Anti-GABA-A receptor antibody encephalitis

Introduction
The GABA-A receptor is a ligand-gated ion channel that controls most of the fast inhibitory synaptic transmission in the brain. Autoimmune encephalitis associated with this receptor was first described in 2014.

In 2014, Petit-Pedrol et al. described 6 patients with high titers of antibodies to the GABA-A receptor who had clinical syndromes of encephalitis and seizures frequently progressing to status epilepticus. They also described 12 patients with more variable symptoms who had lower titers of anti-GABA-A receptor antibodies. Of their initial description, all 6 patients with high antibodies and another 3 patients subsequently had antibodies confirmed to bind on a cell-based assay. They then published an additional 17 patients, totaling 26 patients with the clinical syndrome as well as serum or CSF antibodies as well as binding to subunits on a cell-based assay.

Pathophysiology
An antibody-mediated decrease of synaptic GABA-A receptors was seen in neuronal cultures exposed to patients' antibodies. With less inhibition, seizures can occur. As these receptors are also downregulated in status epilepticus, this turns into a positive feedback loop causing a further decrease in receptors and exacerbation of seizures. This may explain why seizures appear to be more difficult to treat in this condition than in other autoimmune encephalitides.

Importantly, these antibodies can bind to different subunits of the receptor. The initial report by Petit-Pedrol et al. described antibodies to the α1 and β3 subunits. However, one patient in a subsequent report also had an antibody to the γ2 subunit and several additional cases of antibodies to this subunit were subsequently described but antibodies to this subunit always seem to occur concurrently with antibodies to the α1 and β3 subunits.

Although brain biopsy is not usually needed for the diagnosis, one case reports describes a biopsy that showed perivascular lymphocytic infiltrates and reactive gliosis. There may be a specific role for CD8+ T-cells in the disorder, as a specific T-cell clone was identified in the CSF and hippocampus of one patient on autopsy.

Epidemiology

 * Median age 40 years (IQR 14-62 years), youngest 2.5 months old
 * 50% female

Associated conditions
One study of 57 patients with schizophrenia showed that 5 (8.6%) of patients had antibodies to the α1 subunit of the GABA-A receptor but in another series of 70 patients with first-episode psychosis no such antibodies were seen (and only one patient positive for anti-NMDA receptor IgG).
 * Thymoma
 * Other malignancy: the largest series of patients found a history of malignancy in 10 of 25 (40%) patients evaluated (rectal cancer, Hodgkin's lymphoma, multiple myeloma, small cell lung cancer, remote uterine cancer)
 * Other autoimmune conditions: the largest series of patients found a history of autoimmunity in 5 of 26 patients
 * Infections: two cases have been described with prior HSV1 encephalitis, and another with prior HHV-6 encephalitis. Another case occurred after a yellow fever vaccine.

Signs and symptoms

 * Prodrome: fatigue, fever, headache, vomiting
 * Partial and generalized seizures (88% in largest series) and epilepsia partialis continua
 * Altered cognition (67% in largest series)
 * Altered behavior (46% in largest series) . Includes hallucinations
 * Altered consciousness (42% in largest series)
 * Abnormal movements (35% in largest series) especially in younger children.

Diagnosis
Multifocal T2/FLAIR hyperintensities in the cortical and subcortical regions are seen in this form of autoimmune encephalitis but not others.

CSF

 * WBCs: normal to slightly elevated (<150 cells/mcl)
 * Protein: normal to elevated
 * Oligoclonal bands: positive in some cases

MRI

 * Abnormal in 88% of cases
 * Multifocal T2/FLAIR hyperintensity with cortical and subcortical involvement. Most commonly involves temporal (95%) and frontal (65%) lobes, but also basal ganglia, cerebellum, or brainstem. These findings are unique as they do not generally occur in other forms of autoimmune encephalitis.

EEG

 * Generalized slowing
 * Generalized periodic discharges
 * Lateralized periodic discharges
 * Seizures (various locations)

Treatment

 * Immunosuppression: 86% of patients had substantial improvement with immunologic or tumor therapy
 * Methylprednisolone
 * IVIG
 * Plasmapheresis
 * Rituximab
 * Cyclophosphamide
 * Treatment of malignancy, if present
 * Anti-epileptic medications, as needed

Prognosis
In the largest series of patients in whom follow-up was available (n=22), 5 (23%) had complete recovery, 14 (64%) had partial recovery, and 3 (14%) died.