AUTISM

1. ETIOLOGY

GENETICS

Early studies of twins had estimated heritability to be over 90%, meaning that genetics explains over 90% of whether a child will develop autism.[2] However, this may be an overestimate, as new twin data and models with structural genetic variation are needed.[14] Many of the non-autistic co-twins had learning or social disabilities. For adult siblings the risk for having one or more features of the broader autism phenotype might be as high as 30%. The genetics of autism are complex.[2] Linkage analysis has been inconclusive; many association analyses have had inadequate power.[14] More than one gene may be implicated, different genes may be involved in different individuals, and the genes may interact with each other or with environmental factors. Several candidate genes have been located,[16] but the mutations that increase autism risk have not been identified for most candidate genes. A substantial fraction of autism may be highly heritable but not inherited because the mutation that causes the autism is not present in the parental genome.

Research on X- chromosome epigenetic mechanisms may reveal why there is a differential occurrence of ASD between males and females. Females are born with twice as many X-chromosomes as males; through the process of X-inactivation, females are more likely to be protected from expressing X-linked mutations which have been found in ASD. Males do not have the same protection as females do. According to Kirkovski et al., "it has been hypothesized that a paternally imprinted X-gene may increase liability to express the ASD phenotype. As this paternally inherited X-chromosome is not present in males, they are less protected". [18] They said, "those with a paternal X-chromosome displayed greater social skills (potentially mediated by greater executive functioning) and verbal intelligence, and were less likely to receive educational special needs recommendations in comparison to those with a maternal X-chromosome".[18] There is an array of different hypotheses and models that seek to explain the X-linked genes related to autism; some hypotheses are: the X-inactivation/X-linkage hypothesis, the X-linked extreme hypothesis, and the X-imprinted liability threshold model. In regards to the X-linkage, there has been research suggesting that autistic symptoms could be linked to the X-chromosome. Overall, because it is evident that the X-chromosome plays an intricate role in abnormal social behaviors and interactions that are characteristic of ASD, there may be increased heritability of ASD in males.[18]

Risk factors for autism include parental characteristics such as advanced maternal age [19] and advanced paternal age.[20] The risk is greater for advanced paternal age. One hypothesis is that this is caused by older sperm that have greater mutation burden, and another is that men who carry more genetic liability have some features of autism and therefore marry and have children later. These two hypotheses are not mutually exclusive.

Epigenetics

The risk of autism. Epigenetic changes occur as a result not of DNA sequence changes but of chromosomal histone modification or modification of the DNA bases. Such modifications are known to be affected by environmental factors, including nutrition, drugs, and mental stress.[21] Interest has been expressed in imprinted regions on chromosomes 15q and 7q.[22]

Prenatal environment

The risk of autism is associated with several prenatal risk factors, including advanced age in either parent, diabetes, bleeding, and use of psychiatric drugs in the mother during pregnancy .[20] Autism has been linked to birth defect agents acting during the first eight weeks from conception, though these cases are rare.[23]

Infectious processes

Prenatal viral infection has been called the principal non-genetic cause of autism. Prenatal exposure to rubella or cytomegalovirus activates the mother's immune response and greatly increases the risk for autism.[24] Congenital rubella syndrome is the most convincing environmental cause of autism.[25] Infection-associated immunological events in early pregnancy may affect neural development more than infections in late pregnancy, not only for autism, but also for psychiatric disorders of presumed neurodevelopmental origin, notably schizophrenia.[26]

Environmental agents

Teratogens are environmental agents that cause birth defects. Some agents that are theorized to cause birth defects have also been suggested as potential autism risk factors, although there is little to no scientific evidence to back such claims. These include exposure of the embryo to valproic acid,[27] thalidomide or misoprostol.[28] These cases are rare.[29] Questions have also been raised whether ethanol(grain alcohol) increases autism risk, as part of fetal alcohol syndrome or alcohol-related birth defects.[28] All known teratogens appear to act during the first eight weeks from conception, and though this does not exclude the possibility that autism can be initiated or affected later, it is strong evidence that autism arises very early in development.[3]

