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Ch16: pervasive developmental disorders: autism

Pervasive Developmental Disorders: Autism Lisa A. Ruble, PhD, and Shannon Brown, PhD Every primary care physician can expect to treat an indi- ETIOLOGIC THEORIES OF AUTISM
vidual with autism.1 Until recently autism was consid-ered a rare disorder2 resulting from the child’s reaction The etiology of autism remains unknown. Researchers to parental rejection.3,4 Today autism is recognized as a have focused on several primary target areas, including relatively widespread disability5 reported twice as fre- genetic, neuropathologic, and environmental sources.
quently as it was in the past,6 and it is more prevalent Possible metabolic15 and immunologic16 causes have than childhood cancer, diabetes, spina bifida, and Down also been investigated. Although there is agreement that syndrome.5 Autism is now known to be of neuro- autism results from an alteration of normal brain devel- biologic origin,7 and its presence in families is not opment, to date, no single cause for autism has been related to parenting style, social economic status, race, identified. A consensus is building that autism results from multiple etiologies1,10 and is likely present before Although they require the same medical care as other children, children with autism pose unique challenges The possibility that some individuals are genetically for primary care providers (PCPs).1,10 First, as one of the predisposed to developing autism has received much most complex neurodevelopmental disorders, autism is attention. Genetic researchers have reported monozy- a diagnosis based on behaviors instead of medical tests.
gotic concordance rates of 60% for autism and 92% for The lack of a biologic marker for autism requires the the broader symptoms of social and communication dif- diagnostic clinician to have specialized skills and expe- ficulties. The concordance of autism in dizygotic twins is rience in identifying the behavioral phenotype.11 PCPs, 0%, yet 10 to 30% of dizygotic twins develop the broader who are often the first health care providers to learn spectrum of symptoms.17 Research suggests that several about parental concerns,12, 13 are in a critical position to genes, perhaps as few as 318 and possibly more than 15,19 screen for autism in very young children and make contribute to the behavioral features in autism. A sibling appropriate referrals for a comprehensive diagnostic occurrence rate from about 2 to 7% has been reported, assessment.14 A second challenge is that there is no as well as an increased risk of associated genetic and known single cause or cure for autism. Confronted with chromosomal abnormalities.6,20 Autism, for example, this lack of information, parents are often vulnerable to has been linked with fragile X syndrome21,22 and tuber- unproven and invalidated treatments. As a result, physi- ous sclerosis.23,24 Genetic abnormalities on all but two cians have to address many questions regarding therapy chromosomes (chromosomes 14 and 20) have been options and management. Health care providers must associated with autism.25 Because of these associated be equipped with enough knowledge to assist parents conditions and family studies, genetic as well as other in treatment decisions. Today, it is necessary that all sources of etiology continue to be investigated.
physicians be aware of the early features of autism, know Evidence for autism-associated neuropathology when to refer a young child for a comprehensive diag- comes from several sources. First, many individuals nostic assessment, and have enough information on the with autism have additional neurologic conditions.
disability to be able to provide ongoing advice to parents Mental retardation occurs in about 65 to 85%26 and and care givers. In order to help address these chal- epilepsy in about 30% of individuals with autism.27 lenges, this chapter will review current information on Second, neuroimaging and autopsy studies suggest an etiology and recommended practices for screening, alteration of normal brain development during the pre- diagnosis, and treatment in autism. Table 16–1 provides natal period. Reduced size and number of Purkinje cells a list of resources to help clarify the recommendations.
and cerebellar hypoplasia, as well as reduced neuronal Table 16–1 Recommended Resources for Health Care Providers
This article provides a general overview of autism and related Autism questions and answers for health care providers9 research at the National Institute of Child Health and Human Development.
These reports summarize findings from a multidisciplinary NIH The screening and diagnosis of autism spectrum disorders5 Consensus Panel on screening and diagnosis.
Practice parameter: screening and diagnosis of autism59 Developed specifically for pediatricians, this policy statement Technical report: the pediatrician’s role in the diagnosis and summarizes information on diagnosis and management of autism management of autistic spectrum disorder in children1,10 including conventional and alternative treatments.
This report, at the request of the US Department of Education’s Office of Special Education Programs, was sponsored by the National Research Council and summarizes the state of the scientific evidence of the effects of early educational interventionon young children with autism spectrum disorders .
This Web site provides practical information that can be Autism Society of America, online at <www.autism-society.org> printed and shared with families regarding many topics related to ASDs.
This policy statement describes the federal, state, and local The pediatrician’s role in the development and implementation requirements of special educational and early intervention of an Individual Education Plan (IEP) and/or an Individual services, the pediatrician’s role in collaborating with early intervention and educational professionals and parent support groups.
ASD = autism spectrum disorder; NIH = National Institutes of Health.
cell size, truncated dendritic growth, and increased cell are unknown, it is hypothesized that these disorders packing in limbic structures have been reported.28,29 may play a causal role. Research on the correction of the These findings, however, are not specific to autism.
underlying metabolic dysfunction (through diet, drugs, For many years, researchers have studied possible or nutritional supplements), however, has not demon- environmental causes of autism. In the 1970s, a corre- strated a reversal of autism.15 Similarly, no direct evi- lation between congenital rubella and autism was dence has provided a causative link between immune reported.30 Recently, thalidomide exposure has been system abnormalities and pathogenesis of autism.35 linked to autism,31 implicating its onset around the timeof neural tube closure. A few researchers exploring themeasles-mumps-rubella (MMR) vaccine reported a PREVALENCE OF AUTISM
causal association with autism.32 No conclusive scien-tific evidence, however, supports this hypothesis or any The prevalence of autism has recently caught the inter- hypothesis of a combination of vaccines as a cause of est of researchers, service providers, and parents alike.
