other neoplasms (e.g., Hodgkin lymphoma, multiple myeloma) that may cause alterations of the immunologic system, perhaps leading to autoimmunity. Patients with a tumor were older, and less likely to have seizures than those without tumor.

Patients are treated with first-line immunotherapy (corticosteroids, plasma exchange, IVIG), and sometimes second-line immunotherapy (like rituximab, azathioprine, cyclosporine, or cyclophosphamide) is necessary. Antiepileptic medication is also part of the treatment plan. Tumor removal and tumor treatment are done when appropriate.

Despite the severity of their presentation, 80% of the patients reported with anti-GABA_AR encephalitis demonstrate partial or complete recovery with a combination of immunotherapy, antiepileptic drugs, and supportive treatment.

• Spatola et al., Investigations in GABA_A receptor antibody-associated encephalitis, Neurology 2017
• O’Connor et al., GABA_A receptor autoimmunity, A multicenter experience, Neurol Neuroimmunol Neuroinflamm. 2019
• Lancaster E, Encephalitis, severe seizures, and multifocal brain lesions, Recognizing autoimmunity to the GABA_A receptor, Neurol Neuroimmunol Neuroinflamm. 2019
• May Lin Quek and O’Toole, Encephalitis associated with autoantibodies binding to γ-aminobutyric acid-A, γ-aminobutyric acid-B and glycine receptors: immunopathogenic mechanisms and clinical characteristics, Neuroimmunology and Neuroinflammation, 2016