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CLINICAL REPORT |
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONEPIDEMIOLOGYETIOLOGYNEUROPATHOLOGY AND NEUROIMAGINGCLINICAL SIGNSSURVEILLANCE AND SCREENINGCOMPREHENSIVE EVALUATION (SEE...GUIDANCE FOR PEDIATRICIANS...APPENDIX 1: REIMBURSEMENT FOR...Council on Children With...LiaisonsStaffContributorsREFERENCESRESOURCE FOR FAMILIES |
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Key Words: autism • autism spectrum disorders • Asperger syndrome • pervasive developmental disorders • fragile X syndrome • joint attention • self-injurious behaviors • theory of mind • neuropathologic abnormalities
Abbreviations: ASD—autism spectrum disorder • AD—autistic disorder • DSM—Diagnostic and Statistical Manual of Mental Disorders • AS—Asperger syndrome • PDD-NOS—pervasive developmental disorder–not otherwise specified • PCP—primary care pediatrician • AAP—American Academy of Pediatrics • IDEA—Individuals With Disabilities Education Act • MR—mental retardation • GDD—global developmental delay • ADHD—attention-deficit/hyperactivity disorder • FISH—fluorescence in situ hybridization • MMR—measles-mumps-rubella • JA—joint attention • ToM—theory of mind • SLP—speech-language pathologist • CHAT—Checklist for Autism in Toddlers • M-CHAT, Modified Checklist for Autism in Toddlers • CAST—Childhood Asperger Syndrome Test • EEG—electroencephalography
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONEPIDEMIOLOGYETIOLOGYNEUROPATHOLOGY AND NEUROIMAGINGCLINICAL SIGNSSURVEILLANCE AND SCREENINGCOMPREHENSIVE EVALUATION (SEE...GUIDANCE FOR PEDIATRICIANS...APPENDIX 1: REIMBURSEMENT FOR...Council on Children With...LiaisonsStaffContributorsREFERENCESRESOURCE FOR FAMILIES |
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ASDs are not rare; many primary care pediatricians (PCPs) care for several children with ASDs. In fact, a survey completed in 2004 revealed that 44% of PCPs reported that they care for at least 10 children with ASDs; however, only 8% stated that they routinely screened for ASDs.5 Another survey indicated that although PCPs were aware of the current DSM-IV-TR diagnostic criteria, they sometimes held beliefs about ASDs that were outdated.6 It is critical that PCPs recognize the early signs of ASDs and be aware of new data that support better outcomes in children whose conditions are diagnosed early and who participate in appropriate intervention programs.7–11 Because it is a chronic condition, the PCP also needs to feel comfortable with the ongoing care of children with ASDs within the context of the medical home. To support PCPs in the identification and care of children with ASD, the American Academy of Pediatrics (AAP) has developed and distributed several documents:
In addition, the AAP has developed an ASD toolkit and resource guide to assist the PCP with implementation of the principles discussed herein.
Although ASDs are neurodevelopmental conditions with strong genetic underpinnings, their exact etiology is unknown. In 1943, Leo Kanner, a psychiatrist at Johns Hopkins University, first described autism in a small group of children who demonstrated extreme aloofness and total indifference to other people.15 In 1944, Hans Asperger, an Austrian pediatrician who was unaware of Kanner's work, published an article16 that described children who demonstrated symptoms similar to those of Kanner's patients, with the exception that verbal and cognitive skills were higher. The term "infantile autism" first appeared as a diagnostic label in the Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III).17 Since then, terminology has changed and diagnostic criteria have broadened.18 Diagnostic criteria for AS were not included in the DSM until the fourth edition (DSM-IV). The most recent criteria for AD and AS (Asperger's disorder) are found in the DSM-IV-TR4 (Tables 1 and 2, respectively). PDD-NOS, the remaining ASD, is described in the DSM-IV-TR as a subthreshold diagnostic term used when a child demonstrates severe and pervasive impairments in reciprocal social skills associated with deficits in language skills or with the presence of stereotypic behaviors or restricted interests or activities but does not meet full criteria for AD or AS. Although Rett syndrome and childhood disintegrative disorder are included in the DSM-IV-TR listings, they are not considered ASDs but should be considered in the differential diagnosis of each child, depending on the presenting signs and symptoms.
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EPIDEMIOLOGY |
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TOPABSTRACTINTRODUCTIONEPIDEMIOLOGYETIOLOGYNEUROPATHOLOGY AND NEUROIMAGINGCLINICAL SIGNSSURVEILLANCE AND SCREENINGCOMPREHENSIVE EVALUATION (SEE...GUIDANCE FOR PEDIATRICIANS...APPENDIX 1: REIMBURSEMENT FOR...Council on Children With...LiaisonsStaffContributorsREFERENCESRESOURCE FOR FAMILIES |
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With recent heightened public awareness, parents are more likely to raise a concern specifically about autism.35–37 In addition, as screening tools and more reliable evaluation instruments have been developed, professionals have become increasingly proficient in recognizing and diagnosing ASD. Apart from greater awareness and better ascertainment, additional reasons for the apparent increase have been debated hotly in the lay media; in fact, the publicized "autism epidemic" may be one of the most challenging public health issues today.
