Identification, évaluation et prise en charge des enfants atteints de troubles du spectre autistique

Enfants de moins de 18 mois

Un diagnostic précoce du TSA peut conduire à un traitement plus précoce. M-CHAT est l'outil le plus étudié et le plus utilisé pour évaluer les jeunes enfants pour le TSA. Des outils supplémentaires sont à l'étude et sont répertoriés dans le tableau 6 comme des tests de dépistage de l'autisme prometteurs. Le retard de langage peut être identifié en utilisant la liste de contrôle pour les nourrissons et les jeunes enfants (questionnaire des parents) chez les nourrissons à faible risque et les jeunes enfants âgés de 12 à 18 mois.^43,59 Ce questionnaire pourrait être utile pour identifier les jeunes frères et sœurs d'enfants atteints de TSA qui présentent un risque plus élevé de TSA. Des recherches supplémentaires peuvent permettre la détection de jeunes enfants jusqu'à 12 mois grâce à l'utilisation de questionnaires administrés par les parents, tels que le Profil de développement des échelles de communication et des comportements symboliques et la Liste de contrôle pour les nourrissons et les jeunes enfants.⁵⁸

Les prestataires de soins primaires ont pour tâche d'identifier tous les enfants qui bénéficieraient d'une intervention précoce, pas seulement les enfants à risque de TSA (voir le rapport clinique AAP "Promotion du développement optimal: identification des bébés et des enfants) les enfants atteints de troubles du développement grâce à la surveillance et à la détection du développement "⁴⁹ pour plus d'informations). Il est important d'identifier tous les retards cliniquement significatifs chez les enfants avec référence pour une évaluation diagnostique et une intervention appropriées. Les problèmes de sommeil, de nourriture, de constipation et de régulation de l'État sont courants dans la population générale, mais ils peuvent être particulièrement difficiles chez les jeunes enfants atteints de TSA. Les pédiatres peuvent aider les familles à gérer ces symptômes.

Enfants de 18 à 30 mois

L'outil de détection par questionnaire le plus utilisé est le M-CHAT. Il a été validé et le score a été modifié pour faciliter l'administration dans les établissements de soins primaires pour les enfants âgés de 16 à 30 mois.⁵¹ La liste de contrôle modifiée pour l'autisme chez les jeunes enfants, révisée avec suivi (questions) (M-CHAT-R / F) supprime 3 questions de la version précédente. Les enfants dont le score est ≥ 8 présentent un risque élevé de TSA ou d'autres troubles du développement et doivent être référés immédiatement pour une évaluation diagnostique. Pour les enfants avec des scores de 3 à 7, des questions d'entrevue de suivi de script accessibles au public sont requises pour les éléments notés positifs. Les enfants qui continuent d'avoir de 3 à 7 éléments positifs pour le diagnostic de TSA après avoir clarifié les questions de suivi ont un risque de 47% de recevoir un diagnostic de TSA et 95% de chances d'être identifiés avec un autre retard dans le développement qui bénéficierait de l’intervention. Les enfants examinés avec le M-CHAT-R / F sont identifiés avec un TSA à un âge plus précoce que prévu par les statistiques nationales.⁴⁹ Los niños que no pasan las pruebas de detección de ASD o que califican como en riesgo de diagnóstico deben ser referidos tanto para la evaluación diagnóstica como para los servicios de intervención. No es necesario un diagnóstico definitivo para instituir servicios por demoras documentadas que se atenderían mediante intervención temprana o servicios escolares. Aunque el M-CHAT-R / F parece ser útil para la detección general de diversas poblaciones,^{60 60} Disminuir la disparidad en el diagnóstico precoz requerirá adaptar y validar las medidas y abordar las barreras culturales y lingüísticas para el cribado.⁶¹

Las medidas en desarrollo pueden proporcionar una detección rápida al tiempo que abordan las preocupaciones de los médicos sobre la compatibilidad con un sistema de registro electrónico y acceso abierto.⁶² Las adaptaciones adicionales de la Escala de Comportamiento Simbólico de la Comunicación para su uso en la detección de retrasos en el lenguaje además del TEA tienen el potencial de identificar a los niños en riesgo de ambos trastornos (comunicación funcional; edades de 6 a 24 meses).^49,59 El uso de esta u otras herramientas de detección puede combinarse con el soporte en línea de un glosario de síntomas de TEA, como el que se encuentra en el Navegador de autismo (http://www.autismnavigator.com/). Estos y otros enfoques en línea para apoyar las estrategias de detección pueden integrarse en patrones eficientes de práctica. Los resultados de los exámenes de detección realizados en línea, en entornos comunitarios y en centros preescolares deben comunicarse al proveedor de atención primaria para garantizar una evaluación adecuada de la etiología, las condiciones concurrentes, la derivación para el diagnóstico y el seguimiento para garantizar que se acceda a la intervención.⁴⁹

Una revisión sistemática realizada por el Equipo de Trabajo de Servicios Preventivos de EE. UU. (USPSTF) concluyó que la literatura sobre las herramientas de detección existentes no demostraba suficiente especificidad para justificar la detección universal.⁶³ El USPSTF señaló que ningún estudio ha examinado directamente si los niños con TEA detectados por detección temprana tienen mejores resultados que los detectados por otros medios. Sin embargo, dicho estudio requeriría la asignación aleatoria de grandes muestras representativas de todo el país a una condición de detección o no detección, con un seguimiento de los resultados a largo plazo y los costos sociales. Dado que el tratamiento temprano de niños menores de 36 meses ha demostrado resultados positivos,^43,64 Tal estudio sería difícil de apoyar. El USPSTF concluyó que se recomienda realizar más investigaciones para evaluar las edades y poblaciones apropiadas de niños que deberían someterse a pruebas de detección de ASD y que se deberían desarrollar medidas más precisas y culturalmente sensibles. La AAP continúa recomendando la detección utilizando las medidas actuales más válidas a los 18 y 24 meses de edad. Los pediatras no pueden suponer que los sistemas de intervención temprana evaluarán a los participantes que reciben servicios de lenguaje o retrasos globales para TEA en las edades recomendadas. Se recomienda el cribado universal porque los síntomas de ASD pueden identificarse en la primera infancia, y el diagnóstico de ASD por profesionales capacitados es preciso en niños de hasta 18 meses de edad.^{sesenta y cinco} La estabilidad diagnóstica es alta para los niños diagnosticados con TEA entre los 18 y 36 meses de edad.⁴³ La detección temprana no identifica a muchos niños con síntomas más leves y capacidad cognitiva típica como en riesgo de TEA; por lo tanto, la vigilancia continua sigue siendo necesaria.^seize La participación en la intervención temprana en general es mayor entre los niños que tuvieron pruebas de detección y vigilancia.⁶⁶

Niños mayores de 30 meses

En la actualidad, para niños mayores de 30 meses, no hay herramientas de detección validadas disponibles para su uso en la práctica pediátrica, ni hay recomendaciones actuales de la AAP para la detección universal de TEA en ese grupo de edad. El Cuestionario de comunicación social (SCQ) (ver Tabla 6) se ha estudiado en diferentes poblaciones (por ejemplo, muestra clínica, muestra de referencia de población, muestra comunitaria y muestra de conveniencia), con los mejores resultados en muestras de población.⁶⁷ cuando se usa la versión de por vida, y parece tener propiedades psicométricas razonables. Sin embargo, los cuestionarios como el SCQ pueden identificar síntomas que se superponen con otras afecciones, como el TDAH, que afectan la función en la edad escolar.^68,69 Se necesita una validación adicional de las herramientas de detección basadas en la población para niños mayores de 30 meses antes de que se puedan hacer recomendaciones para la detección universal de niños en edad escolar. En este momento, se recomienda la vigilancia continua en el contexto de la atención primaria.

Cognitive Testing

A range of standardized measures are used to determine developmental levels of younger children and IQ in children older than 3 years. The intelligence test selected by the psychologist will depend on the age and language level of the child. Administration of a valid cognitive test is important in ascribing symptoms to ASD as part of the initial diagnosis but also helps to establish co-occurring diagnoses with ASD, such as intellectual disability. There are valid tests that can be used in children who are nonverbal. Although the prevalence of a diagnosis of ASD is increased in children with an intellectual disability,^{91 91} other children diagnosed with intellectual disability may have some symptoms of ASD without meeting diagnostic criteria for the disorder.

