Intravenous immunoglobulin for the treatment of autoimmune encephalopathy in children with autism

Kathleen Connery,Leanna M Delhey,John C Slattery,Uwe Kruger,Marie Tippett,Craig Shimasaki,Shannon Rose,Stephen G Kahler,Richard E Frye,Juergen Hahn,Madeleine W Cunningham

doi:10.1038/s41398-018-0214-7

Abstract

The identification of brain-targeted autoantibodies in children with autism spectrum disorder (ASD) raises the possibility of autoimmune encephalopathy (AIE). Intravenous immunoglobulin (IVIG) is effective for AIE and for some children with ASD. Here, we present the largest case series of children with ASD treated with IVIG. Through an ASD clinic, we screened 82 children for AIE, 80 of them with ASD. IVIG was recommended for 49 (60%) with 31 (38%) receiving the treatment under our care team. The majority of parents (90%) reported some improvement with 71% reporting improvements in two or more symptoms. In a subset of patients, Aberrant Behavior Checklist (ABC) and/or Social Responsiveness Scale (SRS) were completed before and during IVIG treatment. Statistically significant improvement occurred in the SRS and ABC. The antidopamine D2L receptor antibody, the anti-tubulin antibody and the ratio of the antidopamine D2L to D1 receptor antibodies were related to changes in the ABC. The Cunningham Panel predicted SRS, ABC, parent-based treatment responses with good accuracy. Adverse effects were common (62%) but mostly limited to the infusion period. Only two (6%) patients discontinued IVIG because of adverse effects. Overall, our open-label case series provides support for the possibility that some children with ASD may benefit from IVIG. Given that adverse effects are not uncommon, IVIG treatment needs to be considered cautiously. We identified immune biomarkers in select IVIG responders but larger cohorts are needed to study immune biomarkers in more detail. Our small open-label exploratory trial provides evidence supporting a neuroimmune subgroup in patients with ASD.

Highlights

Autism spectrum disorder (ASD) is a behaviorally defined disorder, which affects ~ 2% of children in the United States[1]
Adverse effects were reported for the majority of patients, they were mostly limited to the time around the Intravenous immunoglobulin (IVIG) infusion, resulting in the great majority of patients considering the benefits outweighing any adverse effects
In our cohort of patients who presented to our ASD clinic, very few demonstrated autoantibodies usually associated with autoimmune encephalopathy (AIE) in children

Summary

Introduction

Autism spectrum disorder (ASD) is a behaviorally defined disorder, which affects ~ 2% of children in the United States[1]. The standard-of-care for ASD is behavioral therapy, such therapy requires full-time engagement with one or several therapists for many years. Children with ASD have autoantibodies to brain tissue such as myelin basic protein, serotonin receptors, brain endothelium, cerebellar tissue, and glutamic acid decarboxylase (GAD) as well as Connery et al Translational Psychiatry (2018)8:148 to non-brain tissue such as the folate receptor alpha (FRα)[9] and mitochondria[3]. The role of autoantibodies during gestation is exemplified by maternal antibodies to fetal brain that have high specificity for the development of ASD in the offspring[16] with a relatively more severe phenotype[17] and brain enlargement[18]

Methods

Results

Conclusion