Autoantibody Biomarkers for Basal Ganglia Encephalitis in Sydenham Chorea and Pediatric Autoimmune Neuropsychiatric Disorder Associated With Streptococcal Infections.

Jennifer L Chain,Sean Reim,Kyle Williams,Rebecca Hommer,Ivana Kawikova,Madeleine W Cunningham,Paul Grant,Julie A Stoner,Adita Mascaro-Blanco,Susan E Swedo,Rebecca Bentley,James F Leckman,Kathy Alvarez

doi:10.3389/fpsyt.2020.00564

Abstract

Movement, behavioral, and neuropsychiatric disorders in children have been linked to infections and a group of anti-neuronal autoantibodies, implying dopamine receptor-mediated encephalitis within the basal ganglia. The purpose of this study was to determine if anti-neuronal biomarkers, when used as a group, confirmed the acute disease in Sydenham chorea (SC) and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS). IgG autoantibodies against four neuronal autoantigens (tubulin, lysoganglioside GM1, and dopamine receptors D1 and D2) were detected in SC sera (N=8), sera and/or cerebrospinal fluid (CSF) from two groups of PANDAS cases (N=25 first group and N=35 second group), sera from Tourette's syndrome (N=18), obsessive-compulsive disorder (N=25), attention deficit hyperactivity disorder (N=18), and healthy controls (N=28) by direct enzyme-linked immunosorbent assay (ELISA). IgG specific for neuronal autoantigens was significantly elevated during the acute symptomatic phase, and the activity of calcium/calmodulin-dependent protein kinase II (CaMKII) pathway was significantly elevated in human neuronal cells. Five assays confirmed the disease in SC and in two groups of children with PANDAS. In 35 acute onset PANDAS patients, 32 sera (91.4%) were positive for one or more of the anti-neuronal autoantibodies compared with 9 of 28 healthy controls (32.1%, p<0.0001). Importantly, CSF of 32 (91.4%) PANDAS patients had one or more detectable anti-neuronal autoantibody titers and CaMKII activation. Among healthy control subjects with elevated serum autoantibody titers for individual antigens, none (0%) were positively associated with elevated positive CaMKII activation, which was a striking contrast to the sera of PANDAS subjects, who had 76–89% positive association with elevated individual autoantibody titers and positive CaMKII activity. At 6 months follow-up, symptoms improved for more than 80% of PANDAS subjects, and serum autoantibody titers also significantly decreased. Results reported herein and previously published studies in our laboratory suggest the antibody biomarkers may be a useful adjunct to clinical diagnosis of SC, PANDAS, and related disorders and are the first known group of autoantibodies detecting dopamine receptor-mediated encephalitis in children.

Highlights

Infections and their autoimmune sequelae have been linked to brain pathologies that manifest as adventitious movements and abnormalities of behavior, emotion, and cognition [1,2,3,4,5,6,7,8,9,10,11,12,13]
The data further suggested potential elevation of tubulin autoantibodies in tics and D1R in obsessive-compulsive disorder (OCD). These trends where certain antigens were more positive in certain pathologies is interesting and potentially important in our understanding of basal ganglia encephalitis but the small sample size does limit the power of the study
The four neuronal autoantibody specificities represent a group of autoantibodies present in basal ganglia encephalitis with patterns of overlap of the autoantibodies in different pathologies (SC, PANDAS, Tourette syndrome (TS), and OCD) that affect the basal ganglia

Summary

Introduction

Infections and their autoimmune sequelae have been linked to brain pathologies that manifest as adventitious movements and abnormalities of behavior, emotion, and cognition [1,2,3,4,5,6,7,8,9,10,11,12,13]. The psychiatric symptoms appear 2–4 weeks before the onset of chorea, with rates of OCD increasing from 65% to 100% with recurrences of illness [18, 20]. These observations suggested that abrupt-onset OCD (in the absence of chorea) might represent a nonsuppurative sequela of GAS infections. PANDAS is characterized by the acuity of OCD onset, and by a complex constellation of co-occurring symptoms, including emotional lability, separation anxiety, adventitious movements [ tics and choreiform movements [10, 11]], developmental (behavioral) regression, cognitive decline, and somatic symptoms, including urinary urgency, frequency, and enuresis, as well as insomnia and sleep disruptions. The close relationship between SC and PANDAS is confirmed by the overlapping clinical presentations and by shared genetic vulnerabilities and a growing body of evidence suggesting that the two clinical presentations share disease mechanisms [10,11,12, 22]

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