Journal Article

Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen

Friedman, Daniel, Balice-Gordon, Rita, Grisold, Wolfgang, Ohta, Kouichi, Kimura, Akio, Raizer, Jeffrey, Lancaster, Eric, Graus, Francesc, Peng, Xiaoyu, Hughes, Ethan, Guzman, Miguel, Lai, Meizan, Skeen, Mark B, Dalmau, Josep, Constantinescu, Radu, Iizuka, Takahiro, Moss, Stephen J

2010

Overview

Some encephalitides or seizure disorders once thought idiopathic now seem to be immune mediated. We aimed to describe the clinical features of one such disorder and to identify the autoantigen involved. 15 patients who were suspected to have paraneoplastic or immune-mediated limbic encephalitis were clinically assessed. Confocal microscopy, immunoprecipitation, and mass spectrometry were used to characterise the autoantigen. An assay of HEK293 cells transfected with rodent GABA(B1) or GABA(B2) receptor subunits was used as a serological test. 91 patients with encephalitis suspected to be paraneoplastic or immune mediated and 13 individuals with syndromes associated with antibodies to glutamic acid decarboxylase 65 were used as controls. All patients presented with early or prominent seizures; other symptoms, MRI, and electroencephalography findings were consistent with predominant limbic dysfunction. All patients had antibodies (mainly IgG1) against a neuronal cell-surface antigen; in three patients antibodies were detected only in CSF. Immunoprecipitation and mass spectrometry showed that the antibodies recognise the B1 subunit of the GABA(B) receptor, an inhibitory receptor that has been associated with seizures and memory dysfunction when disrupted. Confocal microscopy showed colocalisation of the antibody with GABA(B) receptors. Seven of 15 patients had tumours, five of which were small-cell lung cancer, and seven patients had non-neuronal autoantibodies. Although nine of ten patients who received immunotherapy and cancer treatment (when a tumour was found) showed neurological improvement, none of the four patients who were not similarly treated improved (p=0.005). Low levels of GABA(B1) receptor antibodies were identified in two of 104 controls (p<0.0001). GABA(B) receptor autoimmune encephalitis is a potentially treatable disorder characterised by seizures and, in some patients, associated with small-cell lung cancer and with other autoantibodies. National Institutes of Health.

• Subject: Adult / Aged / Animals / Antigens, Surface - immunology / Antigens, Surface - metabolism / Autoantibodies - analysis / Autoantibodies - blood / Autoantibodies - cerebrospinal fluid / Autoimmune Diseases of the Nervous System - immunology / Autoimmune Diseases of the Nervous System - metabolism / Autoimmune Diseases of the Nervous System - pathology / Autoimmune Diseases of the Nervous System - therapy / Brain - immunology / Brain - metabolism / Brain - pathology / Cell Line / Cells, Cultured / Female / Humans / Immunoglobulin G - analysis / Immunoglobulin G - immunology / Limbic Encephalitis - immunology / Limbic Encephalitis - metabolism / Limbic Encephalitis - pathology / Limbic Encephalitis - therapy / Lung Neoplasms / Male / Medical and Health Sciences / Medicin och hälsovetenskap / Middle Aged / Neurons - immunology / Neurons - metabolism / Neurons - pathology / Paraneoplastic Syndromes, Nervous System - immunology / Paraneoplastic Syndromes, Nervous System - pathology / Paraneoplastic Syndromes, Nervous System - therapy / Rats / Rats, Wistar / Receptors, GABA-B - genetics / Receptors, GABA-B - immunology / Receptors, GABA-B - metabolism / Seizures - immunology / Seizures - metabolism / Seizures - pathology / Seizures - therapy