Language Testing

Inherent in the core symptoms of ASD are differences in the use of verbal and nonverbal communication for social interaction. Formal assessment of communication by a speech or language pathologist at the time of diagnosis should include the documentation of expressive and receptive language skills as well as the pragmatic or conversational use of language.⁹²

Adaptive Function Testing

A caregiver report and/or teacher report of adaptive functioning complements objective cognitive testing. Determining the extent that ASD affects daily function is necessary to establish eligibility for some publicly funded programs as well as to identify and monitor developmental goals for treatment. Adaptive behaviors are typically delayed in people who have intellectual disability with ASD but can be impaired in people with ASD and an average-range IQ.^93,94 Commonly used adaptive measures include the Vineland Adaptive Behavior Scales and the Adaptive Behavior Assessment System.⁹⁵

Motor Assessment

Children with ASD are more likely to have mild delays in gross motor skills and coordination compared with children in the general population and may meet DSM-5 criteria for developmental coordination disorder in addition to ASD.⁹⁶ General screening tests or adaptive measures may suggest motor delays that would benefit from formal evaluation by an occupational or physical therapist. A relationship of early motor delays and subsequent language and adaptive development in children with ASD has been proposed.^97,98

Sensory Assessment: Hearing

Children with language delay or inattention to language should have an evaluation of their hearing as part of their initial evaluation.⁹⁹ Hearing loss may co-occur with ASD and needs to be considered in children with language delays, behavior problems, or inattention. Appropriate amplification should be offered, if indicated. The clinical utility of auditory processing evaluations available in current practice remain an area of study.^100,101

Sensory Assessment: Vision

Visual function should be considered in the initial evaluation of children who are visually inattentive, have stereotypical behaviors (such as eye poking or close visual scrutiny), or do not make eye contact. Decreased visual acuity may affect interactive gaze and require accommodations in the educational setting.¹⁰² Children with visual impairment may also demonstrate stereotyped motor behaviors.

Sensory Assessment: Sensory Processing

The DSM-5 includes sensory symptoms in the diagnostic criteria for ASD. The DSM-5 does not include sensory processing disorder as a discrete diagnosis. Commonly used evaluation tools (such as the Short Sensory Profile and others) quantify parent perception of sensory differences relative to smell, taste, vision, hearing, and touch.^103,104 In addition to capturing what is conventionally considered as a sensory disturbance, questionnaires that are used to assess sensory symptoms also capture motor hyperactivity and hypoactivity as sensory-seeking or sensory-avoiding behaviors. These latter symptoms may reflect co-occurring ADHD. Sensory symptoms may be more evident at younger ages and may define subtypes of the disorder.^105,106

Genetic Testing

Advances such as the development of CMA and next-generation sequencing technologies and the application of these technologies to well-characterized patient cohorts have led to progress in the understanding of the complex genetics of ASD and other neurodevelopmental disorders in the last decade. Identifying a genetic etiology provides clinicians with more information for families about prognosis and recurrence risk and may help to identify and treat or prevent co-occurring medical conditions, guide patients and families to condition-specific resources and supports, and avoid ordering unnecessary tests (Table 7).^111–117 Most parents find this information to be useful.¹¹⁸ As research progresses, genetic testing may contribute to identifying effective interventions related to specific etiologies.

Etiologic investigation begins with a careful medical, developmental-behavioral, and family history and a thorough physical and neurologic examination.¹⁰⁹ The history should include potential prenatal exposure to teratogens (such as medications, alcohol, drugs) and other factors that increase risk for ASD.^109,119 The physical examination should include assessment of growth relative to typical curves (including head circumference), dysmorphic features, organomegaly, skin manifestations of neurocutaneous disorders (eg, tuberous sclerosis and neurofibromatosis), and neurologic abnormalities.¹⁰⁹ Genetic evaluation should be recommended and offered to all families as part of the etiologic workup. A stepwise general approach is provided in Table 8 as a practical guideline.^110,120 The presence of dysmorphic features or intellectual disability is generally associated with increased likelihood of finding a genetic abnormality.¹²¹ However, authors of some clinical studies have identified similar yield for genetic testing in children without these risk factors.^122,123

In some cases, individuals with clinical genetic syndromes, such as fragile X syndrome, tuberous sclerosis complex, and others (such as those described in Supplemental Table 13), also meet criteria for ASD.^124,125 When a specific syndrome or metabolic disorder is suspected, the clinician should proceed with the appropriate targeted testing or referral to a pediatric geneticist or neurologist. For example, a girl with significant developmental delays, deceleration in head growth velocity, and characteristic midline hand movements should prompt genetic testing for a mutation or deletion or duplication of MECP2, the gene implicated in Rett syndrome.^109,126 Another specific example would be a boy with ASD with marked macrocephaly and pigmented macules on the penis, findings that would warrant sequencing and deletion or duplication analysis of the PTEN gene.¹²⁷ Descriptions of these and other clinical syndromes associated with ASD are provided in Supplemental Table 13.

CMA is recommended if the etiology for developmental disability is not known. CMA identifies copy number variants (CNVs) at this time, which are DNA duplications or deletions that alter the function of genes (Table 8, step 2). CMA reveals a definitively pathogenic CNV in 5.4% to 14% (median 9%) of individuals with ASD in clinical samples.^{121,128–135} When CNVs of uncertain significance are included, approximately 17% to 42% of patients with ASD have findings on the CMA. Some of the variants of uncertain significance may be determined as pathogenic in the future. The most commonly identified recurrent pathogenic CNVs among individuals with ASD are provided in Supplemental Table 14.

Because fragile X syndrome increases risk for ASD, DNA testing for fragile X syndrome should be recommended for all children with ASD, but especially for boys and children with a suggestive family history of male members with intellectual disability. Physical examination might reveal the common features of a large head size, prominent jaw, large ears, ligamentous laxity, and, in male patients, large testes after puberty. The cytosine-guanine-guanine trinucleotide repeat expansion that is responsible for fragile X syndrome is not detected on CMA and must be ordered as a separate test. The current estimate is that approximately 0.45% of individuals with ASD have the full mutation for fragile X syndrome, and many of them are female.^{130,132,135–137} Because fragile X syndrome testing is relatively inexpensive and the condition has important genetic counseling implications, it is reasonable to consider testing both male and female patients with ASD, at least until more data become available to clarify the issue.

When the history and physical examination, CMA, and fragile X analysis do not identify an etiology, the next step at this time in the etiologic evaluation for ASD is whole-exome sequencing (WES). WES technology allows for the identification of single-nucleotide variants, including pathogenic loss-of-function mutations and missense mutations, which have been found to be associated with ASD.^138–142 Examples of ASD risk genes identified or confirmed in WES studies are provided in Supplemental Table 15. As with other tests, clinicians ordering this test should be familiar with both pretest counseling and interpretation of the results. A genetic counselor is helpful in explaining the reason for testing as well as the results. Large clinical WES studies have consistently been used to identify a molecular diagnosis in 26% to 29% of individuals for whom neurodevelopmental disorders were the primary indication for testing.^143–145 Authors of studies of clinical populations with ASD have reported diagnostic yields of 8% to 20%.^121,144 The yield of WES is higher when both the parents and the child who is affected are evaluated¹⁴⁴ to allow for comparison of the child with parents who are unaffected.

Some geographic areas may have limited availability of pediatric subspecialists (eg, in genetics or metabolism) who can guide the genetic workup, so primary care providers may be in the position to consider and direct etiologic evaluation. The complexity of genetic testing is such that most primary care providers may want to consult with a specialist to plan testing and interpret results. The clinical etiologic evaluation should be tailored to the individual patient, taking into consideration information from the history and physical examination^109,110 and the values and wishes of the family. The stepwise general approach summarized in Table 8 can be used to guide this process.

