10 - 31.5 Autism Spectrum Disorder

31.5 Autism Spectrum Disorder

timed speech treatment for preschool children who stutter. Int J Speech Lang Pathol. 2011;13:500–509. Verhoeven L, van Balkom H, eds. Classification of Developmental Language Disorders. Theoretical Issues and Clinical Implications. Mahwah, NJ: Erlbaum; 2004. Wake M, Levickis P, Tobin S, Zens N, Law J, Gold L, Ukoumunne OC, Goldfield S, Le Ha ND, Skeat J, Reilly S. Improving outcomes of preschool language delay in the community: Protocol for the Language for Learning randomized controlled trial. BMC Pediatrics. 2012;12:96–107. Wake M, Tobin S, Girolametto L, Ukomunne OC, Gold L, Levickis P, Sheehan J, Goldfeld S, Reilly S. Outcomes of population based language promotion for slow to talk toddlers at ages 2 and 3 years: Let’s Learn Language cluster randomised clinical trial. BMJ. 2011;343–355. Yaruss JS, Coleman Ce, Quesal RW. Stuttering in school-age children: A comprehensive approach to treatment. Lang Speech Hear Serv Sch. 2012;43:536–548. 31.5 Autism Spectrum Disorder Autism spectrum disorder, previously known as the pervasive developmental disorders, is a phenotypically heterogeneous group of neurodevelopmental syndromes, with polygenic heritability, characterized by a wide range of impairments in social communication and restricted and repetitive behaviors. Prior to the development of the Fifth Edition of the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-5), autism spectrum disorder was conceptualized as five discrete disorders, including: autistic disorder, Asperger’s disorder, childhood disintegrative disorder, Rett syndrome, and pervasive developmental disorder not otherwise specified. Autistic disorder was characterized by impairments in three domains: social communication, restricted and repetitive behaviors, and aberrant language development and usage. A less extensive form of autism spectrum disorder, Asperger’s disorder, did not include language impairment as a diagnostic criterion. Recent clinical consensus has shifted the conceptualization of autism spectrum disorder toward a continuum model in which heterogeneity of symptoms is recognized as inherent in the disorder, and core diagnostic impairments are collapsed into two domains: deficits in social communication, and restricted and repetitive behaviors. Aberrant language development and usage is no longer considered a core feature of autism spectrum disorder. This diagnostic change, is based, in part, on recent studies in siblings with diagnoses of autistic disorder, suggesting that symptom domains may be transmitted separately, and that aberrant language development and usage is not a defining feature, but an associated feature in some individuals with autism spectrum disorder. Autism spectrum disorder is typically evident during the second year of life, and in severe cases, a lack of developmentally appropriate interest in social interactions may be noted even in the first year. Some studies suggest that a decline in social interaction may ensue between the first and second years of life. However, in milder cases, core impairments in autism spectrum disorder may not be identified for several more years. Although language impairment is not a core diagnostic criterion in autism spectrum disorder, clinicians and parents share concerns about a child who by 12 to 18 months has not developed any language, and

delayed language accompanied by diminished social behavior are frequently the heralding symptoms in autism spectrum disorder. In up to 25 percent of cases of autism spectrum disorder, some language develops and is subsequently lost. Autism spectrum disorder in children with normal intellectual function and mild impairment in language function may not be identified until middle childhood when both academic and social demands are increased. Children with autism spectrum disorder often exhibit idiosyncratic intense interest in a narrow range of activities, resist change, and typically, do not respond to their social environment in accordance with their peers. According to the DSM-5, diagnostic criteria for autism spectrum disorder include deficits in social communication and restricted interests, which present in the early developmental period, however, when subtle, may not be identified until several years later. approximately one third of children meeting the current DSM-5 diagnosis of autism spectrum disorder, exhibit intellectual disability (ID). Of interest, is that according to DSM-IV-TR, Rett syndrome or disorder appeared to occur exclusively in females and is characterized by normal development for at least 6 months, followed by stereotyped hand movements, a loss of purposeful motions, diminishing social engagement, poor coordination, and decreasing language use. In the formerly labeled childhood disintegrative disorder, development progresses normally for approximately 2 years, after which the child shows a loss of previously acquired skills in two or more of the following areas: language use, social responsiveness, play, motor skills, and bladder or bowel control. The former Asperger’s disorder is characterized by impairment in social relatedness and repetitive and stereotyped patterns of behavior without a delay or marked aberrant in language development and usage. In Asperger’s disorder, cognitive abilities and major adaptive skills are age appropriate, although social communication is impaired. A survey of children undertaken with the former autism spectrum disorders, revealed that the average age of diagnosis was 3.1 years for children with autistic disorder, 3.9 years for children diagnosed with pervasive developmental disorder not otherwise specified, and 7.2 years for those youth with Asperger’s disorder. Children with autism spectrum disorder who exhibited severe language deficits received an autism spectrum disorder diagnosis, on average, a year earlier than children without impairment in language. Children with autism spectrum disorder who exhibited repetitive behaviors such as hand-flapping, toe-walking, and odd play were also identified with autism spectrum disorder disorders at a younger age than those who did not exhibit such behaviors. The current DSM-5 autism spectrum disorder criteria provide specifiers for severity of the main domains of impairment and also specifiers for the presence or absence of language impairment and intellectual impairment. HISTORY OF AUTISTIC DISORDER “Early infantile autism” was described by Leo Kanner in 1943; however, even as early as 1867, the psychiatrist Henry Maudsley had observed a group of very young children with severe mental disorders characterized by marked deviation, delay, and distortion in development. In that era, most serious developmental disturbance in young children was believed

to fall within the category of psychoses. Kanner’s classic paper “Autistic Disturbances of Affective Contact,” coined the term infantile autism and provided a clear, comprehensive account of the early childhood syndrome. Kanner described children who exhibited extreme “autistic aloneness”; failure to assume an anticipatory posture; delayed or deviant language development with echolalia and often with pronominal reversal (using you for I); monotonous repetitions of noises or verbal utterances; excellent rote memory; limited range of spontaneous activities, stereotypies, and mannerisms; and anxiously obsessive desire for the maintenance of sameness and dread of change. Socially, Kanner’s sample was described as having poor eye contact; awkward relationships; and a preference for pictures and inanimate objects. Kanner suspected that the syndrome was more frequent than it seemed, and suggested that some children with infantile autism may have been misclassified as “mentally retarded” or schizophrenic. Before 1980, children with symptoms of autism spectrum disorder were generally diagnosed with childhood schizophrenia. Over time, it became evident that autism spectrum disorder and schizophrenia were two distinct psychiatric entities. In some cases, however, a child with autism spectrum disorder may develop comorbid schizophrenic disorder later in childhood. EPIDEMIOLOGY Prevalence Autism spectrum disorders have been increasingly diagnosed over the last two decades, with the current prevalence estimated at approximately 1 percent in the United States. Autistic disorder, based on DSM-IV-TR criteria, is believed to occur at a rate of about 8 cases per 10,000 children (0.08 percent). By definition, the onset of autism spectrum disorder is in the early developmental period; however, some cases are not recognized until the child is much older. Because of this delay between onset and diagnosis, the prevalence rates increase with age in young children. Sex Distribution Autism spectrum disorder is diagnosed four times more often in boys than in girls. In clinical samples, girls with autism spectrum disorder more often exhibit intellectual disability than boys. One potential explanation for this is that girls with autism spectrum disorder without intellectual disability may be less likely to be identified, referred clinically, and diagnosed. ETIOLOGY AND PATHOGENESIS Genetic Factors Family and twin studies suggest that autism spectrum disorder has a significant heritable contribution; however, it does not appear to be fully penetrant. Although up to 15 percent of cases of autism spectrum disorder appear to be associated with a known genetic mutation, in most cases, its expression is dependent on multiple genes. Family studies have demonstrated increased rates of autism spectrum disorder in siblings of an index child, as high as 50 percent in some families with two or more children with autism spectrum disorder. Siblings of a child with autism spectrum disorder are also at increased risk for a variety of developmental impairments in communication and social