autism.9,33 In addition, no evidence exists for a link Public agencies such as the US Department of Educa- between autism and the type of mercury containing tion have identified autism as the largest growing preservative (ie, thimerisol) used in the manufacture of low-incidence disability reported by public school per- vaccines. The Institute of Medicine and the American sonnel.36 The California Department of Health and Academy of Pediatrics (AAP) have published indepen- Human Services reported a 273% increase in the num- dent reviews of the scientific evidence of the relation- ber of children with autism seeking services from 1987 ship between vaccines and autism; both reports identify to 1998.37 These alarming statistics have led some to imply an autism epidemic.38 With careful examination, Although the numbers of children with autism who however, evidence suggests otherwise. In a careful study have possible metabolic15 or immunologic disorders16 evaluating the prevalence of autism using a standard- Pervasive Developmental Disorders: Autism ized autism diagnostic instrument,39 Chakrabarti and DIAGNOSTIC CRITERIA OF PDD
Fombonne6,40 calculated a current prevalence rate of62.6 per 10,000 for all pervasive developmental disor- The Diagnostic and Statistical Manual of Mental Disorders, ders (PDDs), a group of disabilities that includes four Fourth Edition, Text Revision (DSM-IV-TR)41 describes other categories besides autism. This number is higher the diagnostic criteria for the PDDs. Each of the PDDs than previous estimates, but analysis of the specific diag- shares some features. But of the five PDDs, three have the nostic groups indicates that there was a disproportion- most overlap with one another (ie, Autistic Disorder, ate increase in the number of children with symptoms Asperger syndrome, or PDD-NOS). Many researchers milder than those typically seen in classic autism.
believe that the shared social impairments are the hall- Subgroup analysis determined that 16.8 per 10,000 pre- mark features of the PDDs that distinguish them from school children had autism, 8.4 per 10,000 had Asperger other childhood disorders.42–44 Also, instead of the term syndrome, 36.1 per 10,000 had Pervasive Develop- PDD, researchers are advocating for the term Autism mental Disorder-Not Otherwise Specified (PDD-NOS), Spectrum Disorder (ASD) to emphasize both the shared 1 per 10,000 had Rett’s disorder, and 1 per 10,000 had overlap and lack of clear distinctions between the PDDs Childhood Disintegrative Disorder. Analysis of the age and the fact that these children often benefit from the of referral indicated that children with autism received same services.45 Next, the detailed DSM-IV-TR criteria an earlier diagnosis than those children who were later for each PDD are presented. Table 16–2 provides a brief diagnosed with Asperger syndrome or PDD-NOS. The children with autism also had more cognitive and lan-guage delays. Overall, Fombonne40 reached the conclu- Diagnostic Criteria of Autistic Disorder
sion that although epidemiologic studies of autism areflawed with methodologic limitations, data on increased Although autism becomes evident within the first 3 numbers of children with autism are more likely to be years of life, it often remains undiagnosed until 4 years reflecting (1) a usage of a broader definition of autism, of age. The relatively late diagnosis is due to many fac- (2) changes in diagnostic criteria over time, and (3) an tors. The identification of autism requires specific improved recognition of autism, especially in children expertise and knowledge. Diagnosticians must have a solid understanding of normal social and communica- Table 16–2 Diagnostic Criteria for Pervasive Developmental Disorders
*One of these must be present.
†Two of these must be present.
Adapted from Ruble L, Stone W.73 tion development in order to determine if a child is in at least one of the following areas prior to 3 years of experiencing difficulties as a result of a developmental age: (1) social interaction, (2) language as used in social delay or autism. For very young children under the age communication, and (3) symbolic or imaginative play. In of 2 years, establishing the consistency between a child’s addition, Rett’s Disorder and Childhood Disintegrative developmental and mental ages and social and com- Disorder, to be described later, must be ruled out.
munication skills may prove difficult, especially if thechild has low nonverbal skills.45 Another issue is that Diagnostic Criteria of Asperger’s Disorder
children with autism can be notably different from oneanother. Two children with autism can meet different The next most closely related PDD is Asperger syn- combinations of the DSM-IV-TR diagnostic criteria. In drome. Debate continues among researchers about addition, the same child with autism may meet a certain whether Asperger syndrome can be distinguished from combination of criteria when younger but a different high-functioning autism (children with autism who do combination when older.46 Despite these challenges, not have cognitive impairment).49,50 In order to meet research indicates that children can be identified reli- criteria for Asperger syndrome, the child must demon- strate impairments in two of the areas previously The first component of the definition of autism, described for Autistic Disorder: (1) social interaction social impairment, is more challenging to detect because and (2) restricted, repetitive patterns of behavior, inter- it represents a relative absence of behavior. Autism is ests, and activities. The child must not demonstrate any distinguished by significant impairment in at least two clinically significant general delay in language and of the following four areas: (1) coordinated use of non- should use single words by age 2 and communicative verbal behaviors to regulate social and communicative phrases by age 3. In addition, the child also must not interactions (eg, eye-to-eye gaze, gestures, facial expres- exhibit any significant delay in cognitive development or sions); (2) development of peer relationships appropri- adaptive behavior (except for social interaction) and ate to the child’s developmental level; (3) seeking to show curiosity about the environment in childhood.41 share enjoyment, interests, and achievements with oth-ers; and (4) establishing social and emotional reciproc-ity (eg, engaging in social play for older children or DIAGNOSTIC CRITERIA OF PDD-NOS
The communication disorder, the second component The next ASD that is most closely associated with of autism, is featured by significant impairment in at least autism and Asperger syndrome is PDD-NOS. PDD- one of the four areas: (1) problems in development of NOS is diagnosed when a child does not meet criteria spoken language (also accompanied by a lack of com- for autism because of late age at onset, atypical symp- pensation through other modes of communication like tomatology, or subthreshold symptomatology. Children gestures); (2) inability to initiate or sustain a conversa- with PDD-NOS do demonstrate the (1) social impair- tion with others in individuals with spoken language; (3) ments and either (2) communication impairments or the presence of stereotyped and repetitive use of language (3) restricted, repetitive, patterns of behavior, interests, or idiosyncratic use of language (eg, repetition of words or phrases without regard to meaning); and (4) a lack ofvaried, spontaneous make-believe play or social imitative Diagnostic Criteria of Rett’s Disorder
play consistent with the child’s developmental level.41 To meet criteria under the third area of impairment Rett’s disorder is an X-linked neurodevelopmental dis- is to demonstrate restricted, repetitive, and stereotyped order with an identified mutation in the gene MECP2.51 patterns of behavior interests and activities in at least Rett’s disorder is unique from the previously described one of the following four areas: (1) preoccupation with PDDs for several reasons. Occurring most often in one or more stereotyped and restricted patterns of females, but also present in males and resulting in mul- interest that is abnormal in intensity or focus; (2) inflex- tiple and specific deficits following a period of normal ible adherence to specific nonfunctional routines or rit- development after birth, children with Rett’s demon- uals; (3) stereotyped and repetitive motor mannerisms; strate all of the following: (1) normal prenatal and and (4) a persistent preoccupation with parts of objects.
