Autism

Author: James Robert Brasic, MD, MPH; Chief Editor: Caroly Pataki, MD

Background
Autism is a condition that manifests in early childhood and is characterized by qualitative abnormalities in social interactions, markedly aberrant communication skills, and restricted repetitive and stereotyped behaviors. Most individuals with autism also manifest mental retardation, typically moderate mental retardation with intelligence quotients (IQs) of approximately 35-50. Although children with autism are often difficult to evaluate with intelligence tests, three fourths of autistic children function in the mentally retarded range. Generally, the lower the IQ, the greater the likelihood of autism. However, the low functioning level hinders assessment for key characteristics of autism in individuals with profound mental retardation and IQs below approximately 20. A small portion of those with autism never develop spoken language. Thus, diagnostic instruments for autism may give spurious results in children with profound mental retardation. This article addresses autism in individuals with mental retardation. For information concerning individuals with autism spectrum disorders and related conditions without mental retardation, please see Asperger Syndrome and Pervasive Developmental Disorder. Seizure disorders are common in individuals with autism. Movement abnormalities are a prominent feature in a subset of individuals. Motion anomalies have been reported at birth in some individuals. Motion analysis may provide evidence of autism in early infancy before other manifestations occur.[1] Although autistic disorder was initially reported in children of high social class, subsequent research has established that autistic disorder equally afflicts all social classes. The motion anomalies demonstrated by children with autism are often highly characteristic. Children with autism who exhibit motion anomalies often stand out as odd because of the motions. An example of a motion typical in autism occurs when the child places a hand with fingers separately outstretched before the eyes and rapidly moves the hand back and forth. A similar experience results from moving up and down while gazing through the slats of Venetian blinds. This action is described as self-stimulation because it produces a visual sensation of movement. Many of the motions of children with autism appear to be attempts to provide sensory input to themselves in a barren environment. Through special education, children may learn to suppress the movements. The movements may then be exhibited at times of particular stress or excitement.

Although the etiology is unknown, hypotheses include genetic abnormalities; obstetric complications; exposure to toxic agents; and prenatal, perinatal, and postnatal infections (see Etiology).[2, 3, 4, 5] Maternal rubella is associated with significantly higher rates of autism and other conditions in children. Additionally, tuberous sclerosis is associated with autism as a comorbid disorder.[6] Approximately 10% of children with a pervasive developmental disorder exhibit a known medical condition. On the other hand, anecdotal reports that autism may be linked with vaccinations for measles, mumps, and rubella have not been confirmed.[7] Parents should be encouraged to fully immunize their children.[8] Effective treatment of associated behavioral problems includes intensive behavioral, educational, and psychological components. Interventions initiated at the time of diagnosis increase the likelihood of a favorable outcome (see Treatment).[9] Regular screening of infants and toddlers for symptoms and signs of autistic disorder is crucial because it allows for early referral of patients for further evaluation and treatment. The initial clinical descriptions of autism suggested that cold, rejecting parents ("refrigerator mothers") caused autism in offspring; however, careful study of children with autism and their parents has disproved this hypothesis. Autism is not caused by a lack of warmth and affection in parents, nor to any other emotional or psychological deficits in the parents. Blaming parents for the development of autism in their children is inappropriate. Several instruments have been developed to diagnose autism and other pervasive developmental disorders. To administer tools for the diagnosis of autism and related conditions in a reliable and valid manner, extensive training and experience is needed. Therefore, unless they have wide experience with children with autism and understand the concepts implicit in the diagnostic criteria and rating scales, pediatricians and other clinicians are advised to refer patients with possible autism to experienced clinicians for definitive diagnostic evaluations. One goal of this article is to convey fundamental concepts related to autism and related conditions. Readers of this article must obtain considerable additional training before they can reliably and validly apply diagnostic criteria and rating tools. Although psychoanalytic approaches to treatment of children with autism were common in the mid-20th century, these approaches were not found to be effective and are no longer used. Pharmacotherapy is ineffective in treating the core deficits of autism but may be effective in treating associated behavioral problems and comorbid disorders. The possible benefits from pharmacotherapy must be balanced against the likely adverse effects on a case-by-case basis (see Treatment). Key general references include the following:

Bettelheim B. The Empty Fortress: Infantile Autism and the Birth of the Self. New York, NY: The Free Press; 1977.

Cohen DJ, Volkmar FR. Handbook of Autism and Pervasive Developmental Disorders. New York, NY: Wiley; 1996. DeMyer MK. Parents and Children in Autism. Washington, DC: Winston; 1979. Filipek PA, Accardo PJ, Ashwal SL. Practice parameter: screening and diagnosis of autism: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Child Neurology Society. Neurology. 2000 August 22;55(4):468-479. Gillberg C, Coleman M. The Biology of the Autistic Syndromes, 3rd ed. London, England: Mac Keith Press. Clinics in Developmental Medicine Number 153/4; 2000. Harris JC. Developmental Neuropsychiatry: Fundamentals. Vol 1. Oxford, England: Oxford University Press; 1995. Harris JC. Developmental Neuropsychiatry: Assessment, Diagnosis, and Treatment. Vol 2. Oxford, England: Oxford University Press; 1995. Hollander E. Autism Spectrum Disorders. Volume 24 of the Medical Psychiatry Series. New York, NY: Marcel Dekker; 2003. Klin A, Volkmar FR, Sparrow SS. Asperger Syndrome. New York, NY: Guilford Publications, Inc; 2000. Lovaas OI. Behavioral treatment and normal educational and intellectual functioning in young autistic children. J Consult Clin Psychol. 1987 Feb;55(1):3-9. Schreibman L. Diagnostic features of autism. J Child Neurol. 1988;3(suppl)l:S57-S64.

Pathophysiology
In patients with autism, neuroanatomic and neuroimaging studies reveal abnormalities of cellular configurations in several regions of the brain, including the frontal and temporal lobes and the cerebellum. Enlargements of the amygdala and the hippocampus are common in childhood. Findings vary in each person. Hughes has observed the presence of underconnectivity in the brains of children with autism and related conditions.[10] Children with autism spectrum disorders on magnetic resonance imaging (MRI) demonstrate greater myelination in bilateral medial frontal cortices and less myelination in the left temporoparietal junction.[11] Postmortem specimens of the brains of people with autism demonstrated reductions for type B receptors for gamma-aminobutyric acid (GABAB) in the cingulate cortex, a key region for the evaluation of social relationships, emotions, and cognition, and in the fusiform gyrus, a crucial region to evaluate faces and facial expressions.[12] These findings provide the basis for further investigation of autism and other pervasive developmental disorders. Abnormalities in affiliative behaviors of other species, which are associated with dysfunction of serotonin and the neuropeptides, oxytocin, and vasopressin, suggest that there may be a neurophysiological dysfunction involving one or more of these substances in autism in humans. Elevations of whole blood serotonin occur in one third of patients. Increased levels are also reported in the parents and siblings of patients. Individuals with autistic disorder and their mothers show elevated levels of C-terminally directed beta-endorphin protein immunoreactivity.

