GABAaR¶

Gamma-aminobutyric acid-A receptor¶

Description¶

Anti-GABAaR is a pathogenic autoantibody directed against a key mediator of fast inhibitory neurotransmission in the brain and is the causative agent in a syndrome of seizures, multifocal FLAIR/T2 lesions on MRI, and encephalitis. It can be detected using serum and CSF on a cell based assay and is associated with thymoma in 30% of cases.

Treatment with imunotherapy has a good chance of complete recovery.

Mechanism of action¶

The GABAaR is a ligand gated mediator of fast inhibitory neurotransmission in the adult brain. It is a heteropentamer made up of five subunits. Mutations of the GABAaR subunits are associated with various forms of epilepsy. Multiple subunits may be the target of a pathogenic autoantibody.

Anti-GABAaR antibodies result in decreased density of GABAaR at synaptic sites from internalisation of receptors however, in contrast to other pathogenic autoantibodies directed against synaptic proteins, the total density of GABAaR is not decreased. This is suggested to be due to relocation of the receptors from synaptic to extrasynaptic sites.

Associated clinical features¶

1. 41% of patients with seizures will experience status epilepticus. Focal and generalised seizures may be present
2. Personality change 39%, hallucinations 30%, anxiety/depression 33%, catatonia 17%
3. Most often chorea but also ataxia, orofacial dyskinesia, involuntary movements
4. May be due to herpes viruses
5. Predominantly multifocal cortical and subcortical FLAIR/T2 lesions however some series report 95% of lesions in the temporal lobes
6. With epileptiform discharges and focal or generalised slowing

Associated neoplasia¶

<30% associated with malignancy but if present is usually malignant thymoma, paraneoplastic cause is present in only 10% of paediatric cases but 60% in adults.

Other neoplasia described include Hodgkin's lymphoma, rectal cancer, multiple myeloma, SCLC, and non-Hodgkin's lymphoma.

Laboratory method¶

CBA transfected to express alpha1beta3 or alpha1beta3gamma2 subunits - there is no subphenotype associated with individual subunit recognition.

Indirect immunofluoresence on rat brain demonstrates intense synaptic staining of the hippocampus, dentate gyrus, cortex, and thalamus. There is sparing of the CA3 hippocampal layer. In the cerebellum there is staining of the granular layer more than the molecular layer. Purkinje cell staining is absent.

Notes of performance characteristics¶

Low serum titres are of uncertain clinical significance and may not be confirmed with indirect immunofluoresence.

Discordant CSF and serum samples are rare (~5% of cases) however only minimal data exists and paired serum and CSF samples are recommended by key studies. If CSF is not available then it is suggested to confirm with indirect immunofluoresence.

No clear data on sensitivity and specificity of serum v CSF in CBA.

36% will have other autoantibodies (most commonly anti-NMDAR and anti-GAD65).

Grade¶

Next steps¶

Antiepileptic medication treatment alone is often insufficient.

In a series of 4 patients 1 had complete recovery and 75% had partial recovery. IVMP, IVIG, or PLEX may confer complete response in 31%, partial response in 52%, and poor outcome in 17%.

Addition of immunomodulators (such as rituximab, aathioprine, MMF, cyclophosphamide, or tacrolimus) may see complete recovery in 70%, partial recover in 15%, and poor outcome in 15%.