perinatal development, (2) normal psychomotor devel- In addition to meeting the criteria described above, opment for the first 5 months after birth, and (3) normal the child must also demonstrate abnormal functioning head circumference at birth. After this period of normal Pervasive Developmental Disorders: Autism development, all of the following are observed: (1) decel- A comprehensive evaluation that can provide both a eration of head growth between 5 and 48 months of age, definitive diagnosis and treatment recommendations (2) loss of previously acquired purposeful hand skills is best conducted by a multidisciplinary assessment between 5 and 30 months of age with subsequent devel- team comprised of a physician, psychologist, speech opment of stereotyped hand movements (eg, hand and language pathologist, occupational therapist, and wringing or hand washing), (3) poorly coordinated gait educational specialist.55 In order to know when to refer or trunk movements, and (4) severely impaired expres- a child for comprehensive evaluation, it is necessary to sive and receptive language development accompanied be familiar with screening tools that identify children with possible developmental problems and instrumentsthat differentiate children with autism from those withother developmental disorders. The AAP recommends Diagnostic Criteria of Childhood
that all physicians know and use at least one screening Disintegrative Disorder
Childhood Disintegrative Disorder is diagnosed when achild experiences marked regression in multiple areas ofdevelopment following a period of at least 2 years of typ- EARLY INDICATORS OF AUTISM
ical development. Age-appropriate development of ver- IN VERY YOUNG CHILDREN
bal and nonverbal communication, social relationships,play, and adaptive behavior is observed. After the age of The DSM-IV-TR criteria for autism may be limited for 2 years, but before the age of 10 years, the child exhibits preschool children because very young children were a significant loss of previously acquired skills in at least excluded in field tests.56 Nevertheless, recognizing the two of the following areas: expressive or receptive lan- red flags of possible autism can lead parents in the right guage, social skills or adaptive behavior, bowel or bladder direction. Researchers, for example, have reported control, play, or motor skills. Typically, acquired skills are behaviors that distinguish very young children with lost in almost all areas of development.41 autism from a developmentally matched sample thatinclude less frequent use of eye contact, responding toname being called, pointing, and showing behav- IMPORTANCE OF IDENTIFYING AUTISM
iors.57,58 More formal methods of identifying autism IN YOUNG CHILDREN
Level 1 screening, which should be conducted on a Despite the published results demonstrating the benefi- routine basis at all well-child visits,59 identifies children cial effects of early intervention,52,53 many children with who are at risk for developmental delays. A list of level autism miss the opportunity for specialized services 1 screening instruments is available in Filipek and col- because the average age of diagnosis is about 4 years.12,13 leagues.59 For children whose screening results are con- Making an early diagnosis of autism is essential for care cerning, the next step is referral to the state early givers and children. Access to services, accurate infor- intervention program or local school system for an mation, and specially designed intervention programs assessment. A level 2 evaluation is comprised of a more are based on a diagnosis. Also, providing parents with in-depth analysis of the developmental problems, information helps them to become more knowledgeable including identifying children who are at risk for and informed consumers of services on behalf of their autism.59 See Table 16–3 for recommended practices for child. It also assists them in becoming organized for advocacy efforts in local and federal arenas on policy Today there are research-based level 1 and 2 screening issues that affect their child and other children and adults tools available for PCP. An effective screen must have with disabilities, such as the identified need for better- a balance between its (1) sensitivity, the number of trained personnel and appropriate services.54 PCPs who children accurately identified by the screen with the dis- have knowledge of early symptoms of autism and listen order, and (2) specificity, the number of children accu- closely to parental concerns of their child’s social and rately identified by the screen without the disorder. The communication development are more likely to refer Checklist for Autism in Toddlers (CHAT) is an example parents and care givers to appropriate diagnosticians, of a parent report and interactive tool geared toward allowing children and families to participate in special- 18-month-olds and developed primarily for PCP to administer at well-child visits.60 The CHAT is comprised Table 16–3 Recommendations of Routine
two or more of the five groups of behaviors were later diagnosed with autism at 30 months of age. Three char- Be familiar with the signs and symptoms of autism and refer for acteristic behaviors were reported as predictive of an autism diagnosis: decreased pointing to share interest,joint attention, and pretend play.60 In a more extensive Provide developmental screening at each well-child visit (see sample of 16,000 children, the CHAT correctly identi- Filipek and colleagues5 for descriptions of instruments) fied 10 of 12 children with autism.61 The CHAT, how- Refer for immediate diagnostic evaluation if ever, may miss some children who are later diagnosed.62 By 12 months, the child is not babbling gesturing (eg, pointing, Therefore, it is inappropriate to replace a comprehen- sive evaluation with a screening tool because the screen- By 16 months, the child is not using single words By 24 months, the child is not using 2-word spontaneous phrases ing tool may be insensitive to all cases of autism. The second screening instrument, called the M-CHAT, is a There is any loss of language or social skills at any age modified version of the CHAT and consists of 23 yes andno parent-report items. It is designed for all parents and Refer for immediate formal audiologic assessment when concerns include a speech, language, or hearing problem; periodic lead can be completed in the waiting room. Six items that screens should be conducted for any child with pica related to social relatedness and communication dis-criminated children with autism from those with other Become familiar with autism screening instruments (see Table 16–4) ASDs.14 Information on the sensitivity and specificity of Monitor the social, communication, play, and behavior the M-CHAT has not yet been reported.
development of siblings of children with autism A third instrument, the Screening Tool for Autism in Refer child to early intervention (zero to three services for those Two-Year-Olds (STAT),63 is an interactive assessment that less than 36 months of age) and to school system (for children elicits specific social and communicative behaviors from older than 36 months of age) for specialized services the child and is designed to discriminate children with Become knowledgeable of the beneficial outcomes of early autism from children with other developmental disabil- intervention for children with autism and the wide range of ities. The STAT consists of 12 items: two requesting, two play, four imitation, and four directing attention items.
The sensitivity and specificity of the STAT are adequate.
Be knowledgeable of the screening tools for older children who may have subthreshold symptoms of autism and make A fourth tool, the Pervasive Developmental Disorders Screening Test (PDDST),64 is composed of three parts.