The basis and importance of these findings is unknown. Test findings suggest that lowfunctioning children with autism may have impairment in the metabolism of phenolic amines. Therefore, symptoms of autistic disorder are possibly aggravated by the consumption of dairy products, chocolates, corn, sugar, apples, and bananas; however, no large population studies have confirmed this. Many individuals with autism and related conditions experienced untoward events in the prenatal and neonatal periods and during delivery. The possible role of obstetric complications in the pathogenesis of autism and related conditions is unclear.[2, 3, 4] Roberts and colleagues and Samson have reported an association between exposure to the organochlorine pesticides dicofol and endosulfan during the first trimester of pregnancy and the subsequent development of autism spectrum disorders in the child.[13, 14] Potential mothers can wisely be advised to avoid exposure to organochlorine pesticides. Some children have developed autism after immunizations, including inoculations for measles, mumps, and rubella. However, several population studies have demonstrated no association between childhood immunization and the development of autism and related conditions.[15, 16, 17] Thompson and colleagues detected no causal association between exposure to vaccines that contain thimerosal and neuropsychological deficits at age 7-10 years.[18] In fact, in early 2010, the Lancet retracted the 1998 article by Wakefield et al that originally linked autism with measles-mumps-rubella (MMR) vaccination, citing flaws in the study and 2 claims in the paper that were "proven to be false."[19] Parents can permit the recommended childhood immunizations without fear of causing autism and related conditions.[20] Many other hypotheses, such as folic acid supplementation in pregnancy, have been proposed as possible causes of autism. None has been established as a definite etiology of autism.

Etiology
Decades ago, researchers conjectured that infantile autism resulted from rejection of the infant by cold parents ("refrigerator mothers"). Careful family studies have disproved the hypothesis that the development of autistic disorder in children is due to faulty parenting. Communicating repeatedly to the parents of the autistic child that they are not responsible is important. The causes of autistic disorder are unknown. Hypotheses include obstetric complications, infection, genetics, and toxic exposures.[21, 22] Obstetric complications are associated with an increased risk of autistic disorder.[3, 4] Whether obstetric complications caused autistic disorder, or autism and obstetric complications resulted from another problem, is unclear. Exposure of the mother to selective serotoninreuptake inhibitors, particularly during the first trimester, may increase the risk of the development of autism spectrum disorders.[23]

An infectious basis for some cases of autistic disorder is suggested by the large number of children with autistic disorder born to women who were infected in the rubella epidemic. This finding supports the hypothesis that this infection triggers a vulnerability to develop autistic disorder in the fetus. Twin studies have demonstrated a moderate degree of genetic heritability for autism and autism spectrum disorders.[24, 25, 26] The environment shared by twins provides a substantial contribution to the heritability of autism and autism spectrum disorders.[26] Multiple family studies have suggested genetic components in many cases of autism.[27, 28, 29] For example, some asymptomatic first-degree relatives of some probands with autism have abnormalities in serotonin and other chemicals similar to the probands. However, a particular individual with autistic disorder may not exhibit familial traits seen in populations. Finding genetic bases for autism is a promising research goal. Factor analysis of datasets from the Autism Genome Project has suggested linkage of a joint attention factor with 11q23 and of a repetitive sensory-motor behavior factor with 19q13.[30] However, the clinical usefulness of the assessment of families of individuals with autism has not been established. While a third of monozygotic twins are concordant for autism, dizygotic twins are concordant for autism at rates of 4%[31] to 8%, which is comparable to siblings. A focused neurogenetic evaluation of children with autism spectrum disorders yields a genetic disorder in two fifths of the children.[32] For example, mutations in the gene SHANK3 are associated with autism spectrum disorders.[33] A mouse model of Rett syndrome, an autism spectrum disorder caused by mutations of the methyl-CpG binding protein 2 (MeCP2),[34] has demonstrated beneficial effects when treated with insulinlike growth factor 1 (IGF-1).[35] Fragile X syndrome, a condition associated with autism, can be identified through genetic testing.[36] Antagonists to metabotropic glutamate receptors can reverse the symptoms of mice with models of fragile X syndrome.[37] Autism[38] has been associated with tuberous sclerosis, a disorder with specific genetic mutations.[39] Exposures to toxins, chemicals, poisons, and other substances have been hypothesized to cause autism. Although anecdotal case reports suggest that such exposures may play a role in isolated cases of autistic disorder, a causative role for toxins in the development of autism in general has not been demonstrated. In certain parts of the world, exposure to specific toxins may influence local autism rates. For example, the high incidence of autism in portions of Japan has been hypothesized to be due to a toxic effect of fish. Although toxins may play a role in the development of isolated cases of autism in Japan, toxins have not been proved to be causative of autism in Japan in general. On the other hand, another possible explanation for the high rates of autism in Japan is the excellent training of Japanese clinicians. Low rates of autism in other countries may reflect the limited abilities of clinicians to diagnose autism.

The development of autism after immunization to measles, mumps, and rubella led to the hypothesis that autism was caused by immunization. Careful research has not demonstrated an association between immunization for measles, mumps, and rubella and the subsequent development of autism and related conditions in the general population. The rate of autism in children who receive immunizations does not appear to be increased. In fact, in early 2010, the Lancet retracted the 1998 article by Wakefield et al that originally linked autism with measles-mumps-rubella (MMR) vaccination, citing flaws in the study and 2 claims in the paper that were "proven to be false."[19] Parents can permit the recommended childhood immunizations without fear of causing autism and related conditions. Adherence to recommended immunization schedules, including immunization for measles, mumps, and rubella, is highly recommended.[20]

Epidemiology
Reported rates of autism spectrum disorder have been rising in many countries over the past 2 decades.[40, 41] It remains unclear how much of these data may represent an actual increase and how much reflect changes in diagnostic definitions and practices and increasing awareness among the general public as well as the medical profession.[42, 43, 44] Current epidemiological studies are needed to identify the incidence, prevalence, and distribution of autistic disorder.
United States statistics

Autism spectrum disorder is one of the most common childhood developmental disabilities. Autistic disorder and related conditions affect up to 10-20 individuals per 10,000 population.[45] Estimates of the prevalence of autism suggest that as many as 400,000 individuals in the United States have autism and related conditions. Epidemiological studies of relatively uncommon conditions such as autism spectrum disorders are expensive. A suitable strategy is the performance of multiple screenings on a population, each time identifying more likely subjects for detailed investigation. For example, a checklist such as the Autism Screening Checklist can be distributed to all parents and guardians of a target population. The Autism Screening Checklist identifies those children with characteristics of autism spectrum disorders. It differentiates children with autism spectrum disorders from children with psychoses other and schizophrenia. (See History).
International statistics

Autistic disorder and related conditions are estimated to affect up to 10-15 people per 10,000 population worldwide. Studies in Japan report much higher rates than in other countries.[46] Japanese investigators suggest that these findings reflect the careful evaluations performed by Japanese clinicians, which may identify cases that would be overlooked in other countries. Alternatively, autism may be more common in Japan because of gastrointestinal and other

infections transmitted through the ingestion of seafood and other aquatic food characteristic of Japan.
Sex- and age-related demographics

The male-to-female ratio is 3-4:1. Autistic disorder is most common in boys who have the 46,XY karyotype (ie, the normal male karyotype). In some studies, fragile X is reported in approximately one tenth of males with autistic disorder.[47, 48, 49, 50, 51, 52] Autistic disorder manifests in early childhood. By contemporary criteria, the absence of abnormalities in the first 30 months of life rules out autistic disorder. For information about individuals with later onset of symptoms consistent with autistic disorder, see the following articles:

Childhood Disintegration Disorder Rett Syndrome Asperger Syndrome Pervasive Developmental Disorder

Many parents report normal development in their child until age 2 years before noticing the deficits in social and communicative skills.
Comorbid disorders

Gastrointestinal disorders, particularly constipation and chronic diarrhea, are more common in children with autism spectrum disorders. The risk of gastrointestinal disorders increases with the severity of the symptoms of autism.[53]

Prognosis
The prognosis in patients with autism is highly correlated with their IQ. Low-functioning patients may never live independently; they typically need home or residential care for the rest of their lives. High-functioning patients may live independently, hold jobs successfully, and even marry and have children. High-functioning individuals with autistic disorder are similar to people with Asperger syndrome. Please refer to Asperger Syndrome for further information and to learn more about high-functioning autism. Remission is reported in anecdotal case reports.