The prevalence of autism and, more recently, ASDs is closely linked to a history of changing criteria and diagnostic categories. Autism first appeared as a separate entity with specific criteria in the DSM-III in 1980.17 In 1987, the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-III-R)38 listed broadened AD criteria and the new subthreshold category of PDD-NOS, both of which promoted inclusion of milder cases. Later, these changes received criticism for being too inclusive and for promoting overdiagnosis.39 The DSM-IV3 criteria published in 1994 reflected the result of years of analyses to reduce the overinclusiveness of the DSM-III-R criteria; however, it included AS for the first time, which, in effect, broadened the range of disorders. Studies have revealed that the DSM-IV criteria have better specificity (0.87) than DSM-III-R criteria.40 The DSM-IV-TR4 criteria for AD and AS are unchanged; however, the text description of PDD-NOS was edited slightly to increase specificity. Collaboration with European groups that worked on the revised International Statistical Classification of Diseases and Related Health Problems (10th edition)41 promoted better conformity between the 2 classification systems.
AD did not become a diagnosis for which children became eligible to receive special education services until passage of the Individuals With Disabilities Education Act (IDEA) in 1990.42 Before the IDEA was enacted, children were labeled as having conditions such as mental retardation (MR), learning disability, speech impairment, or emotional disturbance to obtain eligibility for services.43 Hence, after passage of the IDEA, the resulting increase in the number of children served under the AD category reflected both newly diagnosed young children entering the school system and older children who were previously eligible for special services under a different educational label. This reflects the phenomenon of "diagnostic substitution," whereby the number of children receiving special education under other categories (primarily MR, speech impairment, and learning disabilities) has decreased over the same time period. In addition, some increase in prevalence may be attributable to inaccuracies in diagnosis for a number of reasons, including labeling biases when schools used less rigorous criteria than those needed for a DSM diagnosis,44–48 when educational funding trends influenced diagnosis,49 and/or when parents of children with marginal criteria advocated for the AD label to qualify for supplementary services (eg, year-round schooling) described in the IDEA amendments.50,51 The impact of these factors on current prevalence estimates has been controversial and illustrates the reason why educational administrative data reported in some studies that receive media attention should not be considered for epidemiologic studies.47,48,52–56
Just at the time when school eligibility laws were changing, the Americans With Disabilities Act of 199057 was passed, obliging states to administer their programs in the most integrated settings appropriate to the needs of the person with disabilities. This was the culmination of a long series of state and federal legislation that promoted closure of institutions and encouraged governments to support families in their efforts to raise their children with disabilities at home. Thus, children with autism, especially those with comorbid MR and behavior problems who might have been institutionalized in the past, began to attend community schools and to be "counted" in educational prevalence data.
Other factors that may also be contributing to the perceived increase in prevalence include the recent identification of children with genetic disorders unrelated to ASDs who also sometimes can meet criteria for an ASD, such as Down syndrome58,59 and CHARGE (coloboma, heart disease, choanal atresia, retarded growth and development and/or central nervous system anomalies, genital anomalies and/or hypogonadism, and ear anomalies and/or deafness) syndrome.60 Finally, diagnosis of an ASD may be made in an older family member with milder symptoms that were previously unrecognized until after the diagnosis of a younger child.61
Regardless of the study, the year conducted, or the reported rate of prevalence, more boys than girls are consistently found to be affected with ASDs, with male-to-female ratios ranging from 2:1 to 6.5:1.24,28,29,34,62 The male-to-female ratio is even higher for high-functioning autism and AS, ranging from 6:1 to as high as 15:1.63 (In recognition of these statistics and for the sake of brevity, this report uses masculine pronouns.)
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ETIOLOGY |
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TOPABSTRACTINTRODUCTIONEPIDEMIOLOGYETIOLOGYNEUROPATHOLOGY AND NEUROIMAGINGCLINICAL SIGNSSURVEILLANCE AND SCREENINGCOMPREHENSIVE EVALUATION (SEE...GUIDANCE FOR PEDIATRICIANS...APPENDIX 1: REIMBURSEMENT FOR...Council on Children With...LiaisonsStaffContributorsREFERENCESRESOURCE FOR FAMILIES |
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In a minority of cases (<10%), ASDs may be associated with a medical condition or a known syndrome.20,21 Although ASDs are believed to be mainly genetic in origin, environmental factors may modulate phenotypic expression.64,69 Advanced paternal age70,71 and maternal age71,72 have been shown to be associated with an increased risk of having offspring with ASDs, possibly because of de novo spontaneous mutations and/or alterations in genetic imprinting. Environmental exposures may act as central nervous system teratogens in early gestational life.73 Some researchers have suggested that an epigenetic mechanism (heritable changes in gene expression that occur without changes in DNA sequence) may be responsible.74 Thus, it has become more and more apparent that the etiology is multifactorial with a variety of genetic and, to a lesser extent, environmental factors playing a role.75
