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Article by: Byrd, Robert Department of Pediatrics, University of California Davis Medical Center, Sacramento, California. Publication year: 2014 DOI: http://dx.doi.org/10.1036/1097-8542.062850 (http://dx.doi.org/10.1036/1097-8542.062850)

Content

Characteristics, diagnosis, and etiology Treatments Bibliography Epidemiology Long-term outcomes Additional Readings

A neurodevelopmental condition that impairs the way that a person relates to and communicates with other people. Persons with autism also can have unusual behaviors, such as insistence on sameness, obsessions, or stereotypic behaviors (for example, hand flapping, spinning, and toe walking). The condition varies greatly in the presenting symptoms, the timing of presentation, the range and severity of symptoms, and its association with other conditions. Although recognition of autism is increasingly more common, the cause of autism and the reason for its increase remain unknown. With intensive early intervention, significant improvements in a large percentage of children with autism can be achieved. See also: Developmental psychology (/content/developmental-psychology/189450); Nervous system (vertebrate) (/content /nervous-system-vertebrate/449300); Psychotherapy (/content/psychotherapy/555200)

Characteristics, diagnosis, and etiology

Autism is a spectrum disorder that also includes Asperger disorder, , childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified (PDD-NOS). Leo Kanner first described autism as a condition in 1943, but descriptions matching autism can be found throughout history. Based on his observation of 11 children, Kanner identified characteristic features of “early infantile autism” that are still considered essential in making an autism diagnosis. Three key features are (1) social impairments that affect how a person relates to other people, apparent early in life; (2) peculiar use of language—a failure to use language for interactive conversation; and (3) an “obsessive desire for the maintenance of sameness” associated with a “limitation in the variety of spontaneous activity.” Intelligence quotient (IQ) ranged from 50 to 70 in classic Kanner autism, but currently autism is recognized over a broader range of IQs. As recently as the late 1960s, autism was attributed to disturbed mother-child relationships. The term, “refrigerator mother,” represents a dark period in the history of autism, when misplaced blame was added to the anguish experienced by families with autistic children and delayed investigation into true causes. The recognition that 25% of children with autism developed seizures began the shift in thinking to the more current view that autism is a neurodevelopmental disorder with a biological basis.

Finding the cause (or causes) of autism remains elusive, despite many advances in our understanding of factors associated with autism. Evidence continues to point strongly to genetic factors, but no single genetic factor or metabolic pathway has been associated with the majority of autism cases. Still, twin studies demonstrate concordance rates of 82–92% in identical twins and 1–10% in fraternal twins. Families with one child with autism are 35 times more likely to have another child with autism when compared to previously unaffected families. Autism occurs three to four times more frequently in males than in females. Autism is associated with many single gene mutations (for example, FMR1 in Fragile X, TSC1 or TSC2 in tuberous sclerosis, MECP2 in Rett syndrome, NF1 in neurofibromatosis, and PTEN in macrocephaly/autism syndrome), with certain

1 of 7 7/26/2016 5:30 AM Autism - AccessScience from McGraw-Hill Education https://www.accessscience.com/content/autism/062850 chromosomal rearrangements (for example, maternal duplication of 15q11-q13 involving the same chromosomal region that causes Prader-Willi and Angelman syndromes; trisomy 21 in Down syndrome), and with a growing list of genetic variants associated with increased autism risk in the form of autism susceptibility genes and copy number variations. However, a specific genetic association can be found in only 10–20% of children with autism. See also: Developmental genetics (/content/developmental-genetics/189400); Human genetics (/content/human-genetics/324600); Mutation (/content /mutation/441200)

