Autism Disorder

Autism was first described in the third edition of the DSM (DSM-III) in 1980²⁴ as “Infantile Autism”; the current term, “Autistic Disorder” replaced “Infantile Autism” in the revised version of the DSM-III (DSM-III-R) in 1987.²⁵ Although clinical patterns vary in regard to severity, age at onset, underlying cognitive deficits, and other features, diagnosis of “classic” autistic disorder is dependent on the presence of at least half (six) of the criteria (Table 15-1).²⁰ Symptoms in at least one of these areas must have been present before the age of 3.

TABLE 15-1 Diagnostic Criteria for 299.00 Autism Disorder

Rights were not granted to include this table in electronic media. Please refer to the printed book.

Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision. Washington, DC: American Psychiatric Association, 2000, p 75.

Asperger Syndrome

Asperger syndrome is characterized by the same impairment in social interaction and restricted interests as in autistic disorder; however, language skills are relatively normal (defined as use of single words by age 2 years and phrases by 3 years) (Table 15-2).²⁰ Later language is characterized by pragmatic deficits (problems with the social use of language). In addition, cognitive and adaptive skills are normal. Depending on the child’s age, it is sometimes quite challenging to distinguish between children with Asperger syndrome and children with autistic disorder and normal intelligence. Because of this, controversy exists as to whether Asperger syndrome represents a high-functioning form of autism or a separate entity.^26,27 Children with Asperger syndrome are usually not recognized until after 4 years of age, when social interactions with peers in preschool settings become a concern.

TABLE 15-2 Diagnostic Criteria for 299.80 Asperger Disorder^*

Rights were not granted to include this table in electronic media. Please refer to the printed book.

Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision. Washington, DC: American Psychiatric Association, 2000, p 75.

Pervasive Developmental Disorder, Not Otherwise Specified

Pervasive Developmental Disorder, Not Otherwise Specified is a subthreshold term that is used when a child demonstrates some but not all of the criteria necessary to make a diagnosis of one of the specific PDDs. Unfortunately, there was an error in the DSM-IV text¹⁹: It stated that PDD-NOS should be used when there was an “impairment in… social interaction” or in verbal and nonverbal skills. This allowed clinicians to apply the PDD-NOS label in the absence of social skill deficits, thus broadening the definition of PDD-NOS and causing loss of specificity. This error was corrected in the DSM-IV-TR.²⁰ The PDD-NOS label is reserved for persons who demonstrate “severe and pervasive impairment in the development of reciprocal social interaction” and either communication deficits or restricted interests/repetitive behaviors. Confusion still exists regarding the actual number of criteria that are necessary to apply the PPD-NOS label; by convention, at least two but not more than five should be present. PDD-NOS also includes “atypical autism,” which refers to persons with at least one feature that is dissonant with traditional autism, such as later onset or absence of stereotypies.^28,29

Throughout this chapter, ASD refers to all three disorders as a group. When a specific ASD is discussed, the appropriate term is used. Autism is used in reference to older literature published before the concept of a spectrum of autistic disorders emerged. A broad spectrum does appear to exist, although its external and internal boundaries are hazy.^30,31 Family studies have shown that the entire spectrum may be expressed in the same pedigree. Sometimes the term broader autism phenotype is used for individuals with isolated social deficits, particularly in the context of extended-family relatives of probands with autism.^32,33

Genetic Underpinnings

Studies of twins have revealed concordance rates of classic autism in 60% of monozygotic pairs and in 0% to 3% of dizygotic pairs.^22,88,90 When the broader phenotype was taken into consideration, the rates were 60% to 92% and 0% to 10%, respectively. In addition, family studies have demonstrated a rapid decrease in prevalence among first, second, and third-degree relatives. Using these data, Bailey and colleagues²² calculated that the predisposition for autism was more than 90% heritable, with multiple interacting genetic influences and strong family clustering.⁹¹ In spite of these strong genetic underpinnings, the exact cause or causes are still unknown. The task has been daunting because of genetic complexity and phenotypic variation. First, ASDs appear to be complex heritable disorders involving multiple genes; estimates based on family studies range from 5 to 20 genes.⁸⁹ Each gene or gene combination may result in somewhat different subtype but often with overlapping behavioral phenotypes. The number of genes contributing to the disorder and the relative prevalence of each will increase or decrease the probability of identifying the cause; that is, success is more likely if there are relatively few genes that are somewhat common than if there are many genes that are rarer.⁹¹ A second factor making gene identification more challenging is the variability in the ASD phenotype. The wide spectrum of symptoms sometimes promotes inclusion of participants in a study with various ASDs, sometimes even including individuals with disorders falsely categorized to be in the spectrum. This imprecise diagnosis contaminates the study group and makes identification of a unifying etiological agent elusive.^92,93

Two major strategies have been used in the search for the ASD susceptibility genes: targeted cytogenetic studies and whole genome screens of families of children with ASD.^91,94 The first strategy depends on developing a hypothesis regarding the pathogenesis of ASD, focusing on one or more potential candidate genes and testing them genetically for an association with ASD. Candidate genes in ASD include, among others, those that appear to play a role in brain development (e.g., cerebellar Purkinje cell proliferation)^15,95 or in neurotransmitter function (e.g., serotonin transmitter).⁹⁶ The second strategy entails an indirect method and does not require investigators to make assumptions regarding the mechanism of inheritance. Instead, families with multiple members demonstrating an ASD (multiplex families) are studied to identify recurring DNA markers (breakpoints, translocations, duplications, and deletions) present in affected, but not in unaffected, members. Unfortunately, progress has been limited because the phenotypic endpoints of ASD are not well defined. Changes in DSM criteria and inconsistency in ascertainment strategies, resulting in a hazy delineation between “affected” and “unaffected” family members, contaminate outcomes and challenge interpretation of results. This phenotypic heterogeneity has challenged molecular searches for the ASD gene or genes in spite of several genomewide screens (International Molecular Genetic Study of Autism Consortium [IMGSAC]) and multicenter collaborative efforts since the 1980s.^93,97–99 The results are very enlightening; however, rather than providing conclusions based on replicated findings from multiple labs, these studies have often produced confusion and uncertainty as more susceptibility loci are described. Although at least one autism-linked abnormality has been found on almost every chromosome, few sites have been identified with any frequency. Table 15-4 provides a summary of some of the more consistent findings; however, the reader is advised to consult more extensive reviews.^{7,92,100–104} Large study samples with pooled data from multiple populations (maximizing homogeneous samples) are needed to confirm the validity of reported candidate genes and susceptibility sites in ASD.⁹³

TABLE 15-4 Selected Autism Spectrum Disorder (ASD) Genetic Markers

AGRE, Autism Genetic Resource Exchange; GABA, γ-amino butyric acid; IMGSAC, International Molecular Genetic Study of Autism Consortium.

