doi: 10.2169/internalmedicine.1535-22
Intern Med Advance Publication
http://internmed.jp

【 CASE REPORT 】

Coupling of Cortical Hyperintense Signals and Increased
Glucose Metabolism in a Case of Anti-GABAA Receptor
Antibody-associated Encephalitis
Kentaro Hashimoto 1, Takumi Nakamura 1, Yukio Fujita 1, Minori Furuta 1, Kouki Makioka 1,
Yuki Shimoda 2, Takahiro Iizuka 3 and Yoshio Ikeda 1

Abstract:
We herein report a case of anti-gamma aminobutyric acid type A receptor antibody-associated encephalitis
(anti-GABAA-RE) with progressive aphasia and generalized tonic-clonic seizures. Cerebral magnetic resonance imaging (MRI) showed cortical brain lesions coupled with hypermetabolism on fluorodeoxyglucosepositron emission tomography. After two courses of methylprednisolone pulse therapy, improvements in neurological symptoms without sequelae and the total disappearance of MRI lesions were observed. Upon encountering patients with refractory status epilepticus, multifocal cerebral MRI lesions, and suspected autoimmune encephalitis, especially in cases with thymoma, it would be prudent to suspect anti-GABAA-RE and
consider the evaluation of anti-GABAA receptor antibody and methylprednisolone pulse therapy.
Key words: 18F-fluorodeoxyglucose-positron emission tomography, anti-GABAA receptor antibody,
autoimmune encephalitis, status epilepticus, paraneoplastic syndrome, thymoma
(Intern Med Advance Publication)
(DOI: 10.2169/internalmedicine.1535-22)

Introduction

Case Report

Anti-gamma aminobutyric acid type A (GABAA) receptor
antibody-associated encephalitis (anti-GABAA-RE) is a rare
autoimmune encephalitis characterized by multifocal brain
lesions and convulsive seizures (1). Approximately one-third
of anti-GABAA-RE patients have a tumor, such as thymoma (1).
We herein report a case of anti-GABAA-RE with progressive aphasia and generalized tonic-clonic seizures as well as
neuroimaging abnormalities of multifocal hyperintense lesions coupled with increased metabolism on 18 Ffluorodeoxyglucose-positron emission tomography (18F-FDGPET).

The patient was a 44-year-old man who had been well
until 1 month prior to admission, when aphasia occurred
and progressed. Five days before admission, cerebral MRI
performed at the previous hospital showed bilateral multifocal cortical and subcortical high-intensity lesions on fluidattenuated inversion recovery (FLAIR) images with a leftsided predominance. The patient was thereafter admitted to
our hospital.
A neurological examination revealed non-fluent aphasia,
acalculia, agraphia, right-left disorientation, and finger agnosia. He also showed hypoesthesia on the right side of his
face, hyperreflexia of the right lower extremity, and myoclonic jerks in the right limbs and abdominal muscles. A
blood examination revealed normal liver and renal functions,
creatine kinase and C-reactive protein levels, and blood cell

１

Department of Neurology, Gunma University Graduate School of Medicine, Japan, ２ Department of Diagnostic Pathology, Gunma University
Graduate School of Medicine, Japan and ３ Department of Neurology, Kitasato University School of Medicine, Japan
Received: December 27, 2022; Accepted: March 2, 2023; Advance Publication by J-STAGE: April 14, 2023
Correspondence to Dr. Yoshio Ikeda, ikeday006@gunma-u.ac.jp

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Figure. Neuroimaging and pathological findings of a patient with anti-GABAA receptor antibodyassociated encephalitis. Cerebral MRI before methylprednisolone pulse therapy showed multifocal
cortical and subcortical FLAIR high-intensity lesions in the bilateral frontal, temporal, and parietal
lobes with left-sided predominance (A-C). Cerebral 18F-FDG-PET performed close to MRI showed an
increased metabolism in most lesions coupled with FLAIR hyperintensity (D-F). In contrast, a hyperintense lesion on the left lower temporal lobe showed a decreased metabolism (white arrowheads) (A
and D). Contrast-enhanced chest CT revealed a heterogeneously enhanced anterosuperior mediastinal tumor (G and H, red arrows). Cerebral MRI after two courses of methylprednisolone pulse therapy confirmed the total disappearance of the lesions (I-K). Microscopic findings of the tumor revealed
the features of thymoma: type AB according to the WHO classification (L and M). Immunostaining
labeled by cytokeratin (L) and Hematoxylin and Eosin staining (M) showed spindle-shaped epithelial
tumor cells with the infiltration of lymphocytes. Scale bar=100 μm.