Stage 1, the first part, is for use in pediatric settings; stage2 is designed for developmental clinics, to differentiatechildren with autism from those with other develop- of nine parent questions and five child interaction activ- mental disorders; and stage 3 is for clinics that specialize ities. Five groups of behaviors are evaluated: social inter- in autism to differentiate autism from PDD-NOS. The est, social play, pretend play, joint attention, and pointing sensitivity and specificity of the PDDST are not reported.
to express interest in an object or event. One study A brief comparison of these tools and where they can be demonstrated that 18-month-old children who lacked accessed are available in Table 16–4.
Table 16–4 Comparison of Various Autism Screening Tools
Pervasive Developmental Disorders: Autism TREATMENT
Table 16–5 Practical Guidelines for Promoting
Interactions with Individuals with Autism During
Medical management for children with autism is the same as for any child. Due to the social and communi- cation difficulties, however, children with autism may If possible, start a conversation with the child’s parents before be more responsive to particular interaction strategies used during an evaluation. Tables 16–5 and 16–6 pro- Talk with parents about how their child communicates best.
vide suggestions on ways to promote positive exchanges Also, discuss what stimuli may be most irritating or scary to with individuals with autism during evaluations.
the child (eg,certain objects, noises, words), and what kinds of Treatment approaches alleviate behavioral symp- toms and increase learning and adaptive behaviors by If a child’s behavior is likely to make talking with parents during reversing the social and communicative impairments a visit difficult, use the phone to take histories, discuss progress but do not cure the child of autism. In addition, the made since last visit, or discuss other issues before an office visit.
diagnosis of autism does not specify one treatment Work with parents to implement a desensitization plan to your approach, and all intervention methods should be office/hospital, for procedures, and for equipment.
based on an individualized assessment of the child’sneeds.65 Three broad approaches to treatment have If possible, schedule extra time for appointments for children been pursued, including pharmacologic, educationaland behavioral, and alternative methods. Each mode of Being touched is very unpleasant for some children with autism; Educational and Behavioral Treatments
avoid touching them if it is not necessary. If you do need to touch a child, first tell him/her where and how you will touch Educational and behavioral treatments are the most effi- cacious and, therefore, the primary treatment for chil- View the child’s behavior as one way she/he communicates dren with ASD. It is beyond the scope of this chapter to with you. Disruptive or aggressive behavior may be caused by provide a detailed overview of the research on the edu- confusion, fear, anxiety, pain, or other physical discomfort.
cational and behavioral treatment approaches in autism, Sometimes having items available that the child might enjoy and PCPs are advised to consult other resources.1,10,54 may redirect anxiety and promote calmness, such as squeeze balls or toys that make noises or light up.
Unlike other treatment approaches, an educationalapproach has withstood the test of time and is consid- You may need to change the way you usually communicate with ered the primary intervention method for autism.53 children with autism (Table 16–6).
Fortunately, as a result of federal legislation, the Do not be in a hurry when interacting with these children. They Individuals with Disabilities Education Act (IDEA) may take more time than the typical child to feel comfortable guarantees the education of all children with disabili- with you. Also, they may need extra time to process and under- ties, from birth through the age of 21 years.66 The stand what you say and to respond to your requests.
Committee on Children with Disabilities of the AAP Be kind and compassionate to parents. Nobody cares more published a policy statement on the role of health care providers in the development and implementation ofspecial education programming for children with dis- abilities.67 This report explains the laws behind IDEA Continue supporting and communicating with parents. Phone calls can be a good way to follow up after a visit and to further and describes components of the Individual Education discuss issues that were not thoroughly addressed during an Plan (IEP) and Individual Family Service Plan (IFSP) and the medical role in the IEP and IFSP. Ensuring thatchildren with disabilities have access to services is a pri- *Each child with autism has different characteristics and needs.
Therefore, these guidelines can serve as suggestions that should be mary activity for every primary care physician.
Recognizing its critical role in the education and treatment of children with autism, the US Departmentof Education’s Office of Special Education Programsrequested that the National Research Council develop a It is helpful to share this information with parents who committee to report on the scientific evidence regarding have children under 8 years of age as they consider and educational interventions for young children with autism.
evaluate their child’s educational program.
Table 16–6 Communicating with Persons with Autism
undesirable behaviors. No single teaching method hasbeen reported as being more effective than any other Keep sentences as short and simple as possible. People with autism may process and comprehend only a portion of what approach; in fact, all techniques have demonstrated you say or understand only nouns and verbs.
effectiveness, and it is likely that a multicomponent Example: When you say, “Please stay in the room and do not approach is most effective.73 Regardless of any selected go into the hallway,” the child may process only the end of your approach, it is essential to first generate treatment goals sentence and think you said, “Go into the hallway.” based on the results of individualized assessments of the Provide simple, clear, and concise directions.
child’s various areas of development and make adjust- Example: Instead of gesturing at the examination table and ments of the treatment goals and methods based on the saying, “Time for me to look at your belly,” tell the child what you want him to do and make one request at a time. You couldstart with “Sit on table,” while gesturing toward the table. Oncethe child is on the table, say “Lay down.” When the child is Pharmacologic Treatments
laying, say “Doctor will pull up shirt.” Then “Doctor willtouch belly.” Although pharmacologic treatments have not receivedthe same research attention as behavioral or educational People with autism may not understand who, what, when, where, why, and how questions. Words with multiple meanings approaches, it is estimated that more than 50% of indi- or meanings that are dependent on context (especially viduals with autism are treated with some type of med- prepositions, adjectives, and adverbs) may be confusing.
ication, including psychotropics, vitamins, anticon-vulsants, antidepressants, or stimulants.74 Parents, there- Children with autism may need an extra 5 to 10 seconds to fore, are likely to consult with their PCP regarding thesetreatments. Pharmacologic treatment is considered Some children may communicate best through means other adjunctive therapy and does not address core symptoms than spoken word. Consider the use of visual pictures that of autism, but rather those behaviors that interfere with depict the sequence of events of the examination, writtenwords, gestures, and environmental cues when appropriate.
learning and daily life. Medications have been used toreduce overactivity, aggression, repetitive or compulsive Thank children and tell them when they have done something well.
behaviors, self-injury, anxiety, or depression and improve Example: Say, “Good job being calm” after a procedure that is attention and sleep. Descriptions of many of the classes of normally anxiety provoking for a child.
medications used with individuals who have autism are Use neutral tones of voice and facial expressions when telling a described below and in Table 16–7. Because little is known about the effects of some of these drugs on this Tell children what you would like them to do rather than what population, specialists who have experience with autism should monitor pharmacologic interventions. In addi- Example: Say, “Put hands on lap” rather than “Do not touch tion, before medication is considered for the treatment of problem behavior, it is necessary that the parents and Do not give a child a choice when the child does not have one.
care givers, with the assistance of trained educational and Example: Do not ask “May I look in your ears?” if you intend behavioral specialists, consider environmental modifica- to examine his/her ears whether or not she/he gives you tions as well.1 These types of modifications are briefly described in the educational treatment section.