Table 15-4 describes findings of genetic investigations that have, for the most part, targeted etiological possibilities for “idiopathic ASD,” which represents most cases of ASD. Although the literature provides multiple systems for characterizing ASDs, it is perhaps most helpful in a discussion of etiology to subtype ASDs as either idiopathic or secondary.¹⁰³ For the purposes of this discussion, patients with idiopathic ASD are those who do not have a coexisting associated medical condition or syndrome known to cause an ASD. Most individuals with ASD (perhaps almost all of those with Asperger syndrome) have the idiopathic subtype. Children with idiopathic ASD demonstrate variable behavioral phenotypes, are less likely to have coexisting mental retardation, and do not have dysmorphic features heralding a recognizable syndrome. Nevertheless, twin and family studies have revealed that idiopathic ASD is very heritable, with a recurrence rate of 3% to 7%,²² although phenotypic expression may be modified by other variables.⁹²

Patients with “secondary” ASD are children with a known identifiable syndrome or medical disorder believed to play an etiological role in ASD; this occurs in only 2% to 10% of cases.^{23,66,103–113} In a meta-analysis of 23 epidemiological studies, Chakrabarti and Fombonne⁴⁷ reported that a recognizable condition was identified in an average of 6% of those with a confirmed ASD. The rate of coexisting mental retardation was 26%, the lowest reported prevalence to date. The presence of severe mental retardation, especially when associated with dysmorphic features, increases the likelihood of identifying a genetic etiology.^{10,104,110,114} Genetic syndromes associated with ASD and coexisting mental retardation include

the fragile X syndrome^115–117

tuberous sclerosis^118–120

phenylketonuria¹²¹

Angelman syndrome^122–125

Of these four entities, the fragile X syndrome is the most common known genetic cause for the autistic phenotype, present in 1% to 5% of children with ASD, whereas 30% to 50% of those with genetically confirmed fragile X syndrome demonstrate some characteristics of ASD.^117,126 The presence of a known disorder does not automatically imply causation. A few children with genetic syndromes characterized by features quite different from ASD may also meet full DSM criteria. For example, investigators have reported that that 6% to 7% of children with Down syndrome (usually characterized by relatively good social skills and obvious physical stigmata)^58,127,128 and almost 50% of children with the CHARGE association^59,129 meet criteria for a diagnosis of either autistic disorder or PDD-NOS. Children with severe congenital sensory impairments (visual and/or auditory) are also at risk for the development of symptoms consistent with ASD, especially when appropriate early intervention is not provided.^60,61 Advancing paternal age has been shown to be associated with an increased risk of ASD possibly due to de novo spontaneous mutations and/or alterations in genetic imprinting.^129a

A variety of immunological abnormalities in T cells, immunoglobulins, and anti–brain autoantibodies have all been reported in retrospective case studies,^130–134 but systematic studies have confirmed neither their existence nor their relevance.^102,135 Prospective studies have revealed that, except for a few individuals with recurrent infections, healthy children with ASD generally have normal immune function.¹³⁵ Epidemiological data revealed clustering of autoimmune disorders in ASD families; however there was no increase in autoimmune disorders of the central nervous system and the patients with ASD did not themselves exhibit autoimmune disorders.¹³⁶ Food allergies have also been implicated to play an etiological role in a few case reports,^137,138 but, again, this has not been confirmed with rigorous studies.^12,102,139

Environmental Factors

Regardless of the mechanism, a review of studies published since the 1950s reveals convincing evidence that most cases of ASD result from genetic factors with possible interacting environmental factors.^{22,92,140,141} Environmental influences may represent a “second hit” or “trigger” phenomenon; that is, they may modulate/stimulate preexisting genetic factors to result in the manifestation of ASD in an individual child.

Environmental factors should have their greatest effect during the prenatal period, especially early in gestation, because the developmental brain abnormalities associated with ASD occur during the first and second trimesters.^141–144 Factors already identified to play a role include maternal rubella¹⁴⁵ or cytomegalovirus infections^146,147 and treatment with valproate^148,149 or thalidomide.^144,150 An isolated report¹⁵⁰ indicated that fetal exposure to thalidomide during days 20 to 24 of gestational age was associated with ASD symptoms; later exposure resulted in the more characteristic limb abnormalities but no ASD characteristics. Nelson and associates¹⁵¹ reported increased cord blood levels of brain-derived neurotrophic factor and other neurotrophins in newborns in whom ASD was later diagnosed, which may have implications regarding the mechanism of the characteristic early brain overgrowth. Some investigators feel that fetal toxin exposure might be implicated by studies that have demonstrated higher rates of ASD in offspring of mothers who resided in urban settings during pregnancy^152,153; however, other factors such as better access to diagnostic services in urban areas may be operative.

Seizures and Electroencephalographic Data

Electrophysiological studies were among the earliest used to probe differences in the autistic brain and provided the first evidence that autism was a neurological rather than a behavioral disorder. Abnormal electroencephalographic results are more prevalent in autism than is frank epilepsy (50% vs. 30%, respectively)^176,180 and reflect the disruption of balance between inhibition and excitation, which in turn can negatively affect attention and sensory processing.^179,181

Brain Growth

Kanner⁶ himself noted that 5 of his 11 original patients had large heads, but it was not until the1990s that brain size/volume in ASD was systematically studied through both indirect methods (occipitofrontal circumference measurements) and direct methods (sMRI and postmortem examinations). Although these early studies revealed increased brain size¹⁸² and volume,¹⁸³ the mechanisms and changes in growth velocity over the developmental period in children were not recognized until the late 1990s. Head size does not appear to be large at birth; in fact, it is sometimes reported as somewhat smaller than average.¹⁸⁴ Acceleration of growth, as evidenced by serial occipitofrontal circumference measurements and confirmed with volumetric studies, begins to occur around 6 months and peaks between 2 and 4 years of age, thus occurring in concert with (or even before) the appearance of ASD symptoms.^185–188 Approximately one third of children with ASD meet criteria for macrocephaly, and 90% have greater than average brain volumes.¹⁸⁵ Growth appears to level off in late childhood in the majority; thus, brain volume is not significantly different from that in controls by age 12 years, although macrocephaly (as measured by occipitofrontal circumference) may persist.^186,189,190 Furthermore, increased cortical folding resulting in abnormal gyral patterns, reflecting increased volume, has been noted in affected children but not adolescents or adults.¹⁹¹ These findings appear very consistent, especially when study subjects are matched for intelligence. The main contribution to increased size lies in nonuniform changes in the hippocampus, amygdala, and cerebral white matter and, less consistently, gray matter.^{185,192–194} Although several theories have been proposed for the abnormal growth pattern (e.g., increased neurogenesis, glial cell proliferation, abnormal myelin, and/or decreased apoptosis/pruning), it seems most likely that it is the outer radiate zone, related to intrahemispheric synaptogenesis and connectivity, that matures postnatally and produces the rapid growth in ASD. Interestingly, parents of children with ASD can have macrocephaly in the absence of ASD symptoms. Thus, macrocephaly might be caused by a susceptibility gene that works in concert with other genes to produce ASD.

Although there are numerous published sMRI studies, no consistent abnormalities have been reported with regard to the gross anatomy or growth of other brain structures such as the brainstem, basal ganglia, and cerebellum.^{44,182,183,192,193} Several studies have consistently shown impaired growth (caused by hypoplasia, not atrophy) in the body and posterior regions of the corpus callosum. Only one study has correlated these anatomical findings with deficits in interhemispheric cognitive tasks.¹⁹⁵ Rather than a focal neurological abnormality, ASD seems to be characterized by abnormalities of neural distribution and connectivity with excessive intrahemispheric connectivity and deficient interhemispheric connections (corpus callosum).¹⁷⁶

Cerebellar Purkinje Cells

Although comparisons of sMRI and volumetric studies of the cerebellum have been controversial, one of the most consistent findings over time has been the marked decrease in Purkinje cells noted in postmortem microscopic studies.^15,95,196 The absence of empty baskets suggests that the process is one of hypoplasia rather than atrophy after a noxious event, but some authorities disagree.¹⁹⁷ Reductions in reelin may contribute abnormal regulation of neuronal layering and microscopic abnormalities found in the cerebellum.¹⁹⁸ The absence of glial hyperplasia indicates the pathological process occurs early in brain development, before the time when the brain is able to initiate a reaction to neuronal injury. Furthermore, the number of olivary neurons is preserved, which provides additional evidence that the process must occur before weeks 28 to 30 of gestation. After this time, tight neuronal unions form between the two areas, and cell loss in the cerebellum would prompt an obligatory retrograde cell loss in the ascending olivary neurons.^{15,95,143,175} Although it has long been known that the cerebellum played a role in motor learning, modulation, and coordination, there is growing evidence that it also plays a role in verbal processing, affective behavior, and shifting of attention.¹⁹⁹ Bauman and Kemper¹⁷⁵ suggested that early in embryological life, the climbing olivary neurons might form primitive unions with collateral cells in the lamina dessicans (which disappears at 28 to 30 weeks) of the cerebellar peduncles. These neural units are not as efficient as the primary pathways and cease to function after a brief period. An intriguing question is whether this process may contribute to “autistic regression.”