skills, even when they do not meet criteria for autism spectrum disorder. The concordance rate of autistic disorder in two large twin studies was 36 percent in monozygotic pairs versus 0 percent in dizygotic pairs in one study and about 96 percent in monozygotic pairs versus about 27 percent in dizygotic pairs in the second study. High rates of cognitive impairments, in the nonautistic twin in monozygotic twins with perinatal complications, suggest that contributions of perinatal environmental factors interact with genetic vulnerability differentially in autism spectrum disorder. The heterogeneity in expression of symptoms in families with autism spectrum disorder suggests that there are multiple patterns of genetic transmission. Studies indicate that both an increase and decrease in certain genetic patterns may be risk factors for autism spectrum disorder. In addition to specific genetic factors, gender plays a strong role in the expression of autism spectrum disorder. Genetic studies have identified two biological systems that are influenced in autism spectrum disorder: the consistent finding of elevated platelet serotonin (5-HT), and the mTOR, that is, mammalian target of rapamycin–linked synaptic plasticity mechanisms, which appear to be disrupted in autism spectrum disorder. These will be discussed further in the next section. A number of known genetically caused syndromes include autism spectrum disorder as part of a broader phenotype. The most common of these inherited disorders is fragile X syndrome, an X-linked recessive disorder that is present in 2 to 3 percent of individuals with autism spectrum disorder. Fragile X syndrome exhibits a nucleotide repeat in the 5’ untranslated region of the FMNR1 gene, resulting in symptoms of autism spectrum disorder. Children with fragile X syndrome characteristically exhibit intellectual disability, gross and fine motor impairments, an unusual facies, macroorchidism, and significantly diminished expressive language ability. Tuberous sclerosis, another genetic disorder characterized by multiple benign tumors, inherited by autosomal dominant transmission, is found with greater frequency among children with autism spectrum disorder. Up to 2 percent of children with autism spectrum disorder also have tuberous sclerosis. Researchers who screened the DNA of more than 150 pairs of siblings with autism spectrum disorder found evidence of two regions on chromosomes 2 and 7 containing genes that may contribute to autism spectrum disorder. Additional genes hypothesized to be involved in autism spectrum disorder were found on chromosomes 16 and 17. Biomarkers in Autism Spectrum Disorder Autism spectrum disorder is associated with several biomarkers, potentially resulting from interactions of genes and environmental factors, which then influence neuronal function, dendrite development, and contribute to altered neuronal information processing. Several biomarkers of abnormal signaling in the 5-HT system, the mTORlinked synaptic plasticity mechanisms, and alterations of the γ-aminobutyric acid (GABA) inhibitory system. The first biomarker identified in autism spectrum disorder was elevated serotonin in

whole blood, almost exclusively in the platelets. Platelets acquire 5-HT through the process of SERT (serotonin transporter), known to be hereditary, as they pass through the intestinal circulation. The genes that mediate SERT (SLC64A), and the 5-HT receptor 5-HT 2A gene (HTR2A) are known to be more heritable than autism spectrum disorder, and encode the same protein in the platelets and in the brain. Because 5-HT is known to be involved in brain development, it is possible that the changes in 5-HT regulation may lead to alterations in neuronal migration and growth in the brain. Both structural and functional neuroimaging studies have suggested specific biomarkers associated with autism spectrum disorder. Several studies found increased total brain volume in children younger than 4 years of age with autism spectrum disorder, whose neonatal head circumferences were within normal limits or slightly below. By about age 5 years, however, 15 to 20 percent of children with autism spectrum disorder developed macrocephaly. Additional studies found confirmatory data in samples of infants who were later diagnosed with autism spectrum disorder, who exhibited normal head circumferences at birth; by 4 years, 90 percent had larger brain volumes than controls, with 37 percent of the autism spectrum disorder group meeting criteria for macrocephaly. In contrast, structural magnetic resonance imaging (sMRI) studies of children with autism spectrum disorder ranging from 5 to 16 years did not find mean values of total brain volume increased. One study followed the size of the amygdala in youth with autism spectrum disorder in the first few years of life, and similarly, found an increased size in the first few years of life, followed by a decrease in size over time. The size of the striatum has also been found in several studies to be enlarged in young children with autism spectrum disorder, with a positive correlation of striatal size with frequency of repetitive behaviors. The dynamic process of the atypical and changing total brain volume observed in children with autism spectrum disorder lends support for the overarching hypothesis that there are sensitive periods or “critical periods” within the brain’s plasticity that may be disrupted in ways that may contribute to the emergence of autism spectrum disorder. Functional MRI (fMRI) studies have focused on identifying biomarkers, that is, the functional brain correlates of various observed core symptoms in autism spectrum disorder. fMRI studies of children, adolescents, and adults with autism spectrum disorder have employed tasks including face perception, neutral face tasks, “theory of mind” deficits, language and communication impairments, working memory and repetitive behaviors. fMRI studies have provided evidence that individuals with autism spectrum disorder have a tendency to scan faces differently than controls, in that they focus more on the mouth region of the face rather than on the eye region and rather than scan the entire face multiple times, individuals with autism spectrum disorder focus more on individual features of the face. In response to socially relevant stimuli, researchers have come to the conclusion that individuals with autism spectrum disorder have greater amygdala hyperarousal. In terms of “theory of mind,” that is, the ability to attribute emotional states to others, and to oneself, fMRI studies find differences in activation in brain regions such as the right temporal lobe and other areas of the brain known to become activated in controls during tasks involving theory of mind. This difference has

been hypothesized by some researchers to represent dysfunction of the mirror neuron system (MNS). Atypical patterns of frontal lobe activation have been found in multiple studies of autism spectrum disorder during face processing tasks, suggesting that this area of the brain may be critical in social perception and emotional reasoning. Decreased activation in individuals with autism spectrum disorder in the left frontal regions of the brain during memory and language-based tasks led researchers to hypothesize that individuals with autism spectrum disorder utilized more visual strategies during language processing than controls did. Both sMRI and fMRI research has contributed to demonstrating brain correlates of core impairments observed in individuals with autism spectrum disorder. Immunological Factors Several reports have suggested that immunological incompatibility (i.e., maternal antibodies directed at the fetus) may contribute to autistic disorder. The lymphocytes of some autistic children react with maternal antibodies, which raises the possibility that embryonic neural tissues may be damaged during gestation. These reports usually reflect single cases rather than controlled studies, and this hypothesis is still under investigation. Prenatal and Perinatal Factors A higher-than-expected incidence of prenatal and perinatal complications seems to occur in infants who are later diagnosed with autism spectrum disorder. The most significant prenatal factors associated with autism spectrum disorder in the offspring are advanced maternal and paternal age at birth, maternal gestational bleeding, gestational diabetes, and first-born baby. Perinatal risk factors for autism spectrum disorder include umbilical cord complications, birth trauma, fetal distress, small for gestational age, low birth weight, low 5-minute Apgar score, congenital malformation, ABO blood group system or Rh factor incompatibility and hyperbilirubinemia. Many of the obstetrical complications that are associated with risk for autism spectrum disorder are also risk factors for hypoxia, which may be an underlying risk factor itself. There is not sufficient evidence to implicate any one single perinatal or prenatal factor in autism spectrum disorder etiology, and a genetic predisposition to autism spectrum disorder may be interacting with perinatal factors. Comorbid Neurological Disorders Electroencephalography (EEG) abnormalities and seizure disorders occur with greater than expected frequency in individuals with autism spectrum disorder. Four percent to 32 percent of individuals with autism spectrum disorder have grand mal seizures at some time, and about 20 to 25 percent show ventricular enlargement on computed tomography (CT) scans. Various EEG abnormalities are found in 10 to 83 percent of children with the previously defined autistic disorder, and although no EEG finding is

specific to autistic disorder, there is some indication of failed cerebral lateralization. The current consensus is that autism spectrum disorder is a set of behavioral syndromes caused by a multitude of factors acting on the central nervous system. Psychosocial Theories Studies comparing parents of children with autism spectrum disorder with parents of normal children have shown no significant differences in child-rearing skills. Kanner’s early speculations that parental emotional factors might be implicated as contributing to the development of autism spectrum disorder have been clearly refuted. DIAGNOSIS AND CLINICAL FEATURES The DSM-5 diagnostic criteria for autism spectrum disorder are shown in Table 31.5-1. Table 31.5-1 DSM-5 Diagnostic Criteria for Autism Spectrum Disorder