Autism often manifests after the first year of life, but many studies demonstrate prenatal and perinatal associations. Studies have found maternal antibrain antibodies in mothers of children with autism; these antibodies potentially could cross the placenta and alter fetal brain development. One study showed that 95% of a small sample of children with autism had elevated levels of four neuropeptides and neurotrophins in stored blood that was drawn for their newborn screen. In this study, elevated neurotrophin and neuropeptide levels were also found in children with mental retardation, but not in normal children or those with cerebral palsy. Specifically, the damage that occurs during pregnancy resulting in cerebral palsy does not produce the changes in blood spot data that were found in autism or mental retardation. Another study found that 42% of children with autism have posteriorly rotated ears (compared to 10% of children without autism), representing changes that occur in the first month of pregnancy. Other studies have shown differences in head size and brain structures. Head sizes of autistic children are on average normal at birth, and with age become larger than average. Specific brain structures are differentially affected. Some are larger than normal in autistic children, such as the and amygdala, and some are smaller, such as the cerebellar vermis. The way that nerve cells or neurons are organized in the brain is different in some children with autism. Neurons in the brain are organized in minicolumns, and studies have shown thinning of minicolumns in the frontal and temporal regions of autistic brains when compared to control (normal) brains. Developmental delays, including speech delays, are often apparent early in the course of children with autism. See also: Brain (/content/brain/093200); Mental retardation (/content/mental-retardation/415100)

Autism is currently diagnosed only through behavioral criteria. Typically, children with autism present with language delays, often first prompting a hearing assessment. Stereotypic behaviors, such as arm flapping, rocking, and spinning, usually develop later after communication and social impairments are apparent. About a third of parents of autistic children report regression of previously achieved milestones, and sometimes they attribute the loss of milestones to an identifiable stressor, such as the birth of a younger sibling or the receipt of a vaccination. Two-thirds of the children whose parents reported regression were noted to be developing normally on review of videotape taken around 12 months of age.

The advantages of early diagnosis are many and generally outweigh concerns about potential harm from “labeling” a child. Pauline Filipek and colleagues have authored a consensus statement on the assessment of children suspected of having autism. Developmental surveillance should occur at well-child visits. Developmental concerns about speech, language, or social development warrant further evaluation. First-level evaluations include audiological assessments, lead testing (if indicated by pica behaviors), and screening tests that are specific for autism [for example, CHAT (Checklist for Autism in Toddlers) or the Autism Screening Questionnaire]. Children who screen positive for autism should be referred for a multidisciplinary assessment, which should include a detailed health and developmental history and a physical exam that looks for identifiable conditions that have autistic features. The history and physical findings should determine the necessity for additional laboratory and imaging studies. The assessment should include additional interviews and observations that specifically assess for autism. A complete evaluation also includes additional developmental screening and speech and language assessment, occupational therapy assessment, behavioral assessment, and a social work assessment.

Other disorders (ASDs) retain many of the core features of autism. Deficits in communication and social interactions occur in , but to a lesser degree than autism. Significant delay in the onset or early course of language that is seen in autism is not seen in Asperger syndrome. Overall, affected children have a better facility with

2 of 7 7/26/2016 5:30 AM Autism - AccessScience from McGraw-Hill Education https://www.accessscience.com/content/autism/062850 language and more interest in social activities, but usually have autistic features, such as obsessive preoccupations. Rett disorder, primarily affecting females, has normal early development and then regression some time after five months. Girls with Rett syndrome typically carry a single gene marker, the MECP2 gene, and develop unsteady gait, loss or lack of language, constant hand-wringing and loss of functional use of their hands, social deficits, and mental retardation. Head sizes of affected children are on average normal at birth, but slowing of head growth during early development results in small head size. Childhood disintegrative disorder has normal development for 2–10 years and then severe regression, resulting in complete loss of speech, social interaction, and self-help skills. Recovery has been quite limited in these children. Children with PDD-NOS have some autistic features, including communication and social impairments and repetitive behaviors, but they do not meet the criteria for full syndrome autism and are not better described by one of the other ASDs.

Epidemiology

Autism prevalence estimates have steadily increased over the last few decades, from 4 to 5 per 10,000 prior to 1985, about 12 per 10,000 in studies from 1985 to 1994, and 16 to 40 per 10,000 in more recent studies. Some argue that this increase is created artificially by changes in diagnostic criteria, increased awareness, population increases, migration fluxes, earlier age at diagnosis, recording artifacts, and problems with cross-sectional data, but studies investigating these factors have not confirmed these suppositions.

