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and/or plasma exchange (PLEX). [4,20] Patients who antibodies, 6 of whom had very high antibody
do not respond to these treatments warrant second titers. Patients with high titers in both serum and
[33]
line and maintenance treatments, such as rituximab, CSF developed a particularly rapid, severe progressive
cyclophosphamide, mycophenolate mofetil, and encephalopathy with refractory seizures and/or status
azathioprine. [17,20,23,24] Neurological improvement may epilepticus, for which intensive care admission for
be incomplete or not sustained. Despite optimal pharmacologically‑induced coma was required. Other
immunosuppressive treatment, patients with GABA R reported clinicalmanifestations in GABA R antibody
B A
antibodies can deteriorate due to tumor progression, seropositive patients are opsoclonus‑myoclonus, affective
chemotherapy‑related complications, and/or problems, hallucinations, mutism, aphasia, memory
treatment‑resistant relapses. [4,17,22‑24] Further studies to impairment, hemiparesis, chorea, cerebellar ataxia,
elucidate the optimal treatment regimens are needed. and Stiff‑man syndrome (SMS). [32,33] GABA R, GAD‑65,
B
The presence of an underlying small cell lung cancer N‑methyl‑D‑aspartate receptor (NMDAR), leucine‑rich,
and the co‑existence of other paraneoplastic neural glioma‑inactivated 1 and contactin‑associated protein‑like
antibodies targeting intracellular (neuronal nuclear 2 antibodies frequently co‑exist in these patients. [32,33] A
and cytoplasmic) antigens have been suggested as poor propensity for other neurological autoimmune conditions
prognostic indicators. [17,20] such as myasthenia gravis has also been noted. [32,33]

Anti‑GABA R encephalitis GABA R antibodies are reported in both children
A
A
The GABA R is a ligand‑gated ion channel located at and adults (age 2‑74 years), but larger cohorts need
A
synaptic and extrasynaptic sites that functions to mediate to be characterized. A low frequency of tumors in
[33]
fast inhibitory synaptic transmission. [25,26] Activation seropositive patients has been reported. In the initially
of the GABA R triggers opening of intrinsic chloride published study of 18 patients, only one patient was
A
channels, thereby eliciting an inhibitory postsynaptic found to have cancer (Hodgkin lymphoma). Two recent
[33]
potential. Disruption of GABA R results in increased additionally reported cases had invasive thymoma. [32]
[27]
A
neuronal excitability and seizures. Mutations in the
[27]
α1 and β3 subunits of the GABA R gene have been The electroencephalograms of patients with
A
implicated in epilepsy syndromes. [27‑29] Benzodiazepine anti‑GABA R encephalitis may demonstrate generalized
A
and barbiturate, medications used for the treatment of slowing suggestive of encephalopathy, multifocal
seizures and status epilepticus, enhance GABAergic ictal and interictal discharges, or status epilepticus.
[33]
inhibition to exert an anticonvulsant effect. [30] CSF findings range from normal to lymphocytic
pleocytosis. Distinctive to GABA R antibodies, the
[33]
A
GABA Rs are pentamers comprising combinations majority of patients, especially those with high antibody
A
of five subunits that form chloride ion channels. titers, had extensive temporal and extratemporal MRI
Different combinations of subunits result in functional brain abnormalities which could be a consequence of
[33]
heterogeneity. Synaptic GABA Rs, which contain the autoimmune inflammation in the brain or prolonged ictal
A
α (α1‑3), β, and γ subunits, are responsible for phasic activity. The extensive radiologic changes contrast with
inhibition. By contrast, extrasynaptic and perisynaptic those of patients with limbic encephalitis associated
GABA Rs, which are responsible for tonic inhibition, with other neuronal synaptic and cell surface antibodies,
A
comprise α4 or α6 subunits combined with β and δ such as NMDAR and VGKC‑complex antibodies, in
subunits. The GABA R antibody binds to the α1,β3, which MRI abnormalities are often confined to the
[31]
A
or both subunits of the synaptic GABA R. [32,33] GABA R mesial temporal regions.
A A
antibodies reduce the density of the GABA R at synaptic
A
sites when applied to rat hippocampal neurons, suggesting Despite the severity of their presentation, 80% of the
that antibody binding leads to the relocation of GABA R patients reported with anti‑GABA R encephalitis
A
A
from the synaptic membrane. [32,33] This phenomenon is demonstrate partial or complete recovery with a
similar to the loss of synaptic GABA R and resultant combination of immunotherapy, antiepileptic drugs,
A
neuronal hyperexcitability observed in epilepsy and and supportive treatment. [32,33] In severe cases, multiple
[27]
status epilepticus. The combined reinforcing effects immunotherapies may be required. Treatment options
of antibody‑mediated synaptic GABA R relocation, are the same as with GABA R and GlyR antibody
B
A
together with the status epilepticus‑induced loss of mediated disorders. In addition to immunotherapy,
GABA R, could support a postulated model to explain early recognition and treatment of epilepsy, as well as
A
the severity of seizures in patients with anti‑GABA R supportive treatment (including ventilation support) are
A
encephalitis. [33] pivotal.
Recently, 18 patients with autoimmune encephalitis GlyR antibody encephalitis
and prominent seizures were described with GABA R Glycine, a key neurotransmitter for fast postsynaptic
A
88 Neuroimmunol Neuroinfammation | Volume 3 | March 28, 2016