Core Symptoms of Autism Spectrum Disorder Persistent Deficits In Social Communication and Interaction. Children with autism spectrum disorder characteristically do not conform to the expected level of reciprocal social skills and spontaneous nonverbal social interactions. Infants with autism spectrum disorder may not develop a social smile, and as older babies may lack the anticipatory posture for being picked up by a caretaker. Less frequent and poor eye contact is common during childhood and adolescence compared to other children. The social development of children with autism spectrum disorder is characterized by atypical, but not absent, attachment behavior. Children with autism spectrum disorder may not explicitly acknowledge or differentiate the most important persons in their lives—parents, siblings, and teachers—and on the other hand, may not react as strongly

to being left with a stranger compared to others their age. Children with autism spectrum disorder often feel and display extreme anxiety when their usual routine is disrupted. By the time children with autism spectrum disorder reach school age, their social skills may have increased, and social withdrawal may be less obvious, particularly in higher-functioning children. An observable deficit, however, often remains in spontaneous play with peers and in subtle social abilities that promote developing friendships. The social behavior of children with autism spectrum disorder is often awkward and may be inappropriate. In older school-aged children, social impairments may be manifested in a lack of conventional back and forth conversation, fewer shared interests, and fewer body and facial gestures during conversations. Cognitively, children with autism spectrum disorder are frequently more skilled in visual-spatial tasks than in tasks requiring skill in verbal reasoning. One observation of the cognitive style of children with autism spectrum disorder is an impaired ability to infer the feelings or emotional state of others around them. That is, individuals with autism spectrum disorder have difficulty with making attributions about the motivation or intentions of others (also termed “theory of mind”) and thus have difficulty developing empathy. The lack of a “theory of mind” produces difficulties interpreting the social behavior of others and leads to a lack of social reciprocation. Individuals with autism spectrum disorder generally desire friendships, and higher functioning children may be aware that their lack of spontaneity and poor skills in responding to the emotions and feelings of their peers are major obstacles in developing friendships. Children with autism spectrum disorder are often avoided or shunned by peers who expect them to conform to their mainstream activities, and experience their behavior as awkward and alienating. Adolescents and adults with autism spectrum disorder often desire romantic relationships, and for some, their increase in social competence and skills over time enables them to develop long-term relationships. Restricted, Repetitive Patterns of Behavior, Interests, and Activities. From the first years of life, in a child with autism spectrum disorder, developmentally expected exploratory play is restricted and muted. Toys and objects may not be used typically, instead, are often manipulated in a ritualistic manner, with fewer symbolic features. Children with autism spectrum disorder generally do not show the level of imitative play or abstract pantomime that other children of their age exhibit spontaneously. The activities and play of children with autism spectrum disorder may appear more rigid, repetitive, and monotonous than their peers. Ritualistic and compulsive behaviors are common in early and middle childhood. Children with autism spectrum disorder often seem to enjoy spinning, banging, and watching water flowing. Frank compulsive behaviors are not uncommon among children with autism spectrum disorder, such as lining up objects, and not infrequently a child with autism spectrum disorder may exhibit a strong attachment to a particular inanimate object. Children with autism spectrum disorder who are severely intellectually disabled have increased rates of self-stimulatory and self-injurious behaviors. Stereotypies, mannerisms, and grimacing emerge most frequently when a child with autism spectrum disorder is a less-

structured situation. Children with autism spectrum disorder often find transitions and changes intimidating. Moving to a new house, rearranging furniture in a room, or even a change such as eating a meal before a bath when the reverse was the routine, may evoke panic, fear, or temper tantrums in a child with autism spectrum disorder. Associated Physical Characteristics. At first glance, children with autism spectrum disorder do not show any physical signs indicating the disorder. Children with autism spectrum disorder, overall, do exhibit higher rates of minor physical anomalies, such as ear malformations, and others that may reflect abnormalities in fetal development of those organs along with parts of the brain. A greater than expected number of children with autism spectrum disorder do not show early handedness and lateralization, and remain ambidextrous at an age when cerebral dominance is established in most children. Children with autism spectrum disorder have been observed to have a higher incidence of abnormal dermatoglyphics (e.g., fingerprints) than those in the general population. This finding may suggest a disturbance in neuroectodermal development. Associated Behavioral Symptoms that May Occur in Autism Spectrum Disorder Disturbances In Language Development and Usage. Deficits in language development and difficulty using language to communicate ideas are not among the core criteria for diagnosing autism spectrum disorder; however, they occur in a subset of those individuals with autism spectrum disorder. Some children with autism spectrum disorder are not simply reluctant to speak, and their speech abnormalities do not result from lack of motivation. Language deviance, as much as language delay, is characteristic of more severe subtypes of autism spectrum disorder. Children with severe autism spectrum disorder have significant difficulty putting meaningful sentences together, even when they have large vocabularies. When children with autism spectrum disorder whose language was delayed do learn to converse fluently, their conversations may impart information without typical prosody or inflection. In the first year of life, a typical pattern of babbling may be minimal or absent. Some children with autism spectrum disorder vocalize noises—clicks, screeches, or nonsense syllables—in a stereotyped fashion, without a seeming intent of communication. Unlike most young children who generally have better receptive language skills than expressive ones, children with autism spectrum disorder may express more than they understand. Words and even entire sentences may drop in and out of a child’s vocabulary. It is not atypical for a child with autism spectrum disorder to use a word once and then not use it again for a week, a month, or years. Children with autism spectrum disorder may exhibit speech that contains echolalia, both immediate and delayed, or stereotyped phrases that seem out of context. These language patterns are frequently associated with pronoun reversals. A child with autistic disorder might say, “You want the toy” when she means that she wants it. Difficulties in articulation are also common. Many children

with autistic disorder use peculiar voice quality and rhythm. About 50 percent of autistic children never develop useful speech. Some of the brightest children show a particular fascination with letters and numbers. Children with autism spectrum disorder sometimes excel in certain tasks or have special abilities; for example, a child may learn to read fluently at preschool age (hyperlexia), often astonishingly well. Very young children with autism spectrum disorder who can read many words, however, have little comprehension of the words read. Intellectual Disability. About 30 percent of children with autism spectrum disorder function in the intellectually disabled range of intellectual function. Of those, about 30 percent of children function in the mild to moderate range, and about 45 to 50 percent are severely to profoundly intellectually disabled. The intelligent quotient (IQ) scores of autism spectrum disorder children with intellectual impairments tend to reflect most severe problems with verbal sequencing and abstraction skills, with relative strengths in visuospatial or rote memory skills. This finding suggests the importance of defects in language-related functions. Irritability. Broadly defined, irritability includes aggression, self-injurious behaviors, and severe temper tantrums. These phenomena are commonly encountered in children and adolescents with autism spectrum disorder. Severe temper tantrums may be difficult to subdue, and self-injurious behaviors are often problematic to control. These symptoms are often produced by everyday situations in which these youth are expected to transition from one activity to another, sit in a classroom setting, or remain still when they desire to run around. In children with autism spectrum disorder who are lower functioning and have intellectual deficits, aggression may emerge unexpectedly without an obvious trigger or purpose, and self-injurious behaviors such as head banging, skin picking, and biting oneself may also be noted. Instability of Mood and Affect. Some children with autism spectrum disorder exhibit sudden mood changes, with bursts of laughing or crying without an obvious reason. It is difficult to learn more about these episodes if the child cannot express the thoughts related to the affect. Response to Sensory Stimuli. Children with autism spectrum disorder have been observed to overrespond to some stimuli and underrespond to other sensory stimuli (e.g., to sound and pain). It is not uncommon for a child with autism spectrum disorder to appear deaf, at times showing little response to a normal speaking voice; on the other hand, the same child may show intent interest in the sound of a wristwatch. Some children have a heightened pain threshold or an altered response to pain. Indeed, some children with autism spectrum disorder do not respond to an injury by crying or seeking comfort. Some youth with autism spectrum disorder perseverate on a sensory experience; for example, they frequently hum a tune or sing a song or commercial jingle before saying words or using speech. Some particularly enjoy vestibular stimulation—