Two major strategies have been used in the search for the ASD genes: targeted cytogenetic/molecular studies and whole-genome screens of families of children with ASD.76–79 The first strategy depends on developing a hypothesis regarding the pathogenesis of ASDs, focusing on a potential candidate gene and testing it genetically for an association with ASDs. Candidate genes in ASDs include, among others, those that seem to play a role in brain development (eg, cerebellar Purkinje cell proliferation) or neurotransmitter function (eg, serotonin).80 The second strategy uses an indirect method and does not require investigators to make assumptions regarding the mechanism of inheritance. Instead, families with multiple members who demonstrate an ASD (multiplex families) are studied to identify recurring DNA markers (break points, translocations, duplications, and deletions) present in affected members but not in unaffected members. Unfortunately, progress in determining a genetic etiology using this method has been impaired, because the phenotypic end points of ASDs are not well defined. Changing DSM criteria and inconsistent ascertainment strategies, which results in a hazy delineation between affected versus unaffected family members, obscure outcomes and challenge interpretation of results.67 This phenotypic heterogeneity has challenged molecular searches for the ASD gene(s) despite several genome-wide screens of the International Molecular Genetic Study of Autism Consortium and multicenter collaborative efforts over the past couple of decades.78,81–84 Although at least 1 autism-linked abnormality has been found on almost every chromosome, sites on a few chromosomes (X, 2, 3, 7, 15, 17, and 22) seem to be more promising than others.67,68,75,79,85–90 Maternally derived 15q duplications are common; depending on the investigator, yields vary from 1% to 10%,91 with most in the range of 1% to 3%.92,93 Patients with these duplications may not display dysmorphic features, but they often have hypotonia and/or global developmental delay (GDD) and may develop seizures later. The abnormality can often be identified on high-resolution karyotype analysis. Other less common abnormalities have also been reported.94
Finally, the male predominance noted above also suggests a genetic role in the inheritance of autism. Several genetic processes can lead to male predominance, including causative genes located on the X chromosome (X-linked disorders) and imprinted genes, but the reason for male predominance in autism is not completely understood.95
In a discussion of etiology, subtyping ASDs as either idiopathic or secondary is helpful.67,79,95 For the purposes of this discussion, the term "idiopathic" ASDs refers to cases in which children meet criteria for ASDs but do not have a comorbid associated medical condition known to cause ASDs. Most individuals with an ASD have the idiopathic type. Children with idiopathic ASDs demonstrate variable behavioral phenotypes, are somewhat less likely to have comorbid GDD/MR, and generally do not have dysmorphic features that herald a recognizable syndrome. Nevertheless, twin and family studies have revealed that idiopathic ASDs are heritable and have a recurrence rate of 5% to 6%.67,94,95 The term "secondary" ASDs refers to cases with an identifiable syndrome or medical disorder known to be associated with ASDs. Whereas earlier reviews reported that the proportion of individuals with ASDs who have a comorbid syndrome or medical condition was 10% to 20%,2,96–98 the proportion has decreased to less than 10% when using more recent data sets.79,89,95,99–101 In a meta-analysis of 23 epidemiologic studies, Chakrabarti and Fombonne20,21 revealed that a recognizable condition was identified in only 6% of those with a confirmed ASD. The rate of coexisting MR (cognitive impairment associated with an IQ of <70) in children with ASDs seemed to decrease from 90% before the 1990s to less than 50% after 2000,28,29,34,35,102,103 possibly because of improved methods in testing intelligence in this population and to the increased awareness of children with ASD with milder features and higher functioning. This trend is important, because coexisting severe MR, especially in the presence of dysmorphic features, increases the likelihood of identifying a known disorder.89,104–108 Neurogenetic syndromes that seem to play a causative role or otherwise are associated with ASDs include, but are not limited to:
Whether the aforementioned conditions play a direct or indirect etiologic role or simply are associated with ASDs, they still represent a small minority of patients with ASDs. Conversely, a few children with genetic syndromes that are characterized by features quite different from ASDs also may meet DSM-IV-TR criteria. For example, recent studies have reported that 6% to 7% of children with Down syndrome (typically characterized by relatively good social skills compared with those in other domains)59 and almost 50% of children with CHARGE syndrome (associated with mutations of the CHD7 gene132) meet criteria for one of the ASDs.60 There have also been a few isolated reports of a mitochondrial and/or metabolic abnormality (eg, carnitine deficiency) being associated with an ASD, but the significance of these reports is not clear.133
Increased and decreased levels of T lymphocytes, immunoglobulins, and antibrain autoantibodies in the systemic circulation have been reported.134 These have been observed chiefly in retrospective case studies of patients with idiopathic ASDs, but systematic prospective studies have confirmed neither their existence nor their relevance.87 Prospective studies have revealed that, except for a few individuals with recurrent infections, healthy children with ASDs generally have normal immune function.135 Some studies have reported increased rates of autoimmune disorders in families of children with ASDs,136 particularly in the mothers (eg, thyroid disorders137 and psoriasis138); however, the relevance of these common disorders to ASDs in children is unknown. Furthermore, studies have shown no increase in autoimmune disorders of the central nervous system, and patients with ASDs did not themselves exhibit autoimmune disorders.139 The contribution of possible immunologic dysfunction remains to be further defined.
Environmental Issues
Regardless of the mechanism, a review of studies published in the past 50 years revealed convincing evidence that most cases of ASDs result from interacting genetic factors.67,95 However, the expression of the autism gene(s) may be influenced by environmental factors.66,67,69,140 Although currently under investigation, these factors may represent a "second-hit" phenomenon that primarily occurs during fetal brain development. That is, environmental factors may modulate already existing genetic factors responsible for the manifestation of ASDs in individual children.