counts. A cerebrospinal fluid (CSF) examination showed an
elevated opening pressure of 310 mmH2O but with normal
cell counts and protein and glucose levels. Herpes simplex
virus DNA and varicella-zoster virus DNA evaluated by polymerase chain reaction using CSF were negative. The levels
of lactate and the lactate-to-pyruvate ratio in the serum and
CSF were normal. The serum beta-D-glucan level was normal. An interferon-gamma release assay was negative. Antibodies against thyroid peroxidase, thyroglobulin, cardiolipin,
and aquaporin-4 (AQP4) in the serum were negative, and
antibodies against myelin-oligodendrocyte glycoprotein
(MOG) in the serum and CSF were also negative. Oligoclonal bands in the CSF were negative. Antibodies against amphiphysin, CV2, PNMA2, Ri, Yo, Hu, recoverin, SOX1, titin, zic4, GAD65, and Tr in the serum were negative. The
levels of protein C and protein S were normal.
Electroencephalography (EEG) revealed periodic lateralized epileptiform discharges in the left hemisphere. On the
day of admission, the patient developed generalized tonicclonic seizures, so the intravenous administration of levetiracetam was initiated.
The majority of multifocal cortical and subcortical FLAIR

high-intensity lesions were coupled with increased glucose
metabolism on 18F-FDG-PET (FigureA-F). However, a hyperintense lesion on the left lower temporal lobe showed a
decreased metabolism (FigureA, D, white arrowheads). An
anterosuperior mediastinal tumor was detected on contrastenhanced chest CT (FigureG, H, red arrows). There was no
uptake on 18F-FDG-PET in systemic organs other than the
brain. A random skin biopsy was negative for malignant
cells. Based on the medical history of the patient, neuroimaging findings, and the complication of a mediastinal tumor, anti-GABAA-RE was considered.
Before the identification of the anti-GABAA receptor antibody, methylprednisolone pulse therapy (1,000 mg/day for 3
days) was initiated, followed by oral prednisolone at 30 mg/
day. Marked improvements were obtained in neurological
findings and cerebral MRI lesions, and a second course of
methylprednisolone pulse therapy was performed. Cerebral
MRI performed after two courses of methylprednisolone
pulse therapy confirmed the total disappearance of lesions
(FigureI-K).
On the 54th day of admission, the patient underwent resection of the mediastinal tumor. Microscopic findings of
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show the clinical findings of common types of autoimmune
encephalitis, which frequently affect the limbic system (6).
Since improvements in neurological symptoms without sequelae were observed with methylprednisolone pulse therapy, the involvement of another paraneoplastic neurological
syndrome is unlikely. Therefore, the mixed findings of 18FFDG-PET in the present case may be explained by hypermetabolism due to the involvement of an anti-GABAA receptor antibody and hypometabolism due to concomitantly occurring seizures.
Multifocal brain lesions can be caused by tumors, demyelinating diseases, infections, and mitochondrial encephalomyopathy, as well as autoimmune encephalitis. Infection is
the most common cause of encephalitis, and herpes simplex
virus and varicella-zoster virus are common infectious
agents (9). In cases with viral infection, the clinical presentation and data from MRI and CSF specimens may resemble
those in cases with autoimmune encephalitis (2). Therefore,
herpes simplex virus and varicella-zoster virus infections
should be ruled out by polymerase chain reaction using
CSF.
The most common autoimmune encephalitis in patients
with thymoma was previously reported to be anti-GABAARE (10). Among paraneoplastic autoimmune encephalitis
cases, refractory status epilepticus and FLAIR images showing multifocal cortical and subcortical lesions are specific
features of anti-GABAA-RE (2). Imaging features of lesions
of anti-GABAA-RE were previously reported to show neither
mass effect, enhancement, nor restricted diffusion (2, 11).
These features would be useful for differentiating from other
etiologies, such as metastasis of thymoma.
The present case report highlights the efficacy of steroid
therapy and thymectomy and the characteristic findings of
18
F-FDG-PET in anti-GABAA-RE. Upon encountering patients with refractory status epilepticus, multifocal cortical
and subcortical MRI lesions, and suspected autoimmune encephalitis, especially in cases with thymoma, it would be
prudent to suspect anti-GABAA-RE and consider evaluating
the anti-GABAA receptor antibody and administering methylprednisolone pulse therapy.