Decreased Cell Size, Increased Cell Number, and Increased Packing Density in Limbic Structures

Investigators have targeted the limbic system because it plays an important role in social behavior/cognition (amygdala) and associative social memory, especially relationships among the emotional aspects of an experience (hippocampus). Postmortem microscopic studies have consistently revealed abnormalities in cell number and size and packing density in both the amygdala and hippocampus. However, sMRI and volumetric data have been inconsistent, diverse, and often contradictory.^193,200,201

Abnormal Minicolumns in the Cerebral Cortex

Abnormal cortical minicolumns (defined as the most basic unit of neural organization) have been added to the growing number of neuropathological abnormalities found in ASD. Although Bailey and colleagues²⁰² described several abnormalities of pyramidal neuronal migration (ectopic neurons in white matter zones, misoriented apical dendrites, and disorganized cellular layers) in the superior temporal gyrus. Casanova and coworkers²⁰³ more recently introduced “minicolumn” terminology into ASD literature. Minicolumns in some areas of the autistic frontal cortex were found to be smaller (representing an underdeveloped system) and had abnormal patterning. Both findings are consistent with deviant processes that occur very early in the second trimester. These anatomical abnormalities may result in deficient neuronal “insulation” and serve as the structural basis for increased neuronal “cross-talk” and overstimulation. This, in turn, may cause the sensory gating and processing difficulties found in some individuals with ASD.^203,204 Other autistic symptoms then might be explained by a disregulation of axonal outgrowth, dendritic arborization, and synaptic connectivity.¹⁷⁹ Abnormalities described in cortical frontostriatal circuits may be associated with ritualistic and repetitive behaviors.²⁰⁴ Volumetric sMRI studies of cortical systems serving language functions have revealed the absence of the usual left hemispheric hypertrophy (representing left brain dominance and language specialization). Instead of a larger left hemisphere (specifically, the Wernicke receptive language processing area), the planum temporale volumes were equal in subjects with ASD.²⁰⁵ Furthermore, decreased gray matter in the left inferior prefrontal gyrus or Broca’s area (expressive language center) resulted in actual reversal of the typical hemispheric asymmetry (left larger than right) in language-impaired subjects with ASD.²⁰⁶

Hypoactivity in the Fusiform Gyrus during Face Recognition Tasks

Functional neuroimaging techniques, primarily positron emission tomography and fMRI, have confirmed clinical and neuroanatomical data depicting ASD as a disorder characterized by uneven rather than generalized deficits.²⁰⁷ The most consistent fMRI finding has been hypoactivity in the fusiform gyrus, particularly in the fusiform facial area, confirming the clinical impression that deficits in facial recognition are characteristic of ASD.^208,209 fMRI has also demonstrated associated deficits in related areas of the “social brain,” such as the amygdala, which plays a critical role in emotional arousal and integration of emotional data.²¹⁰ Persons with ASD appear to be less motivated to look at faces or to follow the point of conversational partners.²⁰⁸ Computerized eye tracking techniques have also revealed that they pay less attention to faces and more attention to inanimate details in the background.^209,211,212 When they do look at the face, they target the mouth rather than the eyes. Because oral expressions provide less information about emotional states than the eyes, persons with ASD often fail to detect meaningful social information during interactions.²⁰⁸

Neurochemical Testing

Neurochemical abnormalities may also be present in children with ASD.¹⁷⁸ Increased levels of 5-hydroxytryptamine in whole blood, chiefly platelets, has been a fairly consistent finding. Although 5-hydroxytryptamine is an important neurotransmitter for brain development and modulation of sleep, mood, body temperature, appetite, and hormone release, no consistent abnormalities have been found in central nervous system levels. Age-related differences in serotonin synthesis capacity have also been demonstrated between children with autism and nonautistic controls.²¹³

In conclusion, it is widely accepted that ASD is a “neurodevelopmental disorder,” although the specific underlying abnormalities have not been identified. ASD may actually represent a disorder of neural distribution rather than frank structural abnormalities.¹⁷⁶ A project to create the first ever atlas of the autistic brain at several ages is well under way.²¹⁴ Newer functional brain studies have provided some intriguing links between the neuroanatomical substrate and characteristic clinical features. Well-designed studies with participants matched for IQ levels and with the most sophisticated technology (e.g., diffusion tensor imaging) are needed to unravel the mystery of anatomical differences and white matter “connectivity” and associated discrepancies in learning and neuropsychological functioning. Such studies may provide valuable information that can be used to design, implement, and evaluate new and effective intervention strategies.

Social Skills Deficits

As noted previously, abnormalities in social communication skills are the most unique and consistent findings in infants with ASD. They appear earlier than identifiable speech deficits but are often more subtle. Children with ASD universally demonstrate deficits in social relatedness, defined as the inherent drive to connect with others and share complementary emotional states.²²⁸ Children with other types of disabilities (e.g., mental retardation, sensory disabilities) still attempt to connect with others: Those with hearing deficits compensate with eye gaze and gestures, and those with vision deficits compensate with voice and touch. Children with ASD do not appear to seek this connectedness; they are usually content with being alone, rarely make eye contact or bids for others’ attention with gestures or vocalizations, and react little to praise or bids for attention from others. In later years, they have difficulty in sharing the emotional state of others in cooperative games and group settings and have few, if any, friends.

Communication Deficits

Most children in whom autistic disorder and PPD-NOS are later diagnosed present initially with “speech delay,” although this trend is slowly changing as parents become more aware of social milestones and sense that something is wrong before the child is 18 months old.^230,249 Although lack of or severe deficits in speech without any effort to compensate with gestures has long been thought to be characteristic of autistic disorder, more children who now receive diagnoses of autistic disorder do have some speech. Vocabulary deficits are often the focus of concern, but there are typically earlier communication deficits that, if detected, could promote earlier diagnosis.^241,249

For example,

Lack of the alternating to-and-fro pattern of vocalizations between baby and parent that usually occurs at approximately 5 months (i.e., babies with ASD usually continue vocalizing without regard for the parent’s speech).

Lack of recognition of mother’s (or father’s or consistent caregiver’s) voice.

Disregard for vocalizations but keen awareness of environmental sounds.

Delayed onset of babbling (past 9 months of age).

Decreased or no use of prespeech gestures (waving, pointing, showing).

Lack of expressions such as “oh oh” and “huh.”

Lack of interest or response of any kind of neutral statements (e.g., “Oh, no, it’s raining!”).

Parents are often unaware of these deficits unless the milestones are brought to their attention.

Approximately 25% to 30% of children with autistic disorder and PDD-NOS begin to say words at 12 to 18 months but then stop using them. “Autistic regression” characteristically takes place between 15 and 24 months of age after the child has mastered 5 to 10 words.^219,251 Many such children become completely nonverbal and cease to gesture (wave, point, and so forth). Although this regression is seemingly dramatic, some parents are able to rationalize the regression and attribute the loss of skills to a family event such as the birth of a new sibling or a move to a new house. Home videos recorded before the onset of regression have revealed that, in at least some children, mild delays and subtle early signs were present before the apparent regression, although there is a subset of children who were apparently normal.^168,220

Some children use “pop-up words”: that is, words that are verbalized inconsistently and with no apparent communicative intent. These words are said out of context for a short period of time (days or weeks) and then, as suddenly as they might pop up for no apparent reason, they also disappear.^17,238,249 On occasion, these utterances may be phrases or entire sentences, also said out of context. Spontaneously uttered pop-up words should be distinguished from “echolalia.” Echolalia, sometimes called “parroting” by lay individuals, is the repetition of another’s speech. It is classified as “immediate” when the child repeats another’s words right after they are heard or as “delayed” when repeated at distant time later. Normal children pass through a brief developmental stage (“vocabulary burst stage”) in which they imitate other’s speech, particularly the last one or two words of a sentence. Autistic echolalia can persist throughout the lifespan with little or no apparent communicative function. It often occurs long after the utterance (delayed echolalia) and is also qualitatively different in that the utterances are more exact, have a monotone quality and consist of larger verbal “chunks” (e.g., TV advertisement jingles, video re-enactments, or nursery rhymes). These verbalizations often exceed the child’s functional language skills and may be misinterpreted as “advanced” when in fact the child has difficulty following a simple one-step command. Some children with ASD become quite obsessed with labeling colors, shapes, numbers, and letters of the alphabet, and yet they cannot point to them on request or incorporate the labels into functional language. Later they may develop hyperlexia or advanced oral reading without corresponding comprehension skills.

