Antibodies to GABAa Receptor Associate With Seizures, Status Epilepticus, And Remove The Receptors From Synapses (P3.001)

Objective: To report the identification of a novel syndrome associated with GABAa receptor (GABAaR) antibodies and the effects of patient’s antibodies on neuronal cultures. Background: There is evidence that seizures/status epilepticus can result from synaptic autoimmunity. The GABAaR has not been previously reported as target of autoimmunity. Methods: Sera or CSF of 140 patients with encephalitis, seizures/status epilepticus, and antibodies to unknown antigens were selected for antigen characterization. Techniques included immunoprecipitation, mass spectrometry, cell-based assay (CBA), and analysis of antibody effects in cultured rat hippocampal neurons. Seventy-five normal subjects and 416 patients from several disease-groups served as controls. Results: Neuronal cell-surface immunoprecipitation revealed GABAaR sequences. CBA with α1 and/or β3 subunits of the GABAaR showed high-titer serum antibodies (>1:160) and CSF antibodies in 6/140 patients. All 6 patients (3-63 year-old, median 22; 5 male) developed refractory status epilepticus/epilepsia partialis continua along with extensive cortical-subcortical MRI abnormalities; four patients required pharmacologically-induced coma. Twelve/416 patients from disease-group controls, but none of the healthy group, had low-titer GABAaR antibodies only in serum, 5 along with GAD65 antibodies. These 12 patients (2-74 year, median 26.5; 7 male) developed a broader spectrum of symptoms likely reflecting coexisting autoimmunities: 6 had encephalitis with seizures (1 with status epilepticus/pharmacological coma; 1 epilepsia partialis continua), 4 stiff-person syndrome (1 with seizures), and 2 opsoclonus-myoclonus. Overall, 12/15 assessable patients had full (3) or partial (9) response to treatment, and three died. Patient’s antibodies caused a selective reduction of GABAaR clusters at synapses, but not along dendrites, without altering gephyrin (a protein that anchors GABAaR). Conclusions: High-titer GABAaR antibodies associate with a severe form of encephalitis with seizures and/or refractory status epilepticus. The antibodies cause a selective reduction of synaptic GABAaR. The disorder frequently occurs with gabaergic and other co-existing autoimmunities and is potentially treatable. Study Supported by Instituto Carlos III, FI12/00366, FIS PI11/01780, and PI12/00611, and the National Institutes of Health RO1NS077851, MH094741 and Fundacio la Marato TV3 (101530) Disclosure: Dr. Petit has nothing to disclose. Dr. Armangue has nothing to disclose. Dr. Peng has nothing to disclose. Dr. Davis has nothing to disclose. Dr. McCracken has nothing to disclose. Dr. Balice-Gordon has received personal compensation for activities with Pfizer, Inc. as an employee. Dr. Graus has nothing to disclose. Dr. Dalmau has received personal compensation in an editorial capacity for Up To Date. Dr. Dalmau has received royalty payments from Athena Diagnostics. Dr. Dalmau has received research support from Euroimmun.