the tumor revealed the features of thymoma: type AB according to the WHO classification (FigureL, M). There was
no recurrence of neurological abnormalities with oral levetiracetam and prednisolone at 15 mg/day. The patient was discharged on the 63rd day without any impairments. The antiGABAA receptor antibody was found to be positive in both
serum and CSF specimens before the initiation of steroid
therapy, and the patient was diagnosed with anti-GABAARE. Antibodies against N-methyl-D-aspartate (NMDA) receptor, aminomethylphosphonic acid (AMPA) receptor,
GABAB receptor, mGluR1 receptor, mGluR5 receptor,
leucine-rich glioma-inactivated protein 1 (LGI1), contactinassociated protein 2 (Caspr2), dipeptidyl-peptidase-like
protein-6 (DPPX), Neurexin-3, and Iglon5 in the serum and
CSF were negative.

Discussion
In cases of autoimmune encephalitis, the limbic system is
generally the most frequently affected area, with cerebral
FLAIR MRI showing hyperintensity and hypometabolism
being detected on 18F-FDG-PET (2, 3). In the present case,
18
F-FDG-PET showed hypermetabolism in the majority of
lesions coupled with FLAIR hyperintensity. GABAA and
GABAB receptors exert inhibitory effects on the central
nervous system, and anti-GABAA receptor and anti-GABAB
receptor antibodies may suppress GABA receptor functions (2, 4). The neuronal activation of lesions may occur in
anti-GABAA-RE or anti-GABAB receptor antibody-associated
encephalitis (anti-GABAB-RE), resulting in increased glucose
metabolism on 18F-FDG-PET. Among previously reported
cases of anti-GABAA-RE, only a single case report presented
neuroimaging findings of 18F-FDG-PET, showing hypermetabolism in cortical lesions with FLAIR MRI hyperintensity (5). Similarly, in another report of anti-GABAB-RE, 18FFDG-PET showed hypermetabolism in lesions (6).
The density of GABAA receptors in the brain is higher in
the cerebral cortices than in other areas (7). Consistent with
this finding, cerebral MRI of cases of anti-GABAA-RE often
show multifocal cortical and subcortical lesions (1), while
those of anti-GABAB-RE predominantly show limbic lesions (6). Therefore, the preferentially affected sites of MRI
lesions in anti-GABAA-RE or anti-GABAB-RE are important
for clinically distinguishing between these two disorders.
However, in contrast to a previously reported case of antiGABAA-RE (5), 18F-FDG-PET in the present case also
showed partial hypometabolism in the left lower temporal
lobe. According to previous findings, 18F-FDG-PET of epilepsy patients exhibited hypometabolism during the interictal
phase after complex partial seizures (8). Although clearly
recognizable recurrent seizures were not detected in the present case, EEG revealed epileptic discharges localized at the
left cerebral hemisphere, suggesting nonconvulsive status
epilepticus associated with anti-GABAA-RE. The complication of another autoimmune encephalitis may cause hypometabolism on 18F-FDG-PET; however, the present case did not

Author’s disclosure of potential Conflicts of Interest (COI).
T. Iizuka received a research support from Astellas Pharma Inc.
Acknowledgement
The authors thank Dr. Josep Dalmau, M.D., Ph.D. (Instituto
de Investigación Biomédica August Pi i Sunyer (IDIBAPS) at
Hospital Clínic, the University of Barcelona and the Neuroimmunology Unit of Sant Joan de Déu Barcelona Children’s Hospital)
for testing anti-GABAA receptor antibody.

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