57  Autistic Spectrum Disorders
Deborah G. Hirtz, Ann Wagner, Pauline A. Filipek, and Elliott H. Sherr
The autistic spectrum disorders (ASD) represent a wide con-
tinuum of associated cognitive and neurobehavioral deficits,
including deficits in socialization and communication, with
restricted and repetitive patterns of behaviors. The terms
“autism” and “autistic spectrum disorders” are used inter-
changeably throughout this chapter and refer to the broader
umbrella of autism spectrum disorders, as defined in the fifth
edition of the Diagnostic and Statistical Manual of Mental
Disorders.1
HISTORICAL PERSPECTIVE OF THE DIAGNOSTIC
AND STATISTICAL MANUAL OF MENTAL,
DISORDERS IN RELATION TO AUTISM
Although Leo Kanner2 first described a syndrome of “autistic
disturbances” in 11 children who shared “unique” and previ-
ously unreported patterns of behavior, including social
remoteness, obsessiveness, stereotypy, and echolalia, the first
set of formal diagnostic criteria for this disorder was not for-
mulated until the 1970s.3,4 In the third edition of DSM,5 the
term “autism” was included for the first time and was clearly
differentiated from childhood schizophrenia and other psy-
choses under a new diagnostic umbrella of pervasive develop-
mental disorders (PDD). The revised third edition of DSM6
broadened the spectrum of PDD and narrowed the specific
diagnoses to two: autistic disorder and PDD not otherwise
specified (PDD-NOS). The fourth edition of DSM7 and text-
revised fourth edition of DSM8 included five possible diagno-
ses under the PDD umbrella: autistic disorder, Asperger
syndrome, childhood disintegrative disorder, Rett syndrome,
and PDD-NOS/atypical autism.
The fifth edition of DSM1 was published in 2013 and
includes several major changes related to diagnostic criteria
for autism. These changes were the result of an extensive
review of literature and secondary data analyses conducted
by DSM workgroups.9–11 The most significant change is the
replacement of pervasive developmental disorders with a
single diagnosis—autism spectrum disorder (ASD)—and the
elimination of subcategories. Thus autistic disorder, Asperger
syndrome, childhood disintegrative disorder, and PDD not
otherwise specified are included under the autism spectrum
disorder category. Rett disorder is eliminated from the defini-
tion (Box 57-1).1
The fifth edition of DSM collapses the symptom domains
into two: social-communication impairment and restrictive
and repetitive behaviors. Hyperreactivity or hyporeactivity to
sensory input (which was not included in the fourth edition
DSM) is a characteristic within the restricted and repetitive
behavior domain in the fifth edition. The number of symp-
toms is streamlined (from 12 to 7) by eliminating redundancy
and merging similar symptoms. This edition addresses the
dimensional nature of ASD by allowing severity ratings of the
two functional domains and requiring specification of accom-
panying intellectual impairment, language impairment, or
other known medical, genetic, or neurodevelopmental condi-
tions. The edition does not specify an age of onset criteria
but requires that symptoms have been present in the “early
developmental period.” The fifth edition also requests speci-
fiers to record the presence or absence of several associated
e1104
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conditions: intellectual and/or language impairment; other
known medical/genetic conditions or causal environmental
factors; an associated neurodevelopmental, mental, or behav-
ioral disorder; and catatonia. Finally, this edition developed a
new social communication disorder (SCD) category (not
included in the autism spectrum disorder category) to provide
diagnostic cover for children who present only with social
communication problems, without repetitive behavior. A
diagnosis of SCD requires ruling out ASD. The fifth edition of
DSM states that individuals with a well-established diagnosis
based on the fourth edition of DSM within the pervasive
developmental disorder classification should be given the
diagnosis of autism spectrum disorder.
Several concerns have been raised about the new DSM
(fifth edition) approach to diagnosis of ASD, including that
some individuals with diagnoses within the PDD category
could fall outside this edition’s ASD category and be vulner-
able to losing services. Several attempts to compare the sensi-
tivity and specificity of this edition’s diagnoses compared with
that of the fourth edition of DSM diagnoses have been pub-
lished, with mixed results. Most of these utilized 2011 and
2012 drafts of the fifth edition DSM’s ASD category that were
released for public comment before the publication of the
manual. The final criteria differ from earlier drafts in some
critical ways: the number of criteria necessary was reduced by
one criteria in later drafts; the final criteria allow for symptom
presentation “by history,” relaxed the onset criteria from 36
months to “early childhood,” and eliminated the “trumping
rules” that had previously prevented the codiagnosis of atten-
tion deficit hyperactivity disorder (ADHD) and schizophrenia
with ASD.12 Two studies that utilized “relaxed” draft DSM
(fifth edition) criteria and required one fewer symptom13,14
found diagnostic sensitivity similar to, or better than, that of
both the fourth edition and the text-revised fourth edition
DSM diagnostic approach. However, there have not yet been
any publications reporting on changes in sensitivity of the new
fifth edition DSM approach as it is described in the published
manual.
CLINICAL FEATURES OF ASD
All individuals on the autistic spectrum demonstrate deficits
in two core domains: social communication/interaction and
restricted/repetitive behaviors.1 There is marked variability in
the severity of symptoms across patients, and cognitive func-
tion can range from severe intellectual impairment through
the superior range on conventional IQ tests. DSM (fifth
edition) specifies that in the context of intellectual disability,
the social communication functioning must be more impaired
than would be expected on the basis of general developmental
level. Overall, the symptoms must be sufficient to limit
or impair everyday function to warrant a diagnosis of ASD
(Box 57-1).
Persistent Deficits in Social Communication
and Social Interaction
The criteria in this domain refer to a qualitative impairment in
social communication and reciprocal social interactions,

BOX 57-1  Diagnostic Criteria for 299.00 Autism Spectrum Disorder
A. Persistent deficits in social communication and social
interaction across multiple contexts, as manifested by the
following, currently or by history (examples are illustrative, not
exhaustive; see text):
1. Deficits in social-emotional reciprocity, ranging, for example,
from abnormal social approach and failure of normal
back-and-forth conversation; to reduced sharing of
interests, emotions, or affect; to failure to initiate or respond
to social interactions.
2. Deficits in nonverbal communicative behaviors used for
social interaction, ranging, for example, from poorly
integrated verbal and nonverbal communication; to
abnormalities in eye contact and body language or deficits
in understanding and use of gestures; to a total lack of
facial expressions and nonverbal communication.
3. Deficits in developing, maintaining, and understand
relationships, ranging, for example, from difficulties adjusting
behavior to suit various social contexts; to difficulties in
sharing imaginative play or in making friends; to absence of
interest in peers.
Specify current severity:
Severity is based on social communication impairments and
restricted, repetitive patterns of behavior.
B. Restricted, repetitive patterns of behavior, interests, or
activities, as manifested by at least two of the following,
currently or by history (examples are illustrative, not exhaustive;
see text):
1. Stereotyped or repetitive motor movements, use of objects,
or speech (e.g., simple motor stereotypes, lining up toys or
flipping objects, echolalia, idiosyncratic phrases).
2. Insistence on sameness, inflexible adherence to routines, or
ritualized patterns of verbal or nonverbal behavior (e.g.,
extreme distress at small changes, difficulties with
transitions, rigid thinking patterns, greeting rituals, need to
take same route or eat same food every day).
3. Highly restricted, fixated interests that are abnormal in
intensity or focus (e.g., strong attachment to or
preoccupation with unusual objects, excessively
circumscribed or perseverative interests).
4. Hyper- or hyporeactivity to sensory input or unusual interest
in sensory aspects of the environment (e.g. apparent
indifference to pain/temperature, adverse response to
(From: American Psychiatric Association. Proposed Revisions to 299.00 Autistic Disorder in DSM-V, 2013. Retrieved February 28, 2013, from
http://www.dsm5.org/ProposedRevisions/Pages/proposedrevision.aspx?rid = 94#.)
which is persistent and observable across multiple contexts.
Social communication and interactions are clearly atypical for
the individual’s age and developmental level. Behaviors range
from total lack of responsiveness to other people to an oddly
stilted interaction style or inappropriate approaches and
attempts to interact.
In infants and toddlers, deficits in social-emotional reci-
procity often manifest as the absence of attempts to initiate
social interaction and a lack of responsiveness to social over-
tures. Some autistic children do not lift up their arms or
change posture in anticipation of being held and often do not
look or smile in response to approaches from caregivers or
others. They often do not respond when a caregiver says their
name or says “look” and points to something of interest.
Engagement in give-and-take in play (e.g., peek-a-boo or pat-
a-cake) that is seen in typically developing infants and tod-
dlers is often missing. Older children often do not point
things out or use eye contact to share the pleasure of seeing
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Autistic Spectrum Disorders e1105
57
specific sounds or textures, excessive smelling or touching
of objects, visual fascination with lights or movement).
Specify current severity:
Severity is based on social communication impairments and
restricted, repetitive patterns of behavior.
C. Symptoms must be present in the early developmental period
(but may not become fully manifest until social demands
exceed limited capacities, or may be masked by learned
strategies in later life).
D. Symptoms cause clinically significant impairment in social,
occupational, or other important areas of current functioning.
E. These disturbances are not better explained by intellectual
disability (intellectual developmental disorder) or global
developmental delay. Intellectual disability and autism spectrum
disorder frequently co-occur; to make comorbid diagnoses of
autism spectrum disorder and intellectual disability, social
communication should be below that expected for general
developmental level.
Note: Individuals with a well-established DSM-IV diagnosis of
autistic disorder, Asperger’s disorder, or pervasive developmental
disorder not otherwise specified should be given the diagnosis of
autism spectrum disorder. Individuals who have marked deficits in
social communication, but whose symptoms do not otherwise
meet criteria for autism spectrum disorder, should be evaluated
for social (pragmatic) communication disorder.
Specify if:
With or without accompanying intellectual impairment
With or without accompanying language impairment
Associated with a known medical or genetic condition or
environmental factor
(Coding note: Use additional code to identify the associated
medical or genetic condition.)
Associated with another neurodevelopmental, mental, or
behavioral disorder
(Coding note: Use additional code[s] to identify the associated
neurodevelopmental, mental, or behavioral disorder[s].
With catatonia (refer to the criteria for catatonia associated with
another mental disorder)
(Coding note: Use additional code 293.89 catatonia associated
with autism spectrum disorder to indicate the presence of the
comorbid catatonia.)
something with another person, which is called joint attention
or social referencing.
Some children do make eye contact, often only in brief
glances, but the eye contact is usually not responsive to some-
thing another person has done or said and is not used to get
someone’s attention. Others may make inappropriate eye
contact by turning someone else’s head to gaze into their eyes.
Autistic children may appear to ignore a familiar or unfamiliar
adult or child because of a lack of social interest. Some chil-
dren do make social approaches, although their conversa-
tional turn-taking or modulation of eye contact is often grossly
impaired. At the opposite extreme of social interactions, some
children may make indiscriminate approaches to strangers
(e.g., lack age-appropriate reticence with strangers, ask inap-
propriate questions, or be described as a child that continu-
ously and inappropriately “gets in your face”), reflecting an
inability to respond to the social cues of the other person. For
school-age children and adolescents with ASD, unfamiliar or
e1106 PART VII  Neurodevelopmental Disorders
unstructured social situations (such as recess and lunch room)
are especially challenging due to their difficulty in engaging
in a reciprocal interaction and the inability to understand
social roles and social cues.
Deficits in nonverbal communication behaviors typically
used for social interaction are a hallmark of ASD. Expressive
language function in ASD ranges from complete mutism to
verbal fluency. Regardless of verbal ability, the use of nonverbal
communication behaviors, an aspect of pragmatic language
ability, is impaired. The severity of deficits in nonverbal com-
munication can vary, from a total lack of facial expressions and
nonverbal communication to a lack of integration of gestures
(e.g., eye contact, smiling, nodding, shaking the head, shrug-
ging the shoulders) with verbal communication. Difficulty
understanding nonverbal communication contributes to the
lack of social reciprocity that is characteristic of ASD.
Some children with autism indicate little or no interest in
other children or adults and prefer to play alone, away from
others. Others play with adults nearby or sit on the outskirts
of other children’s play and engage in parallel play or simply
watch the other children. Some children involve other chil-
dren in designated, often repetitive play, but lack age-
appropriate give-and take. Lack of pretend play or very
repetitive “scripted” pretend play is a typical characteristic of
children with ASD.
Friendships that do develop are often formed around a
specific shared interest, and a lack of social reciprocity is still
often apparent. A child may “want friends” but usually does
not understand the concept of the reciprocity and sharing of
interests and ideas inherent in friendship. Often, children
gravitate to either older peers, in which case they play the role
of followers, or to much younger peers, in which case they
become the leaders. Unfortunately, their social awkwardness
often leaves children with ASD vulnerable to teasing and
bullying.
Restricted, Repetitive Patterns of Behavior,
Interests, or Activities
Restricted, repetitive patterns of behavior, interest, or activi-
ties can be manifest in many different ways. A common form
of repetitive speech is echolalia, which may be immediate
or delayed. Immediate echolalia refers to immediate non-
communicative repetition of words or phrases—the child is
simply repeating exactly what was heard without synthesiz-
ing the intrinsic language. This ability is a crucial aspect of
normal language development in infants under the age of
2 years, but it becomes pathologic when still present as the
sole and predominant expressive language after the age of
about 18 to 24 months. Delayed echolalia (or scripted speech)
refers to the use of highly ritualized phrases that have been
memorized, such as from videos, television, commercials, or
overheard conversations. Many older autistic children incor-
porate the scripts in an appropriate conversational context,
which can give much of their speech a rehearsed and often
more fluent quality relative to the rest of their spoken lan-
guage. Repetitive questioning and the persistent use of idio-
syncratic phrases are other forms of repetitive speech that
frequently occur.
Some children have obvious stereotypical movements,
such as florid hand-clapping or arm-flapping whenever excited
or upset, which is pathologic if it occurs after the age of about
18 to 24 months. Running aimlessly, rocking, spinning,
bruxism (teeth grinding), toe-walking, or other odd postures
are commonly seen in autistic children. In higher-functioning
youngsters, the stereotypic movements may become “minia-
turized” as they get older into more socially acceptable behav-
iors, such as pill rolling.15,16
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Many children with ASD demonstrate the classic behavior
of lining up toys, videotapes, or other favored objects, but
others may simply collect things for no apparent purpose.
Some are preoccupied with repetitive actions, such as opening
and closing doors.
Many autistic children are so preoccupied with “sameness”
in their home and school environments or routines that little
can be changed without prompting a tantrum or other expres-
sion of distress. For example, some insist that all home fur-
nishings remain in the same position, that all clothing be a
particular color, or that only one specific set of favored sheets
be used on the bed. This inflexibility may also pertain to
familiar routines, such as taking only a certain route to school,
entering the grocery store only by one specific door, or never
stopping or turning around after the car starts moving. By
adulthood, many of these rituals may evolve to more classic
obsessive-compulsive symptoms.
Restricted and repetitive behavior may take the form of
excessive preoccupation with special interests. For example,
many children are fascinated with dinosaurs, but children
with ASD may amass exhaustive facts about every conceivable
type of dinosaur and about which museums house which
particular fossils; these children often repeatedly “share” their
knowledge with others, regardless of the others’ interest or
suggestions to the contrary. At times, it is the intensity of the
interest that is unusual, and at other times, it may be the inter-
est itself. The inflexibility and idiosyncratic nature of these
preoccupations interferes with the ability to carry on recipro-
cal conversations or sustain friendships.
Many children with ASD overreact or underreact to sensory
input or may be interested in the sensory aspects of their
environment to an unusual degree. They may seem to be indif-
ferent to pain or temperature, or they might react with marked
distress to certain sounds or textures. Younger children with
ASD often repeatedly spin objects or themselves, seemingly
fascinated with movement. Others are often particularly fasci-
nated by water, lights, or patterns in their surroundings.
Extreme rigidity or rituals related to the smell, texture, and
look of food are common and may result in excessive food
restriction.
Onset Patterns in ASD
The onset of ASD may occur early, with abnormalities in social
and communication skills becoming apparent in the first year
of life, or children appear to develop normally until at least
12 months of age, followed by loss of language and/or social
skills, known as regression. A recent meta-analytic review
found the prevalence and onset of regression in ASD at around
30%, with prevalence estimates varying depending on the
sampling method and on the methods used to define and
measure regression.17
Efforts to understand the phenomenon of loss of skills in
ASD have been challenged by the lack of good methods for
prospectively tracking development with the precision needed.
Parents’ recall is often imperfect and may be influenced by
things such as the child’s age, the degree of impairment, and
the type of questions asked.18 Investigators have prospectively
followed infant siblings of children with ASD (a high risk
sample) to look for early signs of autism. Close attention to
the development of these “baby sibs” suggests that develop-
mental plateauing or loss of social communication skills is
common in children who are eventually diagnosed with
ASD.19–21 Using a very comprehensive structured interview
designed to enhance recall, Thurm and colleagues22 examined
the early attainment and loss of social communication skills
in 125 children with autism. Loss of at least one skill was
reported in the majority of children, and delays in attainment
 Autistic Spectrum Disorders e1107