Neuroleptics The neuroleptic drugs are dopamine
antagonists that specifically block D receptors. The degree of affinity of the neuroleptics for D and other Several types of teaching strategies have been evalu- receptors depends on the medication, however. In addi- ated for children with autism, and parents may consult tion to D binding, other dopaminergic, serotonergic, their PCP with regard to these approaches. To name a cholinergic muscarinic, α-adrenergic, and histamine few, these methods include structured teaching,68 inci- receptors may be bound. Because increased motor dental teaching,69 discrete trial training,70 pivotal activity and stereotypic behavior, similar to that response training,71 and functional communication observed in people with autism, is seen with the acti- training.72 All of these approaches fall under the frame- vation of D receptors, neuroleptics could be expected work of applied behavior analysis (ABA), which is com- to reduce these behaviors. It has been demonstrated posed of systematic and planned teaching techniques that some children with autism and low IQ scores have designed to increase desired behaviors and decrease high levels of homovanillic acid, a breakdown product Pervasive Developmental Disorders: Autism Table 16–7 Medications Used for Target Behaviors
α-Adrenergic receptor agonists (clonidine,* guanfacine*) Anxiolytics (buspirone)β-Blocker (propranolol)Dopamine receptor blockers, atypical neuroleptics (haloperidol, thioridazine, chlorpromazine, Opiate receptor antagonist (naltrexone†)Stimulants (methylphenidate,‡ dextroamphetamine,‡ pemoline‡) Tricyclic antidepressant (clomipramine) α-Adrenergic receptor agonists (clonidine, guanfacine)Atypical neuroleptics (risperidone, olanzapine) AnxiolyticsDopamine receptor blockers, atypical neuroleptics (haloperidol,* thioridazine, chlorpromazine, pimozide, risperidone,* olanzapine) Mood stabilizer, anticonvulsants (lithium,† valproic acid,† carbamazepine†) Noradrenergic agents (propranolol,† clonidine, guanfacine) SSRIs, tricyclic antidepressants (fluoxetine, sertraline, fluvoxamine, paroxetine, α-Adrenergic receptor agonists (clonidine,† guanfacine)AnticonvulsantsAnxiolyticsβ-Blocker (propranolol)Dopamine receptor blockers, atypical neuroleptics (haloperidol,* thioridazine, chlorpromazine, pimozide,* risperidone,† olanzapine) Opiate receptor antagonsist SSRIs, tricyclic antidepressants (fluoxetine,‡ sertraline, α-Adrenergic receptor agonists (clonidine,‡ guanfacine) Atypical neuroleptics SSRIs, tricyclic antidepressants (fluoxetine,*sertralin,* fluvoxamine, paroxetine,*clomipramine*) Atypical neuroleptics Mood stabilizers (lithium,† divalproex†)SSRIs,* tricyclic antidepressants* α-Adrenergic receptor agonistsAnxiolytic (buspirone*)SSRIs (fluoxetine,† sertraline,† fluvoxamine, paroxetine†) Anticonvulsants (valproic acid, carbamazepine, lamotrigine, vigabatrin) for EEG abnormalities without seizures: glucocorticoids (corticotropin, prednisone) α-Adrenergic receptor agonists (clonidine,† guanfacine)Antihistamine (diphenhydramine,† hydroxyzine†)Melatonin*Sedating SSRIs (trazadone) Sedative-hypnotics (diazepam, zolpidem)Tricyclic antidepressants (clomipramine) α-Adrenergic receptor agonists (clonidine, guanfacine) Atypical neuroleptics Anxiolyticsβ-Blocker (propranolol) Dopamine receptor blockers (haloperidol, thioridazine, chlorpromazine, pimozide) Opiate receptor antagonsist (naltrexone) SSRIs, tricyclic antidepressants Atypical neuroleptics (risperidone, olanzapine) SSRIs (fluoxetine, sertraline, fluvoxamine) EEG = electroencephalogram; SSRIs = selective serotonin reuptake inhibitors.
*First-line treatment for particular behaviors according to Tsai.132†Preferred alternatives if first-line not effective (Tsai132).
‡First-line treatment for individuals with high-functioning autism (Tsai132).
of dopamine, in their cerebrospinal fluid,75 lending Clozapine differs from other neuroleptics because support to the hypothesis that elevated dopamine lev- it binds D , α-adrenergic, and serotonergic receptors els may cause some of the behaviors exhibited by peo- more potently than either D or D receptors. Double- ple with autism. Dopamine antagonists have been blind placebo-controlled studies of this medication86 shown to decrease aggression and self-injurious behav- and a single-blind dose escalation study with adults87 iors, but whether this is a direct effect of the medication demonstrated decreases in self-injurious behaviors, or the result of sedation is debated.76 Research investi- aggression, and stereotypies. Clozapine may cause seda- gating the effects of four neuroleptics, haloperidol, tion, lethargy, and extrapyramidal side effects that are pimozide, risperidone, clozapine, and other atypical mild at peak effective doses.87 However, clozapine use is limited by its most serious side effect, agranulocytosis.
