Chapter 92. Autistic Spectrum Disorders

In 1943 Leo Kanner, a child psychiatrist, described a group of children with extreme aloofness and “total indifference” to other children, which he labeled autistic disturbances of affective contact. His description is as relevant today as it was back then: “The children use (language) for the purpose of communication. . When sentences are formed, they are for a long time mostly parrot-like repetitions of heard word combinations. They are sometimes echoed immediately. .” “There is a limitation in the variety of his spontaneous activities. . The dread of change and incompleteness seems to be a major factor in the explanation of the monotonous repetitiousness and the resulting variety of spontaneous activity.”1 Hans Asperger independently described children who demonstrated symptoms similar to Kanner’s patients but had higher cognitive and verbal skills. The conceptualization of this disorder has since broadened, and the most recent version of the Diagnostic and Statistical Manual of Mental Disorders2 describes pervasive developmental disorders (PDDs). These include 3 autism spectrum disorders (ASDs): autistic disorder, Asperger disorder, and pervasive developmental disorder not otherwise specified (PDD-NOS). Two other diagnoses, Rett syndrome and childhood disintegrative disorder are also included in the DSM-IV-TR but are not considered ASDs.

Current estimates of the prevalence of autism are 1 in 150 or 6.6 per 1000 8-year-olds.3,4 This accounts for 1 to 1.5 million children in the United States, a 10-fold increase from older studies. The older studies of autism prevalence targeted autism disorder alone, while the newer studies also include individuals with Asperger disorder and PDD-NOS. From a public health perspective, this amounts to a cost of over $90 billion annually, 90% of which is attributable to the cost of adult services.5

The increase in prevalence of autism represents, in part, the broadening of autism spectrum disorder (ASD) diagnostic categories in the DSM, increased public awareness, more reliable screening and evaluation tools, increased physician awareness, better ascertainment of cases, the introduction of a school designation of an educational category of ASD, and the eligibility of children with ASDs to receive special education services under the Individuals with Disabilities Education Act (IDEA).6 This may also reflect increased ascertainment of children with milder ASDs, including higher functioning children. For example, the rate of mental retardation (IQ < 70 with commensurate levels of adaptive functioning) associated with ASDs has gone from 90% in the 1990s to less than 50% in 2000. Diagnostic substitution may also play a role. The number of children receiving special education services under categories such as mental retardation language, language disorders, and learning disabilities has decreased over the same period that the diagnosis of autism has increased. The impact of this process is still considered controversial.

Public concern about whether the increase in prevalence is in part due to receiving the measles-mumps-rubella (MMR) vaccine and/or to the preservative thimerosal mercury in vaccines has led to an extensive public debate. As a recent Web site posting proclaims: “Take one preventive medicine that everyone gets, and one devastating disease that no one understands. Mix them together, add a provocative theory, and you have a recipe for a public health disaster.”7 In 2004, the Institute of Medicine of the American Academy of Science conducted an extensive study and concluded that evidence does not support a causal relationship between MMR or thimerosal mercury and autism.8 They found that a consistent body of epidemiologic evidence shows no association, that biologic models linking MMR and autism are fragmentary, and that there are no relevant animal models linking the 2. They concluded, however, that epidemiologic evidence lacks the precision to say that there is no connection and does not exclude the possibility that MMR vaccines and thimerosal could contribute to ASD in a very small number of children.

The increase in autism spectrum disorder prevalence is often called an “epidemic of autism” but presently, what can be said is that the reported prevalence of autism has certainly increased and this cannot be solely attributed to changes in diagnostic methods. It is unknown whether, and to what extent, this increase is attributable to changes in “real risk” (epigenetic, nutritional, toxic etiologies, etc), because we have only a partial understanding of autism risk factors. However, the increase of prevalence cannot be solely attributable to changes in diagnostic criteria or improved diagnostic methods.