It is important for families to understand that genetic tests may explain the cause of their child’s ASD or provide information about the statistical risk of ASD, but they are not diagnostic of ASD; the diagnosis of ASD is made on the basis of clinical symptoms. Unlike CMA and WES, commercially marketed tests may not have the potential to provide a molecular etiologic diagnosis. Genomic testing technology is evolving rapidly, as is our understanding of the genetic architecture of ASD, and these recommendations for testing will need to be updated as new studies are published.¹⁴⁶ For example, it is anticipated that CMA and WES will soon be combined because of improvements in accurate identification of CNVs using sequence data and that sequencing of the exome will be replaced by sequencing of the entire genome as issues with interpretation and cost become more manageable.^{121,130,147–150}

Parents of a child with ASD should be counseled regarding recurrence risk in subsequent offspring, and the nature of the counseling depends greatly on whether a specific genetic cause of the child’s ASD has been identified. When a specific genetic etiology has been determined, the family can be provided with information about the risk of recurrence in subsequent offspring. However, when genetic testing has not been completed or has not revealed the etiology of the child’s ASD, recurrence risk counseling is based on group averages derived from the existing literature. For a couple with 1 child with ASD of unknown cause, the current best estimate of recurrence in a subsequent child is approximately 10% (range 4%–14%^151–153) If a couple already has ≥2 children with ASD of unknown etiology (idiopathic), the chance of a subsequent child having ASD may be as high as 32% to 36%.^151,154 However, the risk is not limited to ASD. Siblings of children with ASD who do not have ASD themselves may have a 20% to 25% risk for language disorders and other neurodevelopmental and psychiatric disorders.^152,155,156

Neuroimaging

Specific clinical neuroimaging findings are not more prevalent in ASD compared with other neurodevelopmental disorders, nor do specific abnormalities correlate with clinical, etiologic, or pathophysiological aspects of ASD.^120,157,158 Incidental findings are common in neuroimaging studies obtained in the workup of children diagnosed with ASD but rarely provide etiologic information or require intervention.^159,160 The need for clinical MRI should be directed by a history and physical examination. MRI may be indicated in the evaluation of atypical regression, microcephaly, macrocephaly, seizures, intracranial manifestations of genetic disorders, abnormal neurologic examination, or other clinical indications.^{76,109,161,162} Imaging technology used to examine brain structure and function provides valuable insight into the neurobiology of ASD in research settings and may lead to useful clinical applications in the future.

Metabolic Testing

The yield of routine metabolic testing for children with ASD is low and not recommended for regular use.^163–167 However, large population-based studies are lacking, so accurate prevalence and diagnostic yield estimates are not available. Metabolic workup should be informed by history, family history, symptoms, and examination and might include measurement of fasting plasma amino acid levels, urine organic acid levels, and acylcarnitine metabolite levels and other testing for specific metabolic disorders. History of atypical regressions (later than 2 years of age, motor regression, or multiple regressions), family history of early childhood death or diagnosed metabolic disorders, and physical features, such as significant hypotonia or weakness, visual and hearing impairment, and dysmorphic features, would suggest consultation with a specialist to guide evaluation for metabolic or mitochondrial disorders.^109,168 Children who present with motor delay should be evaluated with creatine kinase and thyroid-stimulating hormone testing, according to AAP recommendations.^9,49 Although metabolic disorders are uncommon causes of ASD, the potential impact is high because treatment may be available and the inheritance pattern may be known.^109,124 Examples of metabolic conditions that may be associated with an ASD phenotype are provided in Supplemental Table 16. There is no evidence at this time for routine testing of hair, blood, or urine for environmental toxins or heavy metals outside of laboratory screening for lead exposure.¹⁶⁹

EEG

Children with ASD have an increased risk for seizures, and EEG abnormalities are common in the absence of clinical seizures (see Seizures section for more information).^170–175 However, EEG is not recommended as a routine baseline evaluation in the absence of clinical concern about seizures, atypical regression, or other neurologic symptoms on history or examination that would suggest an EEG is indicated.^{161,170,172,176} Late or atypical loss of language, as might be observed in electrical status epilepticus of sleep with loss of language, should be evaluated with an overnight EEG.^{161,170,172,176} Primary care clinicians should discuss the increased risk and the signs and symptoms of seizures with the families of children diagnosed with ASD, maintain a high index of clinical suspicion for seizures, and consult with a pediatric neurologist when concerned about atypical regression or the possibility of seizures.^170,172,176

Genetics and ASD

ASD is clinically and etiologically heterogeneous yet highly heritable. The rate of ASD in siblings is much higher than the rate in the general population. Twin studies demonstrate substantially higher concordance rates for symptoms of ASD in monozygotic twins than in dizygotic twins.¹⁷⁷ A meta-analysis involving 6413 twin pairs revealed a 98% concordance in monozygotic twins, a 53% to 67% concordance in dizygotic twins, and heritability estimates from 64% to 91%.^177,178 Siblings may also be at risk for symptoms related to ASD that do not meet the threshold for a diagnosis of ASD and have been described as the broader autism phenotype.^141,179 These data provide strong evidence for a genetic contribution to ASD risk.^180–184

Risk for ASD also is increased in the children of both older fathers and older mothers.^185–187 The increased risk with parental age may be related to germline mutations in older fathers.^143,188 Mechanisms mediating the effect of advancing maternal age on ASD risk are less clear.¹⁴³ Increased maternal and paternal age are independently associated with ASD risk, and a joint effect seems to occur as well.^185–187

Important aspects of the genetics of ASD are still poorly understood, including the role of common variants, epistasis (gene-gene interactions), and environmental modification of genotype effects. In contrast, advances such as CMA and next-generation sequencing technologies have resulted in identification of large-effect (pathogenic) rare variants that appear to be causally associated with ASD, including CNVs, which are deletions or duplications ≥1000 bp in size that alter the dosage of genes, and sequence-nucleotide variants.^189–192 Pathogenic rare variants may arise de novo or be inherited as autosomal dominant, autosomal recessive, or X-linked mutations. Researchers of CMA and WES studies have established that although de novo and inherited rare variants of large effect size are collectively common, no individual pathogenic variant accounts for more than 1% of cases of ASD.* Genes that contribute to ASD are involved in a variety of biological functions, with convergence on aspects of brain development and function, including synaptic structure and function, intracellular signaling, transcription regulation, and chromatin remodeling.^{139,190,191,196} It is important to note that no specific mutation has been identified that is unique to ASD; there is substantial genetic overlap between ASD and other neurodevelopmental disorders, including intellectual disability, epilepsy, and schizophrenia.^197–204

Genes, Environmental Exposures, and ASD

The potential environmental factors that may be related to increased reported prevalence of ASD is an area of active study that, as yet, is without firm conclusions.¹¹⁹ Environmental factors associated with ASD include in utero exposure to medications such as valproate and thalidomide. Other prenatal influences, such as short interpregnancy interval, multiple gestation, maternal obesity, gestational bleeding, gestational diabetes, advanced parental age, and infections (eg, rubella and cytomegalovirus), may be associated with increased risk for ASD.^205–209 Perinatal factors, such as preterm birth, low birth weight, fetal growth restriction (ie, small for gestational age), intrapartum hypoxia, and neonatal encephalopathy, are associated with increased ASD risk.^{205,210–212} Environmental factors may present independent risk to prenatal brain development or may affect gene function in individuals with genetic predisposition.²¹³ Population-level associations with ASD have been examined for organophosphates and certain other pesticides, metals, volatile organic compounds, and air pollution, particularly particulate matter and nitrogen dioxide.^214–216 Research on environmental exposures may be of great importance in identifying modifiable risk factors related to ASD and other developmental disorders. It is prudent to limit exposure of children and pregnant women to known neurotoxicants.

Genes, Immunologic Exposures, and ASD

It has been proposed that children with ASD-associated CNVs may be more susceptible to environmental insult in the form of maternal immune activation. Report of maternal infection or fever during pregnancy may be associated with increased severity of ASD-related symptoms in offspring who are affected.²¹⁷ The pathogenic role of circulating maternal antibodies directed to fetal brain tissue and the potential value of maternal antibody panels as biomarkers of ASD are currently being studied.^218–222 Unless otherwise indicated (eg, history suggestive of autoimmune or immunologic disorder), no immune testing is recommended in the etiologic workup of a child with ASD.