Haloperidol (Haldol) and pimozide (Orap) Although Serotonin Agonists Because it has been hypothesized
haloperidol acts primarily at D sites, it does have some that serotonin function may play a role in autism, inter- effect on other dopaminergic, α-adrenergic, and sero- est in medications that influence serotonin levels has tonergic receptors. Double-blind placebo-controlled arisen. Evidence for serotonin-related abnormalities studies involving children with autism have demon- in autism includes high peripheral serotonin levels, strated a decrease in mood lability, temper tantrums, decreased responses to neuroendocrine challenge stud- hyperactivity, stereotypies, and withdrawal and improve- ies,88–89 and changes induced by tryptophan-free ments in attention and social behavior.77–79 The reduc- diets.90 In addition, antibodies to central nervous system tion of interfering behaviors may lead to an increase in serotonin receptors may be found in people with learning as measured by discrimination tasks.77 autism, but the research exploring this possibility has Haloperidol is very sedating for some children. In addi- tion, a small number experience episodes of acute dys- Fenfluramine An early study of the use of fenflu- tonia. Unfortunately, because of the extrapyramidal side ramine in three boys with autism suggested that using effects of tardive and withdrawal dyskinesias, which this medication may have beneficial effects on social, have been observed in children with autism,80,81 the use affective, motor, communicative, and cognitive func- of haloperidol and related neuroleptics is limited to the tioning.94 Since that study, the effect of fenfluramine on treatment of severe behaviors that are unresponsive to children who have autism has been studied further. This medication may not be more effective than placebos in Pimozide mainly affects D receptors. In a double- treating autistic behaviors.95–97 In addition, the nega- blind placebo-controlled study including children and tive effects are thought to outweigh the potential bene- adolescents, pimozide was shown to decrease aggressive fits of this drug.98 Although fenfluramine increases behaviors but to have no effect on self-injury.82 More serotonin levels over the short term by causing pre- information about the side effects of this medication is synaptic release and blocking serotonin reuptake, it even- tually leads to a reduction in brain serotonin and Risperidone (Risperdal), clozapine (Clozaril), olanza- 5-hydroxyindoleacetic acid, the main metabolite of pine (Zyprexia), quetiapine (Seroquel), and ziprasidone serotonin. Fenfluramine also decreases plasma norepi- (Geodon) Because haloperidol has high D potency, nephrine levels and increases dopamine turnover. This which corresponds to extrapyramidal toxicity, the effects drug may cause irreversible changes in serotonergic of atypical neuroleptics, such as risperidone and cloza- neurons,99 decreased norepinephrine levels,100 and car- pine, have been studied. Other atypical neuroleptics, such as olanzapine, quetiapine, and ziprasidone, may be Tricyclic Antidepressants: Clomipramine (Ana-
used, but research on the use of these drugs to treat franil), Desipramine (Norpramin, Pertofrane), and
autism needs to be completed. Risperidone is an equally Imipramine (Tofranil) Tricyclic antidepressants, such
potent antagonist of D and serotonin receptors.
as clomipramine, desipramine, and imipramine, are Treatment of severe behaviors, including self-injury, named after their 3-ringed structure and are used aggression, explosivity, agitation, and hyperactivity in primarily to treat depression and obsessive-compulsive children and adults in open-label trials 83–85 and in a disorder. The tricyclic antidepressants block norepi- double-blind placebo-controlled study of adults,84 has nephrine and serotonin uptake into neurons. Clomi- been demonstrated. Improvement in social relatedness pramine and imipramine are nonselective and inhibit may be observed also.10 Sedation and weight gain, how- the neuronal reuptake of serotonin and norepinephrine.
Clomipramine also has some D blocking and opioid Pervasive Developmental Disorders: Autism effects. Desipramine acts mainly as a noradrenergic ago- with autism make global behavioral, cognitive, lan- nist. It is hypothesized that these medications could be guage, affective, and social progress when taking fluox- useful if the serotonin system is involved in the patho- etine and that those who respond to treatment are more likely to have a family history of major depressive dis- In a double-blind study of the effects of clomipramine order than children who have no response.111 Fluoxe- and desipramine, clomipramine was reported to be tine use was associated with hyperactivity, agitation, superior to placebo in reducing anger and obsessive- aggression, decreased appetite, and sleep disturbance in compulsive behavior. Clomipramine and desipramine some of the participants of the above studies.
were equally effective, but better than a placebo, in In a double-blind placebo-controlled study, fluvox- decreasing hyperactivity.102 In addition, open-label amine was found to decrease aggression and obsessive- trials have shown that clomipramine use may lead to compulsive behaviors and improve language skills in improved social relatedness and reduced obsessive- adults with autism.113 Side effects occurred in only a compulsive behaviors, aggression, and self-injury 103–106 small subset of patients and included nausea and seda- in individuals with autism and other pervasive develop- tion that subsided with time. Fluvoxamine may have very different effects on children. In a double-blind Although tricyclics may prove to be very helpful in placebo-controlled study of children and adolescents the treatment of autism, serious side effects can result with autism and other PDDs, only 1 of 16 children ben- from elevated serotonin levels and anticholinergic activ- efited from the use of fluvoxamine. In addition, more ity. For example, imipramine is not recommended for side effects, including sleep disturbance, hyperactivity, the treatment of children with autism because it may agitation, aggression, ritualistic behaviors, anxiety, produce seizures, withdrawal, abnormal speech, and appetite changes, irritability, problems with concentra- negative behavioral changes.107 Possible side effects of tion, and impulsivity were observed in this study113 than clomipramine include seizures, cardiac abnormalities, in the earlier investigation involving adults.108 aggression, tremor, agitation, sedation, weight gain, Data from open-label trials show that sertaline may sleep problems, and constipation.108 No extrapyrami- be helpful in improving social interaction skills, aggres- dal effects are associated with clomipramine treatment sion, self-injurious behavior, anxiety, irritability, tran- of autism.109 Clomipramine may be more effective and sitioning behavior, and repetitive behavior in adults produce fewer negative side effects in adolescents and and children with autism, other PDDs, or mental retar- dation. Unfortunately, this medication has been asso- Selective Serotonin Reuptake Inhibitors: Fluoxetine
ciated with increased anxiety, agitation, and syncope in (Prozac), Fluvoxamine (Luvox), Sertaline (Zoloft),
some individuals.108 Two case reports114,115 suggest that and Paroxetine (Paxil) Selective serotonin reuptake
paroxetine may be helpful in reducing self-injurious inhibitors (SSRIs) act by blocking serotonin reuptake behaviors, irritability, and tantrums in children with specifically. SSRIs have fewer side effects than tricyclics, autism. Posey and colleagues found that agitation and yet, when treating depression or anxiety in people with insomnia may result from the use of doses above a autism, hyperactivity, agitation, and insomnia may result and smaller doses than those used to treat depres- Anxiolytics: Buspirone (Buspar) Buspirone is used
sion or anxiety may be needed.110 In addition, children in the treatment of generalized anxiety disorder, and with autism appear to be more likely than adults to problems with anxiety are often reported in children develop negative side effects as a result of SSRI use. 108 with autism. Buspirone is a partial serotonin receptor A family history of affective disorders is associated with agonist that may also serve as a D receptor antagonist.
