The Autism Society Event and Education Recordings Archive

Numerous studies have identified inflammation in some individuals with autism. Several studies have demonstrated inflammation in the brain, and many others have described inflammation in the gastrointestinal tract. Furthermore, oxidative stress is often prominent in individuals with autism. Both inflammation and oxidative stress may worsen autistic symptoms, and both are potentially treatable. Several studies will be examined which demonstrate improvements in autistic individuals by treating inflammation and oxidative stress. Several recent studies have revealed that some individuals with autism have evidence of neuroinflammation.  Marked activation of microglia and astroglia with elevations in IL-6 and macrophage chemoattractant protein-1 (MCP-1) were found in autistic brain samples upon autopsy, along with increased proinflammatory cytokines in the cerebral spinal fluid (CSF) of living autistic children.  Activated microglia have been shown to release inflammatory mediators such as IL-1 and TNF-α, and have been implicated as the primary cell type that controls inflammation-mediated neuronal injury.  A recent study revealed that some children with autism had very large elevations in TNF-α in the CSF.  In this study, children receiving anti-inflammatory treatments had much lower levels of TNF-α than children who had not received these treatments.  A cell-mediated immune response to brain tissue in autistic individuals has also been described.  In addition, some autistic children have increased glial fibrillary acidic protein (GFAP) in brain samples and the CSF, which is also indicative of inflammation and reactive injury.  Autoantibodies to neuron-axon filament protein and GFAP were also increased in the plasma of autistic individuals compared to control individuals.  Autistic children make more serum autoantibodies to the brain, including IgG and IgM autoantibodies to brain endothelial cells and nuclei when compared to typical children.  Elevated serum autoantibodies to many neuron-specific antigens and cross-reactive peptides have been found in autistic children, including antibodies directed against cerebellar Purkinje cells, and other neural proteins such as myelin basic protein.  Furthermore, 49% of autistic children in one study created serum antibodies against the caudate nucleus, and 18% produced serum antibodies to the cerebral cortex.  Another recent study demonstrated that autistic children, when compared to control children, developed serum autoantibodies to brain derived neurotrophic factor (BDNF) and had higher levels of serum BDNF.  This is important because an elevation of BDNF predicts abnormalities in intellect and social development.  Finally, maternal neuronal antibodies might play a role in the development of autism in some children.

In addition, some patients with autism have chronic ileocolonic lymphoid nodular hyperplasia (LNH) and enterocolitis characterized by mucosal inflammation of the colon, stomach, and small intestine.  These findings might represent a “new variant inflammatory bowel disease,” and have been described as a “panenteric IBD-like disease.”  As many as 90% of autistic children with gastrointestinal symptoms have evidence of ileal LNH, with up to 68% having moderate to severe ileal LNH.  In one study, the gastrointestinal mucosa was shown to have increased lymphocytic infiltration and density, crypt cell proliferation, and epithelial IgG deposits mimicking an autoimmune lesion.  Another study demonstrated that the gastrointestinal mucosa in autistic individuals had evidence of increased lymphocytes and proinflammatory cytokines including TNF-α and Interferon-γ, and less of the anti-inflammatory cytokine IL-10, which is counter-regulatory.  Some autistic children also had evidence of an eosinophilic infiltrate of the gastrointestinal mucosa.  Autistic children typically make significantly more serum antibodies against gliadin and casein peptides resulting in autoimmune reactions.  More than 25% of autistic individuals make serum IgG, IgM, and IgA antibodies against gliadin, which can cross-react with cerebellar peptides.  Furthermore, when compared to typical children, autistic children produce more pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6.  One study has shown that the genetic loci for autism have a propensity to cluster with recognized loci for inflammatory diseases.

Some individuals with autism also have evidence of increased oxidative stress including lower serum glutathione levels.  Some autistic children have increased red blood cell nitric oxide, which is a known free radical and toxic to the brain.  Lower serum antioxidant enzyme, antioxidant nutrient, and glutathione levels, as well as higher pro-oxidants have been found in multiple studies of autistic children.  Autistic children have evidence of increased lipid peroxidation, including increased malondialdehyde which is a marker of oxidative stress and lipid peroxidation.  Decreased activities of certain antioxidant enzymes have also been described in autistic individuals including superoxide dismutase, glutathione peroxidase, and catalase.  Some autistic children also have decreased activity of paraoxonase, an antioxidant enzyme that prevents lipid oxidation and also inactivates organophosphates in humans.  The gene for Heat Shock Protein 70 (HSP-70), which protects against oxidative stress, was downregulated in multiple cases of autism.  Antioxidants such as ceruloplasmin and zinc tend to be lower in autistic patients, and the ratio of copper to zinc is abnormal in many autistic children.  In one study, clinical regression (loss of previously acquired skills) in some autistic children was associated with lower levels of serum antioxidant enzymes. 

Treatment of inflammation has led to clinical improvements in some individuals with autism.  For instance, children on a gluten-free and/or casein-free diet produced less TNF-α in the colonic mucosa, and had less evidence of eosinophilic infiltration of the mucosa.  In addition, the use of anti-inflammatory treatments appear to improve symptoms in some individuals with autism.  In fact, in one published case report, treatment with corticosteroids of one child who developed an autoimmune lymphoproliferative syndrome and subsequent autism led to objective improvements in speech and developmental milestones.  In another published case report, a child with PDD, whose behavior and language had regressed at 22 months of age, was treated with corticosteroids which ameliorated abnormal behaviors such as hyperactivity, tantrums, impaired social interaction, echolalia, and stereotypies.  Several published studies have examined novel anti-inflammatory medications such as spironolactone and pioglitazone, and have found clinical improvements in some children with autism.  Other published studies have shown that IVIG, which has very strong anti-inflammatory properties, improved symptoms in some individuals with autism.  Furthermore, treatment of oxidative stress had led to clinical improvements in some autistic individuals.  For instance, in one study, treatment with antioxidants raised the levels of reduced glutathione in the serum of autistic children and improved symptoms.  In several published studies, the use of antioxidants, such as Vitamin C, melatonin, Vitamin B6, zinc, and carnosine improved behavior in some children with autism.

The use of anti-inflammatory medications and antioxidants represent novel and promising treatments for some individuals with autism.  Further studies are needed to help identify those autistic individuals who have significant inflammation, oxidative stress, or both.  Additional research may uncover new treatment modalities for these conditions and lead to improvements in autistic symptoms.

Previous conferences: Undersea and Hyperbaric Medical Society, 5th International Symposium on Hyperbaric Medicine, American College for the Advancement of Medicine, DAN! conference, Autism One, National Autism Association, USAAA conference

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