Prenatal Period
Because many of the developmental brain abnormalities known to be associated with ASDs occur during the first and second trimesters of pregnancy,141,142 environmental factors (eg, teratogens, such as thalidomide and valproic acid)73 are more likely to play a role in the fetus via maternal factors. It is possible that maternal illness (eg, rubella) during pregnancy plays a role.143,144 Recently, the possible association between fetal testosterone concentration and certain autistic behaviors such as abnormal social relationships and restricted interests at 4 years of age was investigated.145
Perinatal Period
The effects of birth weight, duration of gestation, and events around the time of birth have been investigated also, but findings have not been consistent.72,146–152 A significant association between term newborn encephalopathy and children later diagnosed with ASD was reported recently.72,150 Badawi et al150 reported that 5% of survivors of newborn encephalopathy were diagnosed with an ASD, which represented an almost sixfold increase compared with matched controls. This increase may represent a genetically derived predisposition (which makes the infants vulnerable to both encephalopathy and ASD) or an independent mechanism.
Postnatal Period
Etiologic possibilities occurring after birth have been proposed—in particular, measles-mumps-rubella (MMR) vaccine153 and mercury-containing vaccines.154–156 In 2001, the Institute of Medicine157 reviewed epidemiologic population-based studies and concluded that there was no evidence of a causal association between the MMR vaccine and autism. Studies that examined the association between MMR vaccine and autism since the publication of that review have supported this conclusion.27,95,103,158–161 Questions also have been raised about the effects of environmental mercury exposure (including mercury-containing vaccines) on brain development in ASDs and other developmental disabilities.154–156 Mercury, in its organic form, is a known neurotoxin with neurologic sequelae, including motor impairment and visual and intellectual deficits, depending on the age at exposure and the type of mercury. There is no evidence to date that children with neurodevelopmental disabilities, including autism, in the United States have increased mercury concentrations or environmental exposures.162 Using large data sets from the United States, Sweden, and Denmark, to date, no consistent association has been found between thimerosal-containing vaccines and neurodevelopmental outcomes or prevalence of ASDs.27,95,162–164 Despite evidence to the contrary, a recent survey of parents of children with ASDs revealed that 54% believed that their child's ASD was caused by immunizations; 53% thought it was caused by genetics.165
Although the previous discussion reveals the wide variety of conditions known to be associated with ASDs, currently, an etiologic investigation of the individual child with an ASD infrequently identifies a known cause in the absence of GDD/MR, dysmorphic features, a positive family history, and/or a focal neurologic examination.2,20,21,89,101,106–108
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NEUROPATHOLOGY AND NEUROIMAGING |
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TOPABSTRACTINTRODUCTIONEPIDEMIOLOGYETIOLOGYNEUROPATHOLOGY AND NEUROIMAGINGCLINICAL SIGNSSURVEILLANCE AND SCREENINGCOMPREHENSIVE EVALUATION (SEE...GUIDANCE FOR PEDIATRICIANS...APPENDIX 1: REIMBURSEMENT FOR...Council on Children With...LiaisonsStaffContributorsREFERENCESRESOURCE FOR FAMILIES |
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Neuropathologic studies of brain tissue from people with autism have revealed several abnormalities166–171 including:
The most consistent neuropathologic findings suggest pathology that arises in utero. The association of increased risk of ASDs associated with prenatal exposure to teratogens, such as thalidomide and valproic acid, suggests that early insults during critical periods of brain development (as early as 20–24 days after conception in the case of thalidomide) may be sufficient to cause ASDs.171 However, all of these neuropathologic findings are based on detailed study of a relatively small number of brains, and further investigation is required. Limited availability of brain tissue from people with well-characterized ASDs and age-matched controls has impeded neuropathologic investigations. Efforts to remedy this are underway with the establishment of the Autism Tissue Project (1-800-272-4622 [for physicians] or 1-877-333-0999 [for families]; www.memoriesofhope.org).168
Kanner, in his initial clinical description of autism, noted large head size in several of his patients.15 Increased head circumference has since been shown to be a common physical finding in children with ASDs, and 20% to 30% have macrocephaly, defined as a head circumference that measures more than 2 SDs above the mean.172,173 MRI studies have supported the finding of increased brain volume in children with ASDs, with 90% of toddlers with ASDs having larger-than-normal brain volumes in 1 study.174,175 Postmortem brain weights also are increased.166 Children later diagnosed with an ASD have been shown, as a group, to have average or below-average head circumference at birth, with acceleration in brain growth during the first year of life, leading to above-average head circumference or overt macrocephaly.176,177 Fewer adults with ASDs have been found to exhibit increased brain size compared with controls, indicating that there may be deceleration of brain growth at some point beyond early childhood.176,178,179 It is interesting to note that increased blood concentrations of brain-derived neurotrophic factor and several other neurotrophins have been detected in newborn infants who are later diagnosed with ASDs.180 This finding, if replicated, may have implications regarding the mechanism of early brain overgrowth. Age-related differences in serotonin synthesis capacity also have been demonstrated between children with ASDs and children in control groups,181 which leads to speculation regarding the neurotrophic role of serotonin in abnormal brain growth and organization in children with ASDs.