Other maternal conditions

Thyroid problems that lead to thyroxine deficiency in the mother in weeks 8–12 of pregnancy have been postulated to produce changes in the fetal brain leading to autism. Thyroxine deficiencies can be caused by inadequate iodine in the diet, and by environmental agents that interfere with iodine uptake or act against thyroid hormones. Possible environmental agents include flavonoids in food, tobacco smoke, and most herbicides. This hypothesis has not been tested.[30]

Diabetes in the mother during pregnancy is a significant risk factor for autism ; a 2009 meta-analysis found that gestational diabetes was associated with a twofold increased risk. A 2014 review also found that maternal diabetes was significantly associated with an increased risk of ASD. [31] Although diabetes causes metabolic and hormonal abnormalities and oxidative stress, no biological mechanism is known for the association between gestational diabetes and autism risk.[20]

Other in utero

It has been hypothesized that folic acid taken during pregnancy could play a role in reducing cases of autism by modulating gene expression through an epigenetic mechanism. This hypothesis is untested.[32]

Prenatal stress, consisting of exposure to life events or environmental factors that distress an expectant mother, has been hypothesized to contribute to autism, possibly as part of a gene-environment interaction. Autism has been reported to be associated with prenatal stress both with retrospective studies that examined stressors such as job loss and family discord, and with natural experiments involving prenatal exposure to storms; animal studies have reported that prenatal stress can disrupt brain development and produce behaviors resembling symptoms of autism.[33]

The fetal testosterone theory hypothesizes that higher levels of testosterone in the amniotic fluid of mothers pushes brain development towards improved ability to see patterns and analyze complex systems while diminishing communication and empathy, emphasizing "male" traits over "female", or in E-S theory terminology, emphasizing "systemizing" over "empathizing". One project has published several reports suggesting that high levels of fetal testosterone could produce behaviors relevant to those seen in autism.[34]

Based in part on animal studies, diagnostic ultrasounds administered during pregnancy have been hypothesized to increase the child's risk of autism. This hypothesis is not supported by independently published research, and examination of children whose mothers received an ultrasound has failed to find evidence of harmful effects.[35]

Some research suggests that maternal exposure to selective serotonin reuptake inhibitors during pregnancy is associated with an increased risk of autism, but it remains unclear whether there is a causal link between the two.[36]

Perinatal environment

Autism is associated with some perinatal and obstetric conditions. A 2007 review of risk factors found associated obstetric conditions that included low birth weight and gestation duration, and hypoxia during childbirth. This association does not demonstrate a causal relationship. As a result, an underlying cause could explain both autism and these associated conditions.[37]

Postnatal environment

A wide variety of postnatal contributors to autism have been proposed, including gastrointestinal or immune system abnormalities, allergies, and exposure of children to drugs, vaccines, infection, certain foods, or heavy metals. The evidence for these risk factors is anecdotal and has not been confirmed by reliable studies.[38]

Amygdala neurons

This theory hypothesizes that an early developmental failure involving the amygdala cascades on the development of cortical areas that mediate social perception in the visual domain. The fusiform face area of the ventral stream is implicated. The idea is that it is involved in social knowledge and social cognition, and that the deficits in this network are instrumental in causing autism.[39]

Autoimmune disease

This theory hypothesizes that autoantibodies that target the brain or elements of brain metabolism may cause or exacerbate autism. It is related to the maternal infection theory, except that it postulates that the effect is caused by the individual's own antibodies, possibly due to an environmental trigger after birth. It is also related to several other hypothesized causes; for example, viral infection has been hypothesized to cause autism via an autoimmune mechanism.[40]