Autism spectrum disorders are a group of heterogeneous disorders. For the majority of presentations, the etiologies are unknown and multifactorial. Autism spectrum disorders can be considered “essential” when children meet DSM diagnostic criteria and a careful history and physical examination does not suggest a specific etiology. Less than 10% of autism spectrum disorders are associated with medical conditions or known syndromes. These presentations are called “syndromic” or “complex.” Examples of etiologies of complex autism include chromosomal syndromes (fragile X, Angelman syndrome, 15q duplications, Down syndrome, del22q11, Ring 20, Rett disorder), syndromes without known chromosome anomalies (Sotos; Smith-Lemli-Opitz; Moebius; coloboma, heart disease, atresia of choana, retarded growth and development, genitourinary anomalies, ear/hearing anomalies [CHARGE] association), neurocutaneous syndromes such as tuberous sclerosis, congenital and acquired infections (rubella and cytomegalovirus), in utero drug exposure (alcohol, thalidomide, valproic acid), and inherited metabolic disorders (phenylketonuria and disorders of purine metabolism).9

Maternal and paternal age and environmental exposures during early gestational life, such as teratogens, have been shown to be risk factors for having a child with essential autism. It has been suggested that fetal testosterone may also play a role. The recurrence risk of essential autism is 5% to 6% when a sibling already has autism spectrum disorder (ASD). Epigenetic influences are also likely involved. The role of immune system dysfunction in the etiology of ASDs has been suggested but remains to be determined. An association with neonatal encephalopathies has also been reported. Several autism-linked chromosomal anomalies have been found, particularly on the X chromosome as well as chromosomes 2, 3, 7, 15, and 22.6 Children with essential autism are more likely to have autism that is heritable, sibling recurrence and relatives with autism, and higher male-to-female ratio (4:1); to develop the regressive form of autism; and to have better outcomes, higher IQs, and fewer seizure disorders than children with complex autism. Children with complex autism have physical findings, including multiple minor physical anomalies and/or microcephaly. They present with a 1:1 male-to-female ratio; have lower IQs; are more likely to have seizures, abnormal electroencephalograms, and more brain anomalies by magnetic resonance imaging; and to have identified syndromes. They are less likely to have a family history of ASDs.10

The pervasive developmental disorders (PDDs) are characterized by delays in socialization and communication, narrow repetitive interest, and behavioral routines. Some are apparent in infancy and in most cases have an onset prior to 3 years of age.

Autistic disorder is the most severe, with disabilities in all 3 domains: socialization, communication, and fixed repetitive interests and routines. Detailed diagnostic criteria for autistic disorder and Asperger disorder are listed in Table 92-1. Pervasive developmental disorder not otherwise specified (PDD-NOS) refers to the presence of severe and pervasive impairment in reciprocal social interaction; verbal and nonverbal communication; and/or stereotyped behavior, interests, and activities where criteria are not met for a specific autism spectrum disorder, schizophrenia, schizotypal personality disorder, or avoidant personality disorder. It includes presentations that do not meet the criteria for autistic disorder because of factors including late age of onset, early identification before the age that restricted repetitive behaviors typically develop, atypical symptomatology, or a presentation in which all criteria for a specific pervasive developmental disorders (PDD) diagnosis are not met but PDD is still the best explanation for the presenting concerns. In PDD-NOS, social skills are often less impaired than in autistic disorder, intellectual deficits less common, and these children often come to professional attention later.

Impairment from autism spectrum disorders depends not only on the severity of these autistic features (atypicalities) but also on the presence of developmental delays or deficits in cognitive abilities. Any degree of atypicality can coexist with any degree of intellectual abilities. Individuals with an IQ and adaptive behaviors lower than standard scores of 70 are typically much more impaired than individuals with higher intellectual functioning. Level of functioning can be thought of as an interaction between autistic features and cognitive abilities.11(see eFig. 92.1)