Epigenetics

Epigenetic modifications, such as DNA methylation and posttranslational histone modification, produce heritable changes in gene expression that do not involve a change in the DNA sequence. Some genetic disorders associated with ASD (eg, Rett syndrome; CHARGE syndrome; 15q duplication; Angelman syndrome; and fragile X syndrome), involve genes that either encode epigenetic regulators or are sensitive to alterations in their epigenetic regulation.^223,224 Because epigenetic modifications can be influenced by environmental factors, such as prenatal maternal exposures and postnatal experience, they represent 1 interface between genes and environment. However, epigenetic modifications are not the only mechanisms by which gene expression is regulated, and epigenetics should not be conflated with the broader category of environmental effects.^223,225 Currently, the evidence that alteration of gene expression by environmental factors plays a causal role in ASD is very limited.^223–228 Investigation of the role of epigenetic and other nongenetic modifications that alter gene activity without changing the DNA sequence is an active area of etiologic research in ASD.

Vaccines

The scientific literature does not support an association of vaccination as an environmental factor that increases the risk for ASD. Children with ASD should be vaccinated according to the recommended schedule. Epidemiological studies do not demonstrate any association of the measles-mumps-rubella vaccine, mercury exposure by thimerosal-containing vaccines, aluminum in vaccines, or increased level of immunologic exposure attributable to a larger number of vaccines (either given at 1 time or cumulatively) with ASD.^{214,229–246} Vaccines used for children in the United States have not contained thimerosal since 2001. The authors of a 2012 Cochrane review²³⁴ and a 2014 quantitative meta-analysis of pooled data from cohort studies involving 1 256 407 children and case-control studies involving 9920 children reviewed the scientific literature and came to this conclusion.²³¹ Evidence implicating immunizations as a “second hit” conferring ASD risk in genetically susceptible subgroups is lacking. It has been shown that the measles-mumps-rubella vaccine is not associated with increased risk for ASD, even among children who are already at higher risk because of having an older sibling with ASD.²²⁹ Media coverage of vaccine issues may inflate the perception of uncertainty by equal coverage of vaccine proponents and opponents. The overwhelming weight of evidence supports vaccine safety.²⁴⁷ Communicating information about vaccine safety is a critical component of pediatric practice.²⁴⁸

Brain Structure and ASD: Neuropathology

Neuropathological research has been limited by the small number of postmortem brains available for study. Developmental brain abnormalities in people with ASD are reported in the cerebral neocortex; limbic system structures, including the hippocampal formation and amygdala; basal ganglia; thalamus; brainstem; and cerebellum. These brain abnormalities include dysplasia, altered neurogenesis, and abnormal neuronal migration.^249–251 The vast majority of abnormalities described originate during prenatal brain development.^249,251,252 Findings in the cerebral cortex may include focal disruption of neuronal migration, minicolumnar abnormalities, and variations in neuronal density.^249,251,252 A decreased number of Purkinje cells in the cerebellum is 1 of the most consistently reported neuropathologic findings associated with ASD. Although it was initially thought to be of prenatal onset, evidence now indicates that this phenomenon is more likely to be an acquired process that occurs postnatally, potentially related to seizures, medications, and/or ischemia near the time of death or factors other than ASD.²⁴⁹ No uniform neuropathology has been identified in people with ASD.

ABA

Most evidence-based treatment models are based on principles of ABA. ABA has been defined as “the process of systematically applying interventions based upon the principles of learning theory to improve socially significant behaviors to a meaningful degree, and to demonstrate that the interventions employed are responsible for the improvement in behavior.”³¹⁰ The use of ABA methods to treat symptoms of ASD suggests that behaviors exhibited can be altered by programmatically reinforcing skills related to communication and other skill acquisition.^311,312 Thus, ABA treatments may target development of new skills (eg, social engagement) and/or minimize behaviors (eg, aggression) that may interfere with a child’s progress.

ABA interventions vary from highly structured adult-directed approaches (eg, discrete trial training or instruction, verbal behavior applications, and others) to interventions in natural environments that may be child led and implemented in the context of play activities or daily routines and activities and are altered on the basis of the child’s skill development (eg, pivotal response training, reciprocal imitation training, and others).^{297,309,312,313} To determine what intervention is most appropriate, the behavioral clinician works with the family and child to determine which skills to target for development and maintenance and what goals are appropriate.

ABA programs are typically designed and supervised by professionals certified in behavior analysis. The majority of states at this time have licensure for board-certified behavior analysts with provisions for payment by insurance. ABA may be prescribed or recommended by a physician or licensed psychologist.

A comprehensive ABA approach for younger children, also known as early intensive behavioral intervention, is supported by a few randomized controlled trials (RCTs) and a substantial single-subject literature.²⁹⁷ When only RCTs are considered, few interventions have sufficient evidence to be endorsed either for children younger than 12 years²⁹⁸ or for adolescents.³¹⁴

Children younger than 12 years receiving more hours per week of ABA were found to be more likely to achieve the individualized goals identified in their programs.³¹⁵ In retrospective studies, more intense ABA therapy was associated with achieving optimal developmental outcomes.³¹⁶ Given the heterogeneity of the ASD phenotype, the service needs of children, youth, and adults need to be individualized by using available clinical data.

In some instances, a behavioral intervention is needed to address acute serious problem behaviors that must be given priority, for example, because of safety issues.²⁹⁵ Whether a student is getting formal ABA under IDEA or not, a family can request that challenging behaviors be evaluated in the school setting by using behavioral principles through a functional behavioral assessment. The target symptoms to treat may then be divided into component parts that are addressed in a stepwise fashion (task analysis).^313,317 Once the reasons for the behavior are understood, a behavior improvement plan may be implemented.

Developmental Relationship–Focused Interventions

Intervention for young children also may be derived from developmental theory, which is focused on the relationship between the caregiver’s level of responsiveness and the child’s development of social communication.^{296,318–320} Through interaction with others, children learn to communicate and regulate emotions and establish a foundation for increasingly complex thinking and social interaction. Therefore, developmental models designed to promote social development in children with ASD are focused on the relationship between the child with ASD and his or her caregiver through coaching to help increase responsiveness to the adult (ie, the interventionist or parent or caregiver) through imitating, expanding on, or joining into child-initiated play activities. This approach may address core symptoms of ASD, such as joint attention, imitation, and affective social engagement.^{296,297,321,322}

Developmental models for intervention are focused on teaching adults to engage in nondirective interactive strategies to foster interaction and development of communication in the context of play. One such approach is known as DIRFloortime (The Developmental, Individual Differences, and Relationship-Based model). In 1 RCT comparing parent coaching using this approach to community intervention alone (norte = 112) in children ages 2 to 5 years, parents who were taught this approach were less directive, and their children were rated as more socially responsive, although IQ and language scores were no different between groups, and half of the children in the control group improved in their affective ratings.³²³ A similar approach is relationship development intervention,³²⁴ and more research is needed to evaluate efficacy and community use.

Naturalistic Developmental Behavioral Intervention

Naturalistic developmental behavioral interventions (NDBIs) incorporate elements of ABA and developmental principles, such as emphasis on developmentally based learning targets and foundational social learning skills, with delivery of interventions in the context of naturally occurring social activities within natural environments. They use child-initiated teaching episodes, naturally occurring opportunities for learning, and turn-taking interactions within play routines and implement ABA-based approaches to address measurable goals.²⁹⁶

The most extensively studied NDBI approach is the ESDM, which prepares children to learn in naturalistic environments.³²⁵ In a multisite trial of ESDM, early age at entry to therapy and more hours of total therapy were associated with improved outcome.³²⁶ Of note, the 48 children randomly assigned to ESDM or community treatment in the original trial were studied by using event-related potentials and spectral power on EEG while viewing faces as opposed to objects and were compared with typical controls on these tasks. This is an early demonstration of improvement on a neurophysiologic measure associated with improvement on a clinical measure of social behavior through an early intervention program.³²⁷

Combined Approaches

Common factors in combined developmental and behavioral approaches include use of principles of ABA to reinforce skill building; a systematic approach with a manual for training practitioners who would use the intervention in a standard fashion; individualized treatment goals for the child and means of measuring progress; child-initiated teaching, imitation, and modeling; and adult prompting that fades over time to promote independence.²⁹⁶ It may be difficult to advise parents on specific programs in community settings because the way the program is conducted may differ from the research settings.³²⁸ However, it is always accurate to describe the common characteristics of empirically supported interventions and recommend that families seek interventions that incorporate these features (Table 9).