Interactions between the immune system and the nervous system begin early during embryogenesis, and successful neurodevelopment depends on a balanced immune response. It is possible that aberrant immune activity during critical periods of neurodevelopment is part of the mechanism of some forms of ASD.[41] A small percentage of autism cases are associated with infection, usually before birth. Results from immune studies have been contradictory. Some abnormalities have been found in specific subgroups, and some of these have been replicated. It is not known whether these abnormalities are relevant to the pathology of autism, for example, by infection or autoimmunity, or whether they are secondary to the disease processes.[42] As autoantibodies are found in diseases other than ASD, and are not always present in ASD,[43] the relationship between immune disturbances and autism remains unclear and controversial.[44] A 2015 systematic review and meta-analysis found that children with a family history of autoimmune diseases were at a greater risk of autism compared to children without such a history.[45]

When an underlying maternal autoimmune disease is present, antibodies circulating to the fetus could contribute to the development of autism spectrum disorders.[46]

Endogenous opiate precursor theory

Main article: Opioid excess theory

In 1979, Jaak Panksepp proposed a connection between autism and opiates, noting that injections of minute quantities of opiates in young laboratory animals induce symptoms similar to those observed among autistic children.[47] Opiate theory hypothesizes that autism is caused by a digestive disorder present from birth which causes gluten (present in wheat-derived foods) and casein (present in dairy products) to be converted to the opioid peptides gliadorphin (aka gluteomorphin) and casomorphin.

According to the theory, exposure to these opiate compounds in young children interferes with normal neurological development by dulling sensory input. Lacking sufficient sensory input, the developing brain attempts to artificially generate the auditory, vestibular, visual, and tactile input on its own. This attempt at generating input manifests itself as behaviors common to autism, such as grunting or screaming (auditory), spinning or rocking back and forth (vestibular), preoccupation with spinning objects or waving of the fingers in front of the eyes (visual), and hand flapping or self-injury (tactile).

The theory further states that removing opiate precursors from a child's diet may allow time for these behaviors to cease, and neurological development in very young children to resume normally. [48] The possibility of a relationship between autism and the consumption of gluten and casein was first

articulated by Kalle Reichelt in 1991.[49] The scientific evidence is not yet adequate to make treatment recommendations regarding diets, such as the GFCF diet, which exclude these substances.[50]

Gastrointestinal connection

Parents have reported gastrointestinal (GI) disturbances in autistic children, and several studies have investigated possible associations between autism and the gut,[51] but the results so far are inconclusive.

There is some research evidence that autistic children are more likely to have GI symptoms than typical children.[52] Even so, design flaws in studies of elimination diets mean that the data are inadequate to guide treatment recommendations.[12]

After a preliminary 1998 study of three children with ASD treated with secretin infusion reported improved GI function and dramatic improvement in behavior, many parents sought secretin treatment and a black market for the hormone developed quickly.[51] Later studies found secretin clearly ineffective in treating autism.[53]

Lack of vitamin D

There is limited evidence for the hypothesis that vitamin D deficiency has a role in autism, and it may be biologically plausible,[54] but more research is needed.[55]

Lead[edit]

Lead poisoning has been suggested as a possible risk factor for autism, as the lead blood levels of autistic children has been reported to be significantly higher than typical. [56] The atypical eating behaviors of autistic children, along with habitual mouthing and pica, make it hard to determine whether increased lead levels are a cause or a consequence of autism.[56]

Locus coeruleus–noradrenergic system[edit]

This theory hypothesizes that autistic behaviors depend at least in part on a developmental dysregulation that results in impaired function of the locus coeruleus–noradrenergic (LC-NA) system. The LC-NA system is heavily involved in arousal and attention; for example, it is related to the brain's acquisition and use of environmental cues.[57]

Mercury[edit]

This theory hypothesizes that autism is associated with mercury poisoning, based on perceived similarity of symptoms and reports of mercury or its biomarkers in some autistic children. [58] This view has gained little traction in the scientific community as the typical symptoms of mercury toxicity are significantly different from symptoms seen in autism.[59] The principal source of human exposure to organic mercury is via fish consumption and for inorganic mercury is dental amalgams. Other forms of exposure, such as in cosmetics and vaccines, also occur. The evidence so far is indirect for the association between autism and mercury exposure after birth, as no direct test has been reported, and there is no evidence of an association between autism and postnatal exposure to any neurotoxicant. [60] A meta-analysis published in 2007 concluded that there was no link between mercury and autism.[61]

