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[19]
receptor on presynaptic, postsynaptic, and extrasynaptic opsoclonus‑myoclonus, [17,18] and brainstem encephalitis
membranes, expressed in both the central and peripheral is now appreciated. Extralimbic presentations may be
nervous systems, particularly the hippocampus, thalamus, explained by the high expression of GABA R outside
B
[9]
and cerebellum. This receptor is a heterodimer comprising of the hippocampus, including the cerebellum. Other
[9]
two subunits: GABA and GABA . Both subunits need to rarer neurological features of anti‑GABA R encephalitis
B1 B2 B
be co‑expressed in order to form a functional receptor. [9,10] include chorea, myelopathy, peripheral neuropathy, and
The extracellular domain of the GABA subunit binds myopathy, particularly in patients with lower antibody
B1
to GABA while the GABA subunit couples the receptor titers. [4,20] It is uncertain, whether all of these extralimbic
B2
[11]
with the effector G protein. Antibodies to GABA R neurologic manifestations can be attributed solely to the
B
[4]
bind to the B1 subunit of the GABA R, the component GABA R antibodies or whether the co‑existence of other
B
B
that is required for GABA binding and receptor function. neural autoantibodies may contribute to the increasingly
diverse neurological features being reported. Known
GABA R exert inhibitory regulatory effects on synaptic neural antibody accompaniments to the GABA R
B B
transmission by inhibiting presynaptic voltage‑gated antibodies include the 65 kDa isoform of glutamate
calcium channel‑mediated neurotransmitter release decarboxylase (GAD‑65), voltage‑gated calcium channels
and by activating postsynaptic potassium channels, (N‑type and P/Q type), voltage‑gated potassium‑complex
resulting in hyperpolarization of neuronal membranes, (VGKC‑complex), and neuronal nuclear and cytoplasmic
and inhibition of adenylate cyclase. [11,12] GABA R antibodies [such as antineuronal nuclear autoantibody
B
dysfunction is implicated in a variety of neurological (ANNA‑1), ANNA‑3, collapsing response mediator
disorders such as epilepsy, in which genetic mutations protein‑5 IgG, and anti‑glial nuclear autoantibody/SOX‑1
may play a role. [13,14] Pharmacological disruption of antibodies]. [4,20‑22]
the GABA R leads to seizures, cognitive deficits, and
B
behavioral changes, [10,15,16] all of which may be seen in In comparison to other cell surface neural antibody
autoimmune anti‑GABA R limbic encephalitis. associated encephalitis, anti‑GABA R encephalitis
B
B
is probably uncommon. In a clinical service
Antibodies to GABA R were first described in 15 laboratory, only 7 of 3,989 (0.2%) patients with
B
patients with limbic encephalitis, in whom subacute suspected autoimmune encephalopathy were found
[20]
early onset of seizures was a distinctive feature. to have the GABA R antibody. There is no obvious
[4]
B
Seizures were predominantly of temporal lobe onset gender predisposition for this neurologic disorder. A
with secondary generalization, and 3 of the 15 patients paraneoplastic etiology is diagnosed in approximately
developed status epilepticus. Memory impairment, half of the patients with GABA R antibodies. [4,17,20,21]
B
confusion, hallucinations, and behavioral changes The neurologic disorder usually precedes the diagnosis
consistent with limbic involvement were frequently of malignancy, and the most frequently encountered
seen. Electroencephalography (EEG) changes included tumor is small cell lung cancer. [4,20] Tumors are more
[4]
epileptiform discharges, electrographic ictal activity, likely to be detected in older patients. Although, lung
and/or temporal lobe slowing. tumors from patients with GABA R encephalitis have
B
not been studied for GABA R expression, samples of
B
Magnetic resonance imaging (MRI) brain imaging archived small cell lung cancers from patients without
typically demonstrates unilateral or bilateral increased encephalitis were found to react with both guinea pig
T2/fluid attenuated inversion recovery signal changes and human GABA IgG. This suggests that the GABA R
B
B
in the medial temporal region, consistent with limbic could be expressed by small cell lung cancer and could
[4]
encephalitis. [4,17] Extratemporal changes in the grey and potentially trigger an autoimmune reaction. Other
white matter, cerebellum, basal ganglia, and brainstem oncologic associations of anti‑GABA R encephalitis
B
have also been reported. [4,17‑19] Cerebrospinal fluid include neuroendocrine lung tumor, multiple myeloma,
(CSF) examination may yield lymphocytic pleocytosis, esophageal carcinoma, malignant melanoma, and
[4]
elevated protein, and oligoclonal bands. As with other carcinoid of the thymus. [4,19,20,22,23]
types of limbic encephalitis, the EEG, MRI brain, and/or
CSF exam may be normal, and should not preclude the Neurological improvement has been reported in up
diagnosis or presumptive treatment when the clinical to 90% of patients with anti‑GABA R encephalitis
B
presentation is suspicious. who received immunotherapy and appropriate cancer
treatment (if the tumor was detected). [4,17,20,21] As the
Limbic encephalitis, the most common neurologic cases reported so far were retrospectively ascertained,
manifestation of anti‑GABA R encephalitis, [4,20,21] there was heterogeneity in the immunotherapies used. A
B
typically occurs in the setting of very high GABA R variety of immunotherapie have been used successfully,
B
antibody titers. [4,20] A widening phenotypic spectrum of including various combinations of first‑line agents,
anti‑GABA R disorders including cerebellar ataxia, [17,20,22,23] corticosteroids, intravenous immunoglobulin (IVIg),
B

Neuroimmunol Neuroinfammation | Volume 3 | March 28, 2016 87