Patient Education
Individualized, intensive behavioral and psychological interventions must be instituted immediately after diagnosis in order to attain the optimal outcome. Although controversy surrounds the appropriate form of special education, some evidence suggests that an

individual educational program must be developed by a special educator familiar with autistic disorder and related conditions. Because local boards of education may be ignorant about the needs of children with autistic disorder and related conditions, pediatricians and parents should seek advice from knowledgeable sources such as the Autism Society of America, which maintains a Web site and offers a toll-free hotline at 1-800-3-AUTISM, providing information and referral services to the public. Legal assistance may be necessary to influence a board of education to fund appropriate education for a child with autistic disorder and related conditions. Because deficits in language and communication are often major impediments to progress in educational, work, and personal settings, specialized communication devices and training are often helpful. Persons experienced in the needs and treatment of individuals with serious communication handicaps (ie, speech and language specialists) may help the patient to maximize communication skills. People with developmental disabilities, including Asperger syndrome, are vulnerable to sexual abuse. The most severely disabled are at highest risk for sexual abuse. For this reason, parents and caregivers must be alert to avoid situations inviting sexual abuse. Additionally, children with Asperger syndrome must be trained to recognize impending sexual abuse and to develop plans of action to abort possible sexual abuse.[54] For patient education information, see the Brain and Nervous System Center, as well as Autism and Asperger Syndrome.
Recommended reading resources for parents

Recommended readings for parents include the following:

Baron-Cohen S, Howlin P. Teaching Children with Autism to Mind-read: a Practical Guide for Teachers and Parents. New York, NY: Wiley; 1998 Cohen S. Targeting Autism. Berkeley, CA: University of California Press; 1998 Hart CA. A Parent's Guide to Autism. New York, NY: Pocket Books; 1993 Hollander E. Autism Spectrum Disorders. Volume 24 of the Medical Psychiatry Series. New York, NY: Marcel Dekker; 2003 Lovaas I. The Autistic Child: Language Development through Behavior Modification. New York, NY: Irvington Press; 1977 Powers M. Children with Autism: A Parents' Guide. Bethesda, Md: Woodbine House; 2000 Quill K. Teaching Children with Autism: Strategies to Enhance Communication and Socialization. Albany, NY: Delmar Publishers; 1995 Wing L. The Autistic Spectrum: A Parent's Guide to Understanding and Helping Your Child. London, England: Ulysses Press; 2001 Obtaining informed consent

People with autism are identified as a highly vulnerable population because of the presence of cognitive, social, and mental impairments. Regulatory agencies have expressed particular

concern that the rights of children with autistic disorder and related conditions be carefully protected. Some have suggested that parents may not be impartial guardians and that third parties be used instead of parents to provide informed consent for clinical and research purposes. However, parents are generally excellent advocates seeking the best for their children. Nevertheless, clinicians must take particular care to ensure that informed consent is obtained in order to prevent misinterpretations and eventual medicolegal problems. Except in emergencies, patients, parents, guardians, and surrogates must be aware of the diagnostic and treatment possibilities. They must provide permission for possible interventions. By recording on videotape the process of explaining to the parent the recommended procedures, in addition to the signing of written release forms, clinicians establish evidence of the informing process. Clinicians should videotape the process of verbally explaining the protocol and answering questions. Permission must be explicitly given to perform the procedure and cannot continue until the parents agree. Parents are asked to give permission to complete this protocol. The entire process is videotaped. Occasionally parents decline to give consent, and then the procedure must cease (see the video below).
Clinicians are advised to videotape the process of verbally explaining the protocol and answering questions. Permission must be explicitly given to perform the procedure and cannot continue until the parents agree. Parents are asked to give permission to complete this protocol. The entire process is videotaped. In this segment, the mother of a healthy, normal control child gives informed consent to participate as a volunteer in a research study of autism. Occasionally, parents decline to give consent, and the procedure must cease. An earlier version of this videotape is in the New York University Medical Library, New York, New York.

Autism Clinical Presentation

Author: James Robert Brasic, MD, MPH; Chief Editor: Caroly Pataki, MD

History
Behavioral and developmental features that suggest autism include the following:

Developmental regression Absence of protodeclarative pointing Abnormal reactions to environmental stimuli Abnormal social interactions Absence of symbolic play Improvement during fever

Developmental regression

From 13-48% of people with autism have apparently normal development until 15-30 months of age, when they lose verbal and nonverbal communication skills. These individuals may have an innate vulnerability to develop autism. This regression may be precipitated by a precipitant such as immune and toxic exposures.
Protodeclarative pointing

Protodeclarative pointing is the use of the index finger to indicate an item of interest to another person. Toddlers typically learn to use protodeclarative pointing to communicate their concern for an object to others. The absence of protodeclarative pointing is predictive of the later diagnosis of autism.[55, 56] The presence of protodeclarative pointing can be assessed by interview of the parent or caregiver. Screening questions include "Does your child ever use his or her index finger to point, to indicate interest in something?" A negative response to this question suggests the need for a specialized assessment for possible pervasive developmental disorder.
Environmental stimuli

In contrast to toddlers with delayed and normal development, toddlers with autism spectrum disorders are much more interested in geometric patterns. Toddlers who prefer dynamic geometric patterns to participating in physical activities such as dance merit referral for evaluation for possible autism spectrum disorders.[57] Parents of autistic children report unusual responses to environmental stimuli, including excessive reaction or an unexpected lack of reaction to sensory input. Certain sounds (eg, vacuum cleaners or motorcycles) may elicit incessant screaming. Playing a radio, phonograph, or television at a loud level may appear to produce hyperacusis, auditory stimulation of a painful magnitude. Sometimes parents must rearrange the family routine so that the child is absent during noisy housekeeping activities. Children with autistic disorder may also display exaggerated responses or rage to everyday sensory stimuli, such as bright lights or touching.
Social interactions

Individuals with autism may display a lack of appropriate interaction with family members. The video files below illustrate the apparent indifference of a boy with autistic disorder to the departure and return of his father and his brother.[58]
The examiner may attempt to establish a sequence of taking turns hitting a plate with a block. The examiner says, "My turn," and then taps the plate. The examiner gives the block to the subject and says, "Your turn." The subject may be physically assisted in the activity if the desired response does not occur. The following is a clinical example: A 7-year-old boy with autistic disorder took daily vitamins and no other medications at the time of assessment. The examiner attempted to elicit turn-

taking by hitting the plate with a block. The child repeatedly jumps and rotates. He exhibits nonfunctional play with the telephone. He tilts his head and peers out of the corner of his eye. He is interested in the feel of the stick. He exhibits quick hand movements with small toys. When his father and his brother leave the room, the child does not acknowledge their departure. When his father returns to the room, he does not run to greet him. He appears indifferent to the departure and the return of his father. He repeatedly touches the surface of the wooden block. He touches the surface of a furlike cloth. He also places this cloth to his mouth to feel the texture on his lips. He is also fascinated with a string of yarn. He moves the string of yarn up and down and back and forth. This is nonfunctional play with ordinary items. The following is a clinical example that continues the segment of prior video: A 7-year-old boy with autistic disorder took daily vitamins and no other medications at the time of assessment. He appears indifferent to the departure of his brother from the room. He also does not respond with a greeting when his brother returns. He appears interested in his nonfunctional play. He displays minimal acknowledgment of the departure and return of his brother. In particular, he does not respond to his brother's touching him on the shoulder to greet him. Instead, he demonstrates inappropriate friendliness with the psychologist who is evaluating the procedures. Although he never saw her before this assessment, he suddenly goes to her to kiss her.