Children with Asperger syndrome may have mild or very limited speech delays and thus escape recognition until around 3 to 4 years of age, when their inability to make friends becomes a concern. Although unnoticed, language development is atypical in that children are often quite verbal about some subjects (usually things or events), but unable to express simple feelings or recognize the feelings and viewpoints of others. Speech may be fluent but limited to only a few topics, typically those that hold a strong, all-consuming interest for the child. It can also be overly formal (pedantic), a reason why they are sometimes described as “little professors.”²⁴⁷ Children with Asperger syndrome also have deficits in the social use of language (pragmatics): how to choose a topic of conversation; understanding and producing appropriate tempo, facial expression, and body language during conversation; turn-taking; recognizing when the partner has lost interest in a topic; knowing when to start, sustain, and end a conversation on the basis of listener cues; knowing when and how to repair a communication breakdown; and using the appropriate degree of formality and politeness. Language may seem odd, pedantic, self-centered, and not listener-responsive and often results in a monotone monologue. These children may demonstrate unique delivery of speech (prosody) in regard to intonation, volume, rhythm, pitch, and personal space, and they tend to disregard listener needs. Children with Asperger syndrome and high-functioning autism have difficulty with abstract reasoning and with discussion of thoughts and opinions of others. Inability to discern and judge the conversational intents of others, especially when their conversation includes words or phrases with ambiguous meanings impairs their ability to understand metaphors, humor, sarcasm, teasing, metaphors, irony, lies, jokes, faux pas, and deception.^245,246

Play Skill Deficits

Play has many attributes. It can be sensorimotor, functional, constructive, pretend, or imaginary. Play can take place in isolation of, in parallel with, or through interaction with other children. It can also be pathological (i.e., ritualistic play). Mastery of pretend play, especially during interaction with others, builds on both communication and social skills. Lack of or significantly delayed pretend play, coupled with persistent sensorimotor and/or ritualistic play, is very characteristic of ASD and serves as a discriminating feature of both screening and evaluation ASD tools. Some children with severe ASD may never progress past the sensorimotor play stage. They mouth, twirl, bang, and manipulate objects in a stereotypic or ritualistic manner. Often they prefer to play with common objects (string, sticks, rocks, or ballpoint pens) rather than store-bought toys. One exception is puzzles, especially shape-matching ones and computerized “puzzle games.” These represent a form of “constructive play” (i.e., using objects in combination to create a product).²⁴¹ Children with ASD are often content to play alone for hours, requiring little attention or supervision. Often this “play” is either constructive (puzzles, computer games, and blocks), ritualistic (lining objects up or sorting/matching shapes or colors), or sensorimotor (mouthing, banging, twirling) in nature. Children with ASD may seem to enjoy chase games and roughhousing, but it is actually the games’ sensorimotor aspects rather than the social aspects that the child enjoys. Even when symbolic play does develop, it may not advance to more sophisticated social play such as role-playing with a peer. These children have trouble interacting in groups and cooperating in the social rules of games. Often they are left out, ignored, and at high risk of being bullied by peers.

Atypical Behaviors

Children with ASD often manifest repetitive, nonfunctional, atypical behaviors or stereotypies (e.g., hand flapping, finger movements, rocking, twirling).^19,20,227 Although most such behaviors are harmless by themselves, they are problematic in that they may prevent the child from accomplishing tasks and learning new skills and may interfere with inclusion in natural environments with typically developing peers. Although stereotypies are very distinctive and obvious, they are not specific to children with ASD. Children with severe mental retardation and/or severe visual deficits also commonly demonstrate stereotypies. Even normal toddlers, especially before the onset of fluent language, may flap their arms briefly when they are excited or frustrated. True autistic stereotypies often do not appear until after age 3 years and may include some behaviors such as habitual toe walking and/or sensory stereotypies (persistent sniffing and licking of nonfood items) that are less common in children with other disorders.

Although most children, at some time during their early development, form attachments with a stuffed animal, special pillow, or blanket, children with ASD often prefer hard items (ballpoint pens, flashlight, keys, action toys). Moreover, the attachment is much more robust; they may even insist on holding the object most of the day, even during meals, and protest violently when the object is removed. On a similar note, children with ASD may insist on “sameness,” again protesting when forced to make a transition from one activity to the next or to perform some activity out of order from the usual routine. Without warning, these protests may quickly escalate to severe and prolonged temper tantrums characterized by aggression or self-injurious behaviors.

Children with ASD, especially those with cognitive deficits, may demonstrate various forms of self-injurious behavior.²⁵² Such behaviors (e.g., head banging, skin picking, eye poking, hand biting) represent a class of stereotypies that, unlike those described previously, may cause bodily harm. Reasons for self-injurious behavior include those that may cause any child, with or without ASD, to display inappropriate behavior. These may include frustration during unsuccessful communication attempts to procure a desired object, protest against transitions, anxiety in new environments, boredom, pain, depression, fatigue, and sleep deprivation. In rare cases, it may result from an endogenous neurochemical abnormality in dopa, serotonin, opioid, or γ-amino butyric acid neural transmitter systems and/or a part of a behavioral phenotype associated with a known genetic syndrome such as the finger and lip biting characteristic in Lesch-Nyhan syndrome.

Additional Clinical Features That Are Common but Are Not Core Features

Screening

The importance of screening for ASD has been emphasized because early identification allows early intervention that can potentially improve outcome and also leads to etiological investigation and counseling with regard to recurrence risk.¹³ Although the clinical practice of developmental-behavioral pediatricians is more likely to involve comprehensive diagnostic evaluations than screening, training of general pediatricians and other primary health care providers in effective autism-specific screening strategies has become a primary obligation. Developmental-behavioral pediatricians may also be in a position to train or advise early intervention multidisciplinary teams with regard to screening for ASD.

Historically, the initial concerns of parents of children who later received diagnoses of ASD were dismissed, and diagnosis and intervention were therefore delayed.^216,217,259 In spite of increased public and professional awareness, the diagnosis of ASD is still often delayed. In a 2006 Centers for Disease Control and Prevention Atlanta-based study, Wiggins and colleagues⁵⁵ reported that the average age at the first documented ASD diagnosis was 60 months (range, 17 to 105 months). The average age at diagnosis was significantly younger (i.e., 41 months) in children with overall impairments. An average delay of 13 months occurred between the first evaluation by a qualified professional and the first ASD diagnosis. To address these ongoing challenges, the AAP now recommends administering a standardized autism-specific screening tool at the 18-month evaluation²⁶⁰ and, perhaps additionally at the 24-month health supervision visits^261,262 and at any age when ASD concerns are raised spontaneously by parents or as a result of clinicians’ observations or surveillance questions about social, communicative, and play behaviors.

ASD-specific screening tools are sometimes described as level 1 or level 2 screens.²⁶³ Level 1 screening measures are administered to all children and are designed to differentiate children at risk for an ASD from the general population, especially those with typical development. Level 2 screening measures are more often used in settings such as early intervention programs or developmental clinics that serve children with a variety of developmental problems; they help differentiate children at risk for ASD from those at risk for other developmental disorders such as mental retardation or specific language impairment. Level 2 screening tools generally require more time and training to administer, score, and interpret than do level 1 measures, and there is considerable overlap between the concept of a level 2 screening tool and that of a diagnostic instrument.^263,264 Level 2 screening measures may be used as part of a diagnostic evaluation, but they should not be used in isolation to make a diagnosis. It is important for developmental-behavioral pediatricians to be familiar with the array of ASD screening tools available in order to train primary care providers and to conduct or assist with advanced level 2 screening.