Parent-Mediated Treatment or Parent Management Training

Increasing evidence reveals that focused interventions delivered by trained parents or other caregivers can be an important part of a therapeutic program.^{297,329–332} More RCTs have been published on parent-mediated therapies than on other nonpharmacologic interventions. What is sometimes called parent management training is divided into 2 categories: parent support and parent-mediated interventions. Parent support interventions, which are knowledge-focused and provide indirect benefit to the child, include care coordination and psychoeducation. Parent-mediated interventions, which are technique-focused and provide direct benefit to the child, may target core symptoms of ASD or other behaviors or skills and may be built on ABA approaches in natural settings.³³¹ Training sessions for caregivers may be delivered in the home, clinic, school, or other community settings or remotely by telehealth.^{297,329–331,333–337} An RCT involving 86 toddlers and their primary caregivers demonstrated that 10 weeks of hands-on parent training in joint attention, symbolic play, engagement and regulation (an NDBI) was superior to a parent-only psychoeducational intervention for increasing joint engagement.³³⁸ A parent training approach may be used to promote compliance with instruction, social communication, and other identified goals of the caregiver, such as reducing maladaptive behaviors.^{331,339–342} Including parents in the intervention process is critically important.^43,326,343

Classroom-Based Models

It is the expectation that school-aged children will be educated in classroom settings with supports for a broad effect on the symptoms of ASD and associated deficits. Educating students with ASD in the least restrictive environment typically requires an individualized program that is modified to meet the Individualized Education Program (IEP) goals set by the family, student, and school team. Some students who do not qualify for an IEP by educational criteria may be supported with accommodations through a Section 504 plan or with classroom-level accommodations. Many students with ASD are educated in inclusive classrooms with supports. Other school-aged children and youth benefit from disorder-specific approaches. Examples of classroom-based models include Learning Experiences and Alternative Programs for Preschoolers and their Parents (LEAP) and TEACCH.³⁴⁴

LEAP blends principles of ABA with special and general education teaching techniques for elementary-aged pupils in inclusive settings for teaching social interaction.^344–346 An RCT of 294 preschool-aged children revealed that LEAP was associated with improvement in socialization, cognition, language, and challenging behavior and that LEAP was superior to a treatment-as-usual method.³⁴⁵

TEACCH class settings are visually organized to promote engagement and learning.³⁴⁴ The TEACCH approach to skill acquisition includes assessment-based curriculum development and an emphasis on structure, including predictable organization of activities and use of visual schedules, organization of the physical environment to optimize learning and avoid frustration (eg, by minimizing distractions and/or sensory dysregulation), and adaptation and organization of materials and tasks to promote independence from adult directions or prompts.^344,347 Instruction is organized in a predictable fashion and uses visual schedules with promotion of independence in activities planned into the instruction.³⁴⁷ This approach is associated with a small, but measurable, benefit in perceptual, motor, verbal, and cognitive skills in students with ASD, with less measured effect on adaptive and motor function³⁴⁷ and challenging behaviors. Rigorous studies of educational interventions for students with ASD at school age and beyond are necessary to understand the effectiveness of different models.²⁹⁸

A comparison of the effects of LEAP and TEACCH classrooms with those of standard special education classes taught by teachers familiar with ASD revealed that the common features of these interventions may be responsible for improvements seen in all students. TEACCH was associated with more reported improvement in ASD severity for students who had greater cognitive delays. This finding may speak to the benefit of the environmental and behavioral supports.³⁴⁴ Research interventions may not be comparable with community-provided school programs. Future research is needed to address how best to provide evidence-based intervention in classroom settings.

Education in the Least Restrictive Educational Environment

Pediatricians have an important role in advocating for children and youth with special health care needs, including ASD, in the educational setting. Students have a right to a free and appropriate public education. Educational programs for school-aged children with ASD should promote language, academic, adaptive, and social skills development and prepare them for postsecondary education or employment.³⁴⁸ Most, but not all, students with ASD will have some individualization of their education under the guidance of an IEP determined by the school multidisciplinary team in conjunction with the family. Others may receive accommodation and/or environmental modifications under Section 504 of the Rehabilitation Act of 1973.³⁴⁹ A medical diagnosis of ASD alone does not automatically translate into eligibility for school-based services. Functional impairment that affects participation in the typical curriculum is required to qualify for supports in the educational setting and may lead to an IEP for the educational handicap of autism. Most youth with ASD and average-range intelligence will likely require academic intervention because of coexisting learning disabilities, executive function challenges, ADHD, motor processing deficits, the effects of their pragmatic language differences on reading and writing, and/or challenges in comprehension of spoken or written language.³⁵⁰ Attention to the needs of the individual student must be central to the IEP process. Social skills of students with ASD may benefit from students being in class and on the playground with peers with typical development.^351,352 However, spending more than 75% of their time in an inclusive educational setting alone was not sufficient in transition-aged youth to increase rates of college attendance, high school graduation, or functional ratings.³⁵³ How to best support students with ASD in the least restricted environment requires further study.

Social Skills Instruction

Social skills deficits may present differently depending on language abilities, developmental level, and age. Examples of social skills deficits include the following:

• challenges with entering, sustaining, and exiting interactions;

• difficulty attending to, understanding, and using nonverbal and verbal social cues, such as eye contact, facial expressions, and gestures;

• difficulty in understanding “unwritten” social rules of the environment;

• not understanding the perspective of others;

• struggling with negotiation, compromise, and conflict resolution; et

• problems with interactive play or participation in leisure activities.

The importance of caregiver involvement in teaching social skills to preschool-aged children needs to be emphasized for families of young children with ASD. Reinforcing social interaction is central to the success of evidence-based ABA, developmental, and NDBI approaches.^296,354 Teaching and coaching social interaction involves both behavioral therapy and speech and language therapy approaches.

School-aged children and adolescents with ASD, including those with typical academic skills, should have social skills support considered in their school and perhaps in other therapeutic settings if indicated.^{351,354–356} Although families identify the need to address social skill developments in settings outside of school, the success of these types of interventions is variable. Interventions may be divided into adult-mediated (skill building with the individual child), peer-mediated (skill building with the child and typically developing classmates), and mixed approaches. Child-directed social skills interventions are often delivered individually or in small groups with other children with similar needs. Therapy may be provided in behavioral health settings to complement the social skills interventions at school.

Interventions addressing social skills may increase the child’s knowledge of the cues for social behavior and teach strategies for social problem-solving. A popular method uses the social narrative to help a child define the social context of an anticipated or experienced situation, put it in perspective, and then develop statements on how it makes the child feel and on what to do in response to the event and feelings.³⁵⁷ This coached rehearsal strategy may be included within other programmatic approaches. Implementation may use a cognitive behavioral intervention strategy in which the child identifies feelings and thoughts and learns to substitute more socially appropriate alternatives.³⁵⁴ Video- and computer-based social skill interventions may extend access to intervention once an evidence base is established. A systematic review of RCTs of social skills training for children aged 6 to 21 years revealed that interventions improved social competence and friendship quality but did not result in differences in emotional recognition and social communication. Transfer of skills to other settings was inconsistent.³⁵⁶

Because child-mediated interventions taught separately from social settings have not had consistently beneficial effects, interventions have been developed for implementation in the social settings that include peers, such as the classroom and playground. These interventions demonstrate improved playground interaction between children with and without ASD and improved identification as friends by typical peers.³⁵¹ Peer-mediated intervention for students with ASD have revealed improved social connectedness and reduced social isolation and provide evidence to support the use of these interventions in the classroom and playground. An evidence-based approach designed for group administration, the Program for the Education and Enrichment of Relational Skills, may improve both teacher-reported social functioning and adolescent-reported social cognition.³⁵⁸ Fewer studies are available to guide programs to promote social skills development for adults with ASD. However, the Program for the Education and Enrichment of Relational Skills group model has been demonstrated to improve social skills in young adults with ASD.³⁵⁹

Families should be counseled to include development of social skills with discrete goals and interventions in the IEP or educational plan as well as to be cognizant of potential opportunities to promote social interaction in the natural environment and in the context of other therapies.³⁶⁰ Implementing IEP goals across the day and generalizing specific skills to promote conversation and nonverbal communication, such as providing eye contact, directing facial expressions, and using appropriate gestures, is important, independent of age, and should involve both the caregivers and professionals. More information about IEPs in general can be found at http://www.wrightslaw.com/info/iep.index.htm.

