Mercury as a hapten: A review of the role of toxicant-induced brain autoantibodies in autism and possible treatment considerations.

BACKGROUND: Mercury has many direct and well-recognized neurotoxic effects. However, its immune effects causing secondary neurotoxicity are less well-recognized. Mercury exposure can induce immunologic changes in the brain indicative of autoimmune dysfunction, including the production of highly specific brain autoantibodies. Mercury, and in particular, Thimerosal, can combine with a larger carrier, such as an endogenous protein, thereby acting as a hapten, and this new molecule can then elicit the production of antibodies. METHODS: A comprehensive search using PubMed and Google Scholar for original studies and reviews related to autism, mercury, autoantibodies, autoimmune dysfunction, and haptens was undertaken. All articles providing relevant information from 1985 to date were examined. Twenty-three studies were identified showing autoantibodies in the brains of individuals diagnosed with autism and all were included and discussed in this review. RESULTS: Research shows mercury exposure can result in an autoimmune reaction that may be causal or contributory to autism, especially in children with a family history of autoimmunity. The autoimmune pathogenesis in autism is demonstrated by the presence of brain autoantibodies (neuroantibodies), which include autoantibodies to: (1) human neuronal progenitor cells; (2) myelin basic protein (MBP); (3) neuron-axon filament protein (NAFP); (4) brain endothelial cells; (5) serotonin receptors; (6) glial fibrillary acidic protein (GFAP); (7) brain derived neurotrophic factor (BDNF); (8) myelin associated glycoprotein (MAG); and (9) various brain proteins in the cerebellum, hypothalamus, prefrontal cortex, cingulate gyrus, caudate putamen, cerebral cortex and caudate nucleus. CONCLUSION: Recent evidence suggests a relationship between mercury exposure and brain autoantibodies in individuals diagnosed with autism. Moreover, brain autoantibody levels in autism are found to correlate with both autism severity and blood mercury levels. Treatments to reduce mercury levels and/or brain autoantibody formation should be considered in autism.

Cerebral hypoperfusion in autism spectrum disorder.

Cerebral hypoperfusion, or insufficient blood flow in the brain, occurs in many areas of the brain in patients diagnosed with autism spectrum disorder (ASD). Hypoperfusion was demonstrated in the brains of individuals with ASD when compared to normal healthy control brains either using positron emission tomography (PET) or single­photon emission computed tomography (SPECT). The affected areas include, but are not limited to the: prefrontal, frontal, temporal, occipital, and parietal cortices; thalami; basal ganglia; cingulate cortex; caudate nucleus; the limbic system including the hippocampal area; putamen; substantia nigra; cerebellum; and associative cortices. Moreover, correlations between symptom scores and hypoperfusion in the brains of individuals diagnosed with an ASD were found indicating that the greater the autism symptom pathology, the more significant the cerebral hypoperfusion or vascular pathology in the brain. Evidence suggests that brain inflammation and vascular inflammation may explain a part of the hypoperfusion. There is also evidence of a lack of normal compensatory increase in blood flow when the subjects are challenged with a task. Some studies propose treatments that can address the hypoperfusion found among individuals diagnosed with an ASD, bringing symptom relief to some extent. This review will explore the evidence that indicates cerebral hypoperfusion in ASD, as well as the possible etiological aspects, complications, and treatments.

An exploratory study of visual sequential processing in children with cochlear implants.

OBJECTIVE: The objective of the study was to compare visual sequential processing in school-age children with cochlear implants (CIs) and their normal-hearing (NH) peers. Visual sequential processing was examined using both behavioral and an event-related potential (ERP) measures. METHODS: Eighteen children with CIs and nineteen children who had hearing within normal limits (NH) participated in the behavioral study. Subtests from the Test of Visual Perceptual Skills and the Sensory Integration and Praxis Test were administered to all children. ERP measures were collected from five children with CI and five age-matched peers. Peak latencies (N200 and P300) and reaction times for visual sequential processing were compared in these two groups. RESULTS: The findings of the study revealed significant group differences in visual sequential memory and visuo-motor sequencing tasks suggesting that children with severe-profound hearing loss may have difficulties in visual sequential tasks. The study also revealed longer P300 latencies and longer reaction times for a visual sequential matching task in children with CI when compared to their NH peers suggesting slower or delayed processing of visual sequential stimuli. CONCLUSIONS: This exploratory study involving behavioral and ERP measures showed that as a group, children with prelingual, severe-profound hearing loss who use CIs have difficulties with visual sequential processing. These findings may have implications for rehabilitation for children with hearing loss in the light of recent evidence that accurate and efficient processing of sequentially presented visual stimuli is important for language and reading outcomes.

Shared Brain Connectivity Issues, Symptoms, and Comorbidities in Autism Spectrum Disorder, Attention Deficit/Hyperactivity Disorder, and Tourette Syndrome.

