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

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.

Cerebrospinal Fluid Findings of 36 Adult Patients with Autism Spectrum Disorder

“…In the healthy population, the prevalence of anti-GAD65 antibodies ranged from 0.5% to 1.1% [ 62 , 63 ]. Small studies in patients with ASD have described a higher incidence in ASD patients, ranging from 5% (three of 60 patients) [ 64 ] to 15% (three of 20 patients) [ 65 ]. There are, however, contradictory findings that may be related to diverse subgroups of ASD patients or to measurement techniques for anti-GAD65 antibodies [ 66 ].…”

“…Case reports have described severe neurological diseases in association with anti-GAD65 antibodies, such as limbic encephalitis and epilepsy, that barely responded to classical immunotherapy, such as steroids or intravenous immunoglobulins (IVIGs), and required more aggressive treatment with monoclonal antibodies, such as basiliximab or rituximab [ 77 , 78 ]. Nevertheless, it has been reported at least in one patient with ASD with clinically relevant high anti-GAD65 antibodies and comorbid type I diabetes, that there was a relevant benefit from therapy with IVIGs [ 64 ].…”

Evaluation of the Cunningham Panel™ in pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS) and pediatric acute-onset neuropsychiatric syndrome (PANS): Changes in antineuronal antibody titers parallel changes in patient symptoms

“…In a 2018 study of 80 patients having a diagnosis of ASD, in which 31 children with autoimmune encephalopathy received IVIg treatment, the Cunningham Panel predicted patient improvement and response to IVIg treatment with an accuracy of 81%, a sensitivity of 90% and a specificity of 67% based on the Aberrant Behavior Checklist (ABC) scores; with an accuracy of 88%, a sensitivity of 100% and a specificity of 75% based on the Social Responsiveness Scale (SRS) scores; and with an accuracy of 88% with a sensitivity of 100% and a specificity of 67% based on parental scores (Connery et al, 2018). The sensitivity and specificity of the Cunningham Panel in predicting IVIg responsiveness in children with autoimmune encephalopathy and diagnosed with ASD (81% to 88%) are similar to the performance accuracy we observed in this study (87% to 90%).…”

The Cunningham Panel is an unreliable biological measure

“…We read Connery et al open-label case series entitled Intravenous immunoglobulin for the treatment of autoimmune encephalopathy in children with autism 1 with great interest. It is undoubtedly important to communicate that children with autism may improve from IVIG treatment; this should be further investigated.…”