Speech and Language Interventions

Delayed language is an early concern for many children who are later diagnosed with ASD. The communication symptoms included in the DSM-5 criteria for ASD reflect core deficits in social communication and interaction, such as failure of back-and-forth communication, deficits in nonverbal communication (such as eye gaze and use of gesture), difficulty adjusting behavior to suit the social context, and restricted and repetitive behaviors leading to perseverative vocalization, echolalia, and preoccupation with restricted topics of interest. All children with ASD should have documentation of specific coexisting speech and language diagnoses so that appropriate intervention might be provided.

Speech-language therapy is the most commonly identified intervention provided for children with ASD.³⁶¹ The strategies used by speech-language pathologists to reinforce sound repetition and word use in children with typical development are often initially used with young children with ASD. Such strategies include reinforcement of speech sounds and communicative acts, imitation of the sounds the child makes, and exaggerated imitation and slowed tempo.³⁶² The literature offers the most support for approaches with preverbal children with ASD in which adult prompts are used for communication, prompt fading, and reinforcement of their own attempts at communication. Intervention in naturalistic settings and involvement of caregivers may help reinforce the initiation of communication and functional use of sounds, gestures, and words.

A significant minority (up to 30%) of individuals with ASD ultimately do not acquire verbal speech.³⁶³ Delayed onset of speech may be complicated by general delays in development (intellectual disabilities) or coexisting speech disorders, such as childhood apraxia of speech. Although using communicative spoken phrases before age 4 years is considered a good prognostic sign for language development in youth with ASD, emergence of phrase speech may occur to at least age 10 years, especially in children with preserved nonverbal skills and evidence of social engagement.³⁶⁴

When children do not spontaneously speak, augmentative and alternative communication (AAC) may be introduced. Examples of AAC strategies include sign language, the Picture Exchange Communication System, and speech-generating devices.^365,366 The use of AAC may help promote social interaction and understanding of the purpose of communication and does not delay onset of speech. Indeed, it may enhance emergence of spoken words by pairing nonverbal and verbal communication.

The Picture Exchange Communication System is used to build communication through picture identification and exchange as communication. With training, pictures can be sequenced to build on communicaiton.³⁶⁷ Picture strips that sequentially explain medical procedures, for example, take advantage of this approach. Use of speech-generating devices and programs that use AAC on digital tablets also are increasing. These devices provide acoustic feedback to the child, and touch-screen tablets are relatively inexpensive and portable. Medical providers are often asked to justify the purchase of touch-screen tablets or AAC devices. It cannot be assumed that the use of AAC alone will lead to functional oral communication without a therapeutic plan.³⁶⁸ Current scientific evidence does not support the use of facilitated communication in which a nonverbal individual is guided to communicate.^369,370 This differs from AAC, in which the individual is taught to communicate independently. Future strategies to promote communication are expected to incorporate evolving knowledge about sensory processing and connectivity of brain functions in people with ASD.

Children and youth with ASD often have deficits in pragmatic language that can affect social interaction with adults and peers and academic performance as more complex language becomes required for reading comprehension and analysis of information. In addition, literal interpretation of language and difficulty in understanding the intent of other people leads to behavioral challenges in some people with ASD and affects success in school, leisure activities, and employment. School-aged students with spoken language should have their pragmatic language assessed as part of their school-related reevaluations, with consideration of pragmatic language testing if academic problems and inattention are noted in the classroom. Interventions may include individual and group approaches that include teaching and practicing conversation. The pediatrician may refer the child for private speech-language therapy if he or she is not eligible for services in school or if increased intensity of intervention is desired. Although the impact of speech-language therapy on structural language improvement has not been adequately studied, improvement in ratings of conversational competence by parents and of classroom learning skills by teachers supports the recommendation for social skills and social language interventions for students with ASD.³⁷¹

Motor Therapies

Children with ASD may have low muscle tone or a developmental coordination disorder. Although the ages for sitting and walking do not differ between children with ASD and children with typical development, both fine and gross motor skills may be delayed in preschool-aged children with ASD.³⁷² Attention to position in space in children with a coexisting diagnosis of ADHD may further complicate delays in coordination.³⁷³ Occupational therapy services may be indicated to promote fine motor and adaptive skills, including self-care, toy use, and handwriting. Almost two-thirds of preschool-aged children with ASD are reported to receive occupational therapy services.³⁷⁴

Similarly, some children with ASD may have gross motor impairment on formal testing that may benefit from therapeutic intervention focused on building strength, coordination, motor planning, or skill acquisition to promote safer mobility or play. Toe walking is common among children with ASD as well as in other developmental disorders in early childhood. The etiology of toe walking in ASD is unclear, although sensory aversion and habit or perseveration have been proposed. Common interventions for toe walking may include passive stretching, orthotics, and casting. Impairment in gross motor function may affect the capacity of a child with ASD to participate in leisure activities with the family or with peers and may impair participation in sports or interactive play beyond the effect of their social skills alone. Impaired motor skills may further decrease opportunities for social skills development and active learning and may be a risk factor for overweight and obesity.³⁷⁵ For motor therapies to be provided in the educational setting, a significant delay for age that affects function in school must be identified on a valid assessment measure.

Sensory Therapies

In 2012, the AAP published a clinical report, “Sensory Integration Therapies for Children With Developmental and Behavioral Disorders,” providing important background information and recommendations for pediatricians.³⁷⁶ Since that publication, the DSM-5 criteria now includes sensory symptoms in the diagnostic criteria for ASD in recognition of the fact that individuals with ASD have sensory challenges that may be related to repetitive and other challenging behaviors.³⁷⁷ Indeed, sensory symptoms exhibited by young children, such as food selectivity, covering their ears for certain sounds, and visual scrutiny of aspects of objects, may be among the earliest differences families identify in their children’s development. Sensory goals may be included in treatment objectives for students with ASD. Adult-directed approaches provided through sensory-based interventions may be included in the context of motor and behavioral therapies and in educational settings. Despite the increasing scientific understanding of the neurobiological basis for sensory symptoms in individuals with ASD, empirical interventions in common practice have modest evidence to support their general use at this time.³⁷⁸ Commonly used sensory-based interventions, including brushing of the skin, proprioceptive stimulation by using weighted vests, or kinesthetic stimulation (such as swinging or use of specialized seating, such as a therapy ball, to modulate level of arousal), are not yet supported in the peer-reviewed literature.

