Investigations in GABAA receptor antibody-associated encephalitis

Abstract

Objective: To report the clinical features, comorbidities, receptor subunit targets, and outcome in patients with anti-GABA_A receptor (GABA_AR) encephalitis.

Methods: Clinical study of 26 patients, including 17 new (April 2013-January 2016) and 9 previously reported patients. Antibodies to α1, β3, and γ2 subunits of the GABA_AR were determined using reported techniques.

Results: Patients' median age was 40.5 years (interquartile range 48.5 [13.75-62.35] years; the youngest 2.5 months old; 13 female). Symptoms included seizures (88%), alteration of cognition (67%), behavior (46%), consciousness (42%), or abnormal movements (35%). Comorbidities were identified in 11 (42%) patients, including 7 tumors (mostly thymomas), 2 herpesvirus encephalitis (herpes simplex virus 1, human herpesvirus 6; coexisting with NMDAR antibodies), and 2 myasthenia without thymoma. Brain MRI was abnormal in 23 (88%) patients, showing in 20 (77%) multifocal, asynchronous, cortical-subcortical T2/fluid-attenuated inversion recovery abnormalities predominantly involving temporal (95%) and frontal (65%) lobes, but also basal ganglia and other regions. Immunologic or tumor therapy resulted in substantial improvement in 18/21 (86%) assessable patients; the other 3 (14%) died (2 status epilepticus, 1 sepsis). Compared with adults, children were more likely to have generalized seizures (p = 0.007) and movement disorders (p = 0.01) and less likely to have a tumor (p = 0.01). The main epitope targets were in the α1/β3 subunits of the GABA_AR.

Conclusions: Anti-GABA_AR encephalitis is characterized by frequent seizures and distinctive multifocal cortical-subcortical MRI abnormalities that provide an important clue to the diagnosis. The frequency of symptoms and comorbidities differ between children (more viral-related) and adults (more tumor-related). The disorder is severe but most patients respond to treatment.

Figure 1. Reactivity of patient's antibodies with the GABA_A receptor (GABA_AR)

Rat brain immunostaining with CSF of a patient with antibodies against the α1, β3, and γ2 subunits of the GABA_AR (A), compared with that of another CSF sample containing antibodies against α1 and β3 subunits (C). Note the remarkable similarity of immunostaining of the samples of both patients. (B, D) Reactivity of the same patients' CSF samples with the corresponding HEK cells expressing the α1β3γ2 subunits (B), and HEK cells expressing the α1β3 subunits (D). For patients with antibodies against α1β3 subunits, adding the γ2 subunit did not increase the intensity of reactivity with α1β3 (data not shown). The CSF of a patient without these antibodies serves as control (E, F). Scale bar rat brain = 2 mm, scale bar HEK cells = 10 μm.

Figure 2. MRI findings in 2 patients with anti–GABA_A receptor (GABA_AR) encephalitis

(A, B) MRI from patient 7, obtained on day 30 after symptom onset, shows extensive, confluent fluid-attenuated inversion recovery (FLAIR) abnormalities involving the left occipital lobe and the frontal and temporal regions, bilaterally, with moderate diffusion restriction (not shown). (C) MRI from patient 14, obtained on day 45 after symptom onset, shows extensive multiple cortical-subcortical FLAIR abnormalities involving bilateral frontal, temporal, and parietal-occipital lobes, without diffusion restriction, but mild gyriform leptomeningeal enhancement in the right temporal pole (not shown). Biopsy was performed in the right frontal region. (D) Follow-up MRI obtained 2.5 months later (4 months after symptom onset) shows substantial improvement and resolution of most abnormalities.