In addition to whole-brain volume differences, specific regional gray- and white-matter volumetric differences have been described. The frontal, limbic, basal ganglia, and cerebellar regions have been implicated most consistently.172,182–184 Abnormalities in sulcal and gyral anatomy have been found by using surface-mapping techniques.185,186 The regional gray- and white-matter volume differences also seem to be age related, although larger cross-sectional studies and longitudinal studies are needed to clarify the meaning of these findings.
A variety of functional MRI studies during cognitive tasks or in response to visual or auditory stimuli suggest that individuals with ASDs use different cognitive strategies and, in some cases, different brain areas to process certain types of information.182,187 For example, functional neuroimaging techniques have indicated the presence of abnormalities in face recognition and executive functioning in adults with high-functioning ASDs.188 Hypoactivation of the fusiform gyrus in face-recognition tasks has been one of the most consistent findings187 and, in concert with abnormalities in amygdala activation, may relate to the abnormalities in gaze fixation that are seen in people with ASDs.189 Functional MRI evidence has also been used to postulate impaired "connectivity" between various cortical regions in the brains of people with ASDs.190–192 Most recently, some investigators have attempted to explain deficits in empathy, imitation, and language as abnormalities in the functioning of mirror neuron systems.193 These systems are a newly discovered subset of cells found in several areas of the brain that seem to fire when an individual simply observes another's actions—that is, it seems they directly reflect actions performed by another in the observer's brain. They also may play a role in the ability to recognize and empathize with or "mirror" the feelings of others. These functional brain differences provide intriguing links between the neuroanatomical substrate and the characteristic clinical features of people with ASDs.
Although neuroimaging research has identified volumetric and other abnormalities in groups of patients with ASDs compared with controls, a reliable marker has not been identified, and routine clinical neuroimaging for individuals with ASDs is not recommended.106,107,183,194
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CLINICAL SIGNS |
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TOPABSTRACTINTRODUCTIONEPIDEMIOLOGYETIOLOGYNEUROPATHOLOGY AND NEUROIMAGINGCLINICAL SIGNSSURVEILLANCE AND SCREENINGCOMPREHENSIVE EVALUATION (SEE...GUIDANCE FOR PEDIATRICIANS...APPENDIX 1: REIMBURSEMENT FOR...Council on Children With...LiaisonsStaffContributorsREFERENCESRESOURCE FOR FAMILIES |
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Although the social deficits occur earlier and may be more specific, they can be subtle and less often recognized or articulated by parents. Speech delays usually prompt parents to raise concerns to their child's PCP. Most parents become concerned between 15 and 18 months of age but may delay discussing their concerns with their child's physician for several months.35,195–198 Recently, the media and public agencies have raised public awareness about the importance of recognizing the early signs, including those present during the first years of life. This being the case, it is anticipated that parents may begin to voice concerns to their infant's pediatrician earlier and that these concerns may now target the often earlier-appearing social deficits. Presentations can differ widely from one child to the next; some are perceived by parents as "different" during the first few months of life, others present with delayed speech development during the second year of life, and still others may appear to be normal only to regress and lose skills after the first year of life.199,200 AS in children may go unnoticed until they are of school age, when teachers notice difficulties with peer interactions. Expanded reviews regarding early signs are available.201–203
Social Skills Deficits
Although more specific than language deficits, social deficits appearing in the first 2 years of life often have escaped parent recognition.204–206 Children with ASDs universally demonstrate deficits in social relatedness defined as the inherent drive to connect with others and share complementary feeling states.207 Children with ASDs often do not appear to seek connectedness; they are content being alone, ignore their parents' bids for attention, and seldom make eye contact or bid for others' attention with gestures or vocalizations. In later years, they have difficulty sharing the emotional state of others in cooperative games and group settings and may have few, if any, friends.
Deficits in JA seem to be one of the most distinguishing characteristics of very young children with ASDs.198,208–216 JA is a normal, spontaneously occurring behavior whereby the infant shows enjoyment in sharing an object (or event) with another person by looking back and forth between the two. Later, gestures and/or speech also can be used to engage another's attention with regard to the objects and events simply for the enjoyment of sharing the experiences. Just like other developmental skills, development of JA skills is stepwise; it occurs in stages beginning in the first few months of life. Similar to language skills, receptive JA skills usually are mastered before expressive ones. JA begins with joyous smiling in recognition of and response to a parent or familiar caregiver's smiles and vocalizations. At approximately 8 months of age, an infant will follow the parent's gaze and look in the same direction when a parent looks away (ie, to check the time). Children begin to "follow a point" at approximately 10 to 12 months of age. If a parent points in the direction of an interesting object or event and says, "Look!" the typically developing child will look in the intended direction and then, after seeing the object/event, look back at the parent in acknowledgment and shared expression. Infants with ASD may not follow a point, even when one tries repeatedly in a loud voice calling their name or uses physical prompts, such as touching the child's shoulder before pointing.204 They may look in the indicated direction eventually, but this is not followed by shared looking and expression.
