Autistic disorder Autism is a neurodevelopmental disorder of unknown etiology, but with a strong genetic basis.

It develops and is typically diagnosed before 36 mo of age. It is characterized by a behavioral phenotype that includes qualitative impairment in the areas of language development or communication skills, social interactions and reciprocity, and imagination and play (Table 29-2). CLINICAL FEATURES. Autism is a neurodevelopmental disorder in which the clinical presentation can vary with the severity of the impairment. Despite the variability in the clinical pattern, all children with autism manifest some degree of impairment in the areas of reciprocal social interaction, communication, and restrictive and repetitive stereotypical patterns of behavior, interests, or activities. Although there is no pathognomonic symptom or behavior seen in all children with autism, most children have some impairment in joint attention or pretend play. Joint attention is the ability to use eye contact and pointing for the purposes of sharing experiences with others. It is a skill that typically develops by 18 mo. Other precursor skills to joint attention that are often absent in children with autism are protoimperative pointing (the use of pointing to obtain an object of desire) and protodeclarative pointing (the use of pointing to an object of interest simply to have another share in the interest with him or her). The symptoms of autism can vary in the severity of their presentation.
Some children with autism may make no eye contact and seem totally aloof, whereas others may show intermittent engagement with their environment and may make inconsistent eye contact, smile, and hug. These social behaviors often come on the child's own terms, and are difficult to e l ~ c f~rot m another person. Children with autism ma! also present w ~ t hv arying verbal abilities. They can range from being nonverbal to having advanced speech, capable of ~n~i t a t insgo ngs, rhymes, or television commercials. What is mosr notable In children with autism is the quality of their speech and language. The speech may have an odd prosody or intonation and may be characterized by echolalia, pronoun reversal, nonsense rhyming, and other idiosyncratic language forms. Intellectual functioning can vary from mental retardation to superior intellectual funct~oningin select areas. Some children with autism show typical development in certain skills and may even show areas of strength in speclfic areas, such as puzzles, art, or music. Play skills in children with autism are typically aberrant, characterized by little symbolic play, ritualistic rigidity, and preoccupation with parts of objects. Stereotypical body movements, a marked need for sameness, and a very narrow range of interests are also common. The autistic child is often withdrawn and spends hours in solitary play. Ritualistic behavior prevails, reflecting the child's need to maintain a consistent, predictable environment. Tantrum-like rages may accompany disruptions of routine. Eve contact is typically minimal or absent. Visual scanning of hand and finger movements, mouthing of objects, and rubb~ngo f surfaces may indicate a heightened awareness of and sensitivity to some stimuli, whereas diminished responses to pain and lack of startle responses to sudden loud noises reflect lowered sensitivity to other stimuli. EPIDEMIOLOGY. The prevalence rate of all pervasive developmental disorders appears to be 58.7 per 10,000 children. This prevalence rate includes autism (22/10,000), Asperger syndrome (11110,000), Pervasive Developmental Disorder not otherwise specified (24.8/10,000), and child disintegrative disorder

(0.9/10,000). This is consistent with previous research that identified the prevalence of all pervasive developmental disorders as 60110,000. The incidence of the d autism may have of i increased. There is evidence that the increase in the number of children identified with autism is likely related to changes in the definition of and diagnostic criteria for autism, as well as improvements in the recognition of autism at younger ages. An increase in the availability of diagnostic services, treatment facilities, and professionals trained in childhood development disorders has greatly increased the capacity of the health care system to identify and treat children with autistic spectrum disorders at younger ages. ETIOLOGY. The exact cause of autism is unknown, but is believed to be multifactorial, with a strong genetic influence. There is a 60-90% concordance rate for monozygotic twins and a 0% concordance rate for dizygotic twins. There is a 92% concordance rate for monozygotic twins and a 30% concordance rate for dizygotic twins for the broader spectrum of social and communication difficulties. The genetic component of autism is believed to

be heterogeneous, attributed to as many as 100 genes, and genetic abnormalities in autism have been identified in mitochondria1 genes and in all chromosomes except 14 and 20. It is believed that multiple genes interact with varied environmental causes to produce the disorder, and that the causative genes may vary from one population to another. Because of the complex heterogeneity and the variable behavioral phenotype of autism, linkage studies have not identified specific chromosomal regions that are universally believed to harbor the genes causing autism. Compared with other disorders of a similar behavioral phenotype, certain genes are believed to be more strongly implicated in the heritability of autism, including chromosome 7q (seen in the similar behavioral phenotype of specific language impairment disorder), chromosome 2q, and chromosome 15qll-13 (seen in Prader-Willi syndrome [see Chapter 1081 and Angelman syndrome [see Chapter 811, both of which manifest traits of rigidity and stereotypical behaviors). Autism and Asperger disorder are 4 and 8 times more prevalent in males than in females, respectively, suggesting a strong X-linked component. Autism has also been linked with other neurodevelopmental disorders, including seizure disorder, fragile X syndrome (see Chapter 81), and tuberous sclerosis (see Chapter 596.2). Various environmental factors have been explored as causative agents in autism. Despite previously held notions, autism is not associated with certain emotionally distant parenting styles ("refrigerator mothers"). Many excellent epidemiologic studies have established that there is no association between the administration of the measles-mumps-rubella vaccine and the development of autism. NEUROANATOMIC FINDINGS. The first 2 yr of life are crucial in early brain development, and this period is characterized by tremendous neuronal and axonal growth, synapse formation, and myelination. Retrospective analysis of head circumference in children with autism, in conjunction with MRI studies, has shown differences in the brain structure of children with autism compared with children without autism. The head circumference of children with autism is normal or slightly smaller than normal at birth until 2 mo of age. Longitudinal studies of children with autism showed an abnormally rapid increase in head circumference from 6-14 mo of age, which was largely concluded by the end of the 2nd yr of life. MRI studies done at 2-4 yr of age show