The prevalence of neurodevelopmental disorders, including autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), and Tourette syndrome (TS), has increased over the past two decades. Currently, about one in six children in the United States is diagnosed as having a neurodevelopmental disorder. Evidence suggests that ASD, ADHD, and TS have similar neuropathology, which includes long-range underconnectivity and short-range overconnectivity. They also share similar symptomatology with considerable overlap in their core and associated symptoms and a frequent overlap in their comorbid conditions. Consequently, it is apparent that ASD, ADHD, and TS diagnoses belong to a broader spectrum of neurodevelopmental illness. Biologically, long-range underconnectivity and short-range overconnectivity are plausibly related to neuronal insult (e.g., neurotoxicity, neuroinflammation, excitotoxicity, sustained microglial activation, proinflammatory cytokines, toxic exposure, and oxidative stress). Therefore, these disorders may a share a similar etiology. The main purpose of this review is to critically examine the evidence that ASD, ADHD, and TS belong to a broader spectrum of neurodevelopmental illness, an abnormal connectivity spectrum disorder, which results from neural long-range underconnectivity and short-range overconnectivity. The review also discusses the possible reasons for these neuropathological connectivity findings. In addition, this review examines the role and issue of axonal injury and regeneration in order to better understand the neuropathophysiological interplay between short- and long-range axons in connectivity issues.

Prospective, blinded exploratory evaluation of the PlayWisely program in children with autism spectrum disorder.

The purpose of the study was to explore a low-cost intervention that targets an increasingly common developmental disorder. The study was a blinded, exploratory evaluation of the PlayWisely program on autism symptoms and essential learning foundation skills (attention, recognition, and memory skills) in children with a diagnosis of autism, autism spectrum disorder (ASD), pervasive developmental disorder - not otherwise specified (PDD-NOS), and Asperger syndrome (AS). Eighteen children, 1 to 10 years of age, were evaluated using the Childhood Autism Rating Scale, Second Edition (CARS2); the PlayWisely Interactive Test of Attention, Recognition, and Memory Skills; Autism Treatment Evaluation Checklist (ATEC), and the Modified Checklist for Autism in Toddlers (M-CHAT). There were significant treatment effects for the PlayWisely measure on the Yellow Sets that examine recognition; Purple Sets that examine brain region agility and early memory skills; Blue Sets that examine phonemic awareness and recognition; and for the Total Sets, with a similar trend toward improvement in the Green Sets that examine perception and Red Sets that examine attention. No other measures reached statistical significance. The results suggest that PlayWisely can improve recognition, brain region agility, phonemic awareness, letter recognition, and early memory skills in ASD. It was observed by the parents, coaches, and study investigators that the children who were less than 3 years of age showed improvements in autism symptoms; however, the group was too small to reach statistical significance. Future studies are needed to see if this intervention can mitigate autism symptoms in very young children with ASD.

Prospective trial of equine-assisted activities in autism spectrum disorder.

BACKGROUND: Anecdotal reports and some studies suggest that equine-assisted activities may be beneficial in autism spectrum disorders (ASD). OBJECTIVE: To examine the effects ofequine-assisted activities on overall severity of autism symptoms using the Childhood Autism Rating Scale (CARS) and the quality ofparent-child interactions using the Timberlawn Parent-Child Interaction Scale. In addition, this study examined changes in sensory processing, quality of life, and parental treatment satisfaction. DESIGN AND PARTICIPANTS: Children with ASD were evaluated at four time points: (1) before beginning a 3-to-6 month waiting period, (2) before starting the riding treatment, and (3) after 3 months and (4) 6 months of riding. Twenty-four participants completed the waiting list period and began the riding program, and 20 participants completed the entire 6 months of riding. Pretreatment was compared to posttreatment with each child acting as his or her own control. RESULTS: A reduction in the severity of autism symptoms occurred with the therapeutic riding treatment. There was no change in CARS scores during the pretreatment baseline period; however, there was a significant decrease after treatment at 3 months and 6 months of riding. The Timberlawn Parent-Child Interaction Scale showed a significant improvement in Mood and Tone at 3 months and 6 months of riding and a marginal improvement in the reduction of Negative Regard at 6 months of riding. The parent-rated quality of life measure showed improvement, including the pretreatment waiting period. All of the ratings in the Treatment Satisfaction Survey were between good and very good. CONCLUSION: These results suggest that children with ASD benefit from equine-assisted activities.

Toxicity biomarkers in autism spectrum disorder: a blinded study of urinary porphyrins.