Oxidative stress[edit]

This theory hypothesizes that toxicity and oxidative stress may cause autism in some cases. Evidence includes genetic effects on metabolic pathways, reduced antioxidant capacity, enzyme changes, and enhanced biomarkers for oxidative stress; however, the overall evidence is weaker than it is for involvement oxidative stress with disorders such as schizophrenia.[62] One theory is that stress damagesPurkinje cells in the cerebellum after birth, and it is possible that glutathione is involved.[63] Autistic children have lower levels of total glutathione, and higher levels of oxidized glutathione.[64] Based on this theory, antioxidants may be a useful treatment for autism.[65]

Refrigerator mother[edit]

Main article: Refrigerator mother

Child psychologist Bruno Bettelheim believed that autism was linked to early childhood trauma, and his work was highly influential for decades both in the medical and popular spheres. Parents, especially mothers, of individuals with autism were blamed for having caused their child's condition through the withholding of affection.[66] Leo Kanner, who first described autism,[67] suggested that parental coldness might contribute to autism.[68] Although Kanner eventually renounced the theory, Bettelheim put an almost exclusive emphasis on it in both his medical and his popular books. Treatments based on these theories failed to help children with autism, and after Bettelheim's death, it came out that his reported rates of cure (around 85%) were found to be fraudulent.[69]

Vaccines[edit]

Scientific studies have refuted a causal relationship between vaccinations and autism.[70][71][72] Despite this, many parents believe that vaccinations cause autism and therefore delay or avoid immunizing their children under the "vaccine overload" hypothesis that giving many vaccines at once may overwhelm a child's immune system and lead to autism,[73] even though this hypothesis has no scientific evidence and is biologically implausible.[74] Because diseases such as measles can cause severe disabilities and death, the risk of death or disability due to not vaccinating a child is higher than the risk for a child who has been vaccinated.[75]

MMR vaccine[edit]Main article: MMR vaccine controversy

The MMR vaccine hypothesis of autism is one of the most extensively debated hypothesies regarding the origins of autism. Andrew Wakefield et al. reported a study of 12 children who had autism and bowel symptoms, in some cases reportedly with onset after MMR. [76] Although the paper, which was later retracted by the journal,[76] concluded "We did not prove an association between measles, mumps, and rubella vaccine and the syndrome described,"[77] Wakefield nevertheless suggested during a 1998 press conference that giving children the vaccines in three separate doses would be safer than a single dose.

In 2004, the interpretation of a causal link between MMR vaccine and autism was formally retracted by ten of Wakefield's twelve co-authors.[78] The retraction followed an investigation by The Sunday Times, which stated that Wakefield "acted dishonestly and irresponsibly". [79] The Centers for Disease Control

and Prevention,[80] the Institute of Medicine of the National Academy of Sciences,[81] and the U.K. National Health Service [82] have all concluded that there is no evidence of a link between the MMR vaccine and autism.

In February 2010, The Lancet, which published Wakefield's study, fully retracted it after an independent auditor found the study to be flawed.[76] In January 2011, an investigation published in the journalBMJ described the Wakefield study as the result of deliberate fraud and manipulation of data. [83]

[84][85][86]

Thiomersal (thimerosal)[edit]Main article: Thiomersal controversy

Perhaps the best-known hypothesis involving mercury and autism involves the use of the mercury-based compound thiomersal, a preservative that has been phased out from most childhood vaccinations in developed countries such as the USA.[87] Parents may first become aware of autistic symptoms in their child around the time of a routine vaccination. There is no scientific evidence for a causal connection between thiomersal and autism, but parental concern about the thiomersal controversy has led to decreasing rates of childhood immunizations [4] and increasing likelihood of disease outbreaks.[88]

[89] Because of public concerns, thiomersal content was completely removed or dramatically reduced from childhood vaccines that contained it in the 1990s; despite this, autism rates continued to climb well into the late 2000s.