Rett syndrome usually appears in girls who develop normally until approximately 6 to 18 months of age. They have normal head size at birth, followed by a diminished rate of head growth, severely impaired expressive language, loss of purposeful hand skills, and development of repetitive hand movements including hand washing, hand wringing, hand clapping, and hand mouthing. They often have shakiness of the torso and, if able to walk, unsteady, wide-based, stiff-legged gait and toe walking. They demonstrate autisticlike regression, especially if they have microcephaly, seizures, and hand-wringing stereotypies. The diagnosis can be confirmed in about 80% of cases with DNA testing for methyl CpG-binding protein 2 (MECP2). Rett syndrome is much less common in males because it occurs on the X chromosome, and males often expire in utero or early in infancy. Childhood disintegrative disorder is extremely rare and presents with significant loss of previously acquired skills (before age 10 years) in at least 2 of the following areas: expressive or receptive language, social skills or adaptive behavior, bowel or bladder control, play and motor skills.

Social deficits are the key feature and often the earliest signs of autism spectrum disorders, but they can be subtle or overlooked by parents and physicians. A parent’s first concerns are often around speech delays between 15 and 18 months. In the case of regressive autism, parents may notice loss of social and speech landmarks at around the same time. eTable 92.1 lists some of the landmarks in typically developing children that are often delayed or absent in children who have an autism spectrum disorder.

Children with autism spectrum disorders can lack speech, or their speech can lack communicative intent. They may not be able to hold a conversation, they may use unusual language or echolalia (parroting), or they may recite scripts from favorite videos. In addition, rich imaginative play relies heavily on communication and language. In addition, restricted, repetitive interests and behaviors often do not start until the third year of life. These include narrow interests, insistence on sameness, stereotypic behaviors such as hand flapping, and interest in parts of objects (like spinning wheels of a train) instead of the object itself. Many of these behaviors can be seen in the Autism Video Gallery at the Web site for Autism Speaks.12

Deficits in joint attention are one of the most striking and distinguishing signs of autism. Joint attention occurs when infants share their gaze between an object or event and another person by looking back and forth between the two. For example, a mother may be looking out the window and say, “Look, its snowing!” The infant shifts his gaze to look out the window to see what his mother is referencing, then looks back to the mother to acknowledge that he has shared the observation. By 8 months, a child follows a parent’s gaze, and at 10 to 12 months, follows a point. Infants initiate protoimperative (“I want”) pointing at 12 to 14 months and protodeclarative pointing (“look, isn’t this interesting!”) at 14 to 16 months. The ability of an infant to mobilize joint attention appears necessary to and predictive of the development of functional language.

Lack of imitation is a key deficit in children with autism spectrum disorders. Social referencing is the ability of typically developing children to recognize the emotional states of others as they encounter different situations. Children learn how to modulate their own behavior in situations by observing adults’ expressions and responses and subsequently learn how to imitate these expressions and responses. Children with autism also have difficulty taking the perspective of others and anticipating what they are thinking and feeling (theory of mind). Theory of mind does not depend on oral communication. The cartoon in eFigure 92.2 demonstrates both joint attention and theory of mind. Children who lack theory of mind have difficulty sharing, comforting, and being empathic.

Between birth and 14 months, about 60% of children with autism (6% of typically developing children) experience brain overgrowth (>2 standard deviation).13 This may reflect a reduction in neuronal pruning and consolidation of synapses during development. If the synaptic strengthening and pruning process is undermined, the enhancement of circuits such as those used for social interactions does not take place. It has been speculated that synapses are developing so rapidly during this period that without a normal synaptic pruning process, experience does not have a chance to determine which are maintained and which are eliminated, leading to the social isolation characteristic of the disorder.

About 25% of children with autism spectrum disorders appear to develop along a typical trajectory until about 15 to 18 months. They then begin to regress and lose skills, most noticeably language, joint attention, and social referencing. The mechanisms leading to this regressive form of autism are not well understood.6

Children with Asperger disorder often present later. They are interested in their environment and do not typically have speech or language delays. They can, in fact, use very pedantic language (“little professors”) and can be quite erudite about subjects of intense interest to them, but they are unable to talk about feelings, lack theory of mind, and may have clumsy motor skills.