Difficulties in social interactions are common. Children may have problems making friends and understanding the social intentions of other children. Instead, they may show attachments to objects not normally considered child oriented. Although children with autistic disorder may want to have friendships with other children, their actions may actually drive away other children. An absence of typical responses to pain and physical injury may also be noted. Rather than crying and running to a parent when cut or bruised, the child may display no change in behavior. Sometimes, parents do not realize that a child with autistic disorder is hurt until they observe the lesion. Parents often report that they need to ask the child if something is wrong when the child's mood changes, and may need to examine the child's body to detect injury. Isolation likely increases in adolescence and young adulthood. In the preceding year, the majority of a representative sample of 725 youths with autism had not gotten together with friends and had not talked to a friend on the telephone.[59]
Communication

Speech abnormalities are common. They take the form of language delays and deviations. Pronominal reversals are common, including saying "you" instead of "I."
Play

Baron-Cohen and colleagues have demonstrated that the absence of symbolic play in infants and toddlers is highly predictive of the later diagnosis of autism.[55, 56] Therefore, screening for the presence of symbolic play is a key component of the routine assessment of well babies. The absence of normal pretend play indicates the need for referral of specialized developmental assessment for autism and other developmental disabilities.

Odd play may take the form of interest in parts of objects instead of functional uses of the whole object. For example, a child with autistic disorder may enjoy repeatedly spinning a wheel of a car instead of moving the entire car on the ground in a functional manner. The nonfunctional play of a boy with autism is illustrated in the video files below.[58]
A 7-year-old boy with autistic disorder took daily vitamins and no other medications at the time of assessment. The examiner repeated movements of the telephone receiver and tapping on the telephone receiver initially exhibited by the subject. The examiner repeated the subject's actions several times in an attempt to elicit repetition of the movement by the subject. Instead, the subject does not acknowledge the presence of the examiner. He looks away from the examiner. He turns his back to the examiner. The subject spins by rotating on a central vertical axis in his body. He exhibits nonfunctional play with the telephone. He displays frequent finger wiggling and the other hand stereotypies. He frequently vocalizes indecipherable sounds and briefly rocks. He tilts his head and looks out of the corner of his eye for a few seconds. The examiner may attempt to establish a sequence of taking turns hitting a plate with a block. The examiner says, "My turn," and then taps the plate. The examiner gives the block to the subject and says, "Your turn." The subject may be physically assisted in the activity if the desired response does not occur. The following is a clinical example: A 7-year-old boy with autistic disorder took daily vitamins and no other medications at the time of assessment. The examiner attempted to elicit turntaking by hitting the plate with a block. The child repeatedly jumps and rotates. He exhibits nonfunctional play with the telephone. He tilts his head and peers out of the corner of his eye. He is interested in the feel of the stick. He exhibits quick hand movements with small toys. When his father and his brother leave the room, the child does not acknowledge their departure. When his father returns to the room, he does not run to greet him. He appears indifferent to the departure and the return of his father. He repeatedly touches the surface of the wooden block. He touches the surface of a furlike cloth. He also places this cloth to his mouth to feel the texture on his lips. He is also fascinated with a string of yarn. He moves the string of yarn up and down and back and forth. This is nonfunctional play with ordinary items. The following is a clinical example that continues the segment of prior video: A 7-year-old boy with autistic disorder took daily vitamins and no other medications at the time of assessment. He appears indifferent to the departure of his brother from the room. He also does not respond with a greeting when his brother returns. He appears interested in his nonfunctional play. He displays minimal acknowledgment of the departure and return of his brother. In particular, he does not respond to his brother's touching him on the shoulder to greet him. Instead, he demonstrates inappropriate friendliness with the psychologist who is evaluating the procedures. Although he never saw her before this assessment, he suddenly goes to her to kiss her.

Children with autistic disorder may enjoy repeatedly lining up objects or dropping objects from a particular height. Children may be fascinated with items that are not typical toys, such as pieces of string. They may enjoy hoarding rubber bands, paper clips, and pieces of paper. They may spend hours watching traffic lights, fans, and running water. Some parents report that they must lock the bathroom door to prevent the child from flushing the toilet all day long.
Response to febrile illnesses

During a febrile illness, children with autistic disorder may show a decrease in behavioral abnormalities that plague the parents when the child is well (eg, self-injurious behaviors,

aggression toward others, property destruction, temper tantrums, hyperactivity). A parent may say, "When he is suddenly an angel, I know that he has an ear infection." This inhibition of negative behaviors may occur with various febrile illnesses, including ear infections, upper respiratory tract infections, and childhood illnesses. The recovery of the child from the febrile illness may be accompanied by an abrupt return of the child's usual problematic behaviors.
Autism screening checklist

Having parents fill out an Autism Screening Checklist can identify children who merit further assessment for possible autism. See the image below for a printable version of the checklist.

Autism screening checklist.

The significance of answers to individual Autism Screening Checklist items is as follows:

Item 1- A "yes" occurs in healthy children and children with some pervasive developmental disorders; a "no" occurs in children with autism, Rett syndrome, and other developmental disorders Item 2 - A "yes" occurs in healthy children, not children with autism Item 3 - A "yes" occurs in healthy children and children with Asperger syndrome (ie, high-functioning autism); a "no" occurs in children with Rett syndrome; children with autism may elicit a yes or a "no"; some children with autism never speak; some children with autism may develop speech normally and then experience a regression with the loss of speech Item 4 - A "yes" occurs in healthy children and children with Asperger syndrome and some other pervasive developmental disorders; a "no" occurs in children with developmental disorders; children with autism may elicit a "yes" or a "no" Items 5-10 - Scores of "yes" occur in some children with autism and in children with other disorders Item 11 A "yes" occurs in healthy children; a "no" occurs in some children with autism and in children with other disorders Items 12, 13 - Scores of "yes" occur in some children with autism and in children with other disorders Items 14-19 - Scores of "yes" occur in children with schizophrenia and other disorders, not in children with autism, Asperger syndrome, or other autism spectrum disorders

The higher the total score for items 5-10, 12, and 13 on the Autism Screening Checklist, the more likely the presence of an autism spectrum disorder.