At approximately 12 to 14 months of age, the typically developing child will begin himself to initiate a point, at first to request a desired object that is out of reach and, a couple of months later, to draw the parent's attention to share an interesting object, person, or event. Depending on his speech skills, he may utter simple sounds ("uh") or actual words while pointing. Pointing to request an object is called "protoimperative pointing." Deficits vary, as some children with ASDs may make rudimentary pointing efforts by opening and closing their hand while it is raised in the direction of the desired item but without any back-and-forth looking between it and the caregiver. Another frequent strategy is to take the parent's hand to lead him or her to the object. At 14 to 16 months of age, the typically developing child will begin to point simply to "comment" about or "share" an interesting object/event (which is called "protodeclarative pointing"). As he points, he will look alternatively between the object/event of interest and the parent. It is the shared social experience, not the tangible object/event, that the child seeks. Children with ASDs consistently fail to point to "comment" at age-appropriate times, and when they do, they are less likely to show positive affect and connectedness during the act. Some high-functioning children with ASDs may point to label objects, shapes, and colors that they have learned in a rote fashion, but this often is done without any intent of communicating in a social context and is not considered JA. Mastery of JA seems to be necessary for functional language development; in fact, mastery of protodeclarative pointing seems to be a reliable predictor of functional language development within 1 year.7,217–219 JA skills progress to involve ongoing back-and-forth bids for attention and social interactions with multiple emotional expressions, sounds, words, and other gestures.
Orienting to social stimuli—in particular, turning consistently to respond to one's own name—is an early skill (8–10 months of age) that often is deficient in children with ASDs.215,220 However, it is not specific to children with ASDs, because children with hearing impairments also may fail to orient to their name. In fact, parents of children later diagnosed with ASDs often raise a concern about hearing. Hearing seems "selective" in that children with ASDs may hear and attend well to environmental sounds but not to human voices.221 Social referencing222 is the ability to recognize the emotional states of others as they respond to various stimuli. When faced with a novel situation, a typically developing infant might look to his mother for an indication of delight, anger, or fear in her facial expression. His facial expression then usually will mimic hers, although he may not fully understand the situation. A child with an ASD engages in less imitation.223
Because children with ASDs lack fundamental social skill building blocks, they may be less likely to develop appropriate peer relationships according to age and language ability. They may have few or no friends, and when they do, the relationships may evolve around the child's own special interests. Another factor that impedes lasting friendships is impaired central coherence or the inability to interpret stimuli in a global way.224,225 Instead, they focus on the parts, make less use of context, and miss the "big picture," which makes social interactions challenging. They also have difficulties understanding the perspective of others or lack "theory-of-mind" (ToM) skills. ToM is the awareness that others have thoughts and emotions that are independent from one's own; it is the ability that allows one to infer states of mind on the basis of external behavior.226,227 Typically developing children begin to have some sense of mental states of others by 4 years of age.197,228,229 Because of ToM impairments, children with ASDs have difficulties with empathy, sharing, and comforting. Baron-Cohen230 coined the term "mindblindedness" when referring to persons with ASDs who demonstrate severe ToM deficits.
Communication Deficits
Most children who are later diagnosed with AD and PPD-NOS present to their PCP with "speech delay," although this may change as parents are becoming more aware of social milestones. As noted previously, most parents sense something is wrong by the time the child is 18 months old.195–198 Lack of speech has been considered a hallmark of AD, especially when it is associated with the lack of desire to communicate and lack of nonverbal compensatory efforts such as gestures. However, children with milder symptoms, especially those with normal cognitive skills, may have some speech. Their speech may not be functional or fluent and may lack communicative intent. It can be scripted (from favorite videos or television programs) and stereotypic. Echolalia, sometimes called "parroting," is the repetition of another person's speech. Echolalia is classified as "immediate" when the child repeats vocalizations promptly after hearing them or "delayed" when there is a time lapse (hours, days, weeks). Typically developing children pass through a "vocabulary-burst stage," when brief periods of immediate echolalia are not unusual.197 On the other hand, echolalia in children with ASDs may persist throughout the life span and consist of a mixture of immediate and delayed varieties. Utterances of children with ASDs may be more clearly articulated, have a more monotone quality, and/or consist of larger verbal "chunks" (ie, entire television advertisement jingles, video reenactments, or recitations of nursery rhymes) than those of typically developing children. Sometimes, echolalia may even give the impression of "advanced" speech because of sophisticated vocabulary, grammar, and syntax. The clinician should be careful to differentiate between typical and autistic echolalia; usually, a formal evaluation by a speech-language pathologist (SLP) is needed. Such an assessment also may reveal a dissociation between these "advanced" expressive skills and delayed receptive ones in that the child may be unable to follow simple 1-step commands, which is a 12- to 14-month-old skill. Some parents will note that their child seems overly "independent" because, rather than ask for desired objects, he uses advanced motor skills to obtain them himself (ie, moving a stool to a counter top to obtain an object at an age younger than typically expected). Some children with ASDs become quite skilled at rotely labeling colors, shapes, numbers, and letters of the alphabet, yet they are unable to point to them when asked to do so by another or incorporate the labels into functional language. A few may later develop hyperlexia or advanced verbal reading without corresponding comprehension skills.
Some children with ASDs say "pop-up words" without any apparent stimulus or communicative intent. They are spontaneous and inconsistent, although sometimes they may occur during acutely stressful situations. 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 disappear.197,119 Children with ASDs also may develop "language" in overlearned or gestalt phrases that are acquired and spoken almost as a single "giant-word" (ie, Whatisit? Idontknow). At the same time, they are unable to combine words in novel or original phrases or sentences that convey true meaning.