A causal link between thimerosal and autism has been rejected by international scientific and medical professional bodies including the American Medical Association,[90] the American Academy of Pediatrics,[91] the American College of Medical Toxicology,[92] the Canadian Paediatric Society,[93] the U.S. National Academy of Sciences,[81] the Food and Drug Administration,[94] Centers for Disease Control and Prevention,[80] the World Health Organization,[95] the Public Health Agency of Canada,[96] and the European Medicines Agency.[97]

Viral infection[edit]

Many studies have presented evidence for and against association of autism with viral infection after birth. Laboratory rats infected with Borna disease virus show some symptoms similar to those of autism but blood studies of autistic children show no evidence of infection by this virus. Members of the herpes virus family may have a role in autism, but the evidence so far is anecdotal. Viruses have long been suspected as triggers for immune-mediated diseases such as multiple sclerosis but showing a direct role for viral causation is difficult in those diseases, and mechanisms whereby viral infections could lead to autism are speculative.[24]

Immunology

Immunological Factors, Genes, and the Environment

A half-day symposium providing insight into research and current trials that point to the potential benefit of medical treatments to address environmentally-triggered impairments associated with autism spectrum disorders.

Recorded June 1, 2013 at UC Davis MIND Institute Auditorium in Sacramento, California.

Is There a Connection Between Immune Function and Autism?

The ideal immune system will:

Recognize all foreign organisms (bacteria, viruses, parasites, fungi, worms). Efficiently and rapidly destroy invaders. Prevent a second infection with the same microbe (have a good memory). Never cause damage to self.Things that can go wrong:

Immune deficiency/dysfunction: defective or ineffective response. Hypersensitivity: Over-reaction to innocuous foreign material, out of proportion to potential

damage (allergy). Autoimmunity: Inappropriate reaction towards self, loss of self-recognition. Inflammation: Too-vigorous attack against invaders with “bystander” damage to normal tissue.Dysregulation of immunity in people with autism can lead to any of these four problems.

There is a tendency towards a positive family history of autoimmunity in families – Rheumatoid Arthritis, Thyroiditis - with an ASD child. Many, many types of autoantibodies [add link on autoantibodies to http://www.pediatricbioscience.com/mar/immunology.html] (against “self” tissues) have been found in ASD children but the significance of the many types of anti-brain antibodies is not yet clear. Several studies find that some ASD children have low immunoglobulins (IgG, IgM, IgA), and/or low T cell numbers, altered cytokine profiles, and/or low-normal functioning and/or low NK cells; a subset of children have true immunodeficiency. Some children have low serum IgA, predisposing them to respiratory and GI infections.

Antibodies are divided up into classes:

IgA: Mucosal surfaces - if this is low, it predisposes to respiratory and GI infections as well as autoimmunity; it is sometimes low in ASD children

IgM: Rapid response bloodstream antibody made at the beginning of an infection; can be high or low in ASD

IgG: Slower but longer lasting bloodstream antibody; can be high or low in ASD IgE: Allergy; can be high or normal in ASDConclusion #1: A child on the autism spectrum with recurrent infections deserves an immune evaluation for immunodeficiency.Conclusion #2: A child on the autism spectrum with eczema, chronic nasal symptoms, asthma, significant GI symptoms, or recurrent respiratory infections deserves an allergy evaluation for IgE inhalant and food allergies.

2. BERA

Synonyms: Brain stem evoked response audiometry, Auditory brain stem response, ABR audiometry, BAER (Brainstem auditory evoked response audiometry).

Definition: Bera is an objective way of eliciting brain stem potentials in response to audiological click stimuli. These waves are recorded by electrodes placed over the scalp. This investigation was first described by Jewett and Williston in 1971.