Physical Examination
Screening well babies for signs predictive of autistic disorder is important. Baron-Cohen and colleagues observed that abnormalities in gaze monitoring, protodeclarative pointing, and pretend play noted in toddlers during well-child visits in the United Kingdom was useful in predicting the later diagnosis of autistic disorder.[55, 56] Baron-Cohen and colleagues developed the Checklist for Autism in Toddlers (CHAT) to screen newborns and toddlers to rule out autism.[55, 56]

CHAT screening

Although the CHAT has been reported to identify infants and toddlers in Britain who develop autism, the reliability and the validity of the CHAT have not been confirmed by other investigators with other populations. The possible cultural biases of the CHAT limit its usefulness outside the United Kingdom. For example, while identifying the inability to engage in symbolic play is important in the diagnosis of autism, an item on the CHAT that addresses symbolic playpretending to pour tea from a toy teapot into a toy teacuphas cultural connotations that may not be relevant to children outside the United Kingdom. Because of its possible cultural biases, direct application of the full CHAT is not recommended. Additionally, the specificity and sensitivity of the CHAT remain to be ascertained in various cultures. The items of the CHAT that are highly correlated with the diagnosis of autistic disorder are recommended. This discussion is limited to those items. The absence of a normal response merits on the following items merits referral for specialized assessment to rule out autism and other developmental disabilities. In one item, the child is asked to pretend to drive a miniature car. Driving a car (unlike pouring tea) is important to most North American children; thus, it is a good screen for this population. The failure of a typical North American child to pretend to drive a miniature car constitutes a definite deficit in pretend play. Other make-believe play may be substituted based on cultural relevance. The child should respond appropriately to a pretend activity compared with most other children of the same culture. The assessment of normal gaze monitoring, suggested by Baron-Cohen and colleagues, is composed of the following steps: The clinician calls the child's name, points to a toy on the other side of the room, and says, "Oh look! There's a [name a toy]!"[55, 56] If the child looks across the room to look at the item indicated by the clinician, then a joint attention is established, indicating normal gaze monitoring. Baron-Cohen and colleagues established the following protocol to assess for the presence of protodeclarative pointing: Say to the child, Where's the light? or, Show me the light. A normal response is for the child to point with his or her index finger at the light while looking up at the clinician's face.[55, 56] If the child does not respond appropriately, the procedure may be repeated with a teddy bear or any other unreachable object.
Body movement

Some children with autistic disorder display choreoathetotic movements that resemble the movements seen in Sydenham chorea and other movement disorders. Stereotypies (patterned repetitive movements, postures, and utterances) constitute a common finding in many individuals with autistic disorder.

Common abnormal motor movements that occur in children with autism include hand flapping, a motion in which the upper extremity is rapidly raised and lowered using a flaccid wrist so that the hands flap like flags in the wind. Hand flapping typically occurs when the child is happy or excited. Hand flapping may occur in combination with movement of the entire body, such as bouncing (ie, jumping up and down) and rotating (ie, constantly spinning around a vertical axis in the midline of the body). Children with autistic disorder also often display motor tics and are unable to remain still. Because children with autistic disorder are often mentally retarded and nonverbal, expressing subjective experiences associated with the movement is often impossible for them. Thus, the diagnosis of akathisia cannot be applied in these cases, because this diagnosis requires the verbalization of a sensation of inner restlessness and an urge to move. In the absence of the ability to verbally describe subjective experiences, the high activity level and apparent lack of ability to remain still, resembling akathisia, has been termed pseudoakathisia.
Head features

Although the head circumference of children with autism may be small at birth, many children with autism experience a rapid increase in the rate of growth from 6 months to 2 years of age.[60] The head circumference is increased in a subgroup of approximately one fifth of the population of children with autistic disorder without known comorbid conditions.[61] Increased head circumference is more common in boys and is associated with poor adaptive behavior. The head circumference may return to normal in adolescence.[62]
Hand features

Aberrant palmar creases and other dermatoglyphic anomalies are more common in children with autistic disorder.
Rating procedures

Patients with autistic disorder merit a careful assessment of movements. The caregiver and clinicians may be asked to look for any motions in the mouth, face, hands, or feet of the patient and, if so, may be asked to describe them and how they bother the patient. The patient may be asked to sit on the chair with legs slightly apart, feet flat on the floor, and hands hanging supported between the legs or hanging over the knees. The patient may be asked to open his or her mouth and then twice to stick out the tongue. If the subject does not perform the requested action, the examiner then repeatedly performs the actions in the direct view of the subject to demonstrate the desired actions. For additional information about the rating of movement disorders, please see Tardive Dyskinesia. The patient may be asked to sit, stand, and lie on a sheet on the floor for 2 minutes in each position. The patient is asked to remain motionless in each posture. In each position, the patient is asked, "Do you have a sensation of inner restlessness?" and "Do you have the urge

to move?" These questions require an appropriate developmental level for a useful response. Therefore, most children with autism cannot respond appropriately. In the absence of a clear verbal response, the subjective items are not rated. Nevertheless, the objective behavior of the child can be observed and rated. For additional information about the rating of movement disorders, including the diagnosis of pseudoakathisia or probable objective akathisia, please see Tardive Dyskinesia.
Assessing stereotypies

Movements observed in individuals with autistic disorder are frequently classified as stereotypies (eg, purposeless, repetitive, patterned motions, postures, and sounds). Stereotypies are divided into the following 3 topological classes:

Oro-facial (eg, tongue, mouth, and facial movements; smelling; sniffing; and other sounds) Extremity (eg, hand, finger, toe, leg) Head and trunk (eg, rolling, tilting, or banging of the head; rocking the body

Stereotypies occur in nonautistic infants and children with mental retardation. Regularly assessing stereotypies is a valuable practice because stereotypies may bother other people and interfere with performance at school, work, and home. Routine assessment of stereotypies before, during, and after treatment is valuable in determining the effects of interventions. Stereotypies are assessed for clinical purposes through regular use of the Timed Stereotypies Rating Scale. For this procedure, the occurrence of stereotypies is noted during 30-second intervals over a 10-minute period. For additional information about the rating of stereotypies, please see Tardive Dyskinesia.
Self-injurious behaviors

A particularly serious form of stereotypy is self-injurious behavior. Self-injury may take the form of skin picking; self-biting; head punching and slapping; head-to-object and body-toobject banging; body punching and slapping; poking the eye, the anus, and other body parts; lip chewing; removal of hair and nails; and teeth banging. Self-injury can result in morbidity and mortality. For example, eye poking and head banging may cause retinal detachments resulting in blindness. Although only a minority of the population of children with autism manifest self-injury, they constitute some of the most challenging patients in developmental pediatrics.
Clinical examples

A 6-year-old boy with autistic disorder who is treated with 75 mg clomipramine (Anafranil) by mouth daily at bedtime exhibits nonstop stereotypies. He frequently peers out of the corner of his eye, tilting his head. He often twiddles his fingers, moving an action figure in a nonfunctional manner. He occasionally grimaces. He repeatedly touches the slits of the blinds at the corner of the window. He rubs his fingers on the blinds, the cabinet drawer, and the

chair. At 8:30 pm, he rocks briefly and utters indeterminable vocalizations. He may be falling asleep. A 7-year-old boy with autistic disorder took daily vitamins and no other medications at the time of assessment. The examiner repeated movements of the telephone receiver and tapping on the telephone receiver initially exhibited by the subject. The examiner repeated the subject's actions several times in an attempt to elicit repetition of the movement by the subject. Instead, the subject does not acknowledge the presence of the examiner. The subject spins by rotating on a central vertical axis in his body. He exhibits nonfunctional play with the telephone. He displays frequent finger wiggling and the other hand stereotypies. He frequently vocalizes indecipherable sounds and rocks briefly. The examiner may attempt to establish a sequence of taking turns hitting a plate with a block. The examiner says, "My turn," and then taps the plate. The examiner gives the block to the subject and says, "Your turn." The subject may be physically assisted in the activity if the desired response does not occur. The following is a clinical example: A 7-year-old boy with autistic disorder took daily vitamins and no other medications at the time of assessment. The examiner attempted to elicit turn-taking by hitting the plate with a block. The child repeatedly jumps and rotates. He exhibits nonfunctional play with the telephone. He tilts his head and peers out of the corner of his eye. He is interested in the feel of the stick. He exhibits quick hand movements with small toys.
Physical abuse

