By Sarah Stuntebeck, MS, CCC-SLP, and Luke Fortney, MD
Ms. Stuntebeck is Clinical Assistant Professor, Department of Communication Sciences and Disorders, University of Wisconsin-Madison. Dr. Fortney is Integrative Family Medicine Physician, Meriter Medical Group, Madison, Wisconsin.
Ms. Stuntebeck and Dr. Fortney report no financial relationships relevant to this field of study.
The story of autism spectrum disorders (ASD) is unique compared to other disorders in that few have seen such an unexplained increase over time, strain on personal and health care resources, rise of social activism and advocacy organizations, and controversial treatment approaches. First reported in 1943, autism poses particular challenges for researchers given the numerous potential contributing factors. Although treatable, it is considered an incurable, multifactorial disorder that is influenced by genetic, neurological, environmental, and immunological aspects.1 That being said, recent developments have helped create a better understanding of the heterogeneity of ASD and its variable phenotypes.2
Autism itself is a biologically based disorder of brain development. This neurodevelopmental disorder is characterized by variable degrees of social and language deficits. Children with ASD demonstrate stereotypically restricted and repetitive behavior. Variants of ASD include conditions such as pervasive developmental delay (PDD) and Asperger disorder (AD). A 2012 Centers for Disease Control and Prevention (CDC) report estimates that of all autism diagnoses in the United States, 47% were PDD and 9% were AD.3 Comorbid conditions — such as ADHD on the other hand — are separate but appear to have a higher prevalence in ASD.
The incidence of ASD has increased 10-fold in the last 25 years. In 1990, the estimated prevalence was 5 per 10,000 children. A report published by the U.S. Department of Health and Human Services indicates that among children aged 6-17, prevalence of autism increased from 1.16% in 2007 to 2.00% in 2012,4 although the CDC estimates that one in 110 children now born in the United States has ASD.5
Although there is controversy regarding the various factors that may contribute to ASD prevalence and severity, perhaps the most frustrating aspect of ASD for both parents and health care professionals is that its cause(s) remain unknown. That being said, most experts agree that ASD is a genetically predisposed disorder that seems to require an inciting environmental trigger (or triggers). For most cases of ASD, no single gene or group of genes has been definitively shown to significantly impact its development. However, there is a 90% concordance between identical twins vs 30% in fraternal twins.6
The pathophysiology of autism is — without surprise — not well understood. A genetic cause can be identified in only 20% of ASD cases, involving genes that converge on common pathways that alter synaptic homeostasis.7 There is good evidence to support the understanding that autism is characterized by inflammatory and abnormal neural connections, particularly underconnectivity of cortical systems leading to abnormal interhemispheric communication. With corroborating advanced imaging from fMRI, this abnormal brain function correlates well with many of the stereotypical behaviors seen in ASD.8
One of the most widely debated aspects of ASD is gastrointestinal (GI) dysregulation — specifically conditions known as dysbiosis and increased intestinal permeability. However, the exact cause for increased prevalence of GI abnormalities in ASD is unknown. Up to one-third of children with autism exhibit some form of GI disorder clinically (e.g., constipation, abdominal pain, diarrhea, gastroesophageal reflux disease). The human gut is home to a dynamic and complex community of microbes that can profoundly influence nervous system growth and development.9 Many of the behavioral challenges associated with autism likely can be explained by gut dysfunction, noting that many autistic children have communication barriers and have challenges expressing their discomfort.
One study found that ASD children treated with vancomycin saw an improvement in both abnormal gut bacteria and GI symptoms, while also seeing improvements in autistic behavior.10 Lactulose-mannitol testing reveals that the majority of these children exhibit abnormal intestinal permeability, which is thought to indicate atrophy of the intestinal mucosa and injury to intercellular junctions. This altered intestinal permeability is thought to allow absorption of incompletely digested peptides that behave as receptor agonists leading to abnormal brain-gut neuro-activity that result in behavior changes.11
Along these lines, duodenal biopsies from 25 autistic children show increased lymphocytic proliferation and other immune abnormalities, indicating a possible autoimmune etiology.12 A separate study of 36 autistic children reported significantly higher levels of IgG, IgM, and IgA to food proteins such as casein and lactoglobulin compared to controls.13 An autoimmune etiology in ASD is supported by an epidemiological study showing that families affected by autism had 1.87 relatives with autoimmune disorders, which is significantly more common when compared to the general population, and surprisingly even more common than families affected by other common autoimmune diseases such as lupus and rheumatoid arthritis.14 Another study even found that 36.7% of autistic patients and 21.2% of their direct relatives demonstrated active "leaky gut" syndrome as compared to 5% of controls.15 These findings suggest an inheritable predisposition for ASD that, when triggered by environmental events, may play a key role in prevalence and severity.