that autistic toddlers have increased brain volume characterized by increased volume of the cerebellum, cerebrum, and amygdala compared with normal volumes. The abnormal growth in the first 2 yr is most marked in the frontal, temporal, cerebellar, and limbic regions of the brain, the areas of the brain responsible for higher-order cognitive, language, emotional, and social functions, which are most impaired in autism. It is believed that the early abnormal growth processes in the brain in the first 2 yr of life underlie the emergence of preclinical behavioral abnormalities seen in autism. This period of early, accelerated brain growth appears to stop early in childhood and is followed by abnormally slow or arrested growth, resulting in areas of underdeveloped and abnormal circuitry in parts of the brain. It is hypothesized that the postnatal growth of the brain is in response to adverse prenatal events; this association remains speculative. Additional studies of neuroanatomy in children with autism have demonstrated anatomic changes in the anterior cingulate gyrus, an area of the brain associated with decision-making and the ascription of feelings and thoughts. Deficits in the reticular activating system, structural cerebellar changes, forebrain hippocampal lesions, and neuroradiologic abnormalities in the prefrontal and temporal lobe areas have been documented, and abnormal neurochemical findings have also been associated with autism; in addition, the dopamine, catecholamine, and serotonin levels or pathways have been implicated. DIAGNOSIS. Aberrant social skill development is the hallmark of autism spectrum disorders (ASDs), and early social skill deficits may include abnormal eye contact, failure to orient to name, failure to use gestures to point or show, a lack of interactive play, failure to smile, lack of sharing, and lack of interest in other children. Combined language and social delays and regression in language or social milestones are important early red flags for an ASD, and should prompt an immediate evaluation. Early signs include unusual use of language or loss of language skills, nonfunctional rituals, inability to adapt to new settings, lack of imitation, and absence of imaginary play. Retrospective analysis of home videos shows that deviations in social and emotional development, such as decreased eye contact, failure to orient to name, and lack of joint attention, are often detected by 1 yr of age. The absence of expected social, communication, and play behaviors often precedes the emergence of odd or stereotypical behaviors or the unusual language usage that is seen in autism in the later years. Several screening tools have been developed to aid in the early detection of children with ASDs. The Checklist for Autism in Toddlers (CHAT) is a screening tool designed for use with 18 mo old children in primary care settings. The CHAT combines parent responses to a brief interview with direct observation in the clinic setting. Although its positive predictive value was high, it showed low sensitivity. The Modified Checklist for Autism in Toddlers (M-CHAT) is a 23-item parent questionnaire modified from the CHAT. It has shown good sensitivity and specificity (0.87% and 0.99%, respectively), which suggests its utility as a screening tool. The Pervasive Developmental Disorders Screening Test (PDDST) is a parent-completed survey that targets children from birth-3 yr of age and incorporates a 3-tiered approach: 1 for the primary care clinic, 1 for the developmental clinic, and 1 for the multidisciplinary autism clinic. All 3 tiers contain items that measure