Children with autism and related conditions may persist incessantly with repetitive behaviors that annoy others, despite instructions to cease. Children with autism spectrum disorders typically do not respond to spanking and other forms of traditional discipline. Parents, teachers, and others may eventually lose control and inflict physical injury on the child. For this reason, children with autism spectrum disorders are at high risk for physical abuse; in addition, when physical abuse occurs, these children may not report it. Therefore, pediatricians and other healthcare providers must maintain a high level of suspicion for the possibility of physical abuse when assessing children with autism spectrum disorders and conduct regular careful physical examinations.
Sexual abuse

Unlike many other children with mental retardation, children with autistic disorder are typically physically normal in appearance, without dysmorphic features. They may be beautiful children and, thus, may attract the interest of those who are sexually aroused by children. Children with autism spectrum disorders may lack ability to communicate inappropriate sexual contact to responsible authorities. Thus, parents, teachers, healthcare providers, and others must maintain a high level of suspicion for the possibility of sexual abuse when assessing children with autism spectrum disorders. On physical examination, external examination of genitalia is appropriate. If bruises and other evidence of trauma are present, then pelvic and rectal examinations may be indicated.

Examination of siblings

Siblings of children with autism are at risk to develop traits of autism and even a full-blown diagnosis of autism. A tenth of the siblings of children with autism meet the diagnostic criteria for an autism spectrum disorder. An additional fifth of siblings of children with autism have delayed development of language.[63]
Proceed to Differential Diagnoses

Autism Differential Diagnoses

Author: James Robert Brasic, MD, MPH; Chief Editor: Caroly Pataki, MD

Diagnostic Considerations
A major problem in the public health of children with autism and other pervasive developmental disorders is the inconsistent diagnosis of autism. Criteria for the diagnosis of autism are included in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR[TM]) and the International Classification of Diseases, Ninth Revision, Clinical Modification, Fourth Edition.[64, 65] Although the criteria for autism and other pervasive developmental disorders differ between the DSM-IV-TR(TM) and the ICD-9-CM, they are both widely accepted and are used around the world by clinicians and researchers. A discussion of the differences in the criteria for autism and related conditions in the DSM-IVTR(TM) and the ICD-9-CM and other nomenclatures is beyond the scope of this article. The key point for pediatricians and other clinicians is that the criteria for autism and related conditions in the DSM-IV-TR(TM) and the ICD-9-CM are presented in an outline form without a discussion of the terms used. The DSM-IV-TR(TM) and the ICD-9-CM are poor textbooks of child development and child psychopathology; they do not fully describe the concepts incorporated in the criteria for autism and related conditions. Therefore, an inexperienced clinician is likely to incorrectly apply the criteria for autism and related conditions in the DSM-IV-TR(TM) and the ICD-9CM. To administer tools for the diagnosis of autism and related conditions in a reliable and valid manner, extensive training and experience is needed. Therefore, unless they have wide experience with children with autism and understand the concepts implicit in the diagnostic criteria and rating scales, pediatricians and other clinicians are advised to refer patients with possible autism to experienced clinicians for definitive diagnostic evaluations. Delayed diagnosis of autistic disorder and related conditions is a serious problem, because early initiation of treatment increases the likelihood of a favorable outcome. Many parents

report raising concerns to their pediatricians about the patient's development in the first months and years and hearing only that the child will outgrow it. Procedures are available for diagnostic screening by practicing pediatricians, including the Checklist for Autism in Toddlers (CHAT). The CHAT has been reported to identify autistic disorder in a British population, but its reliability and validity has not been demonstrated in other populations.[55, 56] Some items of the CHAT appear to have strong cultural biases that rule out the direct application of this instrument to populations outside the United Kingdom. However, the 3 items of the CHAT that are highly predictive of the development of autistic disorder (ie, protodeclarative pointing, gaze monitoring, pretend play) can be quickly assessed by clinicians during well-baby visits (see Clinical section for detailed descriptions of these items). Pediatricians can facilitate early diagnosis of autistic disorder and related conditions by performing a screening procedure at every visit, including well-baby check-ups, school examinations, and immunization appointments. Other disorders to consider in the differential diagnosis of autism are as follows:

44,XXX karyotype 47 chromosomes (7;20) balanced chromosomal translocation Angelman syndrome Deletion 1p35 Duplication of bands 15q11-13 Extra bisatellite marker chromosome Habit disorder Hydrocephalus, infantile Interstitial deletion of (17)(p11.2) Inv Dup (15)(pter->q13) Language disorder: mixed, phonology, receptive, or stuttering Long Y chromosome Minamata disease Moebius syndrome Nonketotic hyperglycinemia (NKH) Partial 6p trisomy Epilepsy Spasms, infantile Tourette disorder Trisomy 22

Differentials

Anxiety Disorder: Obsessive-Compulsive Disorder Anxiety Disorder: Trichotillomania Child Abuse & Neglect: Dissociative Identity Disorder Child Abuse & Neglect: Failure to Thrive Child Abuse & Neglect: Physical Abuse Child Abuse & Neglect: Reactive Attachment Disorder Cornelia De Lange Syndrome

Cri-du-chat Syndrome Fragile X Syndrome Toxicity, Lead

Approach Considerations
Several instruments have been developed to diagnose autism and other pervasive developmental disorders. To administer tools for the diagnosis of autism and related conditions in a reliable and valid manner, extensive training and experience is needed. Therefore, unless they have vast experience with children with autism and understand the concepts implicit in the diagnostic criteria and rating scales, pediatricians and other clinicians are advised to refer patients with possible autism to experienced clinicians for definitive diagnostic evaluations.