Epidemiology of other ASDs is less well established. Some studies estimated Asperger syndrome as three to four times more common than autism. Based on a large population study conducted prior to the identification of the MECP2 gene, Rett syndrome was estimated to occur in about 1 in 23,000. Childhood disintegrative disorder is felt to be rare, or less than 5 per 10,000. PDD-NOS is believed to be more common that autism, but population estimates are hampered by lack of clarity in diagnostic criteria.

A 1999 California Department of Developmental Services (DDS) report showed that, from 1987 to 1998, autism cases in California's Regional Center System increased by 273%. A follow-up study released in 2002 that compared Regional Center patients who were born in 1983–1985 with those born in 1993–1995 concluded that the increase in autism cases was not a result of changes in diagnostic criteria, changes in misclassification of autism, or an influx of out-of-state autism cases. This study was limited by a low response rate, but separate studies of these California data concurred with the major findings. The California DDS issued a 2003 report that documents a 100% increase in autism caseload since 1999. One recent study of these data shows an increase in the cumulative incidence of autism with each successive birth year cohort. A 2009 report of findings from 11 monitoring sites across the United States, conducted by the Centers for Disease Control and Prevention (CDC), shows that these increases are not limited to California. There was a 57% increase in autism spectrum disorders among 8-year-olds from 2002 to 2006.

Absent of a clear cause for the majority of cases of autism and a reason to explain the observed increase in cases, many theories have sprung up. Fears about immunizations were increased by publication of a study that linked the MMR (measles, mumps, and rubella) vaccination to inflammatory changes in the gastrointestinal tract of 12 children with autism. This study was later retracted and many epidemiological studies refuted any population association between receipt of the MMR vaccine and development of autism. Vaccination fears were also focused on a vaccine preservative, thimerosal, which used to be found in a vaccine that was given to newborn infants. Subsequent epidemiologic studies failed to demonstrate an association, and new cases of autism have not decreased following the removal of this mercury-containing preservative from vaccines given to infants. Other theories include a bowel–brain connection that is altered by some potential insult (such as food allergies, antibiotic use, or immunizations), heavy metal exposure, other toxic exposures [for example, polychlorinated biphenyls (PCBs)], defective hepatic detoxification capacity, autoimmune disorder or an imbalance between T-cell response, and yeast overgrowth in the bowel. Some of these theories are interrelated, such as yeast overgrowth and antibiotic use, or

3 of 7 7/26/2016 5:30 AM Autism - AccessScience from McGraw-Hill Education https://www.accessscience.com/content/autism/062850 yeast overgrowth and a bowel–brain connection. The search for a cure or any improvement in their child's condition has led some families to unproven and potentially harmful inventions, which will likely continue until a cause and cure are found. See also: Vaccination (/content/vaccination/725200)

Recent epidemiologic studies have shown a variety of associations. Autism rates are increased among infants whose parents are of either advanced maternal age or paternal age. Increased autism rates have been found associated with mothers who, during early pregnancy, lived near sites containing organochlorine pesticides. Findings from these studies support theories that contribute to the development of autism. Epigenetics is the process by which changes in gene expression can occur without any change in the underlying DNA sequence. Environmental triggers can activate or deactivate genetic expression, and some genetic–environmental interactions could result in changes that lead to autism. Increased age of a parent increases the length of time that a person is exposed to potentially critical environmental triggers, which would explain the increase rates of autism among children with older parents. Likewise, exposures to chemicals such as pesticides may result in epigenetic changes that contribute to development of autism. More study is needed to determine the extent to which such factors contribute to autism.

Treatments

Early identification and early intervention with intensive behavioral programs are the cornerstone of effective treatment for autism. In the past, dismal expectations led to minimal intervention, resulting in dismal outcomes. Expectations improved when O. Ivar Lovaas showed that intensive early intervention could make significant differences for about half of the children enrolled. Subsequently, a number of programs have been developed.