various aspects of language, social skills, pretend play, attachment, sensory responses, and motor stereotypies. In children with ASDs, intelligence, as measured by conventional psychologic testing, usually falls in the functionally retarded range; the deficits in language and socialization make it difficult to obtain an accurate estimate of the autistic child's intellectual potential. Some autistic children perform adequately in nonverbal tests, and those with developed speech may show adequate intellectual capacity. Autistic children also show deficits in their understanding of what the other person might be feeling or thinking, a so-called lack of a theory of mind. On some psychologic tests, children with autism pay more attention to specific details while overlooking the entire gestalt of the object, demonstrating a lack of central coherence. A comprehensive evaluation should always include a thorough physical examination, with special attention paid to head circumference. Twenty-five percent of children with an ASD can have macrocephaly, but enlarged head size may not be apparent until after the 2nd yr of life. In the absence of dysmorphic features or focal neurologic signs, additional neuroimaging for investigation of the macrocephaly is not usually indicated. The presence of other physical stigmata should be noted, and examination of the skin with a Wood lamp should be performed to look for hypopigmented lesions that can be seen in tuberous sclerosis. Special attention should be paid to identify the dysmorphic features of fragile X syndrome (long face, large ears, large testes) and Angelman syndrome (ataxic gait, broad mouth). An audiologic evaluation and a comprehensive speech and language evaluation should be undertaken in any child with language delays. The lead level should be checked if the child shows signs of pica or lives in a high-risk environment. Chromosomal analysis should be performed if the child has evidence of mental retardation and dysmorphic features; an electroencephalogram should be performed in children with ASDs who have symptoms of developmental regression or suspicion of seizures. TREATMENT. There is compelling evidence that intensive behavioral therapy, beginning before 3 yr of age and targeted toward speech and language development, is successful in improving both language capacity and later social functioning. Controlled studies of early intensive interventions involving 40 hrlwk of intensive 1:l behavioral training (applied behavioral analysis) with young children for 2 yr have shown significant cognitive and behavioral gains. The training method focuses on the acquisition of compliance behavior, imitation activities, language acquisition, and integration with peers. Treatment is most successful when geared toward the individual's particular behavior patterns and language function. Parent education, training, and support are always indicated, and pharmacotherapy for certain target symptoms may be helpful. Working with the family of an autistic child is vital to the child's overall care. Children with autism require alternate educational approaches, even when language capacity is near normal. Such services in general have not yet been sufficiently developed to provide adequate support and continuity of care. One successful educational model is the program for the Treatment and Education of Autistic and Related Communication Handicapped Children (TEACCH). The following treatment principles are emphasized: use of objective measures, such as the Childhood

Autism Rating Scale (CARS), to measure behavior and behavioral change; enhancement of skills and acceptance by the environment of autism-related deficits; use of interventions based on cognitive and behavioral theories; use of visual structures for optimal education; and multidisciplinary training for all professionals working with autistic children. Educational programming should begin as early as possible, preferably by age 2-4 yr. Older children and adolescents with relatively higher intelligence, but with poor social skills and psychiatric symptoms (depression, anxiety, obsessive-compulsive disorder) may require psychotherapy, behavioral or cognitive behavioral therapy, and pharmacotherapy. Typically, behavior modification is a major part of the overall treatment for older children with autism. These procedures include enhancement (rewards emphasizing appropriate choice) and reduction (extinction, time-out, punishment). Ethical concerns about vigorous aversive therapy approaches have led to specific guidelines. Social skill training is also currently used as a treatment modality, and it appears effective, especially in a group format. Unfortunately, there are unfounded claims of beneficial results from many unproven therapies for autism, almost all of which have not been subjected to scientific study. Those studies that have been done have discredited the technique of facilitated communication and have shown that auditory integration therapy has no positive effect. Claims of beneficial results from the use of secretin, a peptide hormone that stimulates pancreatic secretion, have not been substantiated. Similarly, the dietary supplement N,N-dimethylglycine has no benefit. Because a subgroup of autistic children presents with psychiatric symptoms, p h a rma ~ o t h e r a ~isy s ometimes used to ameliorate target behaviors. The behaviors include hyperactivity, tantrums, physical aggression, self-injurious behavior, stereotypies, and anxiety symptoms, especially obsessive-compulsive behaviors. The older neuroleptics were limited in their usefulness because of their tendency to produce extrapyramidal symptoms and tardive dyskinesia. Open-label trials of atypical neuroleptics (risperidone, olanzapine) have shown effectiveness in treating these behaviors, and in some instances, have also improved social relatedness (see Chapter 20.1). Naltrexone, an opiate antagonist, was also originally touted as useful, especially for self-injurious behavior, but its utility has not yet been proven. Clomipramine, a tricyclic antidepressant that inhibits serotonin reuptake, has demonstrated usefulness in reducing compulsions and stereotypies in autistic children. However, it does lower the seizure threshold, can cause agranulocytosis, and has cardiotoxic and behavior toxicity effects. Other medications used to treat psychiatric symptoms in autistic children include stimulants, selective serotonin reuptake inhibitor (SSRIs), and clonidine. The SSRIs, in particular, appear to be somewhat effective in diminishing hyperactive, agitated, and obsessive-compulsive behaviors, although there have not yet been sufficient, controlled studies regarding their utility (see Chapter 20.1). PROGNOSIS. Some children, especially those with speech, may grow up to live self-sufficient, employed, albeit isolated, lives in the community. Many others remain dependent on their family for their everyday lives or require placement in facilities outside the home. Because early, intensive therapy may improve language

and social function, delayed diagnosis may lead to a poor outcome. There is no increased risk of schizophrenia in adulthood, but the cost of delayed diagnosis across the life span is high. A better prognosis is associated with higher intelligence, functional speech, and less bizarre symptoms and behavior. The symptom profile for some children may change as they grow older and seizures or self-injurious behavior becomes more common.