BACKGROUND: Recent studies suggest that children diagnosed with an autism spectrum disorder (ASD) have significantly increased levels of urinary porphyrins associated with mercury (Hg) toxicity, including pentacarboxyporphyrin (5cxP), precoproporphyrin (prcP), and coproporphyrin (cP), compared to typically developing controls. However, these initial studies were criticized because the controls were not age- and gender-matched to the children diagnosed with an ASD. METHODS: Urinary porphyrin biomarkers in a group of children (2-13 years of age) diagnosed with an ASD (n= 20) were compared to matched (age, gender, race, location, and year tested) group of typically developing controls (n= 20). RESULTS: Participants diagnosed with an ASD had significantly increased levels of 5cxP, prcP, and cP in comparison to controls. No significant differences were found in non-Hg associated urinary porphyrins (uroporphyrins, hexacarboxyporphyrin, and heptacarboxyporphyrin). There was a significantly increased odds ratio for an ASD diagnosis relative to controls among study participants with precoproporphyrin (odds ratio = 15.5, P < 0.01) and coproporphyrin (odds ratio = 15.5, P < 0.01) levels in the second through fourth quartiles in comparison to the first quartile. CONCLUSION: These results suggest that the levels of Hg-toxicity-associated porphyrins are higher in children with an ASD diagnosis than controls. Although the pattern seen (increased 5cxP, prcP, and cP) is characteristic of Hg toxicity, the influence of other factors, such as genetics and other metals cannot be completely ruled out.

Toxicity biomarkers among US children compared to a similar cohort in France: a blinded study measuring urinary porphyrins.

The purpose of this blinded study was to evaluate potential environmental toxicity in a cohort of neurotypical children (n = 28) living in a suburban area of north-central Texas in the United States (US) with a comparable age- and gender-matched cohort of neurotypical children (n = 28) living in a suburban area of southeastern France using urinary porphyrin testing: uroporphyrin (uP), heptacarboxyporphyrin (7cxP), hexacarboxyporphyrin (6cxP), pentacarboxyporphyrin (5cxP), precoproporphyrin (prcP), and coproporphyrin (cP). Results showed significantly elevated 6cxP, prcP (an atypical, mercury-specific porphyrin), and cP levels, and increasing trends in 5cxP levels, among neurotypical children in the USA compared to children in France. Data suggest that in US neurotypical children, there is a significantly increased body-burden of mercury (Hg) compared to the body-burden of Hg in the matched neurotypical children in France. The presence of lead contributing to the higher levels of cP also needs to be considered. Further, other factors including genetics can not be completely ruled out.

Sensory correlations in autism.

This study examined the relationship between auditory, visual, touch, and oral sensory dysfunction in autism and their relationship to multisensory dysfunction and severity of autism. The Sensory Profile was completed on 104 persons with a diagnosis of autism, 3 to 56 years of age. Analysis showed a significant correlation between the different processing modalities using total scores. Analysis also showed a significant correlation between processing modalities for both high and low thresholds, with the exception that auditory high threshold processing did not correlate with oral low threshold or touch low threshold processing. Examination of the different age groups suggests that sensory disturbance correlates with severity of autism in children, but not in adolescents and adults. Evidence from this study suggests that: all the main modalities and multisensory processing appear to be affected; sensory processing dysfunction in autism is global in nature; and sensory processing problems need to be considered part of the disorder.

The pattern of sensory processing abnormalities in autism.

The study was undertaken to evaluate the nature of sensory dysfunction in persons with autism. The cross-sectional study examined auditory, visual, oral, and touch sensory processing, as measured by the Sensory Profile, in 104 persons with a diagnosis of autism, 3-56 years of age, gender-and age-matched to community controls. Persons with autism had abnormal auditory, visual, touch, and oral sensory processing that was significantly different from controls. This finding was also apparent when the high and low thresholds of these modalities were examined separately. At later ages for the group with autism, lower levels of abnormal sensory processing were found, except for low threshold touch, which did not improve significantly. There was a significant interaction in low threshold auditory and low threshold visual, suggesting that the two groups change differently over time on these variables. These results suggest that sensory abnormalities in autism are global in nature (involving several modalities) but have the potential to improve with age.

Complementing behavioral measures with electrophysiological measures in diagnostic evaluation: a case study in two languages.

This case study focuses on a bilingual, older man who spoke Polish and English and showed weaknesses on clinical measures of dichotic listening in English. It was unclear whether these test results were influenced by the participant's facility with his second language or by other nonauditory factors. To elucidate the nature of this deficit, the authors examined behavioral and electrophysiological responses during dichotic-listening tasks involving linguistic processing in both languages. A diotic (control) condition was included to examine whether nonauditory factors, such as language familiarity, memory, or decline in speed of mental processing, might explain the dichotic results. The results from this participant were compared with those obtained from a bilingual young adult who also spoke both Polish and English. Results showed a substantial left-ear deficit for the older individual on both behavioral and electrophysiological measures of dichotic listening. The pattern of results is consistent with previous findings in demonstrating that the left-ear deficit in this patient derived from an auditory-specific defect rather than from any of the extra-auditory factors associated with language facility or cognitive decline.