Proponents of sensory integration therapies distinguish them from interventions with sensory modalities because of the active engagement with the child in skill building or desensitization. This type of therapy requires a trained clinician, often an occupational therapist, to work with a child by using play and sensory activities to reinforce adaptive responses. The therapist explains the child’s behaviors and responses to caregivers in sensory terms and provides them with strategies to help the caregivers accommodate the child’s sensory needs to decrease functional impairment and tolerate environmental triggers. Advocates of these interventions claim that dysfunction in integration of sensory input contributes to inefficiencies in learning and to behavioral challenges and that therapeutic approaches to sensory integration need to be considered separately from focal sensory-based treatments.³⁷⁹ Although sensory-based therapies are among the most commonly requested therapies by caregivers,³⁶¹ the evidence supporting their general use remains currently limited.^378,379 As with any other intervention, specific goals for sensory-based therapies should be identified, and outcomes should be monitored so that the utility for any given child can be documented.³⁷⁶

Seizures

There is both an increased risk for ASD among children and youth with epilepsy and an increased risk for seizures in those with ASD. The pooled risk for ASD among children with epilepsy is 6.3%, with almost 5 times as many in samples with the highest rates of co-occurring intellectual disabilities.^173,382,383 The rate of seizures among people with ASD in community-based populations has been reported to range from 7% to 23%, with rates as high as 46% reported in clinically ascertained samples.¹⁷⁰ It has been suggested that the risk for seizures is not increased in individuals with ASD without intellectual disability. Risk factors for the increased likelihood of seizures in people with ASD include intellectual disability (as noted), female sex, and lower gestational age.¹⁷⁴ Specific genetic disorders associated with ASD, such as tuberous sclerosis, also may contribute to seizure risk in early childhood. Onset is bimodally distributed, with most first seizures occurring in early childhood and in adolescence; 20% of first seizures occur in adults with ASD.¹⁷⁰ Children with ASD and seizures tend to have more behavioral challenges, independent of cognitive skills.³⁸² Screening EEGs are not recommended for patients who are asymptomatic. An overnight EEG should be considered when the clinical history suggests seizures and atypical regression. Response to conventional antiepileptic drug therapy varies greatly, with some reports suggesting an increased risk for treatment-resistant epilepsy in individuals with early onset of seizures and delayed global development.³⁸⁴

GI Symptoms

GI symptoms, such as abdominal pain, constipation, diarrhea, gastroesophageal reflux, and feeding problems, are more commonly reported in children and adolescents with ASD than in those with developmental delay or typical development.^385–387 A large prospective cohort study revealed differences as early as 6 to 18 months of age in stooling patterns and feeding behaviors in children who were later diagnosed with ASD.³⁸⁸ Because of language delays and atypical sensory perception or report of pain, individuals with ASD may be less likely to report specific GI discomfort and may present with agitation, sleep disruption, or other behavioral symptoms rather than GI discomfort.³⁸⁷ Characteristics of ASD that might affect GI symptoms include resistance to change (feeding and constipation), comorbid anxiety (pain, feeding, and motility disorders),³⁸⁹ and altered sensory perception (pain, feeding, and constipation). At present, there is no evidence of an association of ASD with celiac disease, specific immune dysfunction, or motility disorders (eg, gastroesophageal reflux) in children with ASD.

It would be expected that these disorders would occur at least as frequently among individuals with ASD as among individuals in the general population, and they should be considered when the child has a history of GI symptoms or a change in behavior.^390,391 Ongoing research is focused on whether differences are present in immunologic function, motility, or the microbiome in individuals with ASD.^392–394

Selective eating is common in children with ASD.³⁸⁶ A limited diet may influence GI symptoms, such as constipation,³⁹⁵ and alter the intestinal microbiota. GI disorders should be considered in patients with ASD if they present with typical GI symptoms or with agitation, food refusal, or sleep disturbance.^387,396 The indicated GI workup will depend on the specific symptoms. Children with ASD should be offered the same approaches to treatment of GI disorders as other children. Modifications of conventional interventions to accommodate for symptoms of ASD might include consistent behaviorally informed approaches for constipation and encopresis.

Feeding Disorders

Up to three-quarters of children with ASD have problems related to eating, including food selectivity based on texture, color, or temperature; rituals around food presentation; and compulsive eating of certain foods.^397–399 Behavioral refusal may also present as the child holding food in the mouth, volitional gagging, and emesis. Common related problems include pica (eating of nonfood items) and rumination (self-stimulatory emesis and reswallowing of stomach contents). By age 16 months, children who are later diagnosed with ASD are observed to be more selective in their eating patterns than are other toddlers.⁴⁰⁰ Problems around mealtime behavior and food choice often persist into adolescence. The frequency of feeding challenges in children and youth with ASD may relate to the core symptoms of restrictive and repetitive behavior and differences in sensory perception related to smell, taste, and texture.⁴⁰¹

Children with developmental delays may also have delayed oral motor skill development and may demonstrate food refusal of textures that they cannot physically chew or swallow. Discomfort can lead to food refusal, so initial evaluation should include consideration of gastroesophageal reflux, dental pain, food allergies, lactose intolerance, and significant constipation.³⁸⁷ If oral-motor concerns are observed, speech or occupational therapy assessment is indicated.

Because feeding problems are so common among children with ASD, a dietary history should be obtained at health supervision visits. Physiologic needs for macronutrients and micronutrients are the same for children with ASD as for other children. As with other children in the United States, insufficient intake of fiber, vitamin D, and calcium are common.⁴⁰² Rare cases of severe nutritional deficiencies, such as rickets (vitamin D),⁴⁰³ scurvy (vitamin C),⁴⁰⁴ and keratoconus (vitamin A),⁴⁰⁵ have been reported in children with ASD with severe food aversions. If supplements are used to correct for poor vitamin D or calcium intake, it is important to confirm that the dose is sufficient for the age and sex of the child.⁴⁰⁶ Food fortification in the United States may supply adequate amounts of vitamins and minerals for some children with selective diets, so additional multivitamins may not be necessary.⁴⁰⁷ Consultation with a registered dietitian may be helpful to be able to guide families regarding the nutritional sufficiency of their child’s diet.

The clinician can counsel families about offering children routine meals and snacks, discouraging snacking through the day, promoting self-feeding, and using basic behavioral approaches to encourage mealtime structure and predictability with minimal distraction. Children with ASD need to be offered new foods multiple times to become familiar with them. Feeding problems that affect nutrition or family function or that are specialized, such as mouth packing, rumination, severe pica, and intense aversions, are likely to need the support of professionals with expertise in behavior management and/or oral-motor therapies (speech or occupational therapy).^408,409 Food refusal may stem from discomfort, so consultation with a gastroenterologist may be helpful. Gastrostomy-tube placement and nonoral feeding should only be considered after appropriate behavioral intervention has failed.

ADHD

Changes in DSM-5 criteria have provided flexibility to diagnose other DSM-5 disorders in addition to ASD, which can help guide treatment. Approximately half of children and youth with ASD also may fulfill diagnostic criteria for ADHD.⁴⁵⁹ Pediatricians should keep in mind that some children who are later diagnosed with ASD may have been initially identified as having ADHD.⁶⁹ Symptoms of ADHD may further compromise social skills function in children with ASD because of inattention to social cues and impulsivity. Standard rating scales used to assess symptoms of ADHD have not yet been validated for individuals with ASD. However, they are useful in determining the clinical impact of symptoms for an individual patient and in monitoring treatment. It is important, however, to consider the differential diagnosis of inattention and hyperactivity in the context of the language impairment and perseverative focus that often accompanies ASD. Children with delayed language may appear more inattentive. If they are expected to perform activities (including schoolwork) that they are not able to understand or accomplish, a child with ASD may engage in behaviors to escape, which can be interpreted as inattention and hyperactivity. Patients with ASD may be focused on their perseverative interests and may be internally distracted, as opposed to distracted by the environment. Evaluation of the symptom of inattention or impulsivity includes assessing language and educational abilities. Appropriate educational modifications and use of language for instruction that the student can understand are critical for successful intervention. Behavioral strategies should address reinforcement of on-task behaviors, breaking down tasks into units that can be completed successfully, breaks for activity (often included in sensory activities), and adult supervision appropriate for the demands. The same medications that are used for symptoms of ADHD in children without ASD are used in similar doses for children with ASD.⁴⁶⁶ Routine monitoring is important because children with ASD may be at greater risk for adverse effects⁴⁶⁷ (Table 11). The evaluation of a child for a possible co-occurring diagnosis of ADHD also should include consideration of a co-occurring diagnosis of anxiety.^464,466

Anxiety Disorders

The DSM-5 classification system separates anxiety disorders into separation anxiety disorder, selective mutism, specific phobia, social phobia, panic disorder, agoraphobia, and generalized anxiety disorder as well as unspecified anxiety disorder. As many as 40% to 66% of school-aged children and adults with ASD are reported to also have anxiety disorders.^458,459 Anxiety disorders are most commonly identified in children with ASD and typical cognitive and language abilities.^468,469 Symptoms may be present in early childhood and manifest as behavioral challenges, such as overreactivity. Biological predisposition to both ASD and anxiety may be attributable to common genetic factors and/or altered neurophysiologic responses to stress.⁴⁷⁰