The majority of published studies show a statistically significant benefit of a gluten-free/casein-free (GFCF) diet in ASD. However, specific characteristics of best and non-responders to GFCF intervention have not yet been elucidated. That some children benefit from this dietary intervention and others do not is likely due to variable ASD phenotypes.16 One striking case report in the literature reported significant benefits in a child with severe ASD, morbid obesity, and epilepsy, who after limited response to other interventions, was placed on a GFCF-ketogenic diet that used medium-chained triglycerides and a high intake of vegetables. Over the course of a few years, the child’s Autism Rating Score went from severe to non-autistic, her intelligence quotient increased 70 points, and she became seizure-free with normal follow-up EEGs.17 Needless to say, in keeping with the favorable benefit-harm ratio, it is entirely reasonable for families affected by ASD to implement a GFCF diet.
In addition, many studies demonstrate the need to supplement the diet of autistic patients with omega-3 fatty acids, probiotics, vitamins, and minerals in combination with other medical and psychological interventions.18 However, good data showing conclusive clinical benefit of these additions largely are lacking and there have been calls to investigate the likely beneficial role of probiotics in ASD.19
Mercury and Environmental Toxins
Another popular ASD suspect is thimerisol (ethylmercury), which was previously contained in childhood vaccinations. This, perhaps more than any other aspect of the autism story, has been hotly debated. A review by the FDA found that prior to 1999, the additive sum of childhood vaccinations exceeded EPA limits for safe exposure of methylmercury. Although epidemiological studies have failed to find a connection between the small amounts of mercury in vaccines and incidence of ASD,20 one study demonstrated a 61% associated increase in the rate of autism incidence for every 1000 pounds of mercury released from industrial pollution.21
There is ongoing concern about the growing chemical milieu that children are exposed to early in life. A well-known source of mercury exposure comes from amalgam fillings. However, whether there are any adverse health effects from this remains a subject of debate.22 While mercury is a well-known neurotoxin with no acceptable level of exposure, it is unproven as a significant cause of autism by itself. However, mercury may just be the tip of the iceberg. Children today are exposed to thousands of synthetic chemicals, with at least 200 being known neurotoxins and another 1000 demonstrating neurotoxicity in laboratory tests. According to the CDC’s biomonitoring program, there are more than 100,000 chemicals commonly used every day in household cleaners, solvents, pesticides, food additives, lawn care, and other products. Every year another 1000 chemicals are introduced that do not take into account the mixtures and various combinations of commercial and consumer products to which people are exposed.23
Another alarming study found nearly 300 environmental toxins in the umbilical blood of neonates.24 Animal models show that even low levels of these toxins can negatively affect neurodevelopment. Indirect human evidence points to the sensitivity of the developing brain to lead, mercury, and other toxins. The strongest proof-of-concept evidence comes from research linking ASD to various chemical exposures in early pregnancy.25 Given this information, it is reasonable for parents and practitioners alike to follow the precautionary principle that states, "When an activity raises threats of harm to human health or the environment, precautionary measures should be taken even if some cause and effect relationships are not fully established scientifically."26
That being said, it has been postulated that previously undetected inherited metabolic defects predispose those who would eventually be diagnosed with ASD due to impaired detoxification systems that are not adequately able to handle the same low level of toxic exposure as normally developing children. For example, in a study of more than 200 autistic children treated with the chelating agent DMSA, urinary levels of mercury were significantly higher compared to neuro-typical controls.27 Additional studies lend support to the hypothesis that even though children with autism and neuro-typical children both have similar exposures,28 those with ASD exhibit abnormal urinary porphyrin levels, which indicates abnormal mercury metabolism and elimination.29
Although children with ASD may be susceptible to even "normal" levels of mercury exposure, and although there are some data showing increased urinary output of toxic metals with use of chelating agents,30 evidence showing clinically beneficial outcomes from the use of chelating agents such as EDTA and DMSA is lacking.31 What’s more, NIH-funded trials were halted prematurely due to ethical concerns.32 However, there are reasonable lifestyle approaches to help reduce toxic body burden for would-be-mothers and families with young children (see EWG link in resources).
