ArticlesEncephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies
Introduction
Seizures and status epilepticus can result from immunological responses to excitatory or inhibitory synaptic receptors or associated cell-surface proteins.1, 2, 3 These include the N-methyl-D-aspartate receptor (NMDAR),4 the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR),5 the gamma-aminobutyric acid-B receptor (GABABR),6 leucine-rich glioma inactivated protein 1 (LGI1),7 contactin-associated protein-like 2 (Caspr2),8, 9 dipeptidyl-peptidase-like protein-6 (DPPX),10 and the metabotropic glutamate receptor 5 (mGluR5).11 The seizures that accompany any of these disorders are often refractory to antiepileptic treatment unless the immune mechanism is identified and treated.6, 12, 13 In some patients, generalised seizures or status epilepticus can be the first manifestation of the disease, with patients needing heavy sedation or induced pharmacological coma.6, 14, 15, 16 These treatments might conceal other symptoms such as dyskinesias or psychiatric alterations, delaying the recognition of the syndrome. Hitherto, the main epilepsy-related inhibitory receptor known to be a target of autoimmunity was the GABABR.9, 16, 17 Most patients with GABABR antibodies develop early seizures or status epilepticus as a component of limbic encephalitis. About 50% of these patients have an underlying small-cell lung cancer, and the neurological symptoms usually respond to immunotherapy and treatment of the cancer.9, 16, 17 Although the GABABR belongs to the category of metabotropic G protein-coupled receptors, the GABAA receptor (GABAAR) is a ligand-gated ion channel that modulates most of the fast inhibitory synaptic transmission in the brain and has not been previously recognised as a target of autoimmunity.
The identification of the above-mentioned disorders, all potentially treatable with immunotherapy,1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 has enhanced awareness of autoimmune mechanisms in patients with encephalitis associated with refractory seizures or status epilepticus, leading to an increased recognition of cases in which the antigens are unknown. Some patients might have several autoantibodies, suggesting that they have a propensity to autoimmunity, but also leading investigators to attribute the disorder to intracellular antigens that are not accessible to circulating antibodies, such as thyroid peroxidase or glutamic acid decarboxylase 65 (GAD65),5, 6 and therefore of questionable pathogenic significance. In such patients, other more relevant, yet unknown cell-surface antigens can be overlooked, as occurred in previously reported patients who were eventually shown to have AMPAR or GABABR antibodies.5, 6 We aimed to establish the identity of a novel synaptic antigen in a subset of patients with encephalitis and refractory seizures or status epilepticus. We report the clinical features of this new syndrome, the identity of the antigen, and the effects of patients' antibodies on neuronal cultures.
Section snippets
Study design and participants
Between Aug 20, 2012, and Dec 10, 2012, we identified two patients with encephalitis, refractory seizures, and serum and CSF antibodies with a similar pattern of reactivity against the neuropil of rat brain (appendix). The severity of the symptoms and unknown identity of the antigen prompted us to immunoprecipitate the antigen and to retrospectively review clinical and immunological information from patients with similar symptoms. We assessed serum and CSF samples, collected worldwide between
Results
On immunohistochemistry with rat brain, the serum and CSF samples of the two index patients produced a similar and intense pattern of neuropil reactivity (figure 1, appendix). This neuropil reactivity resembled that reported for GABABR antibodies (figure 1, appendix),6 but specific testing for these antibodies with a cell-based assay was negative in both index patients (data not shown). Findings from a subsequent assessment with cultured live rodent hippocampal neurons showed that the novel
Discussion
We report the identification of high titre serum and CSF antibodies against the GABAAR in a subset of patients with encephalitis and refractory seizures or status epilepticus, who often needed pharmacologically induced coma. This finding is important because the disorder is potentially treatable. However, because of the rapid development of seizures and frequent presence of coexisting autoimmune disorders, recognition of the disorder might be difficult. Findings from the four following sets of
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These authors contributed equally