Although lack of speech, scripted speech, parroting without communicative intent, and pop-up and giant words are common classic presentations, earlier prespeech deficits often exist that, if detected, could facilitate earlier diagnosis.* These deficits include:
The AAP brochure "Is Your One-Year-Old Communicating With You?"13 was developed to help raise parent and physician awareness of these earlier social communication milestones and to promote recognition of symptoms of ASDs before 18 months of age.
Regression
Approximately 25% to 30% of children with ASDs begin to say words but then stop speaking, often between the ages of 15 and 24 months.199,200,208 Regression of skills in children with ASDs may also include loss of gestural communication (wave, point, etc) and social skills (eg, eye contact and response to praise) or a combination of both. Regression can be gradual or sudden, and it may be superimposed on subtle preexisting developmental delays or atypical development, such as an unusually intense interest in objects or other nonsocial stimuli during the first year of life.205 Although it may be tempting to attribute regression to environmental stressors (eg, birth of a new sibling or a move to a new house), this results in a delay in diagnosis. Regression is a well-documented hallmark of ASDs and should always alert the PCP to consider ASDs.
Asperger Syndrome
Children with AS may have mild or limited speech delays (see the DSM-IV-TR4 criteria in Table 2) and escape recognition until preschool or early school age, when their inability to make friends becomes a concern. Although often unnoticed, language development usually is atypical. Children with AS often are quite verbal about a certain topic of interest, but they are 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. Speech also can be overly formal (pedantic), which is a reason why children with AS sometimes are described as "little professors."227 Children with AS 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.197,227 Children with AS especially have difficulty sustaining a conversation on a topic that is initiated by another. Language may seem odd, self-centered, and not listener responsive and results in a monotone monologue. They may demonstrate unique delivery of speech (prosody) in regard to intonation, volume, rhythm, pitch, and personal space that also tends to disregard listener needs. Children with AS may have difficulty with abstract reasoning and 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, teasing idioms, irony, lies, jokes, and faux pas.226,227,229 Older children with high-functioning AD or PDD-NOS and fluent speech also may demonstrate some of the above-mentioned language characteristics.
Play Skills
Lack of, or significantly delayed, pretend play skills coupled with persistent sensory-motor and/or ritualistic play are characteristic of ASDs. Some children with severe ASDs may never progress past the sensory-motor play stage. They mouth, twirl, bang, and manipulate objects in a stereotypic or ritualistic manner. The play of children with ASDs often is repetitive and lacks creativity and imitation.3,4 Typical examples include spinning the wheels or lining up cars instead of "driving" them, arranging crayons instead of coloring with them, or stacking blocks in the same sequence time after time. Often they prefer to play with common objects (string, sticks, rocks, or ballpoint pens) rather than store-bought toys with the exception of trains or characters from favorite videos and television shows. Puzzles, especially shape-matching ones and computerized "puzzle games," also are quite popular.222 Children with ASDs often are 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 sensory-motor (mouthing, banging, twirling) in nature. Children with ASDs may seem to enjoy chase games and roughhousing, but it is often the sensory-motor aspects of these activities, rather than their social aspects, that are enjoyable. They have trouble interacting in groups and cooperating in the social rules of more sophisticated games. Often they are left out, ignored, and at high risk of being victimized and bullied by peers.231
Restricted, Repetitive, and Stereotyped Patterns of Behavior, Interests, and Activities
Children with ASDs can demonstrate atypical behaviors in a variety of areas including peculiar mannerisms, unusual attachments to objects, obsessions, compulsions, self-injurious behaviors, and stereotypies. Stereotypies are repetitive, nonfunctional, atypical behaviors such as hand flapping, finger movements, rocking, or twirling.3,4,203 Although most stereotypies are harmless, they are problematic in that they may prevent the child from accomplishing a task or learning new skills. Although stereotypies are distinctive and obvious, they are not specific to children with ASDs, because many children with profound MR and/or severe sensory deficits also demonstrate stereotypies. Even typically developing toddlers, especially before the onset of fluent language, may flap their arms briefly when they are excited or frustrated. Stereotypies associated with ASDs often do not appear until after 3 years of age232 and commonly manifest as finger flicking, unusual eye gazing, habitual toe walking, and/or persistent sniffing and licking of nonfood items.
Although most children, at some time during their early development, form attachments with a stuffed animal, special pillow, or blanket, children with ASDs may prefer hard items (ballpoint pens, flashlight, keys, action figures, etc). Moreover, the attachment is more persistent, in that they may insist on holding the object at all times, although these are rarely, if at all, used in real "play." Whereas younger children with ASDs may have restricted interests in regards to objects, the restricted interests in those with AS more often relate to topics and facts.227 For example, rather than carrying a toy train at all times, there is an obsession with train schedules. Sometimes the item/topic of interest may be typical for any child, but it is the degree of interest that is abnormal. For example, similar to typically developing children, a child with an ASD may be fascinated with dinosaurs, but he knows far more details about them and persists in playing or discussing them to the exclusion of all else. Perseveration, or continuation of speech or play to an exceptional degree or beyond a desired point, is common in children with ASDs. Children with ASDs may protest vigorously when forced to transition from an activity or topic of interest or when a usual routine is changed. Without warning, these protests may quickly escalate to severe and prolonged temper tantrums characterized by aggression or self-injurious behaviors.