spinning, swinging, and up-and-down movements. Hyperactivity and Inattention. Hyperactivity and inattention are both common behaviors in young children with autism spectrum disorder. Lower than average activity level is less frequent; when present, it often alternates with hyperactivity. Short attention span, poor ability to focus on a task, may also interfere with daily functioning Precocious Skills. Some individuals with autism spectrum disorder have precocious or splinter skills of great proficiency, such as prodigious rote memories or calculating abilities, usually beyond the capabilities of their normal peers. Other potential precocious abilities in some children with autism spectrum disorder include hyperlexia, an early ability to read well (even though they cannot understand what they read), memorizing and reciting, and musical abilities (singing or playing tunes or recognizing musical pieces). Insomnia. Insomnia is a frequent sleep problem among children and adolescents with autism spectrum disorder, estimated to occur in 44 to 83 percent of school-aged children. Both behavioral and pharmacologic interventions have been applied as interventions. Behavioral interventions include modification of parental behavior before and at bedtime, and providing routines that remove reinforcers for remaining awake. Medication interventions have included melatonin, which appears to be a promising agent in doses ranging from 1 mg fast-release to 4 mg controlled-release in the few controlled studies for insomnia in youth with autism spectrum disorder. Minor Infections and Gastrointestinal Symptoms. Young children with autism spectrum disorder have been reported to have a higher-than-expected incidence of upper respiratory infections and other minor infections. Gastrointestinal symptoms commonly found among children with autism spectrum disorder include excessive burping, constipation, and loose bowel movements. Also seen is an increased incidence of febrile seizures in children with autism spectrum disorder. Some children do not show temperature elevations with minor infectious illnesses and may not show the typical malaise of ill children. In other children, behavior problems and relatedness seem to improve noticeably during a minor illness, and in some, such changes are a clue to physical illness. Assessment Tools A standardized instrument that can be very helpful in eliciting comprehensive information regarding autism spectrum disorder is the Autism Diagnostic Observation Schedule-Generic (ADOS-G). Brett was the first of two children born to middle-class parents both in their early 40s after difficult pregnancy, with an induced labor at 36 weeks due to fetal distress.

As an infant, Brett was undemanding and relatively placid; he did not have colic, and motor development proceeded appropriately, but language development was delayed. Brett’s parents first became concerned about his development when he was 18 months of age and still not speaking; however, upon questioning, they noted that, in comparison to other toddlers in his play group, Brett had seemed less uninterested in social interaction and the social games with toddlers and adults. Stranger anxiety became marked at 18 months, much later compared to the other toddlers in his day care program. Brett would become extremely upset if his usual day care worker was not present and would tantrum until his mother took him home. Brett’s pediatrician initially reassured his parents that he was a “late talker”; however, when Brett was 24 months old he was referred for developmental evaluation. At 24 months, motor skills were age appropriate. His language and social development, however, was severely delayed, and he was noted to be resistant to changes in routine and unusually sensitive to aspects of the inanimate environment. Brett’s play skills were quite limited, and he played with toys in repetitive and idiosyncratic ways. His younger sister, now 12 months, was beginning to say a few words, and the family history was negative for language and developmental disorders. A comprehensive medical evaluation revealed a normal EEG and CT scan; genetic screening and chromosome analysis were normal as well. Brett was diagnosed with autism spectrum disorder, and he was enrolled in a special education program in which he gradually began to speak. His speech was extremely literal and characterized by a monotonic voice quality and an occasional pronoun reversal. Brett often spoke and was able to make his needs known; however, his language was odd and the other toddlers did not play with him. Brett pursued mainly solo activities and remained quite isolated. By age 5 years, Brett was quite attached to his mother and often became separation anxious and upset when she went out, exhibiting severe tantrums. Brett also had developed a number of self-stimulatory behaviors in which he engaged, such as waving his fingers in front of his eyes. His extreme sensitivity to change continued over the next few years. Intelligence testing revealed a full-scale IQ in the average range with relative weakness in the verbal subtests compared to the performance subtests. In the 4th grade, Brett began to have serious behavioral problems at school and at home. Brett was unable to complete his class work, would wander around the classroom, and would begin to tantrum when the teacher insisted that he sit in his seat. He would sometimes begin screaming so loudly that he had to be asked to leave the classroom. He would then become upset and throw all of his books off his desk in a rage, sometimes inadvertently hitting other students. It took him up to 2 hours to calm down. At home, Brett would fly into a tantrum if anyone touched his things, and he would become stubborn and belligerent when asked to do anything that he was not expecting. Brett’s tantrum behavior continued into middle school, and by the 8th grade, when he was 13 years old, these behaviors became so severe that the school warned his parents that he was becoming unmanageable. Brett was evaluated by a child and adolescent psychiatrist who

recommended a social skills group for him and prescribed risperidone, starting with 0.5 mg p.o. b.i.d. and titrating up to 1.5 mg p.o. bid. At that dose, Brett’s tantrums were less frequent and less severe. Brett seemed calmer in general, and did not become physically out of control during tantrums. Brett continued in middle school in a combination of special education classes and regular classes. Brett’s social skills group was helpful in terms of teaching him how to approach peers in ways that would lead to less rejection. Brett had made some acquaintances, and by the time he started high school, he had acquired two friends who would come to his home and play video games with him. Brett knew that he was different than the other students, but he had trouble articulating what was different about him. Brett continued in high school with a combination of special and regular education and had plans to attend a community college and live at home for the first year. (Adapted from a case by Fred Volkmar, M.D.) DIFFERENTIAL DIAGNOSIS Disorders to consider in the differential diagnosis of autism spectrum disorder include social (pragmatic) communication disorder, the newly described DSM-5 communication disorder; schizophrenia with childhood onset; congenital deafness or severe hearing disorder; and psychosocial deprivation. It is also difficult to make the diagnosis of autism spectrum disorder because of its potentially overlapping symptoms with childhood schizophrenia, intellectual disability syndromes with behavioral symptoms, and language disorders. In view of the many concurrent problems often encountered in autism spectrum disorder, Michael Rutter and Lionel Hersov suggested a stepwise approach to the differential diagnosis. Social (Pragmatic) communication disorder This disorder is characterized by difficulty in conforming to typical storytelling, understanding the rules of social communication through language, exemplified by a lack of conventional greeting others, taking turns in a conversation, and responding to verbal and nonverbal cues of a listener. Other forms of language impairment may accompany social communication disorder such as delay in learning language or expressive and receptive difficulties. Social communication disorder is found with greater frequency in relatives of individuals with autism spectrum disorder, which increases the difficulty in discriminating this disorder from autism spectrum disorder. Although relationships may be negatively affected by social communication disorder, this disorder does not include restricted or repetitive behaviors and interests, as autism spectrum disorder does. Childhood Onset Schizophrenia Schizophrenia is rare in children younger than 12 years and almost nonexistent before

the age of 5 years. Characterized by hallucinations or delusions, childhood onset schizophrenia has a lower incidence of seizures and intellectual disability and poor social skills. Table 31.5-2 compares autism spectrum disorder and schizophrenia with childhood onset. Table 31.5-2 Autism Spectrum Disorder versus Childhood Onset Schizophrenia Intellectual Disability with Behavioral Symptoms Children with intellectual disability may exhibit behavioral symptoms that overlap with some autism spectrum disorder features. The main differentiating features between autism spectrum disorder and intellectual disability are that children with intellectual disability syndromes generally display global impairments in both verbal and nonverbal areas, whereas children with autism spectrum disorder are relatively weak in social interactions compared to other areas of performance. Children with intellectual disability generally relate verbally and socially to adults and peers in accordance with their mental age, and they exhibit a relatively even profile of limitations. Language Disorder Some children with language disorders also have autism spectrum disorder features, which may present a diagnostic challenge. Table 31.5-3 summarizes the major differences between autism spectrum disorder and language disorders. Table 31.5-3 Autism Spectrum Disorder versus Language Disorder