of skills were also reported in children who lost skills. Dra-
matic, rapid regression after a period of normal development,
particularly after the age of 2 years and when involving more
than social communication skills, is rare and warrants a thor-
ough medical evaluation.1 More typical is a “plateauing” or
deceleration of development after 6 months of age such that
the child’s development gradually becomes more discrepant
from typical development.19–21,23,24 This is often accompanied
by some loss of social communication skills, typically joint
attention, shared affect, and the use of language in a com-
municative way. Children may stop using words that were
once part of their vocabulary. Over the course of early child-
hood, some children with ASD continue on a worsening tra-
jectory, others remain stable, and some improve. Unfortunately,
there is not a reliable way at this time to predict which trajec-
tory will apply to an individual child.
Children who experience a regression with onset of symp-
toms of autism and an epileptiform EEG are to be differenti-
ated from those with a diagnosis of Landau-Kleffner syndrome,
an acquired aphasia associated with an epileptiform EEG, and
from those with continuous spike waves during slow wave
sleep (CSWS). Although in these conditions there are seizures,
regression and epileptiform abnormalities, children with
autistic regression have an earlier age of onset and are less
likely to have bilateral, temporal EEG patterns, or electrical
status during sleep (Table 57-1).
EPIDEMIOLOGY
The reported prevalence of autism has dramatically increased.
In 2006 the reported prevalence in 8-year-olds in the United
States was 9.0 per 1000,25 and in 2010 it was 14 per 1000 or
one in 68 children.26 These CDC studies relied on abstraction
of health and education records. In a 2007 parent-reported
United States diagnostic survey, the prevalence for ASD was 11
per 1000.27 This is a marked increase from earlier studies.
Awareness of autism has been increasing throughout the
world in both developing and developed countries, with
varying but largely similar prevalence estimates to the United
States reported in Europe and Asia.28 In a random adult survey
in England, ASD prevalence was approximately 1 per 100.29
Very similar figures come from a survey of children on the
special needs register.30 In Scandinavia, similar results are
reported. In 2011 in Sweden, prevalence was highest in 13- to
17-year-olds (2.46%).31 In Norway, for 6- to 12-year-olds, 57
autism prevalence is .6%.32 A South Korean study estimated
the highest prevalence of 1.9%, but the participation rate was
63%.33
A number of factors contribute to the apparent increase.
Definitions, screening methods, diagnostic criteria, and
completeness of sampling are important factors affecting
prevalence results.27,34–37 Clearly, autism prevalence was under-
estimated in the past. Diagnostic criteria have evolved and
broadened. The concept of autism in these more recent surveys
included the broadest definitions; there is now codiagnosis
with known medical disorders, such as Fragile X syndrome,
Tourette syndrome (TS), and Down syndrome. There is also
growing public awareness among parents and teachers as well
as availability of services and diagnostic screens.38,39 Children
earlier diagnosed as mentally retarded may have met current
criteria for autism.36,37,39 Bishop and associates found that up
to 60% of adults previously diagnosed with developmental
language disorder would meet more recent criteria for PDD.40
Case ascertainment methodology and sampling strategies are
also factors; using multiple sources and broad population
screening increases the number of cases found.41 Changes in
reporting factors accounted for most (60%) of the increase
in prevalence in Denmark.42 The type of evaluation matters
(school professionals are more likely to diagnose) and region
matters, with more diagnosed in the United States in the
northeast and in metropolitan areas.43 There are few data on
prevalence in older populations.
Although a substantial proportion of the increase seen in
autism is due to factors such as a combination of better, more
population-based studies and changes in the diagnostic crite-
ria and age at diagnosis, the increase cannot be solely attrib-
uted to known factors, and there is likely to be a true increase
in incidence. It is important for etiologic reasons and for
public health and educational planning to ascertain whether
the rise in cases is genuine, if it is continuing, and to what
degree. The CDC is monitoring the prevalence of autism over
time in a number of U.S. sites using consistently applied
ascertainment and diagnostic protocols.26
The proportion of children with ASDs who had IQs less
than or equal to 70 ranged from about 30% to 50% in the
CDC’s Autism and Developmental Disabilities Monitoring

TABLE 57-1  Landau–Kleffner Syndrome-Continuous Spike Waves during Slow-Wave Sleep versus Autistic Regression with Epileptiform EEG
Landau–Kleffner Syndrome-Continuous Spike-Waves
during Slow-Wave Sleep (LKS-CSWS)
Age of regression/ Usually after 3 years; peak age 3–5 years. In CSWS may
(symptoms) be as late as 12 years of age.
Seizures Usually not frequent or intractable. In approximately 25%,
seizures are not present.
EEG Spikes, sharp waves, or spike-and-wave discharges,
usually bilateral and occurring predominantly over the
temporal regions. They increase during sleep; EEG
pattern of electrical status epilepticus during slow-wave
sleep is common.
Treatment Case reports, mostly with use of steroids, suggest
improvement in language. Surgical outcomes with
multiple subpial transections are variable. No controlled
clinical trials.
Outcome/Comments Improvement occurs in late childhood/early adolescence.
Approximately one third recover. Prognosis for seizure
control is excellent but recovery of language is variable
and not as good as for seizures.
Autistic Regression with Epileptiform EEG (AREE)
Usually before age 2 years with a mean age of
regression of 21 months
Seizures are not part of phenotype. In autistic spectrum
disorders, when seizures occur, they are usually
not frequent and respond well to antiseizure
medications.
Infrequent spikes, usually centrotemporal. Rarely
associated with CSWS. No clear correlation with
interictal epileptiform discharges and improvement or
worsening of underlying language and social
dysfunction.
No evidence that present medical interventions
(antiseizure medications) or surgical interventions are
indicated.
Improvement seems related to cognitive skills. No data
to determine whether interictal discharges combined
with regression are marker for worse prognosis.

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e1108 PART VII  Neurodevelopmental Disorders
Network. The mean male to female ratio is 4 to 1 or greater
for the milder forms, but as severity of cognitive impairment
increases, the male to female ratio decreases to 1.3 to 1.44
Children with a measurable IQ of less than 50 are more likely
than those who are high-functioning to be female and to have
minor physical anomalies, neuroimaging abnormalities,
microcephaly, and epilepsy. Those with specific, known inher-
ited conditions, such as tuberous sclerosis or phenylketonuria,
are likely to be more severely cognitively impaired.45
Sibling Studies
An autism diagnosis is about 20 times more likely in siblings
when one child had autism; about 10.1% compared with
.5% prevalence in siblings of controls.46 A report from Japan
found gender differences in the risk for subsequent siblings:
general sibling risk was 10%, 7.7% if the proband was male,
and 20.0% if the proband was female.47 The risk is 25% if there
are already two siblings with ASD.48 In a population-based
cohort of over 2 million Swedish children, the relative risk of
having autism when a monozygotic twin was diagnosed was
153 times that of control children with no autistic sibling.
For dizygotic twins the risk was 8.2 (3.7 to 18), no different
than for siblings, which was 10.2 (9.4 to 11.3), compared with
controls with no autistic sibling. The authors of this study
estimated that genetic factors may explain about half the risk
for autism.49
Infant siblings of children with autism have garnered recent
research attention as a high-risk group with the hope of iden-
tifying the earliest warning signs of ASD, and the rate of an
eventual diagnosis of ASD varies highly with age.50–61 Age at
entry into the studies varies considerably, and bias is intro-
duced in that parents of those infants enrolled at later ages
might have already recognized warning signs that prompted
their participation in the study.
Delays in verbal and nonverbal communication have been
noted in siblings of those diagnosed with ASD, beginning
about 12 months of age.56,59,62 However, no consistent specific
deficits have emerged as characteristic of Sib-ASD. Response
to name at 12 months of age and response to joint attention
were predictive of the degree of social impairment and even-
tual ASD diagnosis at 3 years of age.60
Neonatal Intensive Care and Prematurity
Matsuishi and associates first reported a significantly increased
rate of ASD in children born between 1983 and 1987,63 with
a mean gestational age of 35.4 (plus or minus 4.6 weeks),
requiring neonatal intensive care, and who were followed up
between 5 and 8 years of age; a history of meconium aspira-
tion was significantly more common in those children with
ASD than in the comparison groups of children with cerebral
palsy and those with typical development. Badawi and col-
leagues also have reported an increased rate of ASD at 5% in
term neonatal intensive care unit (NICU) survivors of newborn
encephalopathy.64,65 Breech delivery and low 5 minute Apgar
scores have been associated with an increase in risk.66–69
There is a higher rate of autism and a much higher rate
of positive screening for ASD in infants with extreme prema-
turity using the Modified Checklist for Autism in Toddlers
(M-CHAT)70–72 and other screening instruments. Limperopou-
los and associates found a 25% rate of positive screening for
ASD at 18 to 24 months of age in 91 infants who were less
than 1500 g and 31 weeks’ gestation at birth.73 Kuban and
colleagues noted a 22% rate of positive M-CHAT screens in
988 NICU survivors at 24 months of age who were less than
28 weeks’ gestation at birth and who were followed in the
multicenter ELGAN study.74 Major motor, cognitive, visual,
and hearing impairments appeared to account for more than
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half of the positive M-CHAT screens in this cohort, but even
after the toddlers with those impairments were eliminated,
10% of children—nearly double the expected rate—screened
positive. It has been suggested that perinatal inflammation75
and ventricular enlargement76 contribute to the increased risk
in prematures.
In a large Swedish population-based study, Buchmayer and
associates reported that the increased risk of autistic disorders
related to preterm birth was mediated primarily by prenatal
and neonatal complications that occur more commonly
among preterm infants, predominantly preeclampsia, but also
intracranial hemorrhage, cerebral edema, low Apgar scores,
and seizures.77 Limperopoulos suggests that the incidence of
ASD among survivors of preterm birth is inversely related to
gestational age.78 If so, as survival rates continue to improve
in extremely premature infants, the resulting morbidity of
ASD may also continue to increase. The presence of perinatal
risk factors should lead to systematic screening of toddlers and
preschoolers.
Parental Age and Socioeconomic Factors
Risk of ASD is higher with increasing age of mothers and,
independently, with increasing age of fathers.79,80 In a large
population of children born between 1989 and 1994, mothers
older than 35 years were three times more likely to have
an autistic child than women younger than 20 years.81 One
California study found that, when adjusted for age of the
other parent and other covariates, the risk of autism increases
by up to 40% for each 10-year increase in maternal age and
by 20 to 25% for each 10-year increase in paternal age.82 In
another study, also from California, maternal age was lin-
early correlated with risk but increased paternal age was a
risk factor only in mothers over 30-years-old.83 Some studies
found that socioeconomic level does not affect risk,84,85 but
in other studies, ASD prevalence was higher with increasing
socioeconomic status.86,87 Risk was also increased in multiple
births (RR = 1.7; 95% CI = 1.4–2.0) and in black children (RR
= 1.6; 95% CI = 1.5–1.8).81
Advanced parental age and some of the other risk factors
for autism that have been suggested may act through increas-
ing risk for de novo mutations.88 There could also be contribu-
tory mutagens in the environment, such as mercury, cadmium,
nickel, trichloroethylene, and vinyl chloride. Factors associ-
ated with vitamin D deficiency may cause mutations as
vitamin D contributes to repair of DNA damage.89 The number
of fetal ultrasounds does not seem to be associated with
increased risk.90
Autoimmune and Other Factors
A number of risk factors related to autoimmune dysfunction
have been associated with autism risk. The presence of mater-
nal thyroid peroxidase antibody (TPOAb) increased risk by
nearly 80%.91 One Swedish study found an elevated risk of
ASD associated with maternal infection requiring hospitaliza-
tion during any trimester of pregnancy.92 However, mild
common infectious diseases or febrile episodes were not asso-
ciated with an increase in risk.93 Gestational or type 2 diabetes
in the mother may increase risk.94 Other identified risk factors
include maternal prenatal stress in the first trimester95 and
paternal obesity.96 Children born within 1 year of an autistic
sibling have an increased risk over those born after longer
intervals.97 A decrease in risk for autism has been seen to be
associated with periconceptual folate intake, and the reduc-
tion may be strongest in those with genetically inefficient
folate metabolism.98–100
With the apparent increase in autism prevalence, attention
has naturally been focused on whether exposure to toxins such