Properties of some level 1 and level 2 ASD screening tools designed for use with very young children are reviewed in Table 15-5.^{263,265–276} Several level 1 tools, such as the Checklist for Autism in Toddlers (CHAT) and the Modified Checklist for Autism in Toddlers (M-CHAT), are available to the clinician at no cost. Wong and associates²⁷⁶ translated the M-CHAT into Chinese, modified the response choices and the scoring system, and combined it with the five observational items from the CHAT to form the CHAT-23. The Screening Tool for Autism in Two-Year-Olds (STAT) is an interactive measure developed for use as a level 2 screening measure in children between the ages of 24 and 36 months; investigation of its utility with younger and older children is under way.²⁶³ Completion of a training workshop is required before use of the STAT. Tools such as the Autism Behavior Checklist,²⁷⁷ the Childhood Autism Rating Scale (CARS),^278–281 the Gilliam Autism Rating Scale (GARS),²⁸² and the Social Communication Questionnaire²⁸³ can be used to screen for risk of ASD over a wide age range, including the preschool age group (see Table 15-5). Significant concerns about the psychometric properties of the Autism Behavior Checklist, GARS, and Pervasive Developmental Disorders Screening Test–II have been raised.^263,284,285 The Social Communication Questionnaire was derived from the Autism Diagnostic Interview–Revised and has fairly strong psychometric properties.^283,286 The Social Communication Questionnaire is recommended for use in children older than 4 years and is currently being evaluated to determine the most appropriate cutoff scores for 2- and 3-year-old children.

Many of the ASD-specific screening measures are currently being revised or further evaluated, and new tools are being developed to address some of the weaknesses of existing instruments. Attempts are being made to design instruments capable of detecting ASDs at younger ages. For example, the Early Screening for Autism^287,288 is being developed as a level 1 ASD screen for 14-month-old children, and the Systematic Observation of Red Flags for Autism Spectrum Disorders in Young Children,²⁸⁹ which is based on the Communication and Symbolic Behavior Scales Developmental Profile Behavior Sample, may be a valuable level 2 screening tool for use in the second year of life.

Comprehensive Evaluation

The developmental-behavioral pediatrician, acting either alone or as a member of a multidisciplinary or interdisciplinary developmental team, is ideally suited for making the definitive diagnosis of an ASD. Although other pediatric subspecialists are quite capable of making the diagnosis, especially with the assistance of an experienced psychologist who can perform psychometric testing, the developmental components may be challenging for the younger child. The developmental-behavioral pediatrician is specifically trained to evaluate child’s overall level of functioning, as well as strengths and limitations in specific domains, a task that is critical in providing the framework for evaluating results of ASD-specific tools, in guiding the etiological workup, in planning intervention strategies, and assessing prognosis.

Because there can be a long waiting period for a subspecialty evaluation, the developmental-behavioral pediatrician or clinic staff should ensure at the time of the initial referral that the child has already been referred for an audiological evaluation and to an early intervention program or a school program (depending on the child’s age) by the primary care provider.^260,262 If the child has not, then this should be done immediately so that intervention strategies can be implemented in a timely manner. Immediately available services should address the child’s individual pattern of developmental deficits; strategies can be revised to be more ASD-specific, if necessary, after the definitive diagnosis is made.

There are three major diagnostic challenges in the comprehensive assessment of a child with suspected ASD: determining the child’s overall level of functioning, making the definitive diagnosis of an ASD, and determining the extent of the search for an associated etiological syndrome. To accomplish these three goals, a comprehensive evaluation should include the following components:

When appropriate, the evaluation includes information from multiple sources, because the child’s performance may vary among settings and care providers. The entire process may require several appointments or, in the context of an interdisciplinary team evaluation, it may consist of a single arena-style evaluation or a series of individual evaluations by team members over the course of a day. The child’s developmental level or mental age, capacity for cooperation (especially relating to fatigue in an all-day evaluation), severity of autistic symptoms, family characteristics, and local insurance policies and procedures all play a role in the selection of the most appropriate strategy. Regardless of whether the evaluation is made by a team or an individual clinician, the etiological search usually takes place over a period of time in collaboration with the child’s primary care provider. Referrals to a neurologist and/or a geneticist may be helpful in further evaluating abnormal neurological findings, seizures, regression, dysmorphic features, and/or a complex family history.

For a comprehensive discussion regarding the rationale and strategies for accomplishing these tasks, the reader is referred to published neurology guidelines¹⁰; pediatric guidelines^11,12; the American Speech and Hearing Association Position Statement²⁹⁰ and Technical Report²⁹¹; and chapters in two books, Autism Spectrum Disorders: A Transactional Developmental Perspective¹⁷ and Handbook of Autism and Pervasive Developmental Disorders¹⁴ particularly Chapter 20 (on medical workup), 21 (on diagnostic instruments), 29 (on evaluation components), 30 (on communication assessment), 31 (on behavior assessment), and 32 (on sensorimotor assessment).

LABORATORY INVESTIGATION

The final challenge in the evaluation of ASD, and perhaps the most controversial, is determining the extent of the etiological “search.” Published etiological yields vary and generally are more highly correlated with the presence or absence of coexisting mental retardation rather than with ASD itself. The majority of reports describe finding an underlying cause in 2% to 10% of patients.^{47,48,104,107–110,348} These yields are lower than the 10% to 81% reported in studies of GDD/mental retardation without coexisting ASD.^349,350 Unfortunately, the extent and sophistication of the laboratory investigations vary a great deal among ASD-specific studies and even within the same study. Patient factors such as the presence of coexisting GDD/mental retardation, dysmorphic features, and/or a positive family history are often not addressed. Some investigators report a “positive yield,” whereas, in fact, the identified abnormality is nonspecific, is not related to a known autism-related etiology, and does not affect counseling and/or management (e.g., delayed mylinization on MRI). In other studies, positive test results indicate coexisting conditions that, although they may be common in children with ASD (e.g., gastrointestinal disorders), are not known to play an etiological role. Thus, a positive laboratory test result does not necessarily mean a positive “yield.”

There are certainly many advantages in having a formal diagnosis, such as genetic counseling and information regarding recurrence risks of known syndromes, possibility of a specific treatment strategy, counseling about the natural history of a known disorder, anticipation of a later associated comorbid disorder, prevention of secondary disorders, availability of prenatal diagnosis, access to public supports, access to syndrome-specific parent support groups, and, in some cases, empowering parents to “move on” and to focus on habilitative interventions.

In view of the heterogeneity of ASD and the absence of evidence to support extensive workups in all patients with ASD, the laboratory search should be guided by clinical judgment based on history (e.g., health, birth, developmental, behavioral, family) and clinical presentation (e.g., coexisting mental retardation, regression, seizures, neurodevelopmental findings, dysmorphic features, comorbid medical conditions). Family characteristics (e.g., lack of insurance, concern about the child’s discomfort, interest in pursuing a “no-stone-left-unturned” etiological workup) may also influence parental decisions about the extent of the workup. Finally, the local availability of subspecialists and sophisticated technology, the need for and feasibility of sedation, managed care cost-benefit guidelines, and physicians’ beliefs may each play a role in decisions about the appropriate extent of the diagnostic workup.

The fields of genetic testing and neuroimaging are rapidly becoming more sophisticated. In fact, clinicians caring for children participating in multisite collaborative studies may pursue more extensive laboratory investigations according to standardized research protocols. Many of the tests are investigational, have unknown utility, and are not currently clinically available. Although they may be very valuable in the future in determining the cause or causes of ASD and defining specific subtypes, they do not currently have a role in the routine workup of ASD.