The most well known of the behavioral approaches is as developed by Lovaas and involves breaking down complex skills and teaching each subskill through a series of highly adult-structured, massed teaching trials. Teaching trials are delivered typically in blocks during 20–40 h of training per week over the course of two or more years. They attempt to improve language and social functions, and to foster pre-academic skills. These programs reward mastery of individual small steps that, when combined, results in mastery of a larger task that hitherto was beyond that child's reach. The original studies showed 50% with significant improvement, but replication studies have failed to show such high positive effects. Other behavioral approaches include Responsive Teaching as well as the Developmental Individual-Difference, Relationship-Based (DIR) model (also referred to as ). No single intervention is guaranteed to help every child with autism, but all have their merits. The choice in programs is often dictated by program availability and funding. Even though early intensive interventions have been shown effective, many families have significant difficulties in obtaining services. There are no known medications that cure autism, but some are used to ameliorate some of the behaviors and to improve function of the child. Autism researchers and families of affected children hope that the identification of the cause for autism will lead to more effective treatments.

As more children with autism enter adolescence and adulthood, the need for treatment and supportive services often continues. The emphasis on behavioral interventions in early childhood shifts toward the use of medications in adolescence to treat an array of symptoms, including depression, anxiety, attention deficit hyperactivity disorder (ADHD), and behavioral problems. For those with high-functioning autism (and Asperger syndrome), social skills programs have helped remediate the deficits of social skills associated with autism. Sheltered workshops and day activity centers provide places for adults with autism whose level of function precludes further education or standard employment opportunities.

Long-term outcomes

A diagnosis of autism generally has lifelong implications. Outcomes in adults with autism reveal an overall poor prognosis for independent living and successful employment for the majority. Autistic adults with an IQ below 70 fair poorly, as might be

4 of 7 7/26/2016 5:30 AM Autism - AccessScience from McGraw-Hill Education https://www.accessscience.com/content/autism/062850 expected by the cognitive limitations alone. In a study of autistic adults with IQ scores of at least 50, among those with more normal intelligence (IQ greater than 70), only 17% achieved a high level of independence, having some friends and a job. Another 15% were working, but required some degree of support in daily living and had some friends or acquaintances. Compared to children currently diagnosed with autism, these adults were diagnosed much later (mean age at diagnosis was seven years) and these adults had fewer and less extensive therapeutic interventions. Studies of overall competence and language skills have demonstrated better outcomes for recently diagnosed individuals with autism. Continued advances in early diagnosis and development of effective treatments should further improve outcome for the increasing number of children diagnosed with autism.

Robert Byrd

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Additional Readings

S. E. Bryson and I. M. Smith, : Prevalence, associated characteristics, and implications for research and service delivery, MRDD Res. Rev., 4:97–103, 1998

R. J. Hagerman and R. L. Hendren, Shifting the paradigm for autism treatments, Neurotherapeutics, 7(3):230–231, 2010 DOI:

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P. Howlin et al., Adult outcome for children with autism, J. Child Psychol. Psychiatry, 45(2):212–229, 2004 DOI: 10.1111/j.1469-7610.2004.00215.x (http://dx.doi.org/10.1111/j.1469-7610.2004.00215.x)

J. L. Matson and P. Sturmey (eds.), International Handbook of Autism and Pervasive Developmental Disorders, Springer, New York, 2011

K. B. Nelson et al., Neuropeptides and neurotrophins in neonatal blood of children with autism or mental retardation, Ann. Neurol., 49(5):597–606, 2001 DOI: 10.1002/ana.1024 (http://dx.doi.org/10.1002/ana.1024)

C. Stoltenberg, Autism spectrum disorders: Is anything left for the environment?, Epidemiology, 22(4):489–490, 2011 DOI: 10.1097/EDE.0b013e31821d0b6d (http://dx.doi.org/10.1097/EDE.0b013e31821d0b6d)

Autism Speaks (http://www.autismspeaks.org)

Families for Early Autism Treatment (http://www.feat.org)

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