as those found in air pollution could be an environmental
trigger interacting with genetic susceptibility. Studies from
both the east101 and the west coasts102,103 of the United States
documented that traffic-related air pollution during gestation
and the first year of life was associated with an increase in
risk. In contrast, a Swedish study found no consistent
association.104
Vaccines
Recent resurgence of measles in the United States has focused
attention on parents who have refused the measles-mumps-
rubella (MMR) vaccination for fear of its causing autism.
Symptoms of autism generally are noticed first in the second
year of life, although they may be recognized only in retro-
spect, and this is when the MMR vaccine is given. Targets of
concern have been the MMR vaccine itself and thimerosal, the
mercury-containing preservative that was used in childhood
vaccines until its removal between 1999 and 2002.
Multiple studies concluded that there was no increase
in risk of autistic disorder with exposure to the MMR
vaccine.105–109 Taylor and associates analyzed five methodologi-
cally sound cohort studies involving 1,256,407 children and
five case-control studies of 9920 children and did not find any
increased risk of autism associated with either childhood vac-
cines or the mercury-containing preservative thimerosol,
which has not been used routinely since 2001.110 Additional
data derived from passive surveillance systems also consis-
tently failed to detect an association.111 There has been no
evidence that the incidence of regressive autism has increased
after administration of the MMR vaccine. The MMR vaccine
has been given at a constant rate since 1979 in the United
States, since 1982 in Finland, and since 1998 in the United
Kingdom and Denmark, but rates of autism have steadily
risen.112 Analysis of data from California, Sweden, and
Denmark found that, although thimerosal exposure from vac-
cines was eliminated in Sweden and Denmark by the early
1990s, the incidence of autism was accelerated.113 This finding
was confirmed by a retrospective cohort study.114 Even among
children at higher risk because of autism in older siblings,
there was no harmful association of MMR vaccines and ASD.115
The study claiming measles virus found in the GI tract
of 10 children with autism was causally related has been offi-
cially retracted by the Lancet.116,117 Taylor and associates found
6.6% of children with autism had regression and bowel symp-
toms, but the onset of symptoms was not associated with the
MMR vaccine.109 Another prospective report did not find any
association in a large, prospective sample.106 Further strong
evidence against the association of autism with persistent
measles virus in the gastrointestinal tract or measles-mumps-
rubella exposure came from a case control study, in which
gastrointestinal tissue samples from children with autism,
90% of whom showed behavioral regression, and from con-
trols, were examined for presence of measles virus RNA in a
blind study, with results consistent over three laboratory
sites.118 There were no differences between case and control
groups in the presence of measles virus RNA, and gastrointes-
tinal symptom and autism onset were unrelated to timing of
the MMR vaccine.
Animal Models of Autism
One of the most challenging aspects of autism research is the
development and validation of animal models. Ideally, an
animal model should have three main features that yoke the
model to the human condition: 1) construct validity: having
the same underlying biological causes of ASD; 2) face validity:
having the same clinical features in the animal model as in
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Autistic Spectrum Disorders e1109
patients with ASD; and 3) predictive validity: responding to
treatments in a way that is similar to how patients would 57
ultimately respond. This level of scrutiny is very rigorous, but
is essential if we are to move from our current state of knowl-
edge to the development of effective treatments that work on
the core biologies of these disorders. Although achieving these
goals with idiopathic ASD is quite challenging, as our knowl-
edge of the genetics and underlying biological circuits altered
in the various syndromes that comprise ASD continues to
advance, it is possible that these advances will lead to novel
targeted therapeutics.
Most work on animal models of ASD has been in mice
genetically engineered to have construct validity with human
disorders. Thus there are mice with mutations in the genes
encoding FMRP (Fragile X mental retardation protein), Mecp2
(gene mutated in Rett syndrome119), Shank3, neurexin, neuro-
ligin, and others.120–123 There are also mice generated to have
deletion or duplication of chromosomal regions frequently
associated with autism, including deletion or duplication
at 16p11.2,124–126 or duplication at 15q11.2–13.1127–130 or at
22q11.21.131 Although these genes and regions have a high
degree of homology at the sequence level, their alteration does
not always lead to analogous behavioral changes. For the
FMRP KO mouse, only subtle behavioral changes from wild
type animals are observed, which, interestingly, respond
to pharmacologic intervention (by blocking one of the
metabotropic glutamate receptors (mGluR5)) with behavioral
improvement.132,133 This success in an animal model led to the
development and testing of MGluR antagonists in multiple
human trials, unfortunately none of which were successful,
underscoring the challenges of translating animal work to
patients.134 Additionally, a recent paper that identified a patient
with ASD who had a point mutation in the FMR1 gene pointed
to a previously unappreciated mechanism of signaling through
the BK potassium channels in presynaptic function for FMR1
(http://www.pnas.org.ucsf.idm.oclc.org/content/112/4/949
.long).134a Moreover, further investigation demonstrated a
more complex understanding of abnormal signaling through
mGluR5 than originally anticipated.135
This lack of connection between human and murine
models is also evident for a number of the CNVs disorders
that have recently been identified as causative in ASD in
patients.136,137 In particular, mice harboring the 593 kb dele-
tion at 16p11.2 or the common duplication at 15q11.2–13.1
do not mimic the behavioral phenotypes in patients. For
example, whereas patients who carry the 600 kb deletion at
16p11.2 often have language deficits, ASD, and minimal repet-
itive or self-stimulatory behavior,138,139 two mouse models do
not show social deficits in either juvenile reciprocal tests or
the three chamber social approach paradigm, but do have
significant problems with self-stimulatory behavior.124–126 This
could be a result of a failure of either construct or face validity,
or simply the recognition that genes in mice do not necessarily
function in the same manner as do the homologs in humans.
Whereas 16p11.2 patient deletion carriers are often macroce-
phalic,138,139 the brains of two mouse models are smaller
than their wild-type littermates. These complexities under-
score that rodent models of ASD—even those that have con-
struct validity—are unlikely to replicate all aspects of human
disease, not only in models of developmental disorders, but
in similar challenges with neurodegenerative disorders such
as Alzheimer disease.140
Mouse models have also been studied because of their
potential face validity to ASD. Thus mice can show deficits
in reciprocal social interactions, in social approach, in the
receipt or generation of communication (ultrasonic vocal-
izations) and in the presence of self-stimulatory or repeti-
tive behaviors. One mouse strain, BTBR, has been the most
e1110 PART VII  Neurodevelopmental Disorders
studied of these strains, and a recent investigation pointed
to a complex genetic architecture that may be analogous to
many patients who do not have single gene disorders.141,142
Interestingly, this strain has responded to a number of phar-
macologic interventions that have been considered or tried for
treatment in patients, including mGluR5 antagonists, AMPAk-
ines and Arbaclofen.143–146 These pharmacologic interventions
have been hypothesized to work for Fragile X patients and,
by extension, possibly idiopathic ASD patients but have not
met with success in the clinic.147 In contrast, treatment with
intranasal oxytocin, which has been shown to be effective in
short trials in ASD patients and healthy adult volunteers,148
did not significantly improve social behavior in the BTBR
mouse model.149 These findings of variable response of drugs
between humans and mice provide a cautionary tale for the
heavy reliance on rodent models. Moreover, it is important to
remember that any single inbred animal strain is the equiva-
lent of a single patient in a clinical trial in the sense that there
is one genetic architecture that is present in the entire cohort
tested. A more meaningful analog to a genetically diverse
human population would be the testing of an outbred rodent
strain. Thus rats treated with pharmacologic interventions are
typically outbred, and therefore it is not surprising to observe
that oxytocin is able to enhance social behavior in this animal
model.150
Although outbred animals will have a range of behaviors
and would make observing improvements more challenging,
another reliable method for studying ASD related behaviors
and interventions would be through environmental exposures
that place animals (and patients) at risk for developing ASD.
For example, there is a well-studied ASD-related animal model
that results from in utero exposure of rats to valproic acid.
This phenomenon, valproate embryopathy in humans, is a
well-known risk factor for autism.151,152 Treatment of pregnant
rats results in a number of social deficits in the offspring with
face validity to ASD.153,154 Moreover, this model is also avail-
able for investigation of molecular mechanisms of which a
number have been posited from the available data. These
include a global change in the range and timing of mRNA
translation, as VPA is a known histone deacetylase (HDAC)
inhibitor. This can lead to changes in mRNA levels of key
signaling proteins such as PI3K and AKT that are implicated
in ASD in humans. Moreover, a Nissl staining experiment
revealed an increase in apoptosis early in CNS development
(E12.5), which has also been posited as a mechanism for
causing ASD in patients.
In addition to rodent models of ASD, there is now evidence
that nonhuman primates, principally rhesus macaques, may
be useful for study of the biology of ASD. In one model,
macaques that have been exposed to maternal antibodies that
are increased in the moms of patients at risk for ASD go on
to display behaviors found in ASD, including a reliance on
social interactions with familiar versus strange peers and inap-
propriate social approach for these novel peers.155 These
monkeys also have changes in behavior that responds to intra-
nasal oxytocin treatment, and there are autonomic changes in
response to social versus nonsocial visual cues that parallel
findings in humans.156,157 These animals have a much more
similar genetic architecture and recent technical advances will
make it possible to raise transgenic monkeys that have genetic
variants known to be associated with ASD in patients. Still
untested, this approach may provide better models for drug
development.
Neuropathology in ASD
The underlying genetic complexity and the corresponding
mechanistic diversity have made study of ASD neuropathology
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challenging. With that complexity in mind, there have been
some brain regions that have been frequently implicated in
ASD pathogenesis: the superior temporal sulcus, the amyg-
dala, the fusiform gyrus, the dorsolateral prefrontal cortex, and
the cerebellum.158–160 There are caveats to the available data.
Most autism neuropathology studies are limited to fewer than
10 cases, many of the patients are in their twenties or thirties
when they die and many of the patients with autism also have
intellectual disability.161 Moreover, all of these studies were
done before the advent of whole exome or whole genome
sequencing, or other complementary genome-wide methods
such as chromosome microarrays or RNASeq. Thus a detailed
understanding of the associated “molecular” pathology that
accompanies the anatomic findings is often lacking. With
these caveats in mind, postmortem histopathological studies
have shown some clear differences between ASD and matched
controls. More than one series has shown examples of cortical
dysgenesis, with ectopic gray and white matter162 and evidence
of abnormal lamination (see later in this chapter). Cortical
minicolumns have been demonstrated to be more numerous
and more narrow in ASD brains, and there have been reports
of higher spine densities in pyramidal neurons in the prefron-
tal cortex and in the middle temporal gyrus.162 This increase
in spine density is in concordance to what is seen in Fragile
X syndrome,163 as well as Down syndrome,164 suggesting that
this feature is a common morphologic change to many neu-
rodevelopmental disorders.
New Insights
There are a limited number of good pathology specimens
for autism, and this has implications on the research com-
munity’s ability to study the pathology seen in autism and
to understand how that may be linked to different causes of
ASD. Two recent papers have worked with a small subset of
ASD brains. One group examined the prefrontal and tempo-
ral regions, observing broad-based but patchy disruptions in
cortical lamination.165 This appears to affect neurons and not
glia but is not restricted to a particular cortical layer. Another
group examined the intersection of RNA expression patterns
of ASD genes (or related gene clusters), looking for conver-
gence in developmental time, brain region, and cell types.166
This approach highlighted the involvement of a midfetal ges-
tational period in layer 5/6 cortical projection neurons. These
projection neurons are central to connecting cortical regions,
and thus this work coincides with the disruptions of long-
distance cortical connections seen in ASD, as measured by
functional or structural imaging (see later in this chapter).
These two studies and others highlight the need for more
comprehensive brain banks, particularly coupled with genetic
information, to move the field forward to understand the
details of changes in autism neuroanatomy. One such effort is
the Autism Brain Net (www.autismbrainnet.com), which is a
privately sponsored foundation. Similarly, the National Insti-
tutes of Health (NIH) maintains a tissue bank for many neu-
rologic disorders, including autism (neurobiobank.nih.gov).
Neurotransmitters and ASD
There have been reports of a number of neurotransmitter
abnormalities in the CNS in autism. A comprehensive study
of eight neurotransmitter receptors in the hippocampus dem-
onstrated a reduction in the GABA-ergic system.167 Further
work has implicated the serotonin system as central to ASD
pathology, showing, for example, disruption of the 5HT2a
receptor binding throughout the cingulate cortex in adults
with ASD.167 Serotonin levels in blood platelets also have been
shown to reflect ASD status.168,169 In addition, genetic changes