Congenital Deafness or Hearing Impairment Because children with autism spectrum disorder may appear mute or lack language development, congenital deafness and hearing impairment must be considered and ruled out. Differentiating factors include the following: infants with autism spectrum disorder may babble only infrequently, whereas deaf infants often have a history of relatively normal babbling that then gradually tapers off and may stop at 6 months to 1 year of age. Deaf children generally respond only to loud sounds, whereas children with autism spectrum disorder may ignore loud or normal sounds and respond to soft or low sounds. Most importantly, audiogram or auditory-evoked potentials indicate significant hearing loss in deaf children. Deaf children usually seek out nonverbal social communication with regularity and seek social interactions with peers and family members more consistently than children with autism spectrum disorder. Psychosocial Deprivation Severe neglect, maltreatment, and lack of parental care can lead children to appear apathetic, withdrawn, and alienated. Language and motor skills may be delayed. Children with these signs generally improve when placed in a favorable and enriched psychosocial environment, but such improvement is not the case with children with autism spectrum disorder. COURSE AND PROGNOSIS Autism spectrum disorder is typically a lifelong, albeit heterogeneous, disorder with a highly variable severity and prognosis. Children with autism spectrum disorder and IQs above 70 with average adaptive skills, who develop communicative language by ages 5 to 7 years, have the best prognoses. A longitudinal study comparing symptoms in children with high-IQ autism spectrum disorder at the age of 5 years, with their symptoms at age 13 through young adulthood, found that a small proportion no longer met criteria for autism spectrum disorder. Most of these youth demonstrated positive

changes in communication and social domains over time. Early intensive behavioral interventions have been found to provide a profound positive impact on many children with autism spectrum disorder, and in some cases lead to recovery and function in the average range. The autism spectrum disorder symptom areas that do not seem to improve substantively over time with early behavioral interventions are related to ritualistic and repetitive behaviors. However, currently, evidence-based behavioral interventions specifically targeting repetitive behaviors may ameliorate them. The prognosis of a given child with autism spectrum disorder is generally improved if the home environment is supportive.

TREATMENT The goals of treatment for children with autism spectrum disorder are to target core behaviors to improve social interactions, communication, broaden strategies to integrate into schools, develop meaningful peer relationships, and increase long-term skills in independent living. Psychosocial treatment interventions aim to help children with autism spectrum disorder to develop skills in social conventions, increase socially acceptable and prosocial behavior with peers, and to decrease odd behavioral symptoms. In many cases, language and academic remediation are also required. In addition, treatment goals generally include reduction of irritable and disruptive behaviors that may emerge in school and at home and may exacerbate during transitions. Children with intellectual disability require developmentally appropriate behavioral interventions to reinforce socially acceptable behaviors and encourage selfcare skills. In addition, parents of children with autism spectrum disorder often benefit from psychoeducation, support, and counseling in order to optimize their relationships and effectiveness with their children. Comprehensive treatment for autism spectrum disorder including intensive behavioral programs, parent training and participation, and academic/educational interventions have provided the most promising results. Components of these comprehensive treatments include expanding social skills, communication, and language, often through practicing imitation, joint attention, social reciprocity, and play in a directed but child-centered manner. Five randomized controlled trials (RCTs) of early intensive comprehensive behavioral interventions targeting core features of autism spectrum disorder in children ranging in age from 2 years to 5 years of age have shown increases in language acquisition, social interactions, and educational achievement at the end of the study period compared to control groups. The study periods ranged from 12 weeks to several years, and the settings were at home, in clinic, or at school. The comprehensive treatment models or adapted versions of them were used either alone or in combinations in these RCTs as described below. Psychosocial Interventions Early Intensive Behavioral and Developmental Interventions

1. UCLA/Lovaas-based Model. This intensive and manualized intervention primarily utilizes techniques derived from applied behavior analysis, which is administered on a one-to-one basis for many hours per week. A therapist and a child will work on practicing specific social skills, language usage, and other target play skills, with reinforcement and rewards provided for accomplishments and mastery of skills.
2. Early Start Denver Model (ESDM) Interventions are administered in naturalistic settings such as in day care, at home, and during play with other children. Parents are typically taught to be co-therapists and provide the training at home while educational settings also provide the interventions. The focus of the interventions is

on developing basic play skills and relationship skills, and applied behavior analysis techniques are integrated into the interventions. This approach is focused on training for very young children and is applied within the context of the child’s daily routine. 3. Parent Training Approaches This includes Pivotal Response Training, in which parents are taught to facilitate social and communication development within the home and during activities by targeting gateway or pivotal social behaviors for mastery by the child with the expectation that once these central social skills were mastered, a natural generalizing of social behaviors would follow. Extensive parent and family components are integrated into this type of intervention. Other parent training approaches focus on language acquisition, and for parents, may be administered at a lower intensity such as weekly; however, once parents are trained, the interventions occur throughout the day with the child. Another example of a parent training approach is the Hanen More Than Words Program. Social Skills Approaches

1. Social Skills Training. Typically provided by therapeutic leaders to children of various ages in a group setting with peers; children are given guided practice in initiating social conversation, greetings, initiating games, and joint attention. Emotion identification and regulation are often included in practice with recognizing and learning how to label emotions in given social situations, learning to attribute appropriate emotional reactions in others, and social problem-solving techniques. The goals are that with practice in the group setting, the child will be able to use the techniques in less-structured settings and internalize strategies to interact positively with peers. Behavioral Interventions (BIs) and Cognitive-Behavioral Therapy (CBT) for Repetitive Behaviors and Associated Symptoms
2. Behavioral Therapy. Applied behavioral analysis has been found to be somewhat effective in reducing some repetitive behaviors in children and adolescents with autism spectrum disorder. Early intervention is recommended for repetitive behaviors that are self-injurious; behavioral interventions may need to be combined with pharmacologic treatments to adequately manage the symptoms.
3. Cognitive-Behavioral Therapy. There is a significant evidence base from RCTs for the efficacy of CBT for symptoms of anxiety, depression, and obsessive-compulsive disorders in children. There are fewer controlled trials of this treatment in children with autism spectrum disorder, although there are at least two published studies in which CBT was used to treat repetitive behavior in individuals with autism spectrum disorder. Interventions for comorbid symptoms in autism spectrum disorder
4. Neurofeedback. This modality has been administered in an attempt to influence

symptoms of attention-deficit/hyperactivity disorder (ADHD), anxiety, and increased social interaction by providing computer games or other games in which the desired behavior is reinforced, while the child wears electrodes that monitor electrical activity in the brain. The aim is to influence brainwave activity to prolong or produce electrical activity present during the desired behaviors. This modality is still under investigation in the treatment of symptoms in autism spectrum disorder. 2. Management of insomnia in autism spectrum disorder. Insomnia is a prevalent concern among children and adolescents with autism spectrum disorder, and both behavioral and pharmacologic interventions may be administered to improve this condition. The most common behavioral intervention for insomnia in autism spectrum disorder is based on changing the parents behavior first toward the child at bedtime and throughout the night, such that there is a removal of reinforcement and attention for being awake, leading to a gradual extinction of the “staying awake” behavior. Several studies using massage therapy before bedtime in children with autism spectrum disorder between the ages of 2 years and 13 years provided an improvement in falling asleep and a sense of relaxation. Educational interventions for children with autism spectrum disorder

1. Treatment and Education of Autistic and Communication-related Handicapped children (TEACCH). Originally developed at the University of North Carolina at Chapel Hill in the 1970s, TEACCH involves structured teaching based on the notion that children with autism spectrum disorder have difficulty with perception, and so this teaching method incorporates many visual supports and a picture schedule to aid in teaching academic subjects as well as socially appropriate responses. The physical environment is arranged to support visual learning, and the day is structured to promote autonomy and social relatedness.
2. Broad-based approaches. These educational plans include a blend of teaching strategies that use behavioral analysis and also focus on language remediation. Behavioral reinforcement is provided for socially acceptable behaviors while academic subjects are being taught. TEACCH may also be incorporated into a broader special educational program for autism spectrum disorder.
3. Computer-based approaches and virtual reality. Computer-based approaches and virtual reality teaching are centered on using computer-based programs, games, and interactive programs to teach language acquisition and reading skills. This provides the child with a sense of mastery and delivers a behaviorally based instruction in a modality that is appealing for the child. The Let’s Face It! program is a computerized game that helps to teach children with autism spectrum disorder to recognize faces. It consists of seven interactive computer games that target changes in facial expression, attention to the eye region of the face, holistic face recognition, and identifying emotional expression. A randomized controlled trial of use of this program with children with autism spectrum disorder provided evidence that after 20 hours of face training with Let’s Face It!, compared to the control group, the trained children