To Vaccinate or Not to Vaccinate: The Case of MMR
The MMR vaccine has been implicated by many parents as a triggering event for autism. Although there were early concerns, no link between the MMR vaccination and autism has been found.33 In fact, a recent study found that children with ASD have similar levels of antibodies against the MMR vaccine as same-age neuro-typical controls.34 An infamous study published in the Lancet in 1998 that suggested a link in ASD with colitis and MMR vaccination35 was retracted in 2010 by the journal due to serious irregularities.36 An 8-year U.S. federal court process that finally ended in 2010 concluded that ASD was not caused by an adverse reaction to vaccination.37 To the contrary, it is now estimated that MMR vaccinations administered in the United States from 2001-2010 helped prevent more than 16,000 cases of congenital rubella syndrome — a known cause of ASD — which in turn helped prevent more than 6000 new cases of ASD during that 10-year period.38
Study retractions and court rulings have hardly transformed the thinking of many antivaccine advocacy groups. A recent CNN story reported that measles infections, once considered eradicated in the United States, have increased.39 For example, another story by NPR reported that 21 vaccine-skeptical parishioners of a North Texas Church who had not been adequately immunized with MMR were infected in a measles outbreak.40 For reference, it is estimated that 1 of 1000 children ultimately die from measles infections, even with the best of care.39 As a result, there have been calls to set aside philosophical quarrels and instead respond with empathy and open family-centered dialogue to address misinformation and concerns about vaccinations.41
Alternative childhood immunization schedules (ACIS) are one approach for families that refuse standard CDC vaccine schedules. Despite controversy of a well-known ACIS (the Sears alternative vaccine schedule43 The real advantage of offering ACIS to concerned parents is not about efficacy or promoting a "better or worse" vaccination schedule, but rather in establishing a trusting relationship while ensuring eventual full immunization and protection for children.
Behavioral and Speech Therapies for ASD
Although the cause(s) of autism are unknown, there are reasonable and effective treatments for ASD. The most common, and arguably the most effective approaches address behavioral, communication, and social deficits. Early screening during routine well-child exams can identify signs of ASD, which in turn should lead to initiation of speech-language therapy (see NICHCY link in resources). Effective services should vary with individual children, depending on the child’s age, cognitive level, language skills, behavioral needs, and family priorities. With some children, it is appropriate to incorporate augmentative and alternative communication (AAC), such as the Picture Exchange Communication System, other high- and low-tech assistive technology tools, and/or sign language. A meta-analysis of single-case research studies indicates strong effects for the use of AAC on communication skills. Although effect sizes should be interpreted cautiously due to the small number of studies, social skills, challenging behaviors, and spelling also appear to be positively affected.44
Although behavioral intervention methods appear to have a positive impact on learning, communication, and behavior in children with ASD, intervention studies suffer from methodological problems that make it difficult to form definitive conclusions regarding efficacy. That being said, there is evidence to support the use of applied behavioral analysis for functional skills development, and there are clear benefits of Lovaas therapy compared to no treatment. Furthermore, increased therapy intensity is known to be more effective than no- or low-intensity therapy. The National Research Council suggests that young children with ASD should receive at least 25 hours of individualized and structured intervention per week, 12 months a year.45 In general though, as no definitive behavioral or developmental intervention improves all symptoms for every child, it is recommended that therapy management be guided by each child’s needs and availability of resources.46
Other common and effective behavioral therapies include Greenspan’s Floortime and Developmental Individual Difference Relationship Model, which incorporates play activities with an emphasis on emotional development. Relationship Development Intervention is a parent-based treatment approach that works to improve social skills, adaptability, and self-awareness skills. Social Communication/Emotional Regulation/Transactional Support uses practices from a variety of other approaches in order to promote child-initiated communication and skills in a variety of settings.
Although there are anecdotal reports of benefits from sensory motor interventions, such as sensory integration therapy or use of a sensory diet, results are limited and inconsistent. A review of auditory integration therapy by the American Speech-Language and Hearing Association concluded that efficacy standards for use by audiologists and speech-language pathologists are not yet available. At this time, families should pursue these therapies with some skepticism until further research can be conducted.47