in the serotonin system have also been reported in association
with ASD pathology.170–172
Neuroimaging in ASD
Just as the neuropathology of ASD suffers from etiologic
heterogeneity, so do the imaging findings in ASD. For example,
there are a large number of studies that show either a
decrease173,174 or an increase173,175 globally in the cortical white
matter volume or white matter microstructure in ASD.
However, to underscore the complexity, a recent paper dem-
onstrated that the diffusion imaging changes seen in ASD
patients compared with healthy population controls were
also seen in their apparently unaffected siblings.176 This is
also true with volumetric studies. A recent volumetric study
examined regions of the brain involved in memory (hippo-
campus, amygdala, parahippocampal gyrus, and entorhinal
cortex). There was no group difference, but there was a nega-
tive correlation with performance: the larger the size of the
amygdala, the more impaired the ASD patient was on tasks
of memory.177
Another approach to studying brain imaging in ASD can be
through MRI scans of patients with specific genetic or “syn-
dromic” diagnoses. This can help to identify unexpected find-
ings; for example, patients with Williams syndrome have an
elevation in fractional anisotropy in lateral tracks associated
with language.178 This structural analysis when comparing
Fragile X patients to ASD and controls yielded a similar finding,
in that many of the ASD findings, although discordant com-
pared with controls, were also different than compared with a
cohort of idiopathic ASD.178 Similarly, investigation of patients
who are carriers of the chromosomal deletion at 16p11.2 had
elevated fractional anisotropy, which is not typically seen in
patients with idiopathic ASD.179 In contrast, patients who had
duplication at this same locus had a decrease in fractional
anisotropy using tools that measure globally across the white
matter (tract-based spatial statistics: TBSS). This reciprocal rela-
tionship of elevated and decreased FA in the brains of deletion
and duplication carriers respectively is also evident for the
volume of the white matter, and globally for brain volume in
the 16p11.2 deletion and duplication patients.180 These recip-
rocal findings also shed light on the challenge of brain imaging
studies with idiopathic ASD cohorts. Because both the deletion
and duplication carriers can have ASD,138,139 and both can have
opposing imaging findings, imaging assessments of mixed
idiopathic ASD groups could therefore result in different or no
significant results, depending on the type of genetics that
underlie the ASD patients in any given cohort. This then sug-
gests that future imaging and other phenotyping for ASD,
whether this focuses on biochemical measures or clinical out-
comes, should start from a cohort of ASD patients who have
similar or identical etiologies.
Genetics of ASD
Perhaps the most significant advance in autism biology over
the last decade has been in understanding the genetics of
autism. Although genetic syndromes associated with ASD have
been part of our understanding of the disorder for decades
(e.g., Fragile X, Rett syndrome, Tuberous Sclerosis181–184), the
recent use of powerful genome-wide tools on large cohorts of
apparently nonsyndromic ASD patients has shown just how
powerful this approach can be for finding new genes and
confirming already identified causes of ASD. This approach
has focused initially on de novo genetic events, with new
statistical approaches making inroads into the understanding
of the contribution that inherited genetic changes make to
causing ASD.185
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Autistic Spectrum Disorders e1111
The first large cohort publications examined the risk of ASD
caused by chromosomal copy number variants, principally 57
those that were large, gene rich, and de novo.186 Two of these
studies examined the Autism Genetic Research Exchange
(AGRE; http://agre.autismspeaks.org) cohort, finding that
deletion or duplication of a recurrent 593 kb locus at 16p11.2
was strongly associated with autism.187,188 Interestingly, the
duplication but not the deletion was also associated with
schizophrenia.189 A subsequent study with a cohort of nearly
3000 families confirmed two previously identified loci at
16p11.2 (deletion or duplication) and 15q11.2–13.1 (duplica-
tion), but also identified the reciprocal duplication to the
previously known deletion for Williams syndrome at 7q11.23
as another new locus linked to ASD.190 Other known loci such
as 22q11.21 were also enriched in the ASD cohort, but locus
heterogeneity was considerable, such that many loci that have
since been identified as clinically significant only showed up
in one or two probands in these still large ASD cohorts.191
In these examples, the patients with ASD did not have
physical features that would allow these genetic disorders to
be classified as syndromes and had thus evaded detection by
clinical dysmorphologists. Instead, these carriers of chromo-
some copy number variants (CNVs) were identified through
the use of the newly available genome-wide SNP or oligonu-
cleotide microarrays. These initially identified chromosomal
loci continue to be commonly found in other ASD or neuro-
developmental disorder (NDD) cohorts, and many new loci
continue to be discovered.136,137 One of the other findings that
was evident in both CNVs and in later single nucleotide vari-
ants (SNV; see later in this chapter) was that these variants can
often be found enriched in the more broadly defined neuro-
developmental disorders and not exclusively in ASD.192–194
Thus the genetics of ASD lends support to the hypothesis that
ASD is not a biological entity unto itself, but rather a constel-
lation of symptoms that can occur together in such a way as
to be consistent with a clinical diagnosis.193,195,196 Moreover,
other neurodevelopmental disorders like intellectual disabil-
ity, epilepsy, and global developmental delay can also occur
in patients who carry these same CNVs, exemplifying
the difficulty linking a particular genetic locus to a particular
clinical outcome.
Another aspect of understanding the consequences of these
CNVs relates to their frequency in the general population.
When these CNVs were first identified, if their frequency in
both the patient and control cohorts was low, it was difficult
to ascribe pathogenicity to many of these variants, and clinical
labs reported them as “variants of uncertain significance”
(VUS). However, as more controls and patients underwent
testing on these chromosomal microarray platforms, it was
easier to obtain more accurate frequency estimates for these
CNVs in patient and in control cohorts and thus ascribe rela-
tive pathogenicity. Thus a recent study that combined data
from 29,085 children with developmental delay and 19,584
healthy controls demonstrated the clinical significance of
dozens of new loci, some of which were only seen in patients,
yet not seen in the nearly 20,000 controls tested (e.g., the 1p36
deletion syndrome, seen in 76 patients and 0 controls). In
contrast for some loci, such as the 1q21.1 deletion and its
reciprocal duplication, the CNVs were present in 68 cases, 6
controls and 48 cases, 5 controls, respectively. For CNVs that
are private (occurring uniquely in the patient or family), there
are criteria that aid in the interpretation of the likely pathoge-
nicity of that CNVs. Thus guidelines from a consensus state-
ment from the American College of the Medical Genetics and
the International Standard Cytogenomic Array (ISCA) consor-
tium suggest that inheritance from an affected parent or a de
novo variant that is gene rich and greater than 1Mb would
increase the likely pathogenicity of that variant.186 Clinical
e1112 PART VII  Neurodevelopmental Disorders
testing with this accumulated information identifies a patho-
genic CNVs in ASD patients in approximately 10% to 15% of
unselected patient cohorts.191,197–199 Thus chromosome micro-
arrays (or any platform that reliably detects chromosomal copy
number variants) are a first-line test for determining the cause
of autism in affected patient cohorts. Combining the number
of individuals who have causative chromosomal variants with
those who have previously identified syndromic disorders
explains the cause in less than 20% of patients. However, the
recent introduction of whole exome sequencing has changed
the efficiency of this diagnostic approach considerably.
With advances in next generation sequencing, it is now
feasible to use these new approaches to sequence the 30 to
60 million base pairs (Mbp) that comprise all the exons
and highly conserved regions adjacent to genes (promoters,
enhancers). These genic regions are “captured” by binding to
oligonucleotide probes that are linked via avidin-biotin
binding to sepharose beads. These fragments of genomic DNA
are then subjected to deep sequencing (greater than 50 times)
to reliably call the majority of base pairs and associated vari-
ants and mutations in any given exome. By not sequencing
the rest of the genome, the costs per exome can remain low
enough to be practical. At the time of writing this chapter,
sequencing the exomes of a patient and both parents in a
research laboratory would require approximately $1500 in
laboratory supplies and labor, without informatics analysis.
The current cost of whole genome sequencing in a similar
research setting for the trio would be approximately $4500,
also without informatics analysis. However, at the rate that
sequencing costs are currently declining, whole genome
sequencing (WGS) will soon be the preferred approach.
In addition to CNVs, there is now substantial evidence that
single nucleotide variants (SNV) play a key role in ASD. It is
now possible in both a research and clinical setting to use
whole exome sequencing in ASD patients to diagnose more
than 20% of cases.200 This approach of deep sequencing of
ASD cohorts (as well as candidate gene sequencing of larger
numbers of patients) has identified dozens of new genes that
are linked to ASD, using the conservative genome-wide statis-
tical thresholds. As with the discovery of CNVs, the list of these
genes will continue to grow. Currently, the website, https://
gene.sfari.org/autdb/Welcome.do, houses genes, CNVs, and
the supporting data linking these genetic changes to ASD. The
frequency of the most common CNVs in an ASD cohort is
approximately 0.5% to 1%, for 16p11.2 and 15q11.2–q13.1.
For SNVs, (e.g., mutations in genes CHD8, 0.3%; CHD2,
0.2%; ANK2, 0.2%; ARID1B, 0.2%) the rate of de novo muta-
tions is lower, with the most commonly affected genes in the
initial exome sequencing cohorts lower than the rate of the
most recurrent CNVs, such as 16p11.2 deletion/duplication.
The Simons Foundation Autism Research Initiative (SFARI)
website lists 706 genes associated with ASD, with varying
levels of evidence supporting this link. But there are only 28
genes with the two highest levels of supporting evidence. This
lack of association will change as further exome sequencing
in large patient cohorts is added.
CNVs and SNVs may be principally implicated in ASD
because the genetic mutation is de novo, not present in either
parent, or likely occurring in the paternal or maternal
zygotes.201 However, there has been substantial evidence
linking ASD to a pattern of familial inheritance. Thus there is
a significant inherited component to ASD that is not addressed
in these molecular analyses that identify highly penetrant
single gene de novo mutations. Two recent large scale epide-
miologic studies in Sweden and in the United Kingdom give
a better sense of the heritability of ASD in large population
cohorts, with heritability ranging from 55% to 90%.202,203
Additionally, parallel ongoing studies confirm that inheritance
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of common less penetrant mutations plays a key role in ASD
biology and that by combining findings from both inherited
and de novo mutations, a model can best be assembled of
ASD etiology and pathogenesis.141,185,204
The genes implicated in ASD code for proteins involved a
range of basic functions for neurons and glia, including con-
duction of axon potentials, synapse function, WNT signaling,
and chromatin remodeling.205 There is enrichment for these
genes in the transcripts that are regulated by the protein FMRP
from Fragile X syndrome, and these genes are also seen as
causes of other disorders of intellectual disability.
SCREENING AND DIAGNOSTIC  
EVALUATION FOR ASD
ASDs can be reliably diagnosed in children in the second year
of life,206–208 and early intervention has proven to be clearly
beneficial.209,210 However, the average age at diagnosis in the
United States continues to be high (53 months, with a range
of 46 to 61 months).26 Parents often voice concerns to profes-
sionals long before a formal diagnosis is made. Herlihy and
associates found that the presence of an older child with
typical or, especially, atypical development was associated
with earlier concerns for the affected child.211
There is also clear evidence that age at diagnosis varies as
a function of ethnicity and socioeconomic status (SES).212,213
The mean age at diagnosis in Medicaid-eligible children was
considerably higher than the U.S. average at 64.9 months.214
In addition, Medicaid-eligible African American children were
2.6 times less likely than white children to receive an autism
diagnosis on their first specialty care visit, with ADHD being
the most common diagnosis offered.215 Referrals to child neu-
rologists may be for ADHD instead of ASD because of the
lower recognition of ASD symptoms in nonwhite children,
especially of lower SES.
In the 2010 ADDM cohort, ASD prevalence varied widely
based on race: 1 in 63 white children, 1 in 81 black children,
1 in 93 Hispanic children, 1 in 81 Asian or Pacific Islander
children, and 1 in 68 overall.26 The 1 in 93 prevalence rate for
Hispanic children actually represents a considerable narrow-
ing in the gap relative to white children over the past decade.216
Although a majority of polled primary care practitioners
(PCPs) offered some form of developmental screening, only
29% offered Spanish ASD screening, and only 10% offered
both Spanish general developmental and Spanish ASD screen-
ing217; in addition, PCPs reported more difficulty assessing
ASD risk in Latino children from Spanish-speaking families
than for white children. Therefore, many children, particularly
non-English–speaking families with low SES, are still not
receiving appropriate screenings, and therefore appropriate
referrals, at early ages. Not surprisingly, SES affects outcome
as well as age-at-diagnosis, with children with non-Hispanic,
white, well-educated mothers more likely to become high
functioning, whereas minority children with less-educated
mothers or intellectual disabilities were less likely to experi-
ence rapid gains.218
The CDC has developed a website to increase public and
professional awareness of autism and other neurodevelop-
mental disorders, called “Learn the Signs. Act Early” (http://
www.cdc.gov/ncbddd/actearly/). In addition to downloadable
materials for parents and early childhood professionals
about developmental milestones at different ages (in English,
Spanish, and additional languages), there are materials to
encourage providers to listen to parents’ concerns and to
encourage parents to be assertive in making sure that their
concerns are addressed. The CDC website offers downloadable
educational information and tools for physicians such as
screening instruments at http://www.cdc.gov/ncbddd/actearly/