demonstrated improvement in their ability to focus on the eye region of a face and improved their analytic and holistic face-processing skills. Several studies using virtual reality environments to teach children with autism spectrum disorder social skills and interaction have provided evidence of their value. In one study, a virtual café for children with autism spectrum disorder allowed the children to practice ordering and paying for drinks and food by navigation with the use of a computer mouse. Psychopharmacological Interventions Psychopharmacological interventions in autism spectrum disorder are mainly directed at ameliorating impairing associated behavioral symptoms rather than core features of autism spectrum disorder. Target symptoms include irritability, broadly including aggression, temper tantrums and self-injurious behaviors, hyperactivity, impulsivity, and inattention. Irritability. Two second-generation antipsychotics, risperidone and aripiprazole, have been approved by the Food and Drug Administration (FDA) in the United States for treatment of irritability in individuals with autism spectrum disorder. Risperidone, a high-potency antipsychotic with combined dopamine (D2) and serotonin (5-HT2) receptor antagonist properties, has been shown to subdue aggressive or self-injurious behaviors in children with and without autism spectrum disorder. Starting with the National Institutes of Health supported Research Units on Pediatric Psychopharmacology randomized controlled trial of risperidone for treating irritability in autism spectrum disorder in 2002, there have been seven randomized controlled trials, three reanalysis studies, and two add-on studies, which have converged to confirm risperidone as an efficacious pharmacological treatment for irritability in children and adolescents with autism spectrum disorder in doses ranging from 0.5 mg to 1.5 mg. Some of the preschoolers in this study were also receiving intensive behavioral treatments. Risperidone is considered the first-line of medication treatment for children and adolescents with autism spectrum disorder who exhibit severe irritability. Despite its efficacy, risperidone’s main side effects of weight gain and increased appetite; metabolic side effects such as hyperglycemia, prolactin elevation, and dyslipidemia; along with other common adverse effects such as fatigue, drowsiness, dizziness, and drooling have limited its use in some individuals. Risperidone should be used with caution in individuals with underlying cardiac abnormalities or hypotension, since risperidone may contribute to orthostatic hypotension. In further continuation studies of risperidone in the treatment of irritability in autism spectrum disorder, persistent efficacy and tolerability were found over a 6-month period, with a rapid return of symptoms in good responders when the risperidone was discontinued. Other drugs studied in the treatment of irritability in autism spectrum disorder include aripiprazole and olanzapine. Two large studies utilizing aripiprazole in the treatment of tantrums, aggression, and self-injury in children and adolescents with autism spectrum disorder found that aripiprazole was both efficacious and safe. Doses ranged from 5 mg to 15 mg per day.

Main side effects included sedation, dizziness, insomnia, akathisia, nausea, and vomiting. Although weight gain was not as pronounced as with risperidone, it was still considered a moderate adverse event, with approximately 1.3 to 1.5 kg gained during an 8-week study period. The weight gain was similar at the lower and higher doses. Olanzapine, which specifically blocks 5-HT2A and D2 receptors and also blocks muscarinic receptors, has been studied in children and adolescents with autism spectrum disorder for the treatment of irritability with a trend toward a positive response; however, significant weight gain of approximately 3.5 kg occurred. The main side effect was sedation. Hyperactivity, Impulsivity, and Inattention. Several randomized placebocontrolled trials of methylphenidate have been conducted for the treatment of hyperactivity, impulsivity, and inattention in children and adolescents with autism spectrum disorder. The Research Units of Pediatric Psychopharmacology found methylphenidate to be at least moderately efficacious at doses of 0.25 to 0.5 mg/kg for youth with autism spectrum disorder and ADHD symptoms. Efficacy of methylphenidate in this population was less effective than in children with ADHD without autism spectrum disorder, and children with autism spectrum disorder developed more frequent side effects, including increased irritability, compared to ADHD children. A study of methylphenidate in the treatment of hyperactivity and inattention in preschoolers with autism spectrum disorder found the stimulant safe and relatively efficacious; half of the preschoolers developed side effects including increased stereotypies, gastrointestinal upset, sleep problems, and emotional lability. Among nonstimulants, one double-blind placebo-controlled study of hyperactivity, impulsivity, and inattention using atomoxetine in children with autism spectrum disorder found that it was significantly more effective than placebo. Side effects included sedation, irritability, constipation, and nausea. Clonidine, an α-agonist has also been studied in children with autism spectrum disorder for the treatment of hyperactivity with mixed results. Guanfacine was also found to be of use in some cases. Repetitive and Stereotypic Behavior. These core symptoms of autism spectrum disorder have been studied using selective serotonin reuptake inhibitor (SSRI) antidepressants, second-generation antipsychotics (SGAs), and mood-stabilizing agents such as valproate. One study with fluoxetine found the medication group only slightly better and not significantly better than the placebo group regarding the target symptoms, and another trial with escitalopram found no difference between groups. Risperidone, however, was found to be effective in targeting irritability, and restrictive and repetitive behaviors were improved. One recent study using valproate in a 12-week trial with 55 children with a mean age of 9½ years with autism spectrum disorder, found that those who were considered responders with respect to irritability were also found to be spending less time engaging in repetitive behaviors.

Agents Administered For Behavioral Impairment In Autism Spectrum Disorder Based On Open Trials. Quetiapine is an antipsychotic with more potent 5-H2 than D2 receptor blocking properties. Although only open-label trials have been done with this agent, it is sometimes tried when risperidone and olanzapine are not efficacious or well tolerated. It has been used in clinical practice at doses ranging from 50 to 200 mg per day. Adverse effects include drowsiness, tachycardia, agitation, and weight gain. Clozapine has a heterocyclic chemical structure that is related to certain conventional antipsychotics, such as loxapine (Loxitane), although clozapine carries a lower risk of extrapyramidal symptoms. It is not generally used in the treatment of aggression and self-injurious behavior unless those behaviors coexist with psychotic symptoms. The most serious adverse effect is agranulocytosis, which necessitates monitoring white blood cell count weekly during clozapine use. Its use is generally limited to treatment-resistant psychotic patients. Ziprasidone has receptor-blocking properties at the 5-HT2A and D2 receptor sites and carries little risk of extrapyramidal and antihistaminic effects. No guidelines exist for its use in autistic children with aggressive and self-injurious behaviors, but it has been used clinically to treat the latter behaviors in children who are treatment resistant. In studies of its use in adults with schizophrenia, dose ranges of 40 to 160 mg were found to be effective. Adverse effects include sedation, dizziness, and lightheadedness. An electrocardiography (ECG) recording is generally obtained before use of this medication. Lithium (Eskalith) has been shown to be efficacious in children with aggression without autism spectrum disorder, and it is used clinically in the treatment of aggressive or self-injurious behaviors when antipsychotic medications are not effective. Agents Used For Behavioral Impairment In Autism Spectrum Disorder Without Evidence Of Efficacy. A double-blind study investigated the efficacy of amantadine (Symmetrel), which blocks N-methyl-d-aspartate (NMDA) receptors, in the treatment of behavioral disturbance, such as irritability, aggression, and hyperactivity, in children with autism. Some researchers have suggested that abnormalities of the glutamatergic system may contribute to the emergence of autism spectrum disorders. High glutamate levels have been found in children with the formerly labeled Rett syndrome. In the amantadine study, 47 percent of children on amantadine were rated “improved” by their parents, and 37 percent of children on placebo were rated “improved” by parents in irritability and hyperactivity, although this difference was not statistically significant. Investigators rated the children on amantadine “significantly improved” with respect to hyperactivity. A double-blind, placebo-controlled study of the efficacy of the anticonvulsant lamotrigine (Lamictal) on hyperactivity in children with autism showed high rates of placebo improvement in ratings of hyperactivity, which were similar to response on the medication. Clomipramine (Anafranil) has been used in autism spectrum disorder, without RCTs to provide evidence of positive results. Fenfluramine (Pondimin), which reduces blood