Autism spectrum disorders (ASDs) are often not diagnosed until 4 to 5 years of age in spite of parents having developmental concerns at a much earlier age. Because early detection is the key to early intervention, surveillance (an ongoing process of identifying children at risk for developmental delays) and screening (the application of standardized tools at defined intervals to detect risk for developmental disorders) for ASD are strongly recommended.14 Current recommendations from the American Academy of Pediatrics (AAP) are for developmental surveillance to be incorporated at every well-child care visit. Any concerns raised through surveillance should then be promptly addressed with standardized screening tests. Screening tests should be routinely administered at the 9-, 18-, and 24- to 30-month visits. The AAP in 2007 recommended surveillance and screening specifically for ASD. Concerns from a parent and other caregiver, the pediatrician’s observations, and a history of siblings with ASD should lead to evaluation of social and communication skills in children under 18 months and the administration of ASD-specific screening tools in children 18 months and older. The Modified Checklist for Autism in Toddlers (M-CHAT)15 is an example of an appropriate screening tool for children 18 to 48 months old. It is an easily administered and scored 23-item questionnaire completed by parents and has excellent sensitivity and specificity characteristics; it is available without cost at www.dbpeds.org. If screening results are positive, parent education, a referral for a comprehensive ASD evaluation, and, simultaneously, early intervention/early childhood education and an audiologic evaluation should be planned.

Ideally, the definitive diagnosis of ASD is established by an interdisciplinary team of specialists. Appropriate teams may includes various combinations of a developmental behavioral pediatrician, neurodevelopmental pediatrician, child psychiatrist, neurologist, child psychologist or neuropsychologist, speech pathologist, medical geneticist, occupational therapist, physical therapist, and medical social worker. The recommended elements of a comprehensive evaluation are summarized in eTable 92.2. The goals of a comprehensive evaluation are to come to a diagnostic formulation and define areas of functional disabilities so that a comprehensive intervention plan can be formulated.

Health, development, and behavioral history should include information gathering about behavioral and psychiatric comorbid conditions such as inattention, hyperactivity/impulsivity, oppositional behavior, and depressive and anxious symptoms. Gastrointestinal and sleep histories should be detailed. Several validated scales are available to establish the diagnosis. Tests for high-resolution G-banded chromosomes and a molecular test for fragile X syndrome have the highest yield in identifying etiology. Fluorescent in situ hybridization can be ordered if clinical findings suggest a specific disorder on a known chromosome. Genomic hybridization microarray analysis techniques are available. In children with global developmental delays or cognitive-adaptive disorders (mental retardation), multiple anomalies, or microcephaly, a brain MRI should also be considered. An electroencephalogram, metabolic studies, and other laboratory measures should be considered only if clinically indicated by history and physical examination.

Autism spectrum disorders are chronic disorders. They are most effectively treated in the context of a medical home model. At this time, they are not “curable.” Interventions should address minimizing functional disabilities imposed by social deficits, communication delays and atypicalities, restricted and repetitive behaviors, and coexisting symptoms and conditions. Treatment goals should include maximizing independent functioning, improving quality of life, and supporting families. Interventions targeting core deficits, education, problematic behaviors, social skills, play skills, medical symptoms, and family support can help achieve these goals.

In the United States, children with autism spectrum disorders are eligible for special education through the Individuals with Disabilities Education Act.16 The Act does not mandate specific interventions or assure that treatment programs are of adequate intensity or empirically validated. Educational research has focused the most on early intervention. Many programs use behavior analysis principles, developmental principles, and/or structured teaching. In 2001, the US Department of Education solicited a report on the education of children with autism.

Important components of early educational intervention for children with ASDs include entry into year-round, highly structured, intensive programs emphasizing functional communication, social skills, joint attention, symbolic play, self-management, and reduction of disruptive behaviors as soon as autism spectrum disorder is suspected.17,18 An expanded list of components of sound early intervention programs is found in eTable 92.3.