hcp/index.html. There is also a developmental pediatric cur-
riculum to improve recognition of ASD that would also be
appropriate for child neurologists at http://www.cdc.gov/
ncbddd/actearly/act/class.html.
Screening and Diagnostic Instruments
Although all children with ASDs share core features, there is
great heterogeneity within this population. Some characteris-
tics, such as repetitive behavior, are more common at certain
ages and levels of cognitive functioning. This heterogeneity
poses challenges to recognition during typical well-child and
specialty appointments.
The Child Neurology Society and American Academy
of Neurology (AAN/CNS) published the initial Practice Param-
eter for the Screening and Diagnosis of Autism.219,220 A two-level
approach is recommended: Level 1 involves developmental
screening as part of routine well-child care, followed by an
ASD-specific screen; Level 2 involves formal diagnostic proce-
dures to determine whether the child has ASD, conducted by
an experienced clinician, and using information gleaned from
the medical history, neurologic evaluation, and psychological,
speech/language, and/or developmental testing.
The American Academy of Pediatrics (AAP) Council of
Children with Disabilities subsequently published a set of
guidelines221,222 on the identification and management, respec-
tively, of children with ASD; both were reaffirmed in 2010.
Risk factors that should call attention to the possibility of
ASD include having a sibling with ASD or whenever there
is parental, other caregiver, or pediatrician concern. This
publication provides a comprehensive listing of virtually
all available screening and diagnostic instruments, along
with available validation data221; it is also available on
the website at http://www.medicalhomeinfo.org/downloads/
pdfs/DPIPscreeningtoolgrid.pdf.
• “Red flags” for critical delays in social communication
development can be easily recognized or queried and
should engender prompt evaluation for an ASD (Box 57-2).
ASD screening tools are readily available and should be
used by child neurologists whenever a concern is raised
by a parent or professional about an infant’s or child’s
social communication development (Fig. 57-1). Many addi-
tional ASD screening and diagnostic instruments have
become available, which were recently reviewed by Charman
and Gotham,223 including:
• The Modified Checklist for Autism in Toddlers™ (M-
CHAT),224 a widely used parent-completed tool for ASD,
has been revised as the M-CHAT-R with Follow-Up Inter-
view™ (M-CHAT-R/F).225 There are now 20 questions
(down from 23 in the original version), and the use of
the follow-up interview (FUI) is now categorically recom-
mended for failing three to seven items:
• zero to two items missed means there no concerns.
• Three to seven items missed means a move to item-
specific FUI; if the score persists in this range, proceed
with referrals.
• Eight or more items missed means to proceed directly
to referrals.
The M-CHAT-R/F has been validated for use between 16
and 30 months of age,225 although the AAP recommends its
use to 48 months of age. It is freely available in English in a
digital version at https://m-chat.org/ where it is automatically
scored, or as a paper version available in over 20 additional
languages at http://www.mchatscreen.com/.
• The Communication and Symbolic Behavior Scales Devel-
opmental Profile™ (CSBS DP) and Infant-Toddler Checklist
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Autistic Spectrum Disorders e1113
BOX 57-2  Red Flags for Social Communication 57
Development
Prompt evaluation should occur for any of the following:
No vocalizations by 6 months
A parent should be able to have a reciprocal “conversation”
by this age, consisting of at least several volleys back and forth.
No polysyllabic consonant babbling by 12 months
At least some of these vocalizations should be directed at
someone with communicative intent.
No gestures by 12 months
The earliest gesture an infant learns is to raise his/her arms
to request to be picked up, usually once sitting independently.
Pointing should be with an isolated index finger, not the
whole hand, and should be used “to request” or “to show,” not
just pointing at pictures in a book or pointing to have an adult
label items.
Any use of hand-over-hand by the child (e.g., putting a
parent’s hand on the cabinet door where the cookies are kept
or using the parent’s hand to point at pictures in a book) is a
hallmark of ASD.
No spontaneous (not echoed) single words by 16
months other than mama or dada
Spontaneous words must be beyond those used to simply
label items and must be used by the child to communicate, to
request, to show, or to share.
No spontaneous (not echoed) phrases by 24 months or
sentences by 36 months
Spontaneous phrases and sentences must be used by the
child to communicate, to request, to show, or to share.
Any loss of social communication abilities, including
babbling, single words, phrases, response to name, social
engagement, or gestures
If a parent reports their infant has decreased or stopped any
social communication milestones, this is usually the hallmark of
the onset of regression.
(ITC) are designed as a broadband parent-completed screens
for social communication delays for children from ages 9
to 24 months.226 Pierce and associates used the ITC to rou-
tinely screen infants at the 12-month well-child checkup in
a large pediatric practice in San Diego and found a positive
predictive value of 75% for developmental disabilities
including ASD and language delay.227 The ITC manual with
scoring instructions can be purchased at http://products
.brookespublishing.com/Communication-and-Symbolic or
forms and scoring instructions are currently freely available
at http://www.autismalert.org/uploads/PDF/SCREENING-
D E V E L O P M E N TA L % 20 D E L AY % 20 & % 20 AU T I S M -
CCBS%20DP%20Infant-Toddler%20Checklist.pdf.
• The Social Communication Questionnaire (SCQ) was
developed to identify older, higher-functioning individuals
with ASD.228 It is a 40 item, parent-completed questionnaire
for children 4 years old and older. In a large sample of
children referred for possible ASD diagnoses, the instru-
ment performed well when differentiating ASDs from other
diagnoses. It also demonstrated good sensitivity and speci-
ficity in identifying ASD in school-age children with special
learning needs.229 The SCQ is available for purchase in
multiple languages at http://www.wpspublish.com/store/p/
2954/social-communication-questionnaire-scq.
• The Screening Tool for Autism in Two-Year-Olds (STAT) is
composed of interactive items administered by a clinician
to children 24 to 35 months old.230 It is designed for use by
community service providers who work with young chil-
dren in assessment or intervention settings and who have
e1114 PART VII  Neurodevelopmental Disorders

SCREEN FOR ASDS IF:

Sibling with ASD OR parental concern OR
MD/PCP concern OR other caregiver concern OR
any unusual aspects/behaviors noted or reported in child
e.g., any ‘ADHD’, echolalia, scripted speech, repetitive play, etc.

16 to 48 months1
2M-CHAT-R/F™

Fails Fails Fails

≥8 items 3-7 items 0-2 items

Do FUI on
PASS
failed items only

FUI Score FUI Score

fails 3-7 items fails 0-2 items

Perform ASD Diagnostic Evaluation

CARS-2, KADI, ADOS, etc.

Discuss Diagnostic Evaluation Reslts With Parents

Read A Clinician’s Guide To Providing Effective Feedback To
Families Affected By Autism from Autism Speaks and view videos

Give Referrals to Parents:

3For early 3For IEP Intake evaluation For For private

intervention school state definitive SLP, OT ± PT
<33 months district disability agency audiology & social skills
≥33 months ≥36 months or ABR evaluation and
therapy

Also Consider Giving Parents Some Initial Resources/Links:

• Autism Speaks 100-Day Kit for Young Children (<5 years) or for School-Aged Children (5-13
years).
• Rosenblatt et al. Autism Spectrum Disorders: What Every Parent Needs to Know. AAP; 2013.
• The Arc’s Autism Now Center for information resources, including the IEP process.
• The National Autism Association’s Big Red Safety Toolkit

1For 9-15 months, consider the CSBS DP Infant-Toddler Checklist™; for ages ≥4 years,
the Social Communication Questionnaire™
2Free download in multiple languages at: http://www.mchatscreen.com/
3If child does not qualify for EI or an IEP, refer to Head Start/Early Head Start, and re-refer to
ECI or ISD in 4-6 months
Figure 57-1.  Child Neurology “Road Map” for ASD Screening & Diagnosis. ( C o u r t e s y o f Pauline A. Filipek MD.)

experience with autism; online training is required to
administer the STAT. Preliminary results also suggest that
the tool is useful in identifying autism in at-risk toddlers
down to 14 months of age.231 The STAT is available for pur-
chase in English at http://stat.vueinnovations.com/licensing.
Diagnostic Instruments for ASD
The combined administration of the semistructured Autism
Diagnostic Observation Schedule™—second edition (ADOS-
2)232,233 and the Autism Diagnostic Interview™—revised (ADI-
R),31 a structured parent interview, are considered the gold
standard for the diagnosis of autism in research settings.
Although both have become commercially available for
clinical use, the procedures are time-consuming (average of 45
to 60 minutes for the ADOS-2 and 90 to 150 minutes plus for
the ADI-R) and costly, requiring a 2-day training workshop or
DVD-based Training Package each for clinical use; additional
training and rigorous validation by the authors is necessary
for use in research settings. Many clinical settings do use the
ADOS-2 independently of the ADI-R. Both instruments are
available for purchase (in many languages), and training/
workshop information are available at http://www.wpspublish
.com/app/.
• The ADOS-2232,233 is the revised semistructured, observa-
tional assessment that includes investigator-directed activi-
ties to evaluate communication, reciprocal social interaction,
play, stereotypic behavior, restricted interests, and other