Blood Studies
Whole-blood serotonin is elevated in approximately one third of individuals with autistic disorder. Elevations of whole-blood serotonin occur in parents and siblings of individuals with autistic disorder. Serum biotinidase is reduced in some individuals with autistic disorder. Immunologic studies are helpful to identify abnormalities, such as decreased plasma concentrations of the C4B complement protein. Elevations of C-terminally directed beta-endorphin protein immunoreactivity is common in individuals with autistic disorder and their mothers. Oxidative stress may play a role in the pathogenesis and the pathophysiology of autism.[66] Compared with normal children, children with autism have decrements in the following[66] :

Plasma levels of cysteine, glutathione, and methionine The ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH) The ratio of reduced to oxidized glutathione

Some children with autism display hyperlacticacidemia[67] as well as evidence of mitochondrial disorders[67] including carnitine deficiency.[68]

Magnetic Resonance Imaging

MRI studies in patients with autism are inconsistent. However, typical findings include enlargement of the total brain, the total brain tissue, and the lateral and fourth ventricles, along with reductions in size of the midbrain, the medulla oblongata, the cerebellar hemispheres, and vermal lobules VI and VII.[69, 70] Although vermal hypoplasia is found in some individuals with autism, vermal hyperplasia is identified in others.[71]

The volume of the gray matter is bilaterally decreased in the amygdala, the precuneus, and the hippocampus of people with autism spectrum disorders. Adolescents with autism spectrum disorders showed greater decreases in the volume of the gray matter of the right precuneus than in adults. The volume of the gray matter in the middle-inferior frontal gyrus was slightly increased in people with autism spectrum disorders.[72] Imaging studies in patients with autistic disorder who exhibit head banging may show enlargement of the diploic space in the parietal and occipital bones, with loss of gray matter adjacent to the bony changes. These findings resemble those of professional boxers with encephalopathy (dementia pugilistica).
Diffusion tensor imaging

On MRI studies, diffusion tensor imaging can provide information about connections among different brain regions. Children with autism spectrum disorders demonstrated higher values for the apparent diffusion coefficient (ADC) in the whole frontal lobe as well as the long and short association fibers of the frontal lobe.[73] Children with autism and their healthy siblings demonstrate significant reductions in fractional anisotropy (FA) in the white matter of the frontal, parietal, and temporal lobes compared with control groups.[74] Alterations in FA in the white matter of the frontal, parietal, and temporal lobes suggest an inherited trait characteristic of a vulnerability to develop autism.

Computed Tomography
Results of CT studies of the head are inconsistent in patients with autistic disorder. However, they may reveal deficits, including enlargement of the ventricles, hydrocephalus, parenchymal lesions, and reduction in size of the caudate nucleus.

Positron Emission Tomography

Positron emission tomography (PET) reveals multiple deficits. No finding has characterized all people with autism and the results vary with each individual. With fluorine-18 fluoro-2-deoxyglucose, the anterior rectal gyrus is found larger on the left than the right in some patients, a finding opposite the asymmetry seen in typical individuals. Some individuals also exhibit an increased glucose metabolic rate in the right posterior calcarine cortex and a decreased glucose metabolic rate in the left posterior putamen and the left medial thalamus.[75] See PET Scanning in Autism Spectrum Disorders for further information, including the PET scan of the boy with autism in the video files posted throughout this article.

Single-Photon Emission Computed Tomography

Chiron et al found that the normal asymmetry of regional cerebral blood flow (ie, higher in the left hemisphere, in right-handed individuals), was lacking in some autistic patients. Tests of regional cerebral blood flow with 133 Xe revealed left-hemispheric dysfunction, especially in the cortical areas devoted to language and handedness.[76] Regional cerebral blood flow assessed with technetium-99m labeled to hexamethylpropyleneamine oxide (HMPAO), a lipophilic substance, in children with autistic disorder demonstrates variable anomalies including reductions in the vermis, the cerebellar hemispheres, the thalami, the basal ganglia, and the parietal and temporal lobes. These findings suggest that no single abnormality characterizes all individuals with autistic disorder. Biological classes may have specific types of regional cerebral blood flow dysfunction.

Electroencephalography
Electroencephalography rules out seizure disorder, acquired aphasia with convulsive disorder (Landau-Kleffner syndrome), biotin-responsive infantile encephalopathy, and related conditions. Consultation with an electroencephalographer may help determine appropriate procedures for individual cases. A single normal electroencephalogram does not rule out a paroxysmal abnormality, such as a seizure disorder. When a routine electroencephalogram does not reveal unequivocal evidence of a seizure disorder in a patient with a possible seizure disorder (eg, partial seizures with complex symptomatology), specialized procedures may help to clarify the diagnosis. Measurements of electroencephalographic activity after sleep deprivation and after stimulation with light, noise, and tactile sensations using nasopharyngeal leads and simultaneous video monitoring along with electroencephalogram may be helpful in such cases. Admission to a specialized unit for simultaneous 24-hour videotape monitoring of electroencephalography and movement of the patient for a few days of assessment may facilitate the establishment of or the exclusion of diagnosis of a paroxysmal disorder. See PET Scanning in Autism Spectrum Disorders for further information, including the electroencephalogram of the boy with autism in the video files posted within this article.[77]

Lead Testing
Children with lead poisoning may demonstrate neurobehavioral changes. Constipation, abdominal pain, and/or anorexia are common. Lead poisoning in children at risk should be ruled out through appropriate testing.

Psychophysiological Assessment
Psychophysiological assessment is indicated. Children are not likely to show the response habituation in respiratory period, electrodermal activity, and the vasoconstrictive peripheral

pulse amplitude response to repeatedly presented stimuli seen in typical children. Children with autism may demonstrate auditory overselectivity.

Polysomnography
Polysomnography may facilitate the diagnosis of treatable comorbid disorders. Most children with autism have sleep disturbances, including early morning awakening, frequent arousals, and fragmented sleep.[78] Additionally, children with autism often display prolonged sleep onset and abnormal sleep architecture. Polysomnography may be useful to identify sleep disorders. Polysomnography may also demonstrate seizure discharges.

Autism Treatment & Management

Approach Considerations
Individual 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 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 teach effective ways to modify these challenging behaviors. Parents 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. Adverse effects of interventions must be balanced against potential benefits. In particular, venlafaxine may increase high-intensity aggression in some adolescents with autism.[79]

Special Education
Special education is central to the treatment for 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 and related conditions. Intensive behavioral interventions, instituted as early as possible, are indicated for every child in whom autistic disorder is suspected. 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. These requirements for free appropriate public education apply even if the local public school lacks specialized programs. Pediatricians and parents cannot assume that the community school will provide satisfactory education for a child with autistic disorder and related conditions. 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 and related conditions. The Autism 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, Behavior, and Physical Therapies

Speech, behavior, and physical therapies that are reported to help some individuals with autism include the following:

Facilitated communication, using keyboards, letter boards, word boards, and other devices, 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 are reported to help some people with autistic disorder Social skills training helps some children with autism spectrum disorders, including those with comorbid anxiety disorders.[80] Children with autism spectrum disorders and comorbid attentiondeficit/hyperactivity disorder may not benefit from social skills training.[80]

Dietary Modification
Individuals with autistic disorder and related conditions need 3 well-balanced meals a day. 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 persons with autistic disorder and related conditions.

Physical Activity
Exercise is often therapeutic for individuals with autistic disorder. A regular program of activity prescribed by a physical therapist may be helpful.