serotonin levels, has also been used unsuccessfully in the treatment of autism. Improvement does not seem to be associated with a reduction in blood serotonin level. Naltrexone (ReVia), an opioid receptor antagonist, has been investigated without much success, based on the notion that blocking endogenous opioids would reduce autistic symptoms. Tetrahydrobiopterin, a coenzyme that enhances the action of enzymes was used in a double-blind placebo-controlled crossover study of 12 children with autistic disorder and low concentrations of spinal tetrahydrobiopterin. The children received a daily dose of 3 mg tetrahydrobiopterin per kilogram during a 6-month period alternating with placebo. Results indicated small, nonsignificant changes in the total scores on the Childhood Autism Rating Scale after 3- and 6-month treatment. Post hoc analysis of the three core symptoms of autism—social interaction, communication, and stereotyped behaviors— revealed a significant improvement in social interaction score after 6 months of active treatment. A positive correlation was noted between social response and IQ. These results suggest that there is a possible effect of tetrahydrobiopterin on the social functioning of children with autism. A recent case report suggested that low-dose venlafaxine (Effexor) was efficacious in three adolescents and young adults with autistic disorder with self-injurious behavior and hyperactivity. Dose of venlafaxine used was 18.75 mg per day, and efficacy was reported to be sustained over a 6-month period. Complementary and Alternative Medicine (CAM) Approaches to Autism Spectrum Disorder Complementary and alternative medicine (CAM) is a group of nontraditional treatments that are generally used in conjunction with conventional treatments. Safe interventions that have been applied to target both core and associated behavioral features of autism spectrum disorder with unknown efficacy include the following: music therapy, to promote communication and expression; and yoga, to promote attention and decrease activity level. A biologically based practice that is deemed safe and shown to be efficacious is melatonin, which is effective in reducing sleep-onset latency in children. Other biological practices that are recognized as safe but with unknown efficacy include vitamin C, multivitamins, essential fatty acids, and the amino acids carnosine and carnitine. Secretin has been shown to be ineffective in RCTs in the treatment of autism spectrum disorder. DISORDERS INCLUDED IN AUTISTIC SPECTRUM DISORDER The autistic spectrum covers a range of behaviors which, prior to the change in the DSM5 were listed separately, and which are now no longer diagnosed as separate entities in the diagnostic manual. Nevertheless, the descriptive value of these entities remains important, and it may be some time before the disorders described herein disappear from the psychiatric lexicon. In addition, they remain in use in Europe and around the

world as useful diagnostic entities and are still coded as separate disorders in ICD-10 as discussed. International Classification of Diseases, Tenth Edition (ICD-10) The classification system used in International Classification of Diseases, Tenth Revision (ICD-10) is not congruent with the revisions made in DSM-5 about autistic disorders. ICD-10 still includes separate designations for Rett syndrome, Childhood Disintegrative Disorder, Asperger’s Disorder, and Pervasive Development Disorder Not Otherwise Specified (Table 31.5-4). The authors of Synopsis believe these subtypes to be clinically useful, and each is described below. The reader should be aware, however, that according to DSM-5, each is subsumed under the rubric of Autism Spectrum Disorder and should so be diagnosed. Table 31.5-4 ICD-10 Diagnostic Criteria for Pervasive Developmental Disorders

Rett Syndrome In 1965, Andreas Rett, an Australian physician, identified a syndrome in 22 girls who

appeared to have developed normally for at least 6 months followed by devastating developmental deterioration. Rett syndrome is a progressive condition that has its onset after some months of what appears to be normal development. Head circumference is normal at birth and developmental milestones are unremarkable in early life. Between 5 and 48 months of age, generally between 6 months and 1 year, head growth begins to decelerate. Available data indicate a prevalence of 6 to 7 cases of Rett syndrome per 100,000 girls. Originally, it was believed that Rett syndrome occurred only in females, but males with the disorder or syndromes that are very close to this disorder have now been described. Rett syndrome is not fully included within autism spectrum disorder, and if present along with autism spectrum disorder it should be diagnosed as an associated disorder. Etiology. The cause of Rett syndrome is unknown, although the progressive deteriorating course after an initial normal period is compatible with a metabolic disorder. In some patients with Rett syndrome, the presence of hyperammonemia has led to postulation that an enzyme metabolizing ammonia is deficient, but hyperammonemia has not been found in most patients with Rett syndrome. It is likely that Rett syndrome has a genetic basis. It has been seen primarily in girls, and case reports so far indicate complete concordance in monozygotic twins. Diagnosis and Clinical Features. During the first 5 months after birth, infants have age-appropriate motor skills, normal head circumference, and normal growth. Social interactions show the expected reciprocal quality. At 6 months to 2 years of age, however, these children develop progressive encephalopathy with a number of characteristic features. The signs often include the loss of purposeful hand movements, which are replaced by stereotypic motions, such as hand-wringing; the loss of previously acquired speech; psychomotor retardation; and ataxia. Other stereotypical hand movements may occur, such as licking or biting the fingers and tapping or slapping. The head circumference growth decelerates and produces microcephaly. All language skills are lost, and both receptive and expressive communicative and social skills seem to plateau at developmental levels between 6 months and 1 year. Poor muscle coordination and an apraxic gait with an unsteady and stiff quality develop. Associated features include seizures in up to 75 percent of affected children and disorganized EEG findings with some epileptiform discharges in almost all young children with Rett syndrome, even in the absence of clinical seizures. An additional associated feature is irregular respiration, with episodes of hyperventilation, apnea, and breath holding. The disorganized breathing occurs in most patients while they are awake; during sleep, the breathing usually normalizes. Many patients with Rett syndrome also have scoliosis. As the disorder progresses, muscle tone seems to change from an initial hypotonic condition to spasticity to rigidity. Although children with Rett syndrome may live for well over a decade after the onset of the disorder, after 10 years, many patients are wheelchair-bound, with muscle

wasting, rigidity, and virtually no language ability. Long-term receptive and expressive communication and socialization abilities remain at a developmental level of less than 1 year. Dana was born as a full-term and healthy baby term after an uncomplicated pregnancy. An amniocentesis had been obtained because of advanced maternal age of 40 years, and findings were normal. At birth, Dana received good Apgar scores and her weight, height, and head circumference were all near the 50th percentile. Her development during the first months of life was unremarkable. At approximately 8 months of age, her development seemed to wane, and her interest in the environment, including the social environment, declined. Dana’s developmental milestones failed to progress, and she became markedly delayed; she was just starting to walk at her second birthday and had no spoken language. Evaluation at that time revealed that head growth had decelerated. Self-stimulatory behaviors emerged, and in addition, marked cognitive and communicative delays were noted on formal testing. Dana began to lose purposeful hand movements and developed unusual stereotypical hand-washing behaviors. By age 6, her EEG was abnormal and abnormal hand movements were prominent. Subsequently, Dana developed truncal ataxia and breath-holding spells, and motor skills further deteriorated. (Adapted from Fred Volkmar, M.D.) Differential Diagnosis. Rett syndrome shares some features with autism spectrum disorder; however, the two disorders have some predictable differences. In Rett syndrome, there is deterioration of developmental milestones, head circumference, and overall growth, whereas in autism spectrum disorder, aberrant development is usually present from early on. In Rett syndrome, specific and characteristic hand motor movements are always present; in autism spectrum disorder hand mannerisms may or may not appear. Poor coordination, ataxia, and apraxia are predictably part of Rett syndrome; however, individuals with autism spectrum disorder may have unremarkable gross motor function. In Rett syndrome, verbal abilities are usually lost completely, whereas in autism spectrum disorder language is widely variable from markedly aberrant to relatively mildly impaired. Respiratory irregularity is characteristic of Rett syndrome, and seizures often appear early. In autistic disorder, no respiratory disorganization is seen, and seizures do not develop in most patients; when seizures do develop, they are more likely in adolescence than in childhood. For autism spectrum disorder that is associated with another neurodevelopmental disorder such as Rett syndrome, the latter disorder is diagnosed in association with autism spectrum disorder. Course and Prognosis. Rett syndrome is progressive, and those individuals who live into adolescence and adulthood function at a cognitive and social level equivalent to that in the first year of life.