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abnormal behaviors. Five modules are available, including
a new toddler module for children under 30 months of
age. Each of the other four modules corresponds to a devel-
opmental level, so the instrument can be used with indi-
viduals of all ages and all levels of functional impairment.
An algorithm is available to convert ADOS scores into a
severity metric, which facilitates comparison of scores across
modules and makes it useful to track changes in functioning
over time.234
• The ADI-R235 is a comprehensive structured interview
with a parent or caregiver that probes for symptoms of
autism in the spheres of social relatedness, communica-
tion, and ritualistic or perseverative behaviors. It asks about
current behavior and about behavior in early childhood,
when the classic symptoms of autism are most likely to be
observed.
There are several other diagnostic instruments available to
evaluate children and adults for ASD, and possibly more
suited for use in typical medical settings:
• The Childhood Autism Rating Scale (CARS™) is a widely
recognized diagnostic instrument for use by an experienced
clinician in children from age 2 years and takes 5 to 15
minutes to administer.236 A training video is available and
should be viewed before using the instrument. Psychomet-
ric properties are good to excellent.237 Chlebowski and asso-
ciates238 found that a cut-off score of 25.5 (lower than the
recommended cut-off of 30) reliably distinguished ASD
from other developmental disorders. The revised CARS-2
(second edition)239 now provides two testing versions:
1. Standard Version Rating Booklet (CARS-2-ST) equivalent
to the original CARS and for use in children between 2
to 6 years of age, or communication difficulties or lower
than average estimated IQ.
2. High-Functioning Version Rating Booklet (CARS-2-HF)
for assessing verbally fluent individuals, 6 years of age
and older, with IQ scores higher than 80.
Many have erroneously used the CARS as a parent checklist,
for which there is no validation data. It should only be admin-
istered by an experienced professional drawing on history,
parent reports, and direct observation of the child.
• The Gilliam Autism Rating Scale™—3rd edition (GARS-
3),240 for children aged 3 to 22 years, is a widely used infor-
mant (e.g., parent or teacher) rating scale designed to be
scored and interpreted by an experienced clinician, provid-
ing standard scores, percentile ranks, severity level, and
probability of autism; both its sensitivity and specificity are
reported at .97. The original edition of the GARS was noted
to be far less sensitive to ASD than the gold-standard ADOS/
ADI combination241 that was replicated in a larger indepen-
dent validation study.242 Therefore despite adequate sensi-
tivity and specificity reported by the publishers, the GARS
should be used with caution as a screening or diagnostic
tool for ASD.
There are additional screening/diagnostic instruments which
are being used mostly in educational settings, including the
Autism Spectrum Rating Scale (ASRS),243 the Autism Behavior
Checklist (ABC), part of the ASIEP-3 (Autism Screening Instru-
ment for Educational Planning, 3rd edition),244 and the Social
Responsiveness Scale (SRS).245
Speaking with Parents about a New   1. Evaluation for IDEA services:
Diagnosis of ASD
Many parents have known that “something is wrong” for a
considerable amount of time and may even come into the
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Autistic Spectrum Disorders e1115
evaluation with a chief complaint that “I think my child has
autism.” Other families come to the appointment with no 57
idea why they were referred to a specialist and may have never
heard of autism. Practitioners need to provide sufficient time
toward the end of the appointment to discuss their findings,
provide their recommendations, and answer any questions the
parents may have. Effective communication with the family
can provide support and empower them, improving their
ability to address their child’s needs. Autism Speaks has pub-
lished a manual that specifically addresses these issues, with
a checklist for the clinician at (https://www.autismspeaks
.org/sites/default/files/docs/sciencedocs/atn/delivering_
feedback_manual.pdf), and video clips to further demonstrate
appropriate ways to “break bad news” at (https://www
.autismspeaks.org/science/find-resources-programs/autism
-treatment-network/tools-you-can-use/atn-air-p-guide
-providing-feedback-families#videos).
Clinicians should consider incorporating the following
points during the evaluation and subsequent discussion/ feed-
back on diagnoses (adapted from Austin and associates “A
clinician’s guide to providing effective feedback to families
affected by autism”,246 pages 5–10):
• Families should be encouraged to ask questions, offer obser-
vations, and provide information at any time during the
evaluation. Parents and other caregivers should be explicitly
told that they are part of the evaluation team and shown
that their input is valued.247 They should have an under-
standing of why their child is being evaluated and how clini-
cians are attempting to assess their child’s skills.
• During the course of an evaluation, clinicians should
ascertain whether family members believe that behaviors
seen during the evaluation are typical for this child. If
additional work is needed to obtain a more representa-
tive picture of a child, attempts should be made to do so
(e.g., by scheduling an additional evaluation session, speak-
ing with other providers, or observing a child in another
setting (either through live observation or review of video
recordings).
• Clinicians always need to be aware of any safety issues and
address these in the feedback session, such as children
habitually running and darting from their parents when
they are out in the community.
• The evaluation process should be reviewed, particularly
detailing the child’s strengths noted during the assess-
ment. The diagnosis of ASD should be clearly stated, and
details of ASD should be offered, explaining the core
deficits of social communication and restricted, repetitive
behaviors.
• Prioritize the next steps for the family, providing them with
contact information to accomplish those steps. Discuss
ongoing support, including support from family members
as well as the contact information for external support
groups.
• End the session on a positive note, reminding the parents
about the child’s and family’s strengths.
Recommendations for a Child with Newly
Diagnosed ASD
All initial diagnostic evaluations resulting in a diagnosis of
ASD should provide the following four referrals at a minimum:
• Younger than 33 months of age (Part C): to the local
provider of Early Intervention (EI) services. Many states
have a centralized website that provides contact informa-
tion by zip code or city.
e1116 PART VII  Neurodevelopmental Disorders
• Thirty-three months of age and older (Part B): to the
local school district to perform a Full Individual Evalu-
ation (FIE) in order to prepare an Individualized Educa-
tion Plan (IEP). Parents must make the request for an
FIE in writing and should bring two copies of the request
to the local elementary school for signature by a school
official, keeping one copy for their records.
2. Definitive hearing evaluation, either audiology or auditory
brainstem responses.
3. Private speech, OT and/or PT evaluations, as indicated, to
be covered by insurance, including Medicaid. In most
states, EI cannot simultaneously perform the same thera-
pies that are provided by insurance and/or often provides
only a few hours per month of therapies, and school dis-
tricts often only provide very brief weekly therapy sessions
(e.g., 15 to 30 minutes). Therefore obtaining private thera-
pies in addition to other EI therapies or along with school
district therapies can improve the rate of progress of a child
on the spectrum.
4. For a child 36 months of age and older, refer the child for
an intake evaluation at the state’s agency for developmental
disabilities. Many states have a website to identify the
correct agency contact information.
Safety issues should also be addressed during the initial evalu-
ation. Wandering or elopement is a significant safety problem
in half of all children with ASD, with a substantial number at
risk for bodily harm, primarily from drowning or traffic inju-
ries.248,249 Nonverbal or minimally verbal children who wander
or elope should wear identification bracelets to assist first
responders in contacting their parents once found. In addi-
tion, many YMCA’s provide water safety classes for children
with special needs to minimize the significant rate of drown-
ing deaths occurring during elopement. The Standard Mortal-
ity Ratio for drowning in individuals of all ages with ASD
without intellectual impairment is 3.9 times the rate for the
general population, which increases to 13.7 for all levels of
intellectual disability.250
THE NEUROLOGIC EVALUATION IN AUTISM
The neurologic examination in ASD is usually relatively
benign, with the exception of several possible findings: large
head circumference (HC) or frank macrocephaly, somatic
overgrowth, motor abnormalities including hypotonia, dys-
praxia, stereotypies, gait disturbances,251 and/or self-injurious
behaviors (SIB).
Large HC and Somatic Overgrowth
Many reports have noted that the HC in children with ASD is
shifted upward, with the mean approximately at the 75th
percentile of the norm, with correspondingly increased whole
brain volume.252 This is presumed due to an accelerated growth
rate in infancy, as HC is normal by adolescence and adult-
hood,253 as is postmortem brain weight by adulthood.254
However, others are finding either HC within the normal
range and comparable to typical controls, or large but propor-
tional to somatic overgrowth.255–258 Differences across studies
are most likely not due to the use of different HC charts (e.g.,
Nellhaus,259 CDC,260 or Rollins, et al.261,262). Children with
ASD, particularly boys, are often taller and proportionately
heavier than typically developing children of the same age.
Chawarska and colleagues263 and Campbell and associates264
found that boys with autism were significantly longer by age
5 months, had a larger head circumference by 9 months, and
weighed more by age 11 months than typically developing
peers; those in the top 10% of overall physical size in infancy
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exhibited greater severity of social deficits and lower adaptive
functioning later in childhood.
Motor Disturbances in Tone, Gait, Praxis,
and Stereotypies
Hypotonia is common in children with ASD but not uniquely
so: it was observed in about 25% of 176 autistic children but
also in 33% of 110 nonautistic, developmentally delayed chil-
dren.265 Spasticity was found in less than 5% of either group
(exclusionary criteria for this sample included the presence of
lateralizing gross motor findings).15
Gait disturbances have also been reported in ASD, specifi-
cally abnormal cadence, and hip and ankle kinematics and
kinetics266; such disturbances may be more pronounced in
those with severe than with mild ASD symptoms.267 Longuet
and associates found that motor planning and programming
were relatively preserved in an emotionally positive situation
in a small cohort of school-aged children with ASD, which
were then abnormal when in an emotionally aversive setting.268
Shetreat-Klein and colleagues found that most of the 38
preschool-aged children had significantly greater joint mobil-
ity (p < 0.002), more gait abnormalities (p < 0.0001), and on
average walked 18 months later than same-aged peers.269
Nobile and associates were the first to obtain quantitative
automated motion analysis of gait in a small cohort of school-
aged children with ASD and noted a stiffer gait without the
typical fluidity, highly significant difficulties maintaining a
straight line, and marked loss of smoothness (increased jerk
index) consistent with dysfunction in both cortical and
frontal-cerebellar-thalamic-frontal networks.270
Motor dyspraxia, defined as impaired imitation of skilled
gestures,271 was identified in almost 30% of children with ASD
with normal cognitive function, in 75% of children with ASD
and intellectual disability (ID), and in 56% of a nonautistic,
ID control group.265 Mostofsky and associates found that ASD
is associated with a generalized praxis deficit, rather than a
specific deficit in imitation.271 Dyspraxia in ASD cannot be
accounted for solely by deficits in basic motor skills, as it
strongly correlates with the core social, communicative, and
behavioral impairments, as measured by the ADOS.272 Dys-
praxia appears to be specific to ASD273 and is associated with
impaired formation of spatial representations, implicating dis-
tributed abnormalities across parietal, premotor, and motor
circuitry, as well as anomalous connectivity.274 Miller and col-
leagues found that children with ASD also performed signifi-
cantly worse on tasks of ideational and buccofacial praxis, as
well as a broad range of motor tests, including measures of
simple motor skill, timing and accuracy of saccadic eye move-
ments and motor coordination, and tests of visual-motor inte-
gration, suggesting that both motor function and visual-motor
integration contribute to the dyspraxia seen in ASD.275
Comparison of motor stereotypies seen in ASD versus tics
was presented by Singer276:
The diagnosis of stereotypies requires the exclusion of other
disorders or causes, such as habits, mannerisms, complex
motor tics, obsessive-compulsive behaviors, and paroxysmal
dyskinesias. Most frequently, stereotypies are misdiagnosed as
complex motor tics. Several characteristics are helpful in
differentiating these two conditions, though both may occur in
the same individual. Stereotypies have an earlier age of onset
(younger than 3 years) than do tics (mean onset 5 to 7
years). They are consistent and fixed in their pattern,
compared with the frequent addition and subtraction of tics.
In terms of body location, stereotypies frequently involve arms,
hands, or the entire body, rather than the more common tic
locations of the eyes, face, head, and shoulders. Stereotypies

are more fixed, rhythmic, and prolonged in duration than tics,
which, except for the occasional dystonic tic, are brief, rapid,
random, and fluctuating. Stereotypies, in contrast to tics, are
not associated with premonitory urges, preceding sensations, or
an internal desire to perform. Both occur during periods of
anxiety, excitement, or fatigue, but stereotypic movements are
also common when the child is engrossed in an activity. Tics
and stereotypic movements are both reduced by distraction, but
the effect on stereotypic movements is more instantaneous and
dramatic.
Motor stereotypies, including hand or finger mannerisms,
body rocking, and unusual posturing are reported in 37% to
95% of individuals with ASD, and they often manifest during
the preschool years.265,277,278 There may be considerable overlap
in the repertoire of stereotypic movements that children with
typical development, ASD, or ID display, but they are more
prevalent in children with autism and most particularly those
with ASD and ID.276 Goldman and associates found no cor-
relation between MRI-based structural volumes of cortical or
subcortical structures thought to be particularly linked to the
pathophysiology of stereotypies (e.g., supplemental motor
cortex, anterior cingulate, basal ganglia, or diencephalon).252
Self-Injurious Behaviors (SIB)
Estimates of the occurrence of SIB range between 35% and
50% of individuals with ASD. Despite the variability in preva-
lence estimates, it is clear that SIB is at least two to three times
more common in children with autism than it is in children
with ID (typically estimated at 5% to 17%279). (See refer-
ences280,281 for reviews.) SIB is probably the most difficult
comorbid behavior to treat effectively in ASD. Although not
all SIB is sufficiently severe to be physically harmful to the
individual, severe head banging in a 24-year-old adult with
severe ASD has been reported to cause neuropathological
abnormalities consistent with the chronic traumatic encepha-
lopathy seen in boxers.280,282 Risk factors for developing SIB
include ID283–285; abnormal sensory processing, insistence on
sameness, and severity of social deficits283; a high frequency of
repetitive or ritualistic behaviors285,286; overall severity of autis-
tic symptomatology, adaptive skills, and language level284; and
level of impulsivity.285
Duerden and associates reported that SIB is related to
volumetric alterations in somatosensory cortical (right supe-
rior parietal lobule, bilateral somatosensory cortices) and sub-
cortical regions (left ventroposterior nucleus of the thalamus)
and their supporting white-matter pathways as measured
using MRI morphometry287; in addition, SIB was related to
anomalous fractional anisotropy and diffusivity values using
diffusion-tensor imaging analysis between the somatosensory
cortices and VP nuclei. Wolff and colleagues found a modest
association between left caudate volume and SIB, with a larger
association occurring between bilateral caudate volume and
repetitive compulsive behaviors.288
Clinical Testing
Definitive Evaluation of Hearing and Vision
Many children diagnosed with ASD are first described by
parents as acting “as if deaf.” However, most children with
autism have normal hearing function. Rosenhall and associ-
ates performed audiologic evaluations on 199 children and
adolescents with ASD and found that pronounced to pro-
found bilateral hearing loss or deafness was present in 3.5%
of all cases, a prevalence greater than that for the general
population but similar to the rate for individuals with ID, but
equivalent across all levels of cognitive functioning.289 In
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Autistic Spectrum Disorders e1117
contrast, hyperacusis was commonly found, affecting almost
20% of the ASD sample. Tharpe and colleagues found that, as 57
might be expected, behavioral responses of children with
autism were elevated and less reliable, relative to those of typi-
cally developing children.290 In addition, approximately half
of the children with ASD demonstrated abnormal behavioral
responses to tones (but not to speech sounds), despite having
normal to near-normal hearing sensitivity as determined by
other audiometric measures. Definitive audiologic evaluation
or brainstem auditory-evoked potential testing should be per-
formed in all children with autism so that, if indicated, appro-
priate referrals can be made for aural habilitation.291–295
Autistic symptomatology has also been associated with
congenital blindness (CB), with up to 30% of children with
CB also described as having ASD.296–298 Cass and associates
reported that, of an entire sample of over 600 congenitally
blind children of differing etiologies, only 17% were develop-
ing typically at age 16 months when first studied.296 Subse-
quently, 31% had a regression in their development occurring
between 16 and 27 months of age, which was associated with
disorders of central nervous system/optic nerve/retina; chil-
dren who did not regress had a purely optical cause for their
blindness (e.g., congenital cataracts or glaucoma). Differenti-
ating factors between those CB children with and without
autism included severity of blindness, cerebral palsy, and intel-
lectual level, with greater neurologic impairments and more
severe blindness in those with CB and autism.299 Williams and
colleagues recently provided preliminary evidence in support
of the clinical utility of the ADOS/ADOS-2 and the ADI-R in
the evaluation of children with severe vision impairment.300
The authors made four specific modifications to the ADOS
regarding: (1) free play, in which toys with interesting sounds
and textures were added to the standard ADOS toy set; (2) the
construction task, in which an inset shape puzzle was substi-
tuted for the standard puzzle; (3) the description of a picture,
in which a zoo scene with raised and textured pieces were
substituted for the standard picture; and (4) telling a story
from a book, in which a Braille children’s book was substi-
tuted for the standard book.
Lead Level
Children with developmental delay who spend an extended
period in the oral-motor stage of play (when everything “goes
into their mouths”) are at increased risk for lead toxicity,
especially in certain environments.301 The prevalence of pica
in this group can result in high rates of substantial and often
recurrent exposure to lead and other metals. All children with
developmental delay or who are at risk for autism should have
a periodic lead screen until the pica disappears.302,303
Electroencephalography
There is currently insufficient evidence to recommend routine
screening EEGs in autistic patients. Epileptiform EEG abnor-
malities have been reported in a high proportion of children
with ASD but do not typically correlate with clinical seizure
activity,304,305 even if performed for clinical staring episodes.306
Further empiric evidence is needed before any recommenda-
tions can be addressed (see section on epilepsy).
Neuroimaging Studies
Routine MRI studies to evaluate a child for autism are not
warranted unless there is evidence of lateralizing signs or
other critical symptomatology on neurologic examination.
There is a very low prevalence of focal lesions or other abnor-
malities in ASD, most of which are deemed coincidental find-
ings. PET and single-photon emission computed tomography
e1118 PART VII  Neurodevelopmental Disorders
(SPECT) are not indicated in the routine diagnostic evaluation
of ASD.291,292
Metabolic Testing
Metabolic screening is indicated only in the presence of
suggestive clinical and physical findings (e.g., lethargy, cyclic
vomiting, early seizures, dysmorphic or coarse features), ID,
questionable newborn screening, or birth outside of the
United States.291,292,307 See chapters 36, 51 and 52 for discus-
sions of genetic and metabolic testing.
Tests of Unproven Value
Unsupported claims have led a number of parents to seek to
perform various tests in the hope of finding a treatable cause
of autism. There currently remains inadequate evidence to
support routine clinical testing of undocumented value (e.g.,
trace elements in the hair, celiac antibodies, immunologic or
neurochemical abnormalities, micronutrients such as vitamin
levels, intestinal permeability, stool analysis, urinary peptides,
and so on).291,292
COEXISTENT MEDICAL CONDITIONS
Gastrointestinal Problems
Problem behaviors in patients with ASD may sometimes be a
symptom of underlying medical conditions, including gastro-
intestinal disorders. Feeding habits and food preferences of
children with autism typically are unconventional; however,
the majority of children do eat sufficiently to meet or exceed
dietary reference values.308 Children with ASD do have more
GI symptoms than comparison groups, with an overall odds
ratio of 4.42 (1.90 to 10.28), from a meta-analysis of 15
studies.309 Individuals with ASD should receive the same stan-
dard of care in the diagnostic workup and treatment of gastro-
intestinal concerns, as do patients without ASD (systematic
review310); in addition, an NIH consensus panel found that
available research data do not support the use of a casein-free
diet, a gluten-free diet, or combined gluten-free/casein-free
(GFCF) diet as a primary treatment for individuals with ASD,
despite anecdotal reports of some benefit.311,312
Sleep Disturbances
The majority of children with autism have sleep problems,
often severe, and usually involving extreme sleep latencies,
lengthy nighttime awakenings, shortened night sleep, and
early morning awakenings.313–317 Sleep duration in children
with ASD aged 30 months or older was shortened compared
with controls in the British ALSPAC study.318 Children with
autism also have more unusual and obligatory bedtime rou-
tines. These behaviors may lead to memory and learning
issues, maladaptive daytime behaviors, and parental stress.319
These may be particularly complex in individuals with low-
functioning autism.320
Sleep abnormalities persist throughout life. Adult autistic
individuals demonstrated a significant reduction of rapid-eye-
movement (REM) sleep, increased interspersed wakefulness,
and increased number of awakenings with reduction of sleep
efficiency, relative to normal controls.321
Epilepsy
Epilepsy occurs frequently in children with autism, and all
seizure types occur.322 The overall rate of epilepsy, even in
idiopathic cases of autism with normal IQ, is significantly
higher (13–17%)323–326 than the risk in the general population
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(1% to 2%). There is a bimodal distribution of age of onset,
with peaks occurring at younger than 5 years and during ado-
lescence,323,327 and with the rate of epilepsy increased among
those with intellectual disability or underlying medical condi-
tions. The prevalence of epilepsy was 21.5% in subjects with
ASD and ID compared with 8% in those with ASD and no
ID.328 The presence of cerebral palsy or focal motor findings
also increases risk.
Among children with infantile spasms, the rate of autism
is increased and those with bitemporal glucose hypometabo-
lism were likely to manifest autism with severe language
impairment and mental retardation.329,330 Some studies have
focused on the presence of subclinical epileptiform abnor-
malities.326,330–336 Kim and associates found epileptiform
abnormalities in the absence of electrographic and clinical
seizures in 19 of 32 children referred for prolonged video EEG
monitoring for possible seizure activity.336 Chez and col-
leagues noted epileptiform EEG abnormalities during sleep
in 61% of almost 900 children with ASD without a history
of epilepsy.333 Other studies, however, report much lower
rates,324,326,337 which may be due to differences in sample char-
acteristics and the use of routine EEGs versus prolonged video
monitoring. The high rates of isolated epileptiform abnor-
malities represent a possible objective physiologic finding in
ASD; treatment of these discharges in the absence of docu-
mented seizures is controversial, pending future well-designed
longitudinal studies.323
The focus of a NIH workshop on autism and epilepsy
was the commonality of possible mechanisms and how
we can learn about the pathophysiology of both conditions
when they occur together, for example, in disorders such as
Fragile X syndrome and Tuberous Sclerosis Complex (TSC).
Both abnormal synaptic plasticity and excitatory/inhibitory
imbalance can be contributing factors. Changes associated
with seizures and epileptogenesis may disrupt normal activity-
dependent developmental processes.338
Changes in functional connectivity determined by EEG are
being explored as a biomarker for early identification of ASD.
By 12 months of age, high risk infants later diagnosed with
ASD showed reduced functional connectivity compared with
those who were not later diagnosed.339 A study of 14-month-
old, high-risk infants showed strong correlation of EEG hyper-
connectivity with severity of restricted and repetitive behaviors
at age 3 years.340 EEG spectral coherence from 2- to 12-year-
olds was different in ASD and control subjects341; another
study of spectral power over 6 months to 24 months showed
that high risk infants had lower spectral power and patterns
of change were different from controls.342
Seizures in children with autism should be treated as they
would be in children without autism, with even more atten-
tion than usual paid to the possible behavioral and cognitive
side effects of antiseizure drugs. Repetitive and stereotypic
behaviors could conceivably mimic temporal lobe seizures,
and inattention from absence seizures may be construed as
abnormal, autistic behavior.
PHARMACOLOGIC THERAPY
The goal of pharmacologic treatment for children with autism
is to improve symptoms and specific behaviors (Table 57-2).
Target symptoms include anxiety, repetitive motor behaviors,
obsessive-compulsive symptoms, impulsivity, depression,
mood swings, agitation, hyperactivity, aggression, and self-
injurious behavior. Although medications do not directly
influence cognitive impairment, controlling these symptoms
should allow the child to maximize benefit from educational
and behavioral treatments that are directed toward the core
impairments. The rate of psychotropic medication use in the
 Autistic Spectrum Disorders e1119