a positive response to these medication in people with In a study of 4 children with autism taking buspirone, autism.111 An overview of four SSRIs, fluoxetine, flu- Realmuto and colleagues116 found decreased hyperac- voxamine, sertaline, and paroxetine, is provided.
tivity and stereotypies in two children. Other researchers Fluoxetine has been used successfully to reduce have asserted that buspirone reduces self-injurious obsessive-compulsive behavior and depression in people behaviors in adults with developmental disabilities.117 who do not have autism. One open-label case series Opiate Receptor Antagonist: Naltrexone Theories
demonstrated global behavioral improvements, as mea- that elevated levels of β-endorphin and other brain opi- sured by the Clinical Global Impression Scale, in 15 of oids may cause self-injurious behavior in some individ- 23 participants with autism ranging in age from 7 to 28 uals with autism have provided the basis for the years.112 DeLong and colleagues reported that children hypothesis that opiate receptor antagonists, such as nal- trexone, may reduce these behaviors. Although double- of the study participants was taking neuroleptics or blind placebo-controlled studies have demonstrated mood-stabilizing drugs also. Improvements in aggres- modest decreases in self-injurious behaviors and/or sion, impulsive behavior, self-injurious behavior, social motor hyperactivity with the use of naltrexone in chil- skills and interest, and speech were seen.125,126 dren,118,119 a double-blind placebo-controlled study of Clonidine has been shown to have beneficial effects adults with autism showed that naltrexone produced in studies with double-blinded placebo-controlled no decrease in self-injurious behaviors and led to an designs.127,128 In these studies, parents reported that increase in stereotypic behavior.120 A study that used their children were less hyperactive and irritable and videotapes of six children in natural settings to judge more attentive, calm, and social. Clonidine may not be changes in behavior suggests that naltrexone produces appropriate for treating all children with autism, how- improvements in social behavior (including initiations), ever.128 Side effects experienced by some children stereotypy, and attention relative to a placebo.121 One include fatigue, sedation, hypotension, clonidine toler- benefit of naltrexone is that it does not have to be ance, and increased irritability.127,128 Guanfacine has administered every day because of its long half- been proposed as an alternative α2 noradrenergic ago- life. However, liver function tests should be monitored nist, which may have fewer side effects, but research with while one is taking naltrexone,109 and it may cause an people who have autism needs to be conducted.123 increase in self-injurious behaviors in some people.122 Mood Stabilizer: Lithium Lithium is typically used
In addition, its bitter taste may lead to decreased com- prophylactically to treat mood swings in people with bipolar disorder. This drug’s mechanism of action is Stimulants Stimulants increase the activity of
unknown but may involve ion transport, neurotrans- dopamine and other catecholaminergic neurotransmit- mitters, and/or inositol phosphates. The use of lithium ters. Medications such as methylphenidate (Ritalin) and to change mood or behaviors in individuals with autism dextroamphetamine have been used in attempts to has not been shown to be effective unless the individual improve attention and hyperactivity in children with has been diagnosed with bipolar disorder or has a fam- autism.123 In fact, Aman and Langworthy assert that ily history of this illness. However, lithium has been stimulants may be used more frequently than any reported to decrease the aggressiveness and impulsive- other prescription medication with children who have ness of one adult with autism when used in conjunc- autism.123 Conflicting results have been obtained in studies of stimulant effects on the behavior of children Anticonvulsants: Valproic Acid (Depakote),
with autism. Stimulants may be more effective in reduc- Carbamazepine (Tegretol), and Lamotrigine The anti-
ing inattention and hyperactivity in children with autism convulsants valproic acid, carbamazepine, and lamo- who have high-functioning autism than with those who trigine have been used in individuals with autism who have below-average IQ scores109; however, stimulants have epilepsy or epileptiform electroencephalograms may actually increase stereotypies, activity level, fearful- (EEGs), without clinical seizures. There is some evidence ness, separation anxiety, tachycardia, delusions, tics and based on studies, which did not include participants with autism, that valproic acid and carbamazepine may be Noradrenergic Agents: Propranolol (Inderal),
helpful in reducing aggression regardless of the person’s Nadolol (Corgard), and Clonidine (Catapres) Although
diagnosis or EEG status.129,130 However, the efficacy of there is little evidence that norepinephrine (NE) abnor- these drugs in people with autism has not been proven.76 malities are related to autism, drugs that reduce NE Belsito and colleagues found lamotrigine was not more activity have been used in the treatment of autism.124 effective than placebo in improving a variety of behav- β-Blockers, such as propranolol and nadolol, inhibit NE iors in a double-blind study of children with autism.131 action by blocking NE receptors. Clonidine acts as an α2 Sleep Aids: Melatonin, Clonidine (Catapres),
noradrenergic agonist. Perhaps a decrease in overall level Diphenhydramine (Benadryl), Hydroxyzine (Atarax,
of arousal is responsible for the effect of these drugs on Vistaril), Trazadone (Desyrel), Zolpidem (Ambien),
patients with autism. A review of three noradrenergic Diazepam (Valium) Tsai recommends melatonin as a
agonists, propranolol, nadolol, and clonidine is provided.
first-line pharmacologic treatment for sleep distur- The results of an open-label trial suggested that pro- bances.132 Melatonin is a neurohormone that is associ- pranolol and nadolol may be helpful in the treatment of ated with the regulation of sleep-wake cycles. Although autism. In this open-label study adults with autism little is known about the potential side effects,133 mela- received either propranolol or nadolol. All except one tonin can be an effective treatment of insomnia in peo- Pervasive Developmental Disorders: Autism ple who have autism.134 However, there is a concern claims made about many of these therapies. It is possible about the quality of the products available because that a placebo effect or the changing natural course of melatonin is not classified as a medication so that there the autism underlies the apparent efficacy of some of is less scrutiny over its production. The AAP recom- these approaches; therefore, more research is needed.
