Antibodies to the GABAB receptor in limbic encephalitis with seizures: case series and characterisation of the antigen

doi:10.1016/S1474-4422(09)70324-2

The Lancet Neurology

Volume 9, Issue 1, January 2010, Pages 67-76

https://doi.org/10.1016/S1474-4422(09)70324-2 Get rights and content

Summary

Background

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.

Methods

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.

Findings

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).

Interpretation

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.

Funding

National Institutes of Health.

Introduction

Synaptic plasticity is an essential property of neurons that is involved in memory, learning, and cognition. Plasticity depends on the interactions of ion channels and synaptic receptors, including excitatory glutamate NMDA receptors and AMPA receptors, and inhibitory GABA_B receptors.1, 2 In animal models, pharmacological or genetic disruption of these receptors result in seizures and changes in memory, learning, and behaviour.3, 4, 5, 6 Immune responses against these receptors would therefore be expected to result in similar symptoms. Indeed, two disorders, one associated with antibodies to extracellular epitopes of the NR1 subunit of NMDA receptors⁷ and the other associated with antibodies to GluR1/2 subunits of AMPA receptors,⁸ have recently been identified. These disorders result in encephalitis with prominent psychiatric, behavioural, and memory problems, often accompanied by seizures. The antibodies implicated in these two autoimmune disorders cause a decrease in the amounts of the target receptor in cultured neurons, suggesting the antibodies are pathogenic. Patients with these syndromes often respond to treatment, and in some patients the immune response occurs as a paraneoplastic event. These findings, as well as the prevalence of some of these disorders (eg, anti-NMDA receptor encephalitis7, 9, 10), have raised the possibility that other syndromes in which memory and behaviour are impaired and seizures are common could also be immune mediated. In some of these syndromes an immune-mediated pathogenesis is suggested by the clinical response to immunotherapy, the CSF and MRI findings suggesting limbic encephalitis, and the detection of antibodies to unknown neuronal cell-surface antigens. We aimed to identify the autoantigen involved in a new disorder that has most of these suggestive features.

Section snippets

Study population

Between January, 2006, and June, 2009, we studied 410 patients with encephalitis suspected to be paraneoplastic or immune mediated. These patients were seen by the authors or by clinicians at other institutions and the patients' sera and CSF were sent for analysis of novel autoantibodies to the Center for Paraneoplastic Disorders at the University of Pennsylvania (PA, USA). We identified autoantibodies in the serum or CSF of 357 patients, including 275 patients with antibodies to NMDA receptors

Results

In May, 2008, a 60-year-old woman with a long history of smoking was admitted to hospital with confusion, memory problems, and new-onset generalised tonic-clonic and partial complex seizures refractory to treatment (index patient; patient 1). At examination, she was confused about the time and where she was and had poor concentration and short-term memory (table 1). Although she had saccadic pursuits with lateral gaze, no cranial nerve abnormalities were noted. Strength, sensation, reflexes,

Discussion

15 patients had autoimmune encephalitis associated with antibodies to extracellular epitopes of the GABA_B receptor and nine responded to treatment. On the basis of clinical, MRI, and EEG findings, the brain regions most affected are the hippocampi and temporal lobes. Thus, it is not surprising that the resulting syndrome is similar to other types of limbic encephalitis (eg, encephalitis associated with antibodies against AMPA receptors or voltage-gated potassium channels), although some

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^‡: These authors contributed equally

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Fast track — ArticlesAntibodies to the GABAB receptor in limbic encephalitis with seizures: case series and characterisation of the antigen

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study population

Results

Discussion

Trends Neurosci

Neuron

Mol Cell Neurosci

Lancet Neurol

Brain Res Bull

J Neurosci Methods

Brain Res Mol Brain Res

Biochem Pharmacol

Pharmacol Biochem Behav

Prog Brain Res

Biochem Pharmacol

Biochem Pharmacol

J Neuroimmunol

Receptor trafficking and synaptic plasticity

Nat Rev Neurosci

NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders

Nat Rev Neurosci

The cell biology of synaptic plasticity: AMPA receptor trafficking

Annu Rev Cell Dev Biol

AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location

Ann Neurol

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents

Ann Neurol

Anti-NMDA receptor encephalitis: report of ten cases and comparison with viral encephalitis

Eur J Clin Microbiol Infect Dis

Fast track — Articles
Antibodies to the GABA_B receptor in limbic encephalitis with seizures: case series and characterisation of the antigen