The emergence of new technology and the lack of overall consensus among subspecialty expert panels presents a formidable challenge when clinicians attempt to develop a consistent search strategy for children with ASD, especially those with comorbid GDD/mental retardation. The American College of Medical Genetics^349,351 and the American Academy of Neurology and Child Neurology Society (AAN-CNS)³⁵⁰ have published guidelines for the evaluation of children with GDD/mental retardation that are based on a considerable body of evidence in this population; however, their recommendations are somewhat discordant. Additional recommendations are anticipated in the future from the AAP Committee on Genetics because they will be based on the availability of newer technology (Brad Schaefer, personal communication, March 2006). In the period 2000 to 2001, the first ASD guidelines were published both by the AAN-CNS¹⁰ and by the AAP^11,12 Because there was some overlap of the authoring panels, there is much agreement between the two documents. Although implied, neither of the ASD guidelines specifically addresses the laboratory investigation of children with high functioning autism or Asperger syndrome. Prevalence studies suggest that the yield is extremely low in the absence of GDD/mental retardation and perhaps even lower in Asperger syndrome.^{36,47,104,107,352,353} Etiological yield tends to be highest in isolated GDD/mental retardation (10% to 81%), moderate in ASD with coexisting GDD/mental retardation (2% to 10%), and lowest in isolated ASD with normal intelligence (<5%).

In view of comorbidity, discordant guidelines, limitations in current evidence, and emerging technology, we support a practical approach such as a tiered strategy. The AAP Committees on Children with Disabilities and Genetics are in the process of developing ASD guidelines that will be published at a future date and may deviate somewhat from the following recommendations. The proposed strategy advocates for informed clinical judgment and decision making that is based on the presence or absence of coexistent GDD/mental retardation and/or clinical indicators.

Proposed Strategy for a Tiered Etiological Search

Level 1: studies that should be considered in all children with ASD.

Level 2: studies that should be considered in children with ASD and coexisting GDD/mental retardation.

Level 3: targeted studies that should be considered when specific clinical findings are identified by history or physical examination.

LEVEL 1 SEARCH

All children with language delays, including those with ASD, should have an audiology evaluation. Published ASD-specific guidelines for young children presenting with symptoms of ASD reinforce this recommendation.10–12,^114,262 School-based hearing screening may be adequate in older children with Asperger syndrome who have no significant language deficits, especially in the absence of any academic concerns.

LEVEL 2 SEARCH

The workup of a child with ASD with coexisting GDD/mental retardation should be guided by published guidelines for both conditions. As noted previously, the etiological yield rates are typically lower in children with both ASD and GDD/mental retardation than in those with isolated GDD/mental retardation, especially those with severe GDD. For children who have both conditions, ASD guidelines recommend (1) a high-resolution karyotype and (2) a molecular study for the fragile X syndrome, unless the child has a known etiology to explain the GDD/mental retardation or presents with characteristics of a disorder that can be confirmed by a specific targeted laboratory test (e.g., MECP2 in a girl with classic Rett symptoms).10–12,^114,262 These guidelines also suggest that the tests just described may be helpful in the absence of GDD/mental retardation if there is a family history of mental retardation (especially mental retardation caused by the fragile X syndrome), but it is recognized that the yield will be extremely low. The presence of more than two dysmorphic features increases the likelihood of a positive yield; however, this finding is more highly correlated with GDD/mental retardation than with ASD.^294,350,354 The relative importance of the fragile X syndrome in the cause of ASD has been somewhat controversial and, depending on the study, the prevalence of a positive DNA assay varies between 1.6% and 16%.³⁵⁵ In a review of 40 studies,³⁵⁶ identical pooled proportions of the fragile X syndrome were found in boys with autism and in boys with isolated mental retardation; this raises concern about the relative causative role of the fragile X syndrome in ASD. If the karyotype and fragile X test are negative (as most are), but a recognizable cause is still suspected, then the clinician should consider level 3 tests and/or consultation with a clinical geneticist and/or neurologist, depending on indicators from the history and/or physical examination.

Although the 2003 AAN-CNS practice parameter³⁵⁰ recommends additional “screening” laboratory tests (e.g., MRI, subtelomere fluorescent in situ hybridization [FISH] studies) for all children with GDD/mental retardation, it has not been endorsed by the AAP for GDD/mental retardation or ASD. Published genetic GDD/mental retardation guidelines have recommended fewer “screening” tests and a more targeted approach that is based on clinical judgment.^349,351,354 Although more sophisticated and effective screening techniques may be on the horizon, there are currently no existing data to support more extensive laboratory evaluation in children with ASD. As the apparent prevalence of coexisting GDD/mental retardation continues to decrease, the need to consider GDD/mental retardation guidelines will occur less often.^{47,55–55b,348}

No etiological laboratory tests are recommended in the evaluation of high-functioning children with ASD, including Asperger syndrome, in the absence of suggestive clinical findings. If a child demonstrates regression or new symptoms consistent with a syndrome known to be associated with ASD (e.g., seizures and/or the appearance of an ash leaf or facial angiofibromas characteristic of tuberous sclerosis), then a laboratory investigation becomes necessary. Laboratory recommendations might also change for this population as research reveals more consistent genetic markers in idiopathic ASDs and as more advanced cytogenetic techniques become clinically available and more cost effective.

LEVEL 3 SEARCH

Level 3 investigations include additional subspecialty evaluations and/or additional laboratory investigations that are indicated by specific clinical indicators. On the basis of local availability and the developmental-behavioral pediatrician’s level of confidence in these evaluations, she or he should consider referrals to a clinical geneticist and/or to a child neurologist.

A geneticist can assist with an extended pedigree history and a more meticulous dysmorphic examination. Expensive, more sophisticated laboratory tests may require the assistance of a geneticist for authorization (especially when they are not yet clinically available) and interpretation. When the child’s evaluation includes profound mental retardation, consanguinity, a complex family history, or a vague dysmorphic gestalt, the geneticist may order subtelomere testing.^356b Yields for subtelomere studies are extremely low in those with mild mental retardation and usually zero in studies that target individuals with ASD.^104,112 The geneticist may order single-locus studies (e.g., 15q or 22q) or newer macroarray FISH studies; however, the latter are expensive and may not be clinically available in all settings. When specific indicators are present, the geneticist is also helpful in ordering and interpreting the level 3 targeted tests listed in nos. 1 to 9 below.

A child neurologist can be very helpful in assisting with the evaluation of a child with regression, seizures, or specific neurological examination findings. The neurologist is able to address certain aspects of the history and physical examination in more detail and thus may identify indicators for level 3 laboratory studies. A high index of suspicion and meticulous monitoring is recommended to identify subtle seizures.10–12,^114,350 Some neurologists may recommend “screening” EEG and MRI. Although nonspecific abnormalities have been found in the majority of children, the significance of these abnormalities is not clear, treatment has not been of any proven value,³⁵⁷ and there is currently insufficient evidence to recommend or discourage the use of screening EEG.^358,359 Furthermore, MRI has not been recommended for all children with isolated macrocephaly associated with idiopathic ASD.^10,321

The clinician (developmental-behavioral pediatrician, geneticist, neurologist, neurodevelopmental disabilities specialist, or other qualified specialist) should pursue level 3 tests when clinical findings characteristic of one or more specific disorders become apparent. Identification of these clinical indicators depends, in part, on the thoroughness of the history and physical examination. The following recommendations for a targeted etiological search in the individual child are relatively consistent with the original ASD guidelines.10–12,¹¹⁴ Level 3 testing should be individualized according to the following specific clinical findings:

1. Dysmorphic features: Although children with coexisting GDD/mental retardation should have undergone high-resolution karyotype and DNA testing for the fragile X syndrome, even more thorough dysmorphic examination to identify indicators for targeted testing at this level may be helpful, especially if the screening test results are negative. Children without GDD/mental retardation should also be examined carefully for abnormal physical findings to discern whether a high-resolution karyotype and/or DNA testing for the fragile X syndrome would be helpful, especially when there is a positive family history of mental retardation or genetic disorders.