Core symptoms of ASD decrease the ability of individuals with ASD to predict the actions or interpret the beliefs of others, which may lead to a constant state of heightened worry. Repetitive behaviors may, in part, serve to instill predictability, so anxiety may lead to increased stereotyped behaviors or perseverative thoughts. Evaluation of anxiety requires consideration of the language demands of the environment, academic expectations, social demands, and underlying fears or phobias. Youth with ASD may lack sufficient language or insight to describe their symptoms. Getting information from multiple sources and looking at the behavioral manifestations related to context will help to correctly identify anxiety in patients with ASD.⁴⁷¹

Strong evidence from RCTs supports the use of cognitive behavioral therapy for anxiety symptoms in school-aged children with ASD, especially those with typical-range intelligence.^{295,298,472–475} Anxiety may be associated with reported GI and sensory symptoms.³⁸⁹ Some individuals find that sensory redirection or sensory activities used in the context of a behavioral program are helpful to diminish feelings of anxiety. Other individuals may find symptom relief with the introduction of routine and structure if anxiety is exacerbated by uncertainty or associated with sensory under- and overreactivity.³⁷⁷ Nonpharmacologic approaches, such as neurofeedback and digitally delivered approaches to self-regulation, are being evaluated for their therapeutic potential. Medications used for anxiety in the general population may be considered as part of an overall treatment plan for children and youth with ASD (see Table 11 for psychopharmacotherapy of children with ASD and anxiety).

Mood Disorders

Depressive disorders are more common among children and adults with ASD than in the general population. Reported rates of coexisting depression in adults and children are highly variable, ranging from 12% to 33%.^458,476,477 Symptoms of depression are more likely to lead to dual mental health and developmental disability diagnoses in adolescents and adults with ASD than in children. The coexistence of mood disorders and ASD may be associated with genetic and neurobiological factors as well as environmental factors related to chronic stress and difficulty with understanding social situations. Both elevated and depressed mood may present as behavioral symptoms in youth with ASD. Changes in affect, participation, sleep habits, and eating may be symptoms of an underlying mood disorder. Attempted suicide is reported to occur more frequently in people with ASD than in the general population. Risk factors include peer victimization, behavioral problems, minority race or ethnicity, male sex, lower socioeconomic status, and lower level of education.⁴⁷⁸ The AAP recommends screening for depression in patients older than 12 years. Until ASD-specific measures are developed, the same approaches used for all other adolescents at increased risk for depression should be considered.⁴⁷⁹

As in children and youth with typical development, assessment of depression and other mood disorders must include family history, history of environmental stressors, the potential for toxic ingestions, and evaluation for comorbid conditions. Interventions for depression include supportive therapy, cognitive behavioral therapy, and medication, if indicated, as coordinated interventions (see Table 11 for medication use). Antidepressant use in people with ASD has not been demonstrated to address aggression and has inconsistent effect on anxiety.⁴⁸⁰ Medication recommendations are based on data from the general pediatric population and expert consensus.⁴⁶⁹

The DSM-5 criteria for bipolar illness include changes in activity, energy, and mood. It may be difficult to make a diagnosis in people with ASD with limited language. The co-occurrence of bipolar illness and ASD in individuals with typical intelligence ranges from 6% to 21%.⁴⁸¹ Lifetime diagnosis of bipolar illness in adults with ASD is reported to be 9%.⁴⁵⁸

OCD-Related Disorders

Although restricted and repetitive behaviors are symptoms of ASD, some individuals with ASD may also have coexisting OCD. Obsessions are recurrent, unwanted, and persistent thoughts, images, or urges that cause distress. Compulsions are repetitive behaviors or thoughts with rigid rules performed to reduce anxiety. Unlike the stereotypic behaviors of ASD, compulsions usually follow an obsession, diminish anxiety, and are not desired by the individual or perceived as pleasurable.⁴⁸² Under the DSM-5, OCD-related disorders include hoarding disorder, excoriation (skin-picking) disorder, trichotillomania, substance- or medication-induced obsessive-compulsive and related disorder, and obsessive-compulsive and related disorder due to another medical condition. The perseverations associated with ASD may be qualitatively different and less sophisticated than the repetitive and intrusive thoughts and actions associated with OCD.⁴⁸³ Repetitive behaviors in general may help an individual with ASD regain a sense of predictability. Anxiety, phobias, and/or depression may coexist with OCD in youth with ASD.

Behavioral approaches are recommended as the first line of treatment of symptoms of OCD, depending on the language and cognitive level of the patient. Cognitive behavioral therapy, including exposure and response prevention with or without a selective serotonin reuptake inhibiter, has been demonstrated to be the most effective treatment for youth with OCD who do not have ASD. Cognitive behavioral therapy may be less effective, with fewer remissions, in youth who also have ASD⁴⁸⁴ (see Table 11 for medication management).

Disruptive Behavior Disorders: Aggression, Self-Injurious Behavior, and Tantrums

Disruptive behaviors, such as aggression, self-injury, and tantrums, may complicate home and community management of individuals with ASD. Behavioral outbursts may occur in response to stressful events in the environment, in reaction to a medical condition, as functional communication, or as a symptom supporting diagnosis of a co-occurring mental health disorder.⁴⁸⁵ Functional behavioral analysis and implementation of behavioral strategies can be an important initial step in management.⁴⁸⁶ A proposed pathway for the primary care setting for management of irritability that leads to disruptive behaviors in youth with ASD is proposed by McGuire et al.⁴⁸⁵ Disruptive behaviors may serve as communication to escape from a demand or an undesired situation. If successful, they may become part of a behavioral pattern. New onset of severe behaviors requires consideration of potential medical reasons (see Table 12). Pharmacologic treatment should be considered if no medical etiology is identified and if the behavior is associated with irritability, is not responsive to available behavioral interventions, or is related to a co-occurring diagnosable behavioral health disorder, such as anxiety, mood disorders, thought disorders, and/or ADHD.

It has been reported that between 8% and 68% of children with ASD demonstrate aggressive behavior, depending on how stringent the definition is.⁴⁵⁴ Aggressive behaviors were reported on the Child Behavior Checklist for one-quarter of children attending an ASD clinic, with similar rates from 2 to 16 years of age. Aggression was associated with hyperactivity, lower cognitive skills, sleep problems, and internalizing behaviors such as anxiety. There was no association with sex. Researchers of other studies have observed increased rates of physical aggression in children with ASD who have lower adaptive skills and frequent repetitive behavior.⁴⁸⁷ Management of co-occurring sleep problems and hyperactivity may be helpful in a treatment plan⁴⁸⁸ that includes behavioral intervention to address aggression and targeted pharmacotherapy.⁴⁸⁷

Self-injurious behaviors are reported in 40% to 50% of individuals with ASD at some point across the lifespan⁴⁸⁹ and may occur more frequently in people with ASD who also have aggressive behaviors and sleep problems.⁴⁹⁰ Self-injurious behaviors in individuals with ASD may be repetitive and self-stimulatory (such as scratching, pica, or rumination). Head banging and self-hitting may occur as part of a tantrum. Like aggression and other disruptive behaviors, self-injurious behaviors may serve as communication to escape from demands or situations that the individual does not want to be in. The type of self-injurious behavior may change if the intervention of prevention or blocking is not associated with addressing the underlying reason for the behavior. Persistence of self-injurious behaviors in individuals with ASD is associated with more limited cognitive and language abilities, hyperactivity, impulsivity, repetitive behavior, and more challenges with social interaction.⁴⁹¹ There is an association of self-injury with specific genetic disorders that are not associated with ASD, such as the severe self-biting of Lesch-Nyhan syndrome. Self-injurious behavior is associated with genetic disorders that are also associated with ASD, such as Cornelia de Lange syndrome, fragile X syndrome, and Smith-Magenis syndrome.⁴⁹² In the case of aggressive, self-injurious, and disruptive behaviors, the primary care provider needs to assess the safety of the child and family in an ongoing fashion. Referral to community services and for behavioral intervention should take place if behaviors are unsafe or if the patient is not responding to the treatment plan.