Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients

Abstract

Objective: To report the clinical features of 20 newly diagnosed patients with GABAB receptor (GABABR) antibodies and determine the frequency of associated tumors and concurrent neuronal autoantibodies.

Methods: Clinical data were retrospectively obtained and evaluated. Serum and CSF samples were examined for additional antibodies using methods previously reported.

Results: Seventeen patients presented with seizures, memory loss, and confusion, compatible with limbic encephalitis (LE), one patient presented with ataxia, one patient presented with status epilepticus, and one patient presented with opsoclonus-myoclonus syndrome (OMS). Nineteen (95%) patients eventually developed LE during the course of the disease. Small-cell lung cancer (SCLC) was identified in 10 (50%) patients, all with LE. Treatment and outcome was available from 19 patients: 15 showed complete (n = 7) or partial (n = 8) neurologic improvement after steroids, IV immunoglobulins, or plasma exchange and oncologic treatment when indicated; 1 patient died of tumor progression shortly after the first cycle of immunotherapy, and 3 were not treated. Five patients with SCLC had additional onconeuronal antibodies (Ri, amphiphysin, or SOX1), and 2 without tumor had GAD65 and NMDAR antibodies, respectively. GABABR antibodies were not detected in serum of 116 patients with SCLC without neurologic symptoms.

Conclusion: Our study confirms GABABR as an autoantigen of paraneoplastic and nonparaneoplastic LE and expands the phenotype of GABABR antibodies to ataxia, OMS, and status epilepticus. The long-term prognosis is dictated by the presence of a tumor. Recognition of syndromes associated with GABABR antibodies is important because they usually respond to treatment.

Figure 1. Screening for GABA_BR antibodies in serum and CSF of patients

Indirect immunohistochemistry on rat brain with a patient's serum shows widespread labeling of GABA_B receptor (GABA_BR) in the cortex and subcortical gray matter, with strong positivity of hippocampus and molecular layer of the cerebellum (A), whereas the serum from a healthy individual is negative (B). GABA_BR antibodies of a patient strongly label the surface of a live embryonic rat hippocampal neuron (C). Antibodies of patients are identified on HEK293 cells transfected with the R1 and R2 subunit of the GABA_BR (D; red: commercial antibody against the R1 subunit of the GABA_BR, green: CSF from a patient with GABA_BR antibodies, blue: nuclear staining with DAPI). C, D: ×400.

Figure 2. Survival of patients with SCLC with GABA_BR antibodies does not differ from that of patients with SCLC without PNS

Kaplan-Meier survival curves for 96 patients with small-cell lung cancer (SCLC) without paraneoplastic neurologic symptoms (PNS) (blue) and 10 patients with SCLC and PNS associated with GABA_B receptor (GABA_BR) antibodies (red). Censored cases of surviving patients or patients lost to follow-up are marked by a cross.