Approaches to autism spectrum disorder treatment are on a continuum from strictly behavioral to naturalistic. The behavioral approaches use the principles of behavior modification and are part of a larger field of therapy known as applied behavior analysis. There is a general consensus that entry into intervention as soon as the diagnosis is suspected rather than deferring until a definitive diagnosis is made is beneficial. Provision of intervention, with active engagement of the child for at least 25 hours per week is recommended but the optimal types of intervention and intensity are less clear.17 ABA therapy should be considered when a child is significantly cognitively limited, cannot sit and attend, and has poor joint attention, especially when beginning therapy. It is often the treatment of choice when the natural environment is too distracting for the introduction of a new skill or when it is essential to concentrate on some aspects of a complex task and not on others.

Applied behavior analysis therapy is based on learning theories and seeks to improve social and communication skills and to minimize outbursts of unwanted behavior. It is a method of increasing desirable behaviors, reducing interfering maladaptive behaviors, and teaching new skills and generalizing them to different situations or environments.19 Antecedents and consequences of behaviors are carefully analyzed so that they can be used to change the factors that are contributing to the problem behavior and to substitute acceptable behaviors to get the same need met. This treatment was pioneered by Ivar Lovaas, who reported that almost 50% of young children who received intensive early applied behavior analysis for 40 hours per week for 2 years had outcomes indistinguishable from their typically developing peers.20 Although other studies do not show gains of that magnitude, several show that early applied behavior analysis does lead to significant and sustained gains in IQ, language, academic performance, and adaptive behavior.

Of two recent literature reviews of the effectiveness of applied behavioral intervention programs for preschool children with autism, one concluded that when there was not adequate evidence to show that applied behavioral intervention programs significantly improve cognitive outcomes compared to standard therapy for children with autism, and another concluded that early intensive behavioral interventions (not just applied behavioral therapy) resulted in improved outcomes primarily measured by IQ compared to comparison groups but there was considerable variance in outcomes that may be dependent upon initial IQ (but not age).^{ch92ref20a,ch92ref20b}

Naturalistic or developmental approaches incorporate natural situations in which the child is already interacting and reward the child through creating opportunities to do more of what the child already enjoys doing. Naturalistic approaches are indicated when components of a skill can be taught in the course of normal daily routines (eg, meals, toy play, bathing, recreational activities) and if initial components of a difficult-to-learn skill have already been acquired (eg, using an applied behavior analysis approach). Naturalistic methods should be used only if the therapist is sufficiently skilled to recognize teachable opportunities in the context of ongoing daily activities. The TEACCH (Treatment and Education of Autistic and Related Communication Handicapped Children) has a long history and well-developed curriculum but lacks the kind empiric support that applied behavior analysis enjoys.21 TEACCH emphasizes improving skills and modifying the environment to accommodate deficits of children with autism spectrum disorders.21

Developmental models have less empiric support. These include the Denver model, floor time, and relationship-development interventions. The Denver model focuses on remediating deficits in imitation, emotion sharing, theory of mind and social perception with play, interpersonal relationships, and activities to enhance communication and symbolic thought. Other more naturalistic relationship-focused models include Greenspan and Wieder’s developmental, individual-difference, relationship-based model (floor time) and Gutstein and Sheely’s relationship-development intervention. Empirical research for these interventions is lacking at this time.

Speech and language therapy are components of many home- and school-based educational programs and behavioral therapies. Even children with lower cognitive functioning can develop some functional language and benefit from appropriate speech and language interventions. However, more intensive interventions than the typical pull-out services available in schools are generally needed. In addition, gestures, sign language, and picture communication programs like the Picture Exchange Communication System (PECS) are often used for nonverbal children and can be useful precursors to speech by teaching about symbolic communication. Promoting communication skills is one of the best ways of preventing the emergence of behavior problems.