2. Characteristic behavioral phenotype: When a child manifests a constellation of behaviors that are classic for a known syndrome (e.g., Angelman syndrome, Smith-Magenis syndrome) that can be confirmed by a specific laboratory test (e.g., targeted FISH or methylation studies), the child should be referred to a laboratory capable of performing and interpreting the appropriate test.

3. Regression: There is some controversy whether every child with regression needs an in-depth workup. Clinical judgment should be exercised for a child with idiopathic ASD who demonstrates “typical autism regression” between the ages of 18 and 36 months, especially if he or she is being evaluated after the regression has subsided and developmental progress has resumed, albeit usually at a slower pace.³⁵⁹ On the other hand, those with regression characteristic of Landau-Kleffner syndrome or other acquired epileptic aphasias should always be studied, especially in the presence of seizures.²¹⁹ Studies will probably include MRI and electrencephalography (sleep or 24-hour). Girls with ASD symptoms who exhibit regression, show deceleration of head growth, develop seizures, and/or demonstrate other features of the Rett phenotype should be evaluated for MECP2 mutations.

4. Seizures: Children with known seizures or suspected of having subclinical seizures should be referred to child neurologist for an evaluation, MRI, and prolonged sleep electrencephalography.²¹⁹ There is currently insufficient evidence to recommend the use of screening EEG,³⁵⁸ but a high index of suspicion and meticulous monitoring are recommended for subtle signs of seizures. Functional neuroimaging is not indicated for clinical use, although it has been quite informative from a research perspective with regard to neural processing in higher functioning individuals with ASD.

5. Abnormal neurological examination: Children with microcephaly, a midline facial abnormality, neurocutaneous findings, or focal neurological signs should be referred for an MRI study and to a child neurologist. Isolated macrocephaly is not in itself an indication for MRI.^{10,18,114,321}

6. Metabolic symptoms: Children with cyclic vomiting, hypotonia, lethargy (especially when associated with mild illnesses), poor growth, unusual odors, multiple organ involvement, ataxia or other movement disorder, or evidence of a storage disease (e.g., coarse features) are probably best referred to a geneticist and/or a neurologist for an evaluation of a possible metabolic disorder, including mitochondrial and storage diseases.^349,360 One study³⁶¹ revealed some support for a limited metabolic battery (lactate, pyruvate, ammonia and free/total carnintine), but replication studies are needed.

7. Lack of confirming evidence of a negative result of a neonatal screening test for phenylketonuria: Children should undergo a quantitative plasma amino acid assay to rule out phenylketonuria when it is suspected and neonatal screening results are not available.

8. Indicators of the association of toxoplasmosis, other infections, rubella, cytomegalovirus, and herpes simplex infections (TORCH): Children with a history and/or chronic symptoms consistent with one of the intrauterine infections (e.g., rubella syndrome) should have a TORCH titer drawn.¹⁴⁵

9. Pica: Although lead toxicity is not believed to cause ASD, it can have a detrimental effect on learning and cognition, which may indirectly intensify ASD symptoms. Children with pica, especially when they live in at-risk environments, should be monitored with blood lead levels as long as the behavior persists.²⁹³

Additional tentative suggestions for a level 3 targeted search that were based on new data since the original ASD guidelines were published include the following:

Because Rett mutations can sometimes occur in boys (especially those with Klinefelter syndrome), MECP2 assays should also be considered in boys who present with regressive ASD. Universal screening as part of a research protocol has revealed that MECP2 mutations are present in a few ASD children without evidence of the Rett phenotype; if these findings are replicated, universal screening of all children with ASD may be recommended in the future.^361a,362,363

Because an association has been found between Angelman syndrome and assisted reproductive techniques,³⁶⁴ methylation testing for Angelman syndrome should be considered if children conceived by assisted reproductive techniques present with ASD features, because some overlap with the Angelman phenotype.

Because an association between ASD and a mild variant of Smith-Lemli-Opitz syndrome has been described, 7-dehydrocholesterol testing might be considered when a child with ASD presents with hypotonia and syndactyly of the second and third toes. This suggestion is important for genetic counseling because Smith-Lemli-Opitz syndrome is an autosomal recessive disorder.³⁶⁵

Reviews¹⁸ continue to support the recommendations published in previous guidelines^10–12,114 that the following tests are not indicated in the typical workup of a child with ASD: hair analysis for trace elements, vitamin levels, celiac antibodies, immunological workup, allergy testing, intestinal permeability studies, stool analysis, urinary peptide measurements, thyroid function tests, or erythrocyte glutathione perioxidase level measurements.

Patients enrolled in one of several multicenter research studies may also undergo a number of additional tests (e.g., functional imaging, immunological studies, fibroblast karyotypes, neuroligan gene testing, mitochondrial gene sequencing, and additional metabolic studies)¹⁷³ that may not currently be universally available or clinically indicated in most children with idiopathic ASD, especially those with Asperger syndrome and high-functioning autism. Insurers rarely pay for such tests, evidence does not support doing these routinely, and the results may promote unrealistic expectations. As information regarding genetic markers for ASD expands and technology continues to become more sophisticated, the yield of complex genetic and laboratory investigations may increase in children with idiopathic ASD and eventually become clinically useful as part of the routine ASD workup. Currently the most promising probes are those that target 15q duplications, 22q deletions, and abnormalities on the X-chromosome and chromosomes 2, 3, 7, and 17. Some investigators have already suggested screening FISH for the 15q and 22q abnormalities¹¹¹ (Brad Schaefer, personal communication, March 2006); however, more evidence is needed before this becomes standard of care. Testing for 22q deletions, may be particularly important for genetic counseling purposes because about half of the cases in one study were caused by balanced translocations.^366–367

Educational Interventions

In the late1960s and the 1970s, when the psychogenic theory of causation faded and Section 504 of the Rehabilitation Act of 1973 (Public Law 93-112)³⁶⁸ and the Education of All Handicapped Children Act of 1975 (Public Law 94-142)⁶² mandated appropriate public education for all children with disabilities, education of the child began to replace psychodynamic treatment of the parents as the primary intervention for autism. Education has been defined as fostering of acquisition of skills and knowledge to assist a child in developing independence and personal responsibility; it encompasses not only academic learning but also socialization, adaptive skills, communication, amelioration of interfering behaviors, and generalization of abilities across multiple environments.¹³ Teachers, behavior therapists, speech and language therapists, occupational therapists, paraprofessional staff, parents, and other experts commonly play key roles in the education of children with ASD. Physicians and other clinicians are often in a position to guide families to empirically supported practices and help them evaluate the appropriateness of the educational services that are being offered.

Medical Aspects of Habilitation

Children with ASD have the same basic health care needs as children without disabilities and benefit from the same health promotion and disease prevention activities, including immunizations. In addition, they may have unique health care needs related to underlying etiological conditions, such as fragile X syndrome or tuberous sclerosis, or to other conditions, such as epilepsy, that are often associated with ASD.

