Relevance of Neuroinflammation and Encephalitis in Autism

Abstract

In recent years, many studies indicate that children with an autism spectrum disorder (ASD) diagnosis have brain pathology suggestive of ongoing neuroinflammation or encephalitis in different regions of their brains. Evidence of neuroinflammation or encephalitis in ASD includes: microglial and astrocytic activation, a unique and elevated proinflammatory profile of cytokines, and aberrant expression of nuclear factor kappa-light-chain-enhancer of activated B cells. A conservative estimate based on the research suggests that at least 69% of individuals with an ASD diagnosis have microglial activation or neuroinflammation. Encephalitis, which is defined as inflammation of the brain, is medical diagnosis code G04.90 in the International Classification of Disease, 10th revision; however, children with an ASD diagnosis are not generally assessed for a possible medical diagnosis of encephalitis. This is unfortunate because if a child with ASD has neuroinflammation, then treating the underlying brain inflammation could lead to improved outcomes. The purpose of this review of the literature is to examine the evidence of neuroinflammation/encephalitis in those with an ASD diagnosis and to address how a medical diagnosis of encephalitis, when appropriate, could benefit these children by driving more immediate and targeted treatments.

Transcriptomic metaanalyses of autistic brains reveals shared gene expression and biological pathway abnormalities with cancer

“…On the other hand, some biological processes were found to be deregulated in the same direction in both ASD and SDDCs, providing theoretical support for hypothetical direct comorbid associations between ASD and cancer. For instance, in agreement with previous data(65–70), our analysis suggests the presence of brain inflammation in ASD patients. Inflammatory processes are well-established drivers of carcinogenesis(71, 72) and are a factor that exerts direct influence on cancer-related features, such as proliferation, survival, and migration(72).…”

Glycan susceptibility factors in autism spectrum disorders

“…This approach has led to new theories on the etiology of ASD, which place alterations in developmental transcriptional regulation, brain growth, changes in the excitatory/inhibitory balance of the neural network, and abnormalities in neural plasticity at the crux of disease pathogenesis. It is also known that inflammation in the developing brain can lead to ASD-like behaviors (Kern et al, 2015). Thus genetic heterogeneity in the patient population may reflect a series of different genetic insults that converge on common neurodevelopmental processes that when perturbed have a similar impact on brain function.…”

A pilot study of high‐dose intravenous immunoglobulin 5% for autism: Impact on autism spectrum and markers of neuroinflammation

“…In addition, these three studies each used a much lower dosage of IVIG (≤400 mg/kg), with infusions at 4‐week intervals and a relatively short duration of treatment and follow‐up (6 months for two studies and only four infusions in the third study). In contrast, two case reports were recently published describing children with ASD whose symptoms improved following IVIG infusion in combination with steroids and/or rituximab [Gonzalez‐Toro et al, ; Kern et al, ; Scott et al, ]. Our study is therefore the first to assess inflammatory biomarkers involved in ASD using a higher dosage of IVIG (intermediate between a replacement and immunomodulatory dosage) over an extended period of time.…”

“…Our study is therefore the first to assess inflammatory biomarkers involved in ASD using a higher dosage of IVIG (intermediate between a replacement and immunomodulatory dosage) over an extended period of time. At present, IVIG is the most‐studied of the immunomodulatory treatments in ASD, but it is possible that other therapies that reduce microglial activation and/or levels of inflammatory cytokines may also contribute to symptom improvement in ASD [Kern et al, ].…”

“…In addition, mast cells have been proposed to play a crucial inflammatory role in some children with ASD. Mast cell‐derived mediators may disrupt the blood‐brain barrier and stimulate microglia, leading to sustained focal inflammation and increased vascular permeability [Kern, Geier, Sykes, & Geier, ; Theoharides, Stewart, Panagiotidou, & Melamed, ; Theoharides, Tsilioni, Patel, & Doyle, ]. In susceptible individuals, the resultant chronic neuroinflammation can cause the loss of synapses and neural tissue, which may ultimately contribute to the pathogenesis of ASD in these patients [Kern et al, ; Young et al, ].…”