Even though BERA provides information regarding auditory function and sensitivity, it is not a substitute for other methods of audiological evaluation. It should be always viewed in conjunction with other audiological investigations.

Procedure: The stimulus either in the form of click or tone pip is transmitted to the ear via a transducer placed in the insert ear phone or head phone. The wave froms of impulses generated at the level of brain stem are recorded by the placement of electrodes over the scalp.

Electrode placement: Since the electrodes should be placed over the head, the hair must be oil free. The patient should be instructed to have shampoo bath before coming for investigation. The standard electrode configuration for BERA involves placing a non inverting electrode over the vertex of the head, and inverting electrodes placed over the ear lobe or mastoid prominence. One more earthing electrode is placed over the forehead. This earthing electrode is important for proper functioning of preamplifier.

Since the potentials recorded are in far field, well displaced from the site of impulse generation, the wave forms recorded are very weak and they need to be amplified. This amplification is achieved by improving the signal : noise ratio.

How to improve signal to noise ratio: Three parallel approaches are designed to achieve this goal.

Filtering: This is employed to reduce the recording bandwidth so that only the important components of the siganal generated are recorded.

Repeated stimulation: This is done with synchronous time domain averaging to increase the amplitude of the components of the signal. In real time situations these two can be achieved by connecting the recording electrodes to a preamplifier, with appropriate filter settings.

Polarity alteration: By altering the polarity of impuses recorded, the artifacts are cancelled making the brain stem waves stand out.

In auditory brain stem evoked response audiometry, the impulses are generated by the brain stem. These impulses when recorded contains a series of peaks and troughs. The positive peaks (vortex positive) are referred to by the Roman numerals I - VII.

These peaks are considered to originate from the following anatomical sites:

1. Cochlear nerves - waves I and II

2. Cochlear nucleus - wave III

3. Superior olivary complex - wave IV

4. Nulclei of lateral lemniscus - wave V

5. Inferior colliculus - waves VI and VII

These peaks occur in most readable form in response to click stimuli over a period of 1 - 10 milliseconds after the stimulus in normal hearing adults.

BERA is resistant to the effects of sleep, sedation, sleep and anesthesia. Its threshold has been found to be within 10dB as elicited by conventional audiometry.

3. AUTISM EMEDICINE

Approach ConsiderationsIndividual intensive interventions, including behavioral, educational, and psychological components, are the most effective treatments of autistic disorder. Beginning the treatment early in infancy increases the likelihood of a favorable outcome. Thus, regular screening of infants and toddlers for symptoms and signs of autistic disorder is crucial because it allows for early identification of these patients.

Individuals with autism spectrum disorder and unspecified pervasive developmental disorder typically benefit from behaviorally oriented therapeutic programs developed specifically for this population. Autistic children should be placed in these specialized programs as soon as the diagnosis is entertained.

Parents, teachers, pediatricians, and other health care providers are advised to seek the assistance of people who are familiar with early intervention programs for children with autistic disorder. The Autism Society can help parents to obtain appropriate referrals for optimal interventions.

Parents understandably become exhausted by the relentless performance of challenging behaviors by their child with autism. A specially trained educator or behavioral psychologist can help to teach them effective ways to modify these challenging behaviors. Parents also frequently benefit from temporary respite from the child.

The possible benefits from pharmacotherapy must be balanced against the likely adverse effects on a case-by-case basis. In particular, venlafaxine may increase high-intensity aggression in some adolescents with autism.[8]

Limited, largely anecdotal evidence suggests that dietary measures may be helpful in some children with autism. Avoidance of certain foods, notably those containing gluten or casein, and supplementation with specific vitamins and minerals have reportedly proved helpful in select cases.

The National Autism Center has initiated the National Standards Project, which has the goal of establishing a set of evidence-based standards for educational and behavioral interventions for children with autism spectrum disorders. The project has identified established, emerging, and unestablished treatments.