Self-injurious behaviors (head banging, skin picking, eye poking, hand biting) are stereotypies that may cause bodily harm and are more common in children with severe GDD/MR (intellectual disabilities) or ASDs with comorbid GDD/MR.233 Self-injurious behaviors may be precipitated by frustration during unsuccessful communication attempts, transitions, anxiety in new environments, boredom, depression, fatigue, sleep deprivation, or pain. The presence of self-injurious behaviors, aggression, and other extreme behaviors may prevent the child from participating in integrated activities in the community with typically developing peers and cause significant family stress.
Additional Coexisting Conditions That Are Not Core Features in the DSM-IV-TR
Cognitive Abnormalities (GDD/MR or Intellectual Disability, Learning Differences, and Splinter/Savant Skills)
The prevalence of comorbid GDD/MR or intellectual disability (the appropriate term depends on age and availability of both a standardized IQ score and a formal assessment of adaptive skills) with ASDs was estimated to be approximately 90% before 1990.62 On the basis of later studies published in the 1990s, consensus guidelines reported the prevalence as approximately 70% to 75%.1,2,106,107,234 Prevalence studies published in the new millennium have reported rates of ASDs with comorbid GDD/MR of just under 50%,28,29,34,103 whereas 2 English studies reported rates as low as 26% to 29%.20,21 Better ascertainment of children without cognitive deficits (in particular AS, which by definition is characterized by normal intelligence), improved professional training, and more effective strategies/tools for evaluating cognitive abilities in children with ASDs all may contribute to the decreasing prevalence of comorbid GDD/MR.
One unique characteristic of ASDs is the "unevenness" of skills. Abilities may be significantly delayed in some areas of development yet "advanced" in others, often because of exceptional focusing, memory, calculation, music, or art abilities.235 They may be labeled as "splinter skills" when they serve no purpose in day-to-day life and do not improve functional outcomes. Rarely, highly developed talents or savant skills may promote a vocation that provides financial independence and, occasionally, national recognition.236–238
Sensory-Motor Symptoms
Although sensory symptoms (eg, hyperacusis) are more frequent and prominent in children with ASDs, there is no evidence that sensory symptoms differentiate children with ASDs from children with other developmental disabilities.239 Children with ASDs may demonstrate simultaneous hyposensitivities and hypersensitivities for stimuli within the same sensory modality.240 For example, they may seem overly sensitive to certain environmental noises but lack response to human voice, or they may visually inspect the details of an object but not notice the comings and goings of other people in the room. Others may have oral aversions and/or total-body "tactile defensiveness" to soft touch (fabric bumps on socks and sweatshirts) or hugs yet be insensitive to pain.241 Sensory factors related to food, such as texture, color, and taste, may lead to highly restricted diets. More research is needed to operationalize the concept of sensory integration and possible interventions and define its role in ASDs.
In addition to unusual motor stereotypies that serve as defining characteristics of ASDs discussed previously, some children with ASDs also may demonstrate atypical motor development, poor coordination, or deficits in praxis (motor planning, execution, and sequencing).240 Some investigators believe that, although not a defining characteristic by DSM standards, motor clumsiness is a distinguishing characteristic of AS.86,242 Finally, some children may appear to be "hyperactive" and motor driven with an exterior focus of attention and actually meet criteria for comorbid ADHD (although current DSM-IV-TR criteria exclude making the diagnosis of ADHD in the presence of an ASD).8,240,243 Other children may be hypoactive and withdrawn and have an interior focus of attention.240
In summary, ASDs are characterized by a broad array of clinical features; some are more specific to ASDs than others (JA deficits versus stereotypies). Familiarity with the early social and preverbal communication deficits will help the PCP recognize ASDs earlier, which should, in turn, facilitate the prompt initiation of appropriate interventions.
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SURVEILLANCE AND SCREENING |
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TOPABSTRACTINTRODUCTIONEPIDEMIOLOGYETIOLOGYNEUROPATHOLOGY AND NEUROIMAGINGCLINICAL SIGNSSURVEILLANCE AND SCREENINGCOMPREHENSIVE EVALUATION (SEE...GUIDANCE FOR PEDIATRICIANS...APPENDIX 1: REIMBURSEMENT FOR...Council on Children With...LiaisonsStaffContributorsREFERENCESRESOURCE FOR FAMILIES |
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The goal of this clinical report is to help pediatricians identify children at an earlier age who are at risk of an ASD. An ASD-specific surveillance and screening algorithm (Fig 1) has been developed to facilitate the identification process. It builds on the developmental surveillance and screening algorithm for pediatric preventive care visits that was published in the 2006 policy statement "Identifying Infants and Young Children With Developmental Disorders in the Medical Home: An Algorithm for Developmental Surveillance and Screening."246
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Surveillance for ASD
Surveillance at the first preventive care visit (Fig 1, Steps 1a and 2) should begin with a family history to determine if there are any family members, especially a sibling, who have been diagnosed with ASDs. Because the risk of having symptoms of ASDs in younger siblings of children with A