mends occasionally withdrawing sleep aids so the effects Reviews of the evidence supporting or refuting the of these medications can be monitored over time.1 effectiveness of many alternative treatments are provided Medication with sedating effects may be helpful by the AAP,10 Dawson and Watling,135 Farber,136 in inducing or maintaining sleep. Clonidine, an Goldstein,137 Gupta,16 Johnston,138 Nickel,139 Page,15 α-adrenergic blocker discussed above, has been used to improve sleep patterns in children with autism.134Antihistamines with sedating side effects, such asdiphenhydramine and hydroxyzine, may be useful in CHOOSING TREATMENTS
some patients; however, these medications may produceexcitation rather than sedation in some children.132 With regard to any treatment, it is essential to help fam- Other drugs are available for the short-term treat- ilies to understand the important cost-benefit issues.
ment of severe sleep problems that do not respond to What are the costs of a particular treatment? Con- other medications. Trazadone is an SSRI with sedating sider the physical, emotional, and financial burdens properties. Benzodiazepines, such as diazepam, bind imposed by particular therapies. Have the potential central nervous system GABA receptors, producing harmful short- and long-term effects of a treatment hyperpolarization and neuronal inhibition. Some ben- been explored? Can ongoing approaches be continued zodiazepines induce sleep, but psychological and phys- while a new one is implemented? This question is par- ical dependence may develop. The hypnotic zolpidem ticularly important to consider if the new treatment is also produces a GABA-mediated reduction in neuronal not successful. Parents should be reassured that it is okay firing. Zolpidem is not a benzodiazepine and is less to not attempt treatments that may come at too high a price for the child and his or her family, especially whenthe efficacy of such treatments is questioned.
What is the evidence supporting the use of a partic- ALTERNATIVE TREATMENTS
ular treatment? Anecdotal accounts are important toconsider, but pediatricians can educate families about Because neither the cause nor the cure of autism is the importance of scientific investigation and how to known, alternative approaches to treatment will con- evaluate different types of evidence. Consider the com- tinue to be pursued by parents and care givers. Many of munication, language, social, cognitive, and physical the approaches used for autism, including some of the characteristics and age of the individuals with which a pharmacologic treatments discussed in the previous sec- treatment has been successful in the past when evaluat- tion, have not been proven to be beneficial using rigor- ing whether or not a treatment is likely to be effective ous studies. Some alternative treatments that have been endorsed in the past or that are currently being used How will outcomes be evaluated? Health care pro- with some children include the administration of mega- viders can emphasize the importance of gathering infor- vitamins and trace minerals (particularly a pyridoxine/ mation as systematically as possible about a child’s magnesium combination), dimethylglycine, intravenous baseline level of functioning and his or her progress so immunoglobulin, adrenocorticotropic hormone (ACTH), that future decisions about whether or not to continue and secretin. In addition, special diets (including a low- a treatment can be made. Additionally, changing only casein and/or low-gluten diet), anti-Candida therapy, one aspect of a child’s treatment plan at a time is crucial and chelation of toxic substances (especially lead) have in being able to attribute success to the appropriate been used. Alternative behavioral approaches, such as Dolman-Delcato patterning, holding therapy, imitation Freeman offers other considerations.140 These in- of autistic behaviors, sensory integration and auditory clude approaching new treatments with hopeful skepti- integration training, and facilitated communication, cism; beware of programs that claim to be appropriate have been attempted also. Impressive anecdotal accounts for all individuals with autism; beware of programs that of success exist for most of these methods. Nevertheless, obstruct an individualized treatment approach; know there is a paucity of well-designed studies exploring the that there are several treatment options for individuals with autism; know that all treatments should be based Table 16–8 Quality of Life Variables to Judge
on individualized assessment; know that no new treat- Outcomes for Older Individuals with Autism146 ments should be provided until the treatment givers demonstrate assessment procedures that determine its Participate in activities with family members and friends appropriateness for the person with autism; and know Included in family or friends’ events (eg, holidays, weddings, that new treatments have often not been scientifically Contact with family and friends as much as desired LONGITUDINAL OUTCOMES OF AUTISM
Assess transportation (eg, use bus, walk, ride bike, ride in car) Shop for items (eg, groceries, clothes, gifts) Many myths are associated with autism. People, for Make choices (eg, what video to watch, movie to see, place to eat) example, often mistakenly believe that all children with Attend special events (eg, sports, concerts) autism have hidden savant skills. Two other miscon- Participate in extracurricular activities (eg, YMCA, bike club, ceptions are that people with autism can be cured and that as adults, individuals with autism will be depen-dent and nonparticipating members of their commu- nity. These latter two myths reflect the traditional Work at job that is enjoyable and provides self-satisfaction method of judging outcomes, the comparison of the abilities of people with autism to the development of those who do not have disabilities. The traditional view defines outcome as a function of typical social devel- opment and levels of achieved independence,141–145 Opportunity to learn to try new things and meet new which are best predicted by level of IQ and develop- ment of speech. It is not surprising that researchers have reported poor outcomes for most individuals with autism using these outcome criteria.141, 142 Opinions and choices are considered valid and important Because autism is a lifelong disability that causes Is provided time and space to be alone when desired and has most people with it to have persistent social problems and is often associated with some degree of mental Is provided enough information to make valid choices and not retardation, an alternative view of outcome may be have to refuse them because of a lack of information, more useful and valid for parents, care givers, and treat- ment providers.146 Using an alternative framework, outcome is based on the achievement of individualized Takes responsibility for personal and home chores as much as goals that are established for each person. Also, this possible and in return takes pride through this accomplishment conceptualization of outcome encourages the con- and receives recognition as contributing to the family sideration of an individual’s quality of life (QOL). As Bathe, wash and style hair, shave, maintain personal hygiene individuals with autism grow older, QOL becomes especially important. A list of QOL variables for fami- Maintain health and wellness through understanding of lies and care givers to consider is provided in Table 16–8. Enhancing competence is the goal of interven- tion and results from the interactions between childrenand their environments. This definition of competencede-emphasizes the degree to which pathology existsonly within the child and recognizes the contribution positive research results on the effects of early inter- of the environment to development and learning.
vention.52 Thus, the influence of the environment on Competence, defined as the achievement of functional development and outcome is substantial and ongoing and meaningful life skills, serves as a protective factor that offsets risk factors such as underlying impairmentsseen in autism.146 The evidence for the environmental We would like to acknowledge Gail Williams, MD for her influences on outcome in autism is confirmed by the helpful suggestions on previous revisions of this chapter. Pervasive Developmental Disorders: Autism REFERENCES
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