Special EducationSpecial education is central to the treatment of autistic disorder. Although parents may choose to use various experimental treatments, including medication, they should concurrently use intensive individual special education by an educator familiar with instructing children who have autistic disorder or a related condition. Intensive behavioral interventions, instituted as early as possible, are indicated for every child in whom autistic disorder is suspected[118, 119] .

The Education for All Handicapped Children Act of 1975 requires free and appropriate public education for all children, regardless of the extent and severity of their handicaps. Amendments to the Education of the Handicapped Act of 1986 extended the requirement for free and appropriate education to children aged 3-5 years.

Pediatricians and parents cannot assume, however, that their community’s school will provide satisfactory education for a child with autistic disorder or a related condition. The Individuals with Disabilities Education Act authorized states to determine how to provide educational services to children younger than 3 years. Pediatricians and parents need to determine the best way to proceed with local agencies.

Legal assistance may be necessary to influence a board of education to fund appropriate education for a child with autistic disorder or a related condition. TheAutism Society maintains a Web site and offers a toll-free hotline (1-800-3-AUTISM/1-800-328-8476). This resource provides information and referral services to the public.

Speech, Behavioral, Occupational, and Physical TherapiesTherapies that are reported to help some individuals with autism include the following:

Assisted communication - Using keyboards, letter boards, word boards, and other devices (eg, the Picture Exchange Communication System [120] ), with the assistance of a therapist

Auditory integration training - A procedure in which the individual listens to specially prepared sounds through headphones

Sensory integration therapy - A treatment for motor and sensory motor problems typically administered by occupational therapists

Exercise and physical therapy - Exercise is often therapeutic for individuals with autistic disorder; a regular program of activity prescribed by a physical therapist may be helpful

In addition, social skills training helps some children with autism spectrum disorder, including those with comorbid anxiety disorders.[7] Children with autism spectrum disorder and comorbid attention deficit hyperactivity disorder may not benefit from social skills training.[7]

In a 2-year randomized, controlled trial, children who received the Early Start Denver Model (ESDM), a comprehensive developmental behavioral intervention for improving outcomes of toddlers diagnosed with autism spectrum disorder, showed significant improvements in IQ, adaptive behavior, and autism diagnosis compared with children who received intervention commonly available in the community.[121]A follow-up electroencephalographic study showed normalized patterns of brain activity in the ESDM group.[122]

In contrast, a 12-week study of parent-delivered ESDM intervention found no effect on child outcomes compared with usual community treatment. However, starting intervention at an earlier age and providing a greater number of intervention hours both related to the degree of improvement in children's behavior.[123]

DietWhen compared with their typically developing (TD) peers, children with ASD are significantly more likely to experience GI problems and food allergies. According to one study, children with ASD were 6 to 8 times more likely to report frequent gas/bloating, constipation, diarrhea, and sensitivity to foods than TD children. Researchers also discovered a link between GI symptoms and maladaptive behavior in children with ASD. When these children had frequent GI symptoms, they showed worse irritability, social withdrawal, stereotypy, and hyperactivity scores compared with those without frequent symptoms. [124,

125]

Individuals with autistic disorder or a related condition need 3 well-balanced meals daily. Dietary consultation may be useful to evaluate the benefits of special diets, including those lacking gluten and casein. Vitamin B-6 and magnesium are among the vitamins and minerals hypothesized to help some patients.[126]

In a randomized, double-blind, placebo-controlled trial, 3 months of treatment with a vitamin/mineral supplement produced statistically significant improvement in the nutritional and metabolic status of children with autism. In addition, the supplement group had significantly greater improvements than did the placebo group in its Parental Global Impressions-Revised (PGI-R) Average Change scores.[127]

Pharmacologic TreatmentAlthough 70% of children with autism spectrum disorder receive medications, only limited evidence exists that the beneficial effects outweigh the adverse effects.[128]No pharmacologic agent is effective in the treatment of the core behavioral manifestations of autistic disorder, but drugs may be effective in treating associated behavioral problems and comorbid disorders.[129, 130]