Research regarding the efficacy of physical and sensory integration therapies is lacking.21 Sensory integration is based on the observation that children with autism spectrum disorders often exhibit unusual sensory responses and sensitivities, such as aversions to certain textures. Techniques of sensory integration include brushing of the skin, swinging to stimulate vestibular responses, and deep-pressure massage to promote calming. Because of the lack of empirical evidence, sensory integration therapies should not be considered primary interventions for children with autism spectrum disorders.

Approximately 11% to 39% of children with autism have seizures, as many as 10% have tics, 30% to 75% have significant problems with inattention and/or hyperactivity/impulsivity, and 25% to 40% have depression and/or anxiety.9,17

Behavioral exacerbations are often considered part of the natural history of autism spectrum disorder. These may stem, in part, from parents inadvertently reinforcing behaviors that they do not want to see. Functional behavioral analyses can help to sort this out. It consists of identifying the antecedents and consequences that keep a behavior going, and then analyzing the purpose of the behavior (whether it is to escape a situation, get attention, or get something tangible or is due to sensory overload). The analyst then suggests more adaptive behaviors that can be substituted for the problem behavior to meet the same need. However, it is not uncommon to find that these behavioral exacerbations are secondary to pain and discomfort from medical problems, particularly in children who have difficulty communicating. This may be particularly the case with aggressive or self-injurious behaviors. Possible sources include dental abscesses, otitis media, sinusitis, urinary tract infections, constipation, and gastroesophageal reflux.

Gastroesophageal reflux, chronic constipation, and diarrhea in children with autism have received increasing attention. Endoscopic studies show a high rate of lymphonodular hyperplasia, mild esophagitis, gastritis, duodenitis, and colitis; these findings suggest a chronic inflammatory process may be associated with autism spectrum disorders.17

Children with autism spectrum disorders often have problems with initiating and maintaining sleep. Sleep deprivation can interfere with daytime functioning. There is some evidence that it may be caused by dysregulation of melatonin.22 Controlled release melatonin may be very helpful in regulating these sleep problems.

There is no medication that reverses the core symptoms of autism spectrum disorder, but pharmacotherapy has been used for aggression, agitation, and irritability; repetitive and compulsive behaviors; inattention and hyperactivity/impulsivity; affective instability; social withdrawal; anxiety and hyperarousal; and sleep dysregulation. Psychopharmacologic approaches to these symptoms are reviewed in Table 92-2. Psychopharmacologic treatments have not been studied sufficiently to have FDA approval or offer an evidence-based approach to management. Risperidone has been approved by the FDA for irritability, aggressive behavior, self-injury, and temper tantrums in children and adolescents with autism. Stimulant medications have also been found useful in children with autism spectrum disorder and accompanying attention deficit hyperactivity disorder symptoms. The efficacy of stimulants is more variable with this group of children, and adverse effects more prominent.

Complementary and alternative treatments are commonly used by parents. Popular nutritional supplements include vitamins, dimethylglycine, essential fatty acids, and probiotics. Gluten-free and casein-free diets are currently under scientific investigation. Immunologic interventions include intravenous immunoglobulins, antiviral medication, chelation, antibiotics, and antiyeast therapy. Secretin is an example of an off-label use of a prescription medication. Several controlled studies have found it ineffective. It is essential for physicians treating families with autism to know the goals of treatment and the evidence and potential side effects of these treatments to help families in their decision making.23 Parents should be cautious about adopting these therapies when they claim to “cure” autism spectrum disorders, rapid effects are promised, promoters benefit financially or otherwise from adoption of the therapy, and negative findings from scientific studies are ignored or dismissed.

Outcome is related to age at diagnosis, language and cognitive skills at 2 years, lack of joint attention at 4 years, cognitive and social interaction level, and the presence of significant developmental delays and atypical features at the time of diagnosis. Early identification followed by intensive behavioral interventions may have a significant impact on prognosis.19 Many children improve but still retain autism spectrum disorders features. Adult prognosis correlates better with IQ than with severity of autistic symptoms. Within the subgroup of children with normal developmental and cognitive abilities, the degree of atypical behaviors becomes the most important prognostic feature.