STIMULANTS, α₂ AGONISTS, AND ATOMOXETINE

Although early studies of the effects of stimulants yielded negative results, more recent double-blind, placebo-controlled trials of methylphenidate have demonstrated improvement in hyperactivity, impulsivity, and inattention in children with ASD.^459–461 Methylphenidate is effective in some children with ASD, but the response rate is lower than in children with isolated ADHD, adverse effects are more frequent, and it is unclear whether the results can be generalized to other stimulants.^461,462 Two very small, double-blind, placebo-controlled trials have documented modest benefits of clonidine in reducing hyperarousal symptoms, including hyperactivity, irritability and outbursts, impulsivity, and repetitive behaviors in children with ASD.^463,464 A retrospective record review study revealed that open-label treatment with guanfacine was effective in 19 (24%) of 80 children with ASD.⁴⁶⁵ Patients without mental retardation were more likely to show improvement in target symptoms, including hyperactivity, inattention, insomnia, and tics. Atomoxetine has not been evaluated in controlled trials in children with ASD, but a retrospective study suggested that it might be effective for ADHD-like symptoms in this population.⁴⁶⁶

ATYPICAL ANTIPSYCHOTIC AGENTS

Atypical antipsychotic medications currently available in the United States include clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole. There is evidence that atypical antipsychotics are efficacious in the treatment of children and adolescents with severe disruptive behaviors associated with intellectual disability.^467–469 in addition to those with psychosis, bipolar disorder, Tourette syndrome, and, potentially, conduct disorder and severe ADHD.⁴⁷⁰ Two large, multisite, randomized controlled trials have confirmed the short-term efficacy of risperidone for severe disruptive behaviors such as tantrums, aggression, and self-injurious behavior in youths with ASD.^471–474 Results of two open-label studies, each with a double-blind discontinuation component, have suggested long-term benefits and tolerance.^475,476 The effect of risperidone on core symptoms of ASD is less dramatic. The Research Units on Pediatric Psychopharmacology Autism Network trial revealed that treatment with risperidone improved the restricted, repetitive, and stereotyped patterns of interests and behavior but did not significantly affect impairments in social interaction or communication.⁴⁷³

SELECTIVE SEROTONIN REUPTAKE INHIBITORS

Selective serotonin reuptake inhibitors (SSRIs) include fluoxetine, sertraline, fluvoxamine, paroxetine, citalopram, and escitalopram. Double-blind, placebo-controlled trials have demonstrated efficacy of fluoxetine⁴⁷⁷ and fluvoxamine^478,479 in the treatment of repetitive and other maladaptive behaviors in patients with ASD. Open-label trials of various serotonin reuptake inhibitors in children and adults with ASD report response rates in the range of 50% to 75% but are susceptible to publication bias and other shortcomings of uncontrolled studies.⁴⁸⁰ Improvements in target symptoms, including repetitive behaviors, irritability, depressive symptoms, tantrums, anxiety, aggression, difficulty with transitions, social interaction, and language, have been reported.^477–480

ANTICONVULSANT MOOD STABILIZERS AND LITHIUM

In small open-label trials, valproate,⁴⁸¹ levetiracetam,⁴⁸² and topiramate^482a were effective in reducing symptoms such as aggression, impulsivity, hyperactivity, conduct problems, and mood lability in children with ASDs. In an open-label valproate trial⁴⁸¹ and several case reports,^483,484 improvements in language and social skills were also described. A small double-blind, placebo-controlled trial⁴⁸⁵ demonstrated significant improvement in repetitive behavior in children with ASDs who were treated with valproate. Valproate may also be associated with significant improvement in electrencephalographic recordings and subjective clinical status.⁴⁸⁶ Uvebrant and Bauziene⁴⁸⁷ reported a decrease in “autistic symptoms” in 8 of 13 patients treated with lamotrigine for intractable epilepsy, regardless of efficacy in controlling the seizures. However, in a double-blind, placebo-controlled study, Belsito and coworkers⁴⁸⁸ did not find significant differences between lamotrigine and placebo. Several case reports describe children with ASD and atypical bipolar disorder or mania who responded well to open-label treatment with lithium.^489–491

PARENT/CAREGIVER SUPPORT

Physicians and other professionals can provide support to parents by educating them about ASD, providing anticipatory guidance and training, involving them as cotherapists, assisting them in obtaining access to resources, providing emotional support through traditional strategies such as empathic listening and talking through problems, and assisting them in advocating for their child’s needs.⁵²⁶ In some cases, referral of parents for counseling or other appropriate mental health services may be required. These families need ongoing support, with the specific constellation of needs varying through the family life cycle.

One of the chief strategies in helping families raise children with ASD is providing them with access to needed ongoing supports, as well as additional services during critical periods and/or crises. Natural supports include spouses, extended family members, neighbors, religious institutions, and friends who can help with caregiving and who can provide psychological and emotional support. Informal supports include social networking with other families of children with ASD and community agencies that provide training, respite, social events, and recreational activities. Formal supports include publicly funded, state-administrated programs such as early intervention, special education, vocational and residential/living services, respite services, Medicaid, In-Home and Community-Based Waiver Services, Supplemental Security Income (SSI) benefits, and other financial subsidies. The breadth and depth of services vary, even within the same state or region. Few services exist in many rural areas, and public programs may have long waiting lists.

SIBLING SUPPORT

The impact of ASD on a family is not limited to the parents or primary caregivers. Depression and psychosocial problems are also common in siblings of children with ASD,^530,531 who often are plagued by questions and concerns about the reason for their sibling’s disability, how to cope with embarrassment or the reaction of peers to the sibling’s behavior, and what the future holds with regard to their role in long-term care.⁵²⁶ Family financial difficulties and lack of knowledge about the disability may exacerbate adjustment problems in the unaffected sibling, and the relationship may be influenced by a number of other external factors, including the availability of support services, especially respite services.

Sibling support groups offer the opportunity to learn important information and skills while sharing experiences and connecting with other siblings of children with ASD.⁵²⁶ Although the research on support groups for siblings of children with disabilities is difficult to interpret because of study design problems and inconsistent outcome effects on sibling adjustment, these groups have generally been evaluated positively by participating siblings and parents.^526,532

FINANCIAL SUPPORT AND RELATED ISSUES

Several publicly funded programs provide financial assistance (e.g., SSI benefits, Food Stamps, Medicaid, and In-Home and Community-Based Waiver Services). Access to some public benefits, such as SSI, depends on financial need. Because eligibility depends on the financial status of the family, need-based supports such as SSI can be lost, if, for example, a well-meaning family member bequeaths the child a monetary gift. However, the government has established rules allowing assets to be held in trust for SSI and Medicaid recipients through a Supplemental Needs or Special Needs Trust. The Special Needs Trust can be used to fund needs that go beyond the bare necessities of food, clothing, and shelter provided by SSI and the medical supports and services covered by Medicaid. The laws governing such trusts are complex, and the help of an attorney knowledgeable in special needs planning is usually required. More information about Special Needs Trust can be found at http://www.nichcy.org/pubs/outprint/nd18.pdf.

In addition to supports provided through SSI and health-care programs (Medicaid), families of children with ASD, especially those with coexisting mental retardation, may be eligible for additional supports to assist them in raising their child. Although funding for community-based supports has been increasing since the 1970s, the degree of funding allocated for these services varies a great deal among states. The most common funding mechanism for families, Home and Community-Based Waiver Services, is called a “waiver option” because the family’s income and assets are waived, which makes access equitable across all income levels. Eligibility depends entirely on the severity of the child’s disability and the circumstances it imposes upon the family. Unfortunately, many states have long waiting lists (e.g., 5 to 7 years) before the child becomes eligible for this funding. Once the child becomes eligible, a case manager works collaboratively with the family to design an annual service plan that may include various types of respite, medical equipment, home modifications for safety reasons, and other needed supports.

Because each state’s services and access mechanisms are organized differently, physicians and families must learn their own state’s idiosyncrasies to access supports by contacting the state or county offices of the Department of Health and Human Services, the Department of Mental Health and Mental Retardation, or the state developmental disabilities organization. In addition, local parent advocacy organizations, national organizations such as the Autism Society of America and The Arc, Early Intervention Program administrators, and school district special education coordinators are often knowledgeable about various programs and their respective eligibility requirements.

At the age of 18, teenagers with ASD (with or without coexisting mental retardation) automatically become their own legal guardians. If parents and the professionals working with such a teenager do not believe that he or she is capable of making responsible decisions, a formal evaluation should be conducted to determine the need for guardianship. The parents should consult the child’s primary physician or a developmental-behavioral pediatrician who knows the child well, because medical forms are often necessary to initiate the evaluation process. If guardianship turns out to be in the individual’s best interests, then legal services can be sought to help the parents navigate the judicial system and to designate a legal guardian for the individual.