The second-generation antipsychotic agents risperidone and aripiprazole provide beneficial effects on challenging and repetitive behaviors in children with autism spectrum disorder, although these patients may experience significant adverse effects.[131] Risperidone and aripiprazole have been approved by the US Food and Drug Administration (FDA) for irritability associated with autistic disorder. The second-generation antipsychotic agent ziprasidone may help to control aggression, irritability, and agitation.[132]

Serotonergic drugs are reportedly beneficial for improving behavior in autism. Hyperactivity often improves with methylphenidate therapy.

Additionally, treatments may be indicated for an underlying condition. For example, children with biotin-responsive infantile encephalopathy improve with the addition of biotin.

SSRIs

Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed for children with autism and related conditions. Beneficial effects on children and adolescents with autism and other pervasive developmental disorders have been reported with fluoxetine,[133] escitalopram,[134] and citalopram[135, 136] .

On the other hand, a multicenter, randomized, controlled trial by King and colleagues in 149 children with autism spectrum disorders found no difference between citalopram and placebo among children rated as much improved or very much improved. Participants in the treatment arm received liquid citalopram daily for 12 weeks at a mean maximum daily dose of 16.5 mg (maximum 20 mg). Nearly all the citalopram recipients reported adverse effects (eg, impulsiveness, hyperactivity, diarrhea).[137]

Serotonin syndrome

Children with autistic disorder are at risk of developing a serotonin syndrome when treated with serotonergic agents. Therefore, children who are treated with serotonergic agents should be evaluated at baseline before beginning treatment and then regularly evaluated for symptoms of a serotonin syndrome using the serotonin syndrome checklist. See the image below for a printable version.

Serotonin syndrome checklist.Adverse effects and treatment efficacy

Children with autistic disorder appear sensitive to medication and may experience serious adverse effects that outweigh any beneficial effects. For example, children may develop catatonia when treated with haloperidol and other traditional neuroleptics.[138, 139] Additionally, Kem et al noted priapism in an adolescent with autism who was treated with trazodone.[140]

Practice guidelines from the American Academy of Pediatrics stress the importance of having some quantifiable means of assessing the efficacy of medication used for the treatment of children with autism. Validated, treatment-sensitive rating scales that have been used in clinical practice to measure the effects of treatment on maladaptive behavior include the Clinical Global Impression Scale, the Aberrant Behavior Checklist, and the Nisonger Child Behavior Rating Form.[141]

Experimental ApproachesVarious interventions, including chiropractic manipulations, are reported to help with autistic disorder. The results of individual case reports, however, cannot be generalized to the overall autistic population; scientific research is needed to investigate whether treatments truly are generally helpful.

Secretin therapy

Several anecdotal reports suggested that secretin, a gastrointestinal hormone that may function as a neurotransmitter, was an effective intervention for the symptoms of autism. This led to several scientific studies of secretin for children with autism spectrum disorders.[142, 143, 144] However, 2 reviews of these trials failed to demonstrate that secretin had a beneficial effect on these children.[145, 146]

Hyperbaric oxygen therapy

Beneficial effects from hyperbaric oxygen therapy have been reported in 6 patients with autism. The risks of this procedure must be weighed against the benefits for individual patients. Controlled clinical trials and other studies are needed to confirm the potential value of this intervention.

Intranasal oxytocin

Research suggests that administration of a single intranasal dose of the hormone oxytocin increases activity in brain regions associated with reward, social perception, and emotional awareness and temporarily improves social information processing in children with autism spectrum disorder (ASD).[147, 148]

In the study of 17 high-functioning children and adolescents with ASD, brain centers associated with reward and emotion recognition responded more during social tasks when children received oxytocin instead of a placebo.

Although behavioral studies in children and adults suggest that a single dose of intranasal oxytocin improves social interaction and comprehension of affective speech, results from clinical trials examining the effect of daily administration of the drug have been mixed.