Infection-induced autoimmune encephalopathy: Treatment with | 56530

Текущие исследования в области вирусологии и ретровирусологии


Infection-induced autoimmune encephalopathy: Treatment with intravenous immune globulin therapy. A report of six patients

Denis A Bouboulis

Objective: To present illustrative patients Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS) and are successfully treated with an anti-infective and immune modulatory protocol. Methods: Six children age 5 to 17 years with the diagnosis of IIAE associated with various infections and comorbid conditions including humoral immunodeficiency and Autism Spectrum Disorder (ASD) are described. Pertinent literature from 1958 to the present is reviewed. Antimicrobial and high dose (1 gram per kilogram total body weight) intravenous immune globulin (IVIg) therapy was administered every 8 weeks according to an established anti-infective and immune modulatory protocol. Informed consent by the parents and legal authorization was obtained in all cases. Neuro-radiological testing was not performed in any of the cases. Results: The combination of antimicrobial medication followed by IVIg in this cohort was well-tolerated leading to improvement in symptoms and signs of IIAE allowing tapering or discontinuation of maintenance medications. Conclusion: IVIg is a safe and beneficial therapy in IIAE, PANDAS and ASD impacting favorably on underlying humoral immune deficiency and infectious-induced CNS autoimmunity in this small and highly selected cohort. The present findings are awaiting further replication by other investigators and should be further explored relative to the optimal dose and duration of therapy. Autism spectrum disorder (ASD) is a behaviorally defined disorder, which now affects ~ 2% of children in the United States. Although the standard-of-care for ASD is behavioral therapy, such therapy requires full-time engagement with one or several therapists for many years. In many cases, outcomes are suboptimal and/or incomplete. Thus, medical therapies that can augment behavioral therapy are urgently needed. Recent studies suggest that ASD is associated with a variety of physiological abnormalities including immune system dysfunction. For example, a maternal immune response induced during gestation results in ASD-like behavior in offspring in the maternal immune activation (MIA) rodent and replacing the immune system 
using bone marrow transplant corrected many symptoms in a mouse model of Rett syndrome, a syndrome closely aligned with ASD6. In individuals with ASD, inflammatory cytokines are elevated in the blood and brain and microglia are active in the brain. 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 to nonbrain tissue such as the folate receptor alpha (FRα)  and mitochondria. Children with autoantibodies are reported to have a more severe form of ASD10–15. 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 offspring16 with a relatively more severe phenotype and brain enlargement. Methods: The Institutional Review Board at the University of Arkansas for Medical Sciences (Little Rock, AR) approved the study. Parents of participants provided written informed consent. The study is registered as NCT02003170 on All patients evaluated in our ASD multispecialty clinic for AIE were included in this study. The majority of the patients (80/82) were diagnosis with ASD, except for two females, one who was a sibling of a male with ASD and AIE who was treated for severe atypical learning disabilities and attention deficit and one with severe tics and behavioral dysregulation.ASD was diagnosed based upon one of the following criteria: (i) a gold-standard diagnostic instrument such as the Autism Diagnostic Observation Schedule and/or Autism Diagnostic Interview-Revised; (ii) the state of Arkansas diagnostic standard, defined as agreement of a physician, psychologist and speech therapist; and/or (iii) Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnosis by a physician along with standardized validated questionnaires and diagnosis confirmation by the Principal Investigator (R.E.F.). We have validated that this criteria captures an accurate diagnosis of ASD in our previous studies by re-evaluating a portion of the participants with the ADI-R. Statistical analysis: Statistical analyses were performed with SAS 9.4 (SAS Institute Inc., Cary, NC) and MATLAB (The Mathworks, Natick, MA). Graphs were produced using Excel version 14.0 (Microsoft Corp, Redmond, WA). To determine whether any significant change occurred in behavior questionnaires with treatment an analysis of variance implemented as a mixed-model regression was utilized. The models included random effect of time (before/during treatment) and intercept to account for individual symptom level. The models tested the a priori hypothesis that a significant change in