The clinical relevance of anti-glutamic acid decarboxylase antibodies in children with encephalitis/encephalopathy

Abstract

Anti-glutamic acid decarboxylase (anti-GAD) antibodies are associated with different types of syndromes. However, few studies have investigated the correlation between anti-GAD antibody titers with clinical severity and outcomes in children with encephalitis/encephalopathy. In this single-center retrospective cohort study, we consecutively enrolled hospitalized children who had encephalitis and/or encephalopathy with positive anti-GAD antibodies in serum and/or cerebrospinal fluid (CSF) from February 2010 to October 2021. Thirty-seven patients were included and divided into high-titer and low-titer groups. The patients with high anti-GAD antibody titers were associated with initial symptoms of language difficulty and ataxia. The level of titers was not associated with severity or outcomes. Anti-GAD antibody titers decreased after immunotherapy, however, the clinical response to immunotherapy was variable. A transient elevation in anti-GAD antibody titers during immunotherapy was noted. Further studies are warranted to investigate the role of anti-GAD antibodies in the pathogenesis and immune mechanisms of encephalitis/encephalopathy.

Keywords: GAD; anti-glutamic acid decarboxylase antibody; antineuronal antibodies; ataxia; encephalitis; encephalopathy; immunotherapy.

FIGURE 1

Examples of abnormal brain magnetic resonance imaging (MRI) findings in three patients with pediatric encephalitis/encephalopathy with anti-GAD antibody. Patient 1: A 10-year-old boy with clinical diagnosis of encephalitis with preceding influenza B infection 6 days ago. (A,B) Axial fluid-attenuated inversion recovery (FLAIR) sequences show multiple increased signals in the basal ganglia and cortical/subcortical regions of bilateral cerebral hemispheres (frontal, parietal, temporal lobes). (C) MRI follow-up at 9 months show progressive atrophy with stationary hyperintensities in bilateral putamen, bilateral insular regions, and left temporal tip. Patient 2: A 9-year-old girl with clinical diagnosis of rhombencephalitis with preceding HSV-1 infection 6 days ago. (D–F) Axial FLAIR sequences demonstrate multiple increased signals in the corpus callosum, bilateral insular regions, bilateral posterior capsules, and multiple cortical areas and white matter of bilateral hemispheres (all lobes), the brainstem, and left middle cerebellar peduncles. Patient 3: A 6-year-old girl with clinical diagnosis of febrile infection-related epilepsy syndrome (FIRES) without detected pathogen. (G) An axial FLAIR sequence and (H) a coronal T2 sequence show increased signals in right hippocampus and mesial temporal lobe. (I) Progressive cortical atrophy and right hippocampal atrophy were noted at the 30-month follow-up. GAD, glutamic acid decarboxylase.

FIGURE 2

The anti-GAD antibody titers decreased after immunotherapy in 14 patients. The dashed lines represents the high-titer group. Serum anti-GAD antibodies in the high-titer group (n = 6) showed a median reduction of 86% (range 58–99%). The median titer reduction in the low-titer group (n = 8) was 95% (range 36–99%). GAD, glutamic acid decarboxylase.

FIGURE 3

Serial changes in the titers of serum anti-GAD antibodies during immunotherapy were measured in four patients. The titers were transiently elevated during immunotherapy, and then decreased after immunotherapy during follow-up. The arrows indicated the start of immunotherapy (IVMP and IVIG in all of them). GAD, glutamic acid decarboxylase; IVMP, intravenous methylprednisolone pulse therapy; IVIG, intravenous immunoglobulin.