Specialist Resources
Children with autism and related conditions typically benefit from intensive, thorough evaluations performed by experienced professionals. Intensive diagnostic evaluation and treatment are accomplished quickly and effectively by well-trained clinicians at well-staffed centers. Valuable resources are listed below. Division of Developmental and Behavioral Pediatrics Pediatric Ambulatory Center University of Maryland Medical Center 700 West Lombard St Baltimore, MD Phone: 410-328-5437 Developmental Disabilities Clinic Child Study Center Yale University School of Medicine 230 South Frontage Rd PO Box 207900 New Haven, CT 06520-7900 Phone: 203-785-2510 (For appointments, call 203-785-2874.) Fax: 203-737-4197 Developmental Disorders Clinic The Harris Center for Developmental Studies Section of Child and Adolescent Psychiatry

Department of Psychiatry The University of Chicago 5841 South Maryland Ave MC3077 Chicago, IL 60637 Seaver Autism Research Center Department of Psychiatry Mount Sinai School of Medicine, Box 1230 One Gustave L Levy Place New York, NY 10029-6574 Phone: 212-241-2994 Bellevue Hospital Center 462 First Ave New York, NY 10016-9103 Phone: 212-562-4504 Center for Autism and Related Disorders Kennedy Krieger Institute Pierce Building, Third Floor 3825 Greenspring Avenue Baltimore, MD 21211 Phone: 410-404-6252 Fax: 443-923-7695 Division of Child Psychiatry New York State Psychiatric Institute, Room 2521

722 West 168th St New York, NY 10032 Phone: 212-543-5280, 212-543-6782, 212-579-5557 Fax: 212-543-5966 Division of Child and Adolescent Psychiatry Department of Psychiatry University of California at Los Angeles 760 Westwood Plaza, Room 48-270 Los Angeles, CA 90095 Phone: 310-825-0470 Fax: 310-206-4446 Medical Investigation of Neurodevelopmental Disorders (MIND) Institute University of California Davis Medical Center 4860 Y Street, Room 3020 Sacramento, CA 95817 Phone (toll-free): 888-883-0961 Phone: 916-734-5153 Strong Center for Developmental Disabilities Department of Pediatrics Children's Hospital at Strong University of Rochester Medical Center 601 Elmwood Ave Rochester, NY 14642

Phone: 716-275-2100

Pharmacologic Treatment
Although 70% of children with autism spectrum disorders receive medications, scant evidence exists that the beneficial effects outweigh the adverse effects.[81] 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. Although children with autism spectrum disorders may experience significant adverse effects, risperidone and aripiprazole provide beneficial effects on challenging and repetitive behaviors.[82] Serotonergic drugs and opioid antagonists, including naltrexone, are reportedly beneficial for this purpose. Ziprasidone may help to control aggression, irritability, and agitation.[83] Risperidone and aripiprazole have been approved by the FDA for irritability associated with autistic disorder. Hyperactivity often improves with methylphenidate therapy. Additionally, treatments are indicated for the underlying condition. For example, children with biotin-responsive infantile encephalopathy improve with the addition of biotin. 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,[84] escitalopram,[85] and citalopram[86, 87] . 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).[88] Multiple controlled randomized clinical trials have failed to demonstrate a beneficial effect of secretin for children with autism spectrum disorders.[89] Children with autistic disorder are at risk to develop 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.

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. Additionally, Kem et al noted priapism in an adolescent with autism who was treated with trazodone.[90]

Experimental Approaches
Various interventions, including chiropractic manipulations, are reported to help with autistic disorder. The results of individual case reports cannot be generalized to the overall autistic population. However, scientific research is needed to investigate whether treatments are generally helpful.
Secretin therapy

Secretin, which is supplied by the Repligen Corporation, is an experimental agent being studied for the treatment of autism.[91, 92, 93] Several anecdotal reports suggested that secretin helps some children with autism; however, 6 controlled clinical trials of secretin have demonstrated no effect. The study of secretin for autism is continuing.
Hyperbaric oxygen therapy

Beneficial effects of 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.

Research Studies and Clinical Trials

In New York, New York, Abigail Connolly is investigating connections among pragmatic language and behavioral needs of children with autism spectrum disorders, maternal stress, and family functioning. Further information may be obtained from her at ConnollyCUNY@aol.com. Trials sponsored by the National Institutes of Health are listed at http://clinicaltrials.gov. Research studies at the intramural program of the National Institute of Mental Health (NIMH) are listed at http://intramural.nimh.nih.gov/pdn/. The NIMH can be reached by telephone at 301-435-7962. Clinical trials for fragile X syndrome are listed at http://www.fraxa.org/ra_Paribello.aspx.

Consultations
Neuropsychological consultation can be helpful to assess intelligence. Deficits in simple and complex problem-solving tasks, both verbal and nonverbal, are likely to be demonstrated on the Wisconsin Card Sorting Test, the Trail Making Test, and the Stanford-Binet Intelligence Test. Metabolic consultation may help identify any deficiencies.

Immunologic consultation may be useful to rule out immune abnormalities. The possible benefits must be weighed against the risks of experimental treatments such as intravenous (IV) immunoglobulin therapy. Otolaryngologic consultation may be indicated to rule out deficits in the auditory apparatus. Additionally, audiography is indicated to rule out hearing deficits. Ophthalmologic consultation may be indicated to rule out a treatable visual deficit. Special lenses are reported to help some individuals with autistic disorder. Neurologic consultation with a movement disorder specialist is indicated to evaluate tics and other movement disorders when present. Infectious disease consultation may be helpful to rule out bacterial or fungal infections.

Autism Medication
Medication Summary
The established therapies for autistic disorder are nonpharmacologic. These therapies may include behavioral, educational, and psychological treatment. No pharmacologic agent is effective in the treatment of the core behavioral manifestations of autistic disorder. However, medication may be effective in the treatment of comorbid disorders, including self-injurious behaviors and movement disorders.

Antipsychotic agents
Class Summary

Risperidone and aripiprazole were recently approved by the US Food and Drug Administration for irritability associated with autistic disorders.
View full drug information Risperidone (Risperdal, Risperdal M-Tab)

Risperidone is an atypical antipsychotic agent that is indicated for irritability associated with autistic disorder in children and adolescents aged 5-16 years. Risperidone binds to the dopamine D2-receptor and has 20 times lower affinity than typical antipsychotics for the 5-

HT2-receptor. Risperidone improves negative symptoms of psychoses. The incidence of extrapyramidal adverse effects is lower with risperidone than with conventional antipsychotics.
View full drug information Aripiprazole (Abilify, Abilify Discmelt)

Aripiprazole is indicated for irritability associated with autistic disorder in children and adolescents aged 6-17 years. Aripiprazole is thought to be a partial dopamine (D2) and serotonin (5HT1A) agonist, and to antagonize serotonin (5HT2A). This agent is indicated for irritability associated with autistic disorders. No QTc interval prolongation was noted in clinical trials. Aripiprazole is available as a tablet, orally disintegrating tablet, or oral solution.
View full drug information Ziprasidone (Geodon)

This agent is used off-label. It antagonizes dopamine D2, D3, 5-HT2A, 5-HT2C, 5-HT1A, 5HT1D, alpha1-adrenergic and has a moderate antagonistic effect for histamine H1. It moderately inhibits the reuptake of serotonin and norepinephrine. This agent is used to treat serious behavior disorders, like self-injurious behavior.

Antidepressants
Class Summary

Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed for children with autism and related conditions.These agents help with intractable repetitive behaviors like compulsion and are used off-label. Dose-dependent QT prolongation has been reported with citalopram.[94,
95]

View full drug information Fluoxetine (Prozac)

Fluoxetine selectively inhibits presynaptic serotonin reuptake, with minimal or no effect in the reuptake of norepinephrine or dopamine.
View full drug information Citalopram (Celexa)

Citalopram enhances serotonin activity by selective reuptake inhibition at the neuronal membrane. Contraindicated in congenital long QT syndrome.

View full drug information

Escitalopram (Lexapro)

This agent is a selective serotonin reuptake inhibitor (SSRI) and S-enantiomer of citalopram. It is used for the treatment of depression. The mechanism of action is thought to be potentiation of serotonergic activity in the CNS, resulting from the inhibition of CNS neuronal reuptake of serotonin.