TABLE 57-2  Medications Used to Decrease Specific Symptoms Associated with Autism Spectrum Disorder*
57
Drug Dose Age† N Efficacy Side Effects Reference
Neuroleptic Agents
Risperidone 0.25–2.5 mg/d <20 kg 5–17 101 Decreased tantrums, Weight gain; increased 349
0.5–2.5 mg/d 20–45 kg aggression, self-injury, appetite; transient
0.5–3.5 mg/d >45 kg hyperactivity sedation
Mean = 2.4 mg/d
Risperidone 1.2–2.9 mg/d child 8–56 36 Decreased irritability, Increased appetite; weight 351
Mean = 2.0 mg/d hyperactivity gain; sedation
2.4–5.3 mg/d adult
Mean = 3.6 mg/d
Risperidone .125–.175 vs. 1.25–1.75 5–17 96 Higher dose improves global Somnolence sedation 353
vs. placebo function and irritability increased appetite
Risperidone 0.01–0.06 mg/kg/d 5–12 79 Decreased irritability, Weight gain; transient 352
Mean = 1.17 mg/d hyperactivity, noncompliance, somnolence; mildly
conduct problems increased heart rate and
blood pressure
Risperidone 0.5–1.5 mg/d 2.5–6 24 Minimal improvement in global Weight gain; increased 354
Mean = 1.14 mg/d autism severity scores prolactin levels
Risperidone 1.0–10.0 mg/d 18–43 n =? Reduced repetitive behavior, Transient sedation 467
aggression, self-injury,
property destruction
Aripiprazole 5 mg/d, 10 mg/d, or 6–17 218 Reduced irritability, Sedation, EPS, weight gain 355
15 mg/d hyperactivity, stereotypy at all
doses
Aripiprazole 2–15 mg/d 6–17 98 Reduced irritability, Decreased prolactin level, 464
hyperactivity, stereotypy, weight gain, EPS
inappropriate speech; global
improvement
Aripiprazole 2–15 mg/d Continuation 6–17 85 No difference in time to relapse 465
active tx vs. placebo
Opiate Antagonists
Naltrexone 1.0 mg/kg/d 3–8 41 No improvement over placebo None greater than placebo 362
in behavior and learning;
improved hyperactivity
Naltrexone 1.0 mg/kg/d 2 weeks 3–8 24 No improvement in Transient sedation 361
only communication skills
Naltrexone 40 mg/d 3–7 23 Decreased hyperactivity, Not reported 466
Single dose improved attention
Naltrexone 1 mg/kg /dose 3–7 23 Decreased hyperactivity and No side effects 468
improved attention by
teacher, but not parent,
report
Serotonin Reuptake Inhibitors
Fluvoxamine Mean dose = 18–53 n = 30 Reduced repetitive thoughts Transient nausea and 370
276.7 mg/d and behavior, and sedation
aggression; improved social
communication
Buspirone 2.5 mg or 2–6 166 Improvement in repetitive 374
5 mg /d behaviors not total ADOS
Clomipramine 5–10 mg/d 8–17 34 No improvement executive fcn Diarrhea, headache, fatigue 399
Fluoxetine 4.8–20 mg/d 5–17 39 Modest reduction in repetitive Agitation requiring dose 372
Mean = 10.6 mg/d; behaviors, but no reduction
0.38 mg/kg/d improvement in global
functioning
Citalopram 2.5–20 mg/d 5–17 149 No improvement in repetitive Increased energy, 373
Mean = 16.5 mg/d behavior or global functioning inattention, impulsivity,
hyperactivity, stereotypy,
diarrhea, insomnia, dry
skin
Stimulants
Methylphenidate 0.125, 0.25, or 0.5 t.i.d. 5–14 72 Reduced inattention, Irritability, decreased 371
mg/kg /day distractibility, hyperactivity, appetite, difficulty falling
and impulsivity asleep, emotional
outbursts
Methylphenedate .25, .5 mg/kg/dose 5–13 33 Positive efforts on social None discussed 469
behavior
Methylphenedate 10–40 LA AM, 7–13 24 Decreased hyperactive and Loss of appetite, insomnia 33
2.5-10 mg afternoon impulsive behavior
Atomoxetine 20–100 mg/d 5–15 16 Reduced hyperactivity, Transient nausea and 374
Mean = 44.2 mg/d impulsivity, social withdrawal fatigue

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e1120 PART VII  Neurodevelopmental Disorders
TABLE 57-2  Medications Used to Decrease Specific Symptoms Associated with Autism Spectrum Disorder* (Continued)
Drug Dose Age†
Antiseizure Drugs
Lamotrigine Mean = 5.0 mg/kg/d 3–11
Levetiracetam 20–30 mg/kg/d 5–17
Divalproex 500–1500 mg/d 5–17
sodium
Divalproex 125 mg QD titrated up 5–17
sodium to 500 bid
Bumetanide .5mg bid 3–11
*Includes only double-blind, randomized, placebo-controlled trials.
†
Age in years.
EPS, Extrapyramidal symptoms.
2853 children enrolled in the Autism Treatment Network343
was 27%. Use was much less common in children age 5 and
under and was associated with GI symptoms and sleep prob-
lems. In children with comorbid diagnoses of ADHD, bipolar
disorder, OCD, depression, or anxiety, use was 82%, com-
pared with 16% in those children with no psychiatric
comorbidity.
Dosing should start with low amounts and be slowly esca-
lated with careful attention to possible side effects, the most
common of which is activation, defined as overactivity, agita-
tion, or emotional lability. Weight gain and metabolic changes
are common side effects of neuroleptics,344 and the long-term
consequences are of particular concern in children, as they
may require treatment for an extended time. Target symptoms
should be clearly defined, and new drugs should be tried for
a sufficient length of time to determine their usefulness. Seda-
tion in response to pharmacotherapy may be mistaken for a
positive response.345 Drug treatment should be one facet of a
comprehensive, multidisciplinary treatment approach that
includes structured special educational techniques, language
or communication interventions, behavior modification, and
parent training.
Neuroleptic Agents
Neuroleptics that block dopamine receptors, such as haloperi-
dol, thioridazine, and trifluoperazine, were used until the
development of drugs that were more effective in blocking
serotonin receptors. Haloperidol decreased motor stereoty-
pies, hyperactivity, withdrawal, and negativism in children
with autism,346 but use is limited by the risk of extrapyramidal
symptoms.347
Risperidone and aripiprazole are the only two medications
approved by the Federal Drug Administration (FDA) for
the treatment of irritability (including aggression, self-
injurious behavior, temper tantrums, and mood swings) in
school-age children and adolescents with autistic disorder.
However, these agents have been associated with weight gain,
prolactin increases, hyperglycemia, and sedation in some
patients.348
In an 8-week, multisite, double-blind, randomized trial of
risperidone in 101 children with ASD,349 a relatively low dose
of 0.5 to 3.5 mg/d improved irritability, hyperactivity, and
stereotypies. Treatment effects were maintained over 16 weeks
of treatment, and discontinuation of the medication resulted
in return of behavioral symptoms.350 Side effects included
weight gain that averaged 6 pounds over 8 weeks and mild to
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N Efficacy Side Effects Reference
28 No improvement greater than Aggression, insomnia, 390
placebo in disruptive behavior echolalia
and autism symptoms
20 No improvement in disruptive Aggression, agitation 391
behavior or irritability
13 Reduction in compulsive-type Irritability, weight gain, 392
repetitive behavior aggression
27 Reduction in irritability Irritability 393
60 Improved autistic behaviors and Diarrhea, increased 393
global function irritability
moderate fatigue in about half of the children. There was a
very low incidence of acute extrapyramidal symptoms. These
results have been replicated in children351,352 and adults.351 In
a study of 96 children, a dose of 1.25 to 1.75mg/day improved
irritability but a lower dose did not.353 Luby and associates
conducted a small trial of risperidone with 24 younger chil-
dren (ages 2.5 to 6) with ASD.354 There was a modest but
statistically significant improvement on a global autism rating
scale compared with the placebo group after 6 months. Sig-
nificantly greater weight gain and elevated prolactin levels
were observed in the treatment group. An 8-week, double-
blind, randomized, placebo-controlled trial with aripiprazole
in 218 children and adolescents with autistic disorder com-
pared three doses of the drug (5, 10, or 15 mg/d) to placebo.355
All doses demonstrated improvement in irritability, although
only the 5 mg/day group reached statistical significance, pos-
sibly due to a high placebo response (35%). Improvement was
reported within 2 weeks, at a point at which all participants
were taking the lowest dose. About 10% of the participants
withdrew from the study because of adverse effects, most com-
monly sedation. Extrapyramidal symptoms were reported in
23.1% of the treatment group, compared with 11.8% in the
placebo group, and more subjects in the treatment groups
received medication to treat these symptoms. Aripiprazole was
associated with a higher incidence of weight gain than placebo,
although no participants discontinued treatment for this
reason. A relapse prevention trial with similar doses did not
find any difference between aripiprazole and placebo in time
to relapse.348 Other atypical neuroleptics studied with similar
results include olanzapine and ziprasidone, although they
were assessed only in open trials357 or with a very small
number of participants.358
Concern about side effects has led to some comparison
studies. Miral and associates compared haloperidol and ris-
peridone in 30 children and adolescents with autistic disor-
der.359 Both agents were effective in reducing tantrums,
aggression, and self-injury. Risperidone was slightly superior
to haloperidol in improving disruptive behavior. There was a
significant worsening of extrapyramidal symptoms reported in
the group treated with haloperidol. Similar levels of weight
gain occurred in each group, and there was a greater increase
in prolactin in individuals taking risperidone. Remington and
colleagues compared haloperidol to the serotonin reuptake
inhibitor, clomipramine, in 36 children and adults (ages 10 to
36 years) with ASD.360 Haloperidol was superior to clomip-
ramine in reducing irritability and hyperactivity. Neither med-
ication was superior to placebo in reducing stereotypies or