Treatment. Treatment is symptomatic. Physiotherapy has been beneficial for the muscular dysfunction, and anticonvulsant treatment is usually necessary to control the seizures. Behavior therapy, along with medication, may help control self-injurious behaviors, as it does in the treatment of autistic disorder, and it may help regulate the breathing disorganization. Childhood Disintegrative Disorder The previous diagnosis of childhood disintegrative disorder, now included in autism spectrum disorder, is characterized by marked regression in several areas of functioning after at least 2 years of apparently normal development. Childhood disintegrative disorder, also called Heller’s syndrome and disintegrative psychosis, was described in 1908 as a deterioration over several months of intellectual, social, and language function occurring in 3- and 4-year-olds with previously normal function. After the deterioration, the children closely resembled children with autistic disorder. Epidemiology. Epidemiological data have been complicated by the variable diagnostic criteria used, but childhood disintegrative disorder is estimated to be much less common than the formerly diagnosed autistic disorder. The prevalence has been estimated to occur in about 1 in 100,000 boys. The ratio of boys to girls is estimated to be between 4 and 8 boys to 1 girl. Etiology. The cause of childhood disintegrative disorder is unknown, but it has been associated with other neurological conditions, including seizure disorders, tuberous sclerosis, and various metabolic disorders. Diagnosis and Clinical Features. The diagnosis is made based on features that fit a characteristic age of onset, clinical picture, and course. Cases reported have ranged in onset from ages 1 to 9 years, but in most, the onset is between 3 and 4 years. Whereas previously diagnosed as a separate entity, DSM-5 conceives of childhood disintegrative disorder as a subset of autism spectrum disorder. The onset may be insidious over several months or relatively abrupt, with abilities diminishing in days or weeks. In some cases, a child displays restlessness, increased activity level, and anxiety before the loss of function. The core features of the disorder include loss of communication skills, marked regression of reciprocal interactions, and the onset of stereotyped movements and compulsive behavior. Affective symptoms are common, particularly anxiety, as is the regression of self-help skills, such as bowel and bladder control. To receive the diagnosis, a child must exhibit loss of skills in two of the following areas: language, social or adaptive behavior; bowel or bladder control; play; and motor skills. Abnormalities must be present in both of the following categories: reciprocal social communication skills, and restricted and repetitive behavior. The main neurological associated feature is seizure disorder.

Ron’s early history was within normal limits. By age 2, he was speaking in sentences, and his development appeared to be proceeding appropriately. At 3½ years of age, he abruptly exhibited a period of marked behavioral regression shortly after the birth of a sibling. Ron lost previously acquired skills in communication and was no longer toilet trained. Ron became more withdrawn and less interested in social interaction, exhibiting various self-stimulatory behaviors repeatedly. Comprehensive medical examination failed to reveal any conditions that might account for this developmental regression. Behaviorally, Ron exhibited features of autism spectrum disorder. At follow-up at age 12, he spoke only an occasional single word and had severe mental retardation. (Adapted from Fred Volkmar, M.D.) Differential Diagnosis. The differential diagnosis of the formerly diagnosed childhood disintegrative disorder includes receptive and expressive language disorder, mental retardation with behavioral problems, and Rett syndrome. Childhood disintegrative disorder is characterized by the loss of previously acquired development. Before the onset of childhood disintegrative disorder (occurring at 2 years or older), language has usually progressed to sentence formation. This skill is strikingly different from the premorbid history of even high-functioning patients with autistic disorder, in whom language generally does not exceed single words or phrases before diagnosis of the disorder. Once the disorder occurs, however, those with childhood disintegrative disorder are more likely to have no language abilities than are high-functioning patients with autistic disorder. In Rett syndrome, the deterioration occurs much earlier than in childhood disintegrative disorder, and the characteristic hand stereotypies of Rett syndrome do not occur in childhood disintegrative disorder. Course and Prognosis. The course of childhood disintegrative disorder is variable, with a plateau reached in most cases, a progressive deteriorating course in rare cases, and some improvement in occasional cases to the point of regaining the ability to speak in sentences. Most patients are left with at least moderate mental retardation. Treatment. Treatment of childhood disintegrative disorder includes the same components available in the treatment of autistic disorder. Asperger’s Disorder The former diagnosis of Asperger’s disorder is characterized by impairment and oddity of social interaction and restricted interest and behavior. Unlike the former autistic disorder, in Asperger’s disorder there are no significant delays in language or cognitive development. In 1944, Hans Asperger, an Austrian physician, described a syndrome that he named “autistic psychopathy.” His original description of the syndrome described individuals with normal intelligence who exhibit a qualitative impairment in reciprocal social interaction and behavioral oddities without delays in language development.

Asperger’s disorder occurs in a wide variety of severities, including cases in which very subtle social cues are missed, but overall social interactions are mastered. Etiology. Asperger’s disorder, a version of autism spectrum disorder, has a complex etiology including genetic contribution and potentially environmental and perinatal contributing factors. Diagnosis and Clinical Features. The clinical features include at least two of the following indications of qualitative social impairment: Markedly abnormal nonverbal communicative gestures, the failure to develop peer relationships at the expected level. Restricted interests and patterns of behavior are present, but when they are subtle, they may not be immediately identified or singled out as different from those of other children. According to DSM-IV-TR, individuals with Asperger’s disorder exhibit no language delay, clinically significant cognitive delay, or adaptive impairment. Currently, the clinical phenotype of Asperger’s disorder is subsumed within the DSM-5 diagnosis of autism spectrum disorder. Jared was an only child. Birth, medical, and family histories were unremarkable. His motor development was slightly delayed, but language milestones were within normal limits. His parents became concerned about him at age 4 when he was enrolled in a nursery school and was noted to have difficulties in peer interaction, joining activities, and following the rules that were so pronounced that he could not continue in the program. In grade school, he was enrolled in regular education classes and was noted to have difficulties making friends and playing sports with the other students, and he often played alone and spent time alone at lunch and recess. His greatest difficulties arose in peer interactions—he was viewed as eccentric and did not seem to understand how to interact with peers. At home, he seemed captivated by watching the weather channel on television, which he insisted on watching and pursued with great interest and intensity. On examination at age 13, Jared had markedly restricted and intense interests and exhibited pedantic and odd patterns of communication with a monotonic voice quality. Psychological testing revealed an IQ within the normal range. Formal communication examination revealed ageappropriate skills in receptive and expressive language but marked impairment in pragmatic language skills. (Adapted from Fred Volkmar, M.D.) Differential Diagnosis. The differential diagnosis includes social anxiety disorder, obsessive-compulsive disorder, and schizoid personality disorder. According to the previous DSM-IV-TR, the most obvious characteristics of Asperger’s disorder compared to autistic disorder are the absence of language delay and dysfunction. The lack of language delay and impaired use of language were previous requirements for Asperger’s disorder; however, social and communication deficits are present. Studies comparing

children with Asperger’s disorder and autistic disorder found that children with Asperger’s disorder were more likely to seek social interaction, and due to their awareness of their impairment sought more vigorously to make friends. Although in this subgroup within autism spectrum disorder significant delay in language is not a feature, some delay in the acquisition of language, and some impairment in verbal communication has been noted in more than one third of clinical samples. Course and Prognosis. The factors associated with a good prognosis in this subgroup within autism spectrum disorder are a normal IQ and more competencies in social skills. Reports of some adults diagnosed with Asperger’s disorder indicate that their social and communication deficits remain and they continue to relate in an awkward way and appear socially uncomfortable. Treatment. Treatment of individuals who meet the criteria for the previous Asperger’s disorder diagnosis aims to promote social communication and peer relationships. Interventions are initiated with the goal of shaping interactions so that they better match those of peers. Very often children with Asperger’s disorder are highly verbal and have excellent academic achievement. The tendency of children and adolescents with Asperger’s disorder to rely on rigid rules and routines can become a source of difficulty for them and be an area that requires therapeutic intervention. A comfort with routines, however, can be utilized to foster positive habits that may enhance the social life of a child with Asperger’s disorder. Self-sufficiency and problemsolving techniques are often helpful for these individuals in social situations and work settings. Some of the same techniques used for autistic disorder are likely to benefit patients with Asperger’s disorder with severe social impairment. Pervasive Developmental Disorder Not Otherwise Specified Whereas the DSM-IV-TR defines pervasive disorder not otherwise specified as a condition with severe, pervasive impairment in communication skills or the presence of restricted and repetitive activities and associated impairment in social interactions, DSM-5 conceives of this as encompassed within a diagnosis of autism spectrum disorder. Anna was the older of two children. She had been a difficult baby who was not easy to console but her motor and communicative development seemed appropriate. She was socially related and sometimes enjoyed interaction, but she was easily overstimulated. She exhibited some hand flapping behavior, especially when she was excited. Anna’s parents sought evaluation when she was 4 years of age because of problems with getting along with other children. At evaluation Anna was found to have language and cognitive function within the normal range. Anna had difficulty relating to her parents as sources of support and comfort. She displayed behavioral rigidity and a tendency to impose routines on social skills. Anna was placed in a special education kindergarten and did well academically, although problems in peer

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