inappropriate speech. There was a higher dropout rate in the
clomipramine group due to side effects, particularly behav-
ioral activation. No randomized studies have evaluated any of
the newer neuroleptics such as paliperidone, iloperidone ase-
napine, or lurasidone.
Opiate Antagonists
Several published trials evaluated naltrexone, a long-acting
opiate antagonist that can be taken orally. The hypothesis for
benefit is that autism is associated with hypersecretion of
brain opioids, including beta-endorphins, and that many
symptoms of autism are similar to those induced by opiate
administration, such as decreased socialization, repetitive ste-
reotypic movements, and motor hyperactivity.361 Naltrexone
in doses of 1.0 mg/kg daily in 23 autistic children decreased
restlessness and hyperactivity362 in a parallel study design. Side
effects were mild gastrointestinal symptoms, appetite decrease,
and drowsiness. In a randomized, double-blind, crossover
design, naltrexone was associated with modest improvement
of behavior in 11 of 24 children, but no improvement in learn-
ing occurred.363
Serotonin Reuptake Inhibitors
Symptoms causing major disruption in autism, such as anxiety
and repetitive and ritualized behaviors, can impair learning.
Because of the efficacy of serotonin reuptake inhibitors (e.g.,
clomipramine, fluoxetine, sertraline, fluvoxamine, and parox-
etine) on anxiety and obsessive-compulsive symptoms and
the finding of serotonin system abnormalities in individuals
with autism,364 there has been considerable interest in treating
disruptive behaviors in autism with these agents. Results of
open label and observational studies have been mixed for
the reduction of ritualistic behavior, anxiety, and aggression,
as well as behavioral rigidity, obsessive-compulsive disorder
symptoms, and stereotypies.365–369 Results of double-blind,
placebo-controlled, randomized trials have been mixed and
suggest that efficacy of SRIs may be moderated by age, with
better responsivity in adults than in children.
A randomized, double-blind, placebo-controlled trial
enrolling adults with autism found improvement in one half
of the fluvoxamine-treated patients compared with placebo,
with reduction of repetitive thoughts and behavior, maladap-
tive behavior, language, social relatedness, and aggression.370
There were few side effects at a mean dose of 270 mg/day. A
crossover trial of six adults using the selective SRI fluoxetine
demonstrated significant improvement in obsessive behaviors
and anxiety, and PET scans demonstrated fluoxetine-elevated
metabolic rates in the right frontal lobes.371
Results of trials in children, however, have been less encour-
aging. Low-dose liquid fluoxetine (mean dose of 10 mg/day)
was superior to placebo on a measure of repetitive behaviors,
but not on a measure of clinician-rated global improvement,
in 39 children and adolescents with autism in a randomized,
crossover trial.372 Agitation resulted in a dose reduction in 16%
of the subjects in the fluoxetine group, compared with 5% in
the placebo group, but this difference was not statistically
significant.
A large, double-blind, randomized, placebo-controlled
trial of 149 children and adolescents with ASD (ages 5 to 17
years) failed to find any effect of citalopram on repetitive
behaviors. A multisite study evaluated the efficacy of citalo-
pram in reducing those behaviors.373 In 12 weeks of treatment
with a flexible dose schedule, citalopram did not separate
from placebo in the primary outcome measures of repetitive
behavior and global improvement. The mean citalopram dose
was 16.5 (SD = 6.5) mg/d. Citalopram levels and high
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Autistic Spectrum Disorders e1121
parent-reported compliance to treatment suggest that this was
an adequate trial, and the doses were similar to those previ- 57
ously reported to be effective in open trials. Adverse events
were significantly more likely to occur in the citalopram-
treated group. The most frequently reported side effects were
activation, stereotypy, diarrhea, insomnia, and dry skin or
pruritus. Two subjects treated with citalopram had seizures. Of
note, there was a high placebo response rate (34%), which
underscores the need for placebo-controlled clinical trials.
The evidence for possible developmentally sensitive altered
regulation of serotonin synthesis in autistic children provides
a rationale for giving serotonergic drugs to very young
autistic children in order to improve synaptic plasticity during
periods of brain development. The 5HT1A serotonin agonist
buspirone was evaluated in a randomized, blinded trial of 166
children ages 2 to 6 years, in doses of 2.5 mg or 5 mg/bid
compared with placebo. The primary outcome was the ADOS
composite score, which was not affected in either treated
group. However, those given the lower dose did improve on
the repetitive behavior score. This study evaluated pretreat-
ment blood serotonin and regional patterns of metabolism
on PET scan. Those children with pretreatment elevated
blood serotonin and regional patterns of tryptophan on PET
scan suggesting brain inflammation were less likely to
improve.374
A Cochrane review of SSRIs did not find overall evidence
of benefit in children with ASD, although reduction in anxiety
or depressive symptoms in older children may be of benefit.375
Whereas SRIs appear to be generally safe, children may be
particularly sensitive to the behavioral activation of these
drugs.376 Seizures have emerged under SRI treatment in clinical
trials in a few instances, although this is a seizure-prone popu-
lation, and it is not clear whether the medications were causal.
Additionally, there has been concern about reports of an asso-
ciation of fluoxetine and possibly other selective SRIs with
suicidal ideation in depressed children, and the FDA has rec-
ommended that children on these medications should be very
carefully monitored.
Stimulants and Drugs to Treat Hyperactivity
Hyperactivity is an important target symptom that can be
potentially improved with psychostimulant medication.377,378
The Research Units on Pediatric Psychopharmacology (RUPP)
Autism Network379,380 conducted a randomized, double-blind,
placebo-controlled trial of methylphenidate in children with
ASDs and high levels of hyperactivity and/or impulsiveness.
Doses at the 0.25 and 0.5 mg/kg/day level were effective in
reducing hyperactivity and impulsivity, but less effective in
reducing inattention, at 4 weeks and after 8 weeks’ continua-
tion. The response rate was about 35% compared with typical
response rates of around 70% in nonPDD children with
ADHD. About 18% of subjects withdrew due to side effects,
primarily irritability. Other common side effects included
decreased appetite and trouble falling asleep. Some children
responded best to lower doses of methylphenidate. Observa-
tional data were available on a subset of 33 study participants,
suggesting that the benefits of methylphenidate extended
to some aspects of social interactions, self-regulation, and
affect.381
A randomized, crossover study of 24 children ages 7 to 12
showed that extended release MPH improves hyperactivity
and impulsivity.382 Atomoxetine is a nonstimulant medication
for ADHD that inhibits the presynaptic norepinephrine
transporter. In a placebo-controlled, double-blind crossover
study with 16 children with ASD and ADHD symptoms, ato-
moxetine was more effective than placebo in reducing hyper-
activity. The response rate was similar to that reported for
e1122 PART VII  Neurodevelopmental Disorders
methylphenidate in children with ASD, and the mean highest
dose was 44.2 (SD = 21.9) mg/d. Side effects, including
gastrointestinal symptoms, fatigue, and racing heart, were
common but transient.383 Only one participant terminated
the study due to intolerance of side effects. A trial of 97 chil-
dren also demonstrated a beneficial effect of atomoxetine on
hyperactivity in children with ASD.384,385 A trial of 128 chil-
dren also found some benefit on ADHD symptoms in
autism.393 Adverse events included fatigue, decreased appetite,
and mood lability.
Two small, placebo-controlled trials found that clonidine,
an adrenergic receptor agonist, had some effect in decreasing
irritability and hyperactivity386,387 in children and adults with
autistic disorder.
Antiseizure Drugs
Several antiseizure drugs have been used for behavioral mani-
festations of autism, particularly for treating intense rapid
mood shifts. In open label studies, levetiracetam388 and dival-
proex sodium389 appeared to be well tolerated and to improve
repetitive behavior, impulsivity, and mood stability. A retro-
spective study of topiramate in children and adolescents with
ASDs suggested that the drug reduced misconduct, hyperactiv-
ity, and inattention in 8 of 15 patients. Two randomized,
placebo-controlled trials, however, have had mixed results.348
Lamotrigine was not better than placebo on several parent-
report and clinician ratings of disruptive behavior and autism
symptoms in a double-blind, randomized, controlled trial of
28 children.390 Children in both groups showed improvement.
In a small, placebo-controlled, double-blind trial of levetirace-
tam in 5- to 17-year-olds (n = 20), there was no difference
from placebo on measures of behavioral disturbance, repeti-
tive behavior, and autism symptoms.391 In a randomized,
double-blind, controlled trial with 13 individuals (mean age
of 9 years), divalproex sodium was better than placebo in
decreasing repetitive behavior,392 and an additional trial in 27
children confirmed a reduction in irritability.393 Patients with
the most robust response had repetitive behaviors of the com-
pulsive type, as opposed to stereotypies. Bumetanide, used to
treat neonatal seizures, was compared with placebo in 60
children at a dose of .5 mg bid and improved both global
functioning and some autistic behaviors.394
It has been hypothesized that the mechanism of benefit
from these medications might be their effect on subclinical
seizures, which have been reported to occur in this popula-
tion. However, there is no evidence and no controlled trials
investigating whether treatment with anticonvulsants in chil-
dren with autism who have epileptiform discharges but no
clinical seizures might improve behavioral outcomes in chil-
dren with autism.323
Cholinesterase Inhibitors
Acetylcholine (ACh) plays a significant role in attention and
memory performance. Acetylcholinesterase inhibitors (AChE)
slow the breakdown of ACh. This is the presumed mechanism
by which cholinesterase inhibitors, such as donepezil, slow
decline in memory, attention, and learning in Alzheimer
disease. Animal studies have suggested that administration of
these agents early in development may also enhance learning
in a prospective way. Because postmortem studies have found
abnormalities of the cholinergic system and its nicotinic recep-
tors in the brains of individuals with autism,395,396 there is
growing interest in the potential benefit of these drugs in
ameliorating neurodevelopmental disorders.397
A retrospective examination of effects of donepezil in eight
children with autism suggested improvements in irritability
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and hyperactivity, but memory and attention were not
measured.398 A randomized, controlled, 6-week trial was con-
ducted with 43 children with ASDs, examining the effects of
donepezil (2.5 mg/d).399 The investigators concluded that the
drug improved language and reduced overall autistic features.
However, the statistical analyses pooled blinded and non-
blinded data, leaving the results susceptible to confounders
such as placebo effects. A prospective, open label study with
13 children and adolescents with autism treated for 12 weeks
with galantamine found reductions in irritability and social
withdrawal.400
Glutaminergic and Gamma-aminobutyric  
Acidergic Agents
On the theory that there is a disturbance of excitatory and
inhibitory transmission in ASD, NMDA and GABA receptor
modulators have been tried. Neither memantine401 nor aman-
tadine402 have produced improvement in ASD symptoms.
A pilot trial of 33 children given N-acetylcysteine did show
some improvement in irritability although side effects
included agitation.403 One trial of the gaba-antagonist arba-
clofen showed some benefit on global function.404 Trials of
oxytocin, a hormone indentified as involved in social behav-
ior, are ongoing. Although two previous trials did not show
benefit,405,406 one study using functional MRI showed enhanced
brain activity for social stimuli with intranasal oxytocin.407
Summary
A number of medications, particularly atypical neuroleptics,
psychostimulants, and SRIs, can help decrease specific symp-
toms associated with autism (Table 57-2). Reduction in these
behaviors can improve quality of life and promote better
opportunities for learning. Neuroleptics such as risperidone
(.5 to 3.5 mg/d) and aripiprazole (5 mg/d) may improve irri-
tability and aggression. Serotonin reuptake inhibitors may
benefit older adolescents and adults. The serotonin agonist
buspirone, at a dose of 2.5 mg/d, improved repetitive behav-
iors in young children. Methylphenidate and atomoxine
reduce symptoms of hyperactivity. More data from well
designed clinical trials are needed on possible benefits of
AEDs and donepezil. There must be careful attention to
matching the medication with the targeted behavior, and to
possible developmental differences in treatment response.
Side effects are common, and must be monitored closely and
weighed carefully against the benefits of the drugs.
COMPLEMENTARY AND ALTERNATIVE
MEDICINE
A significant number of families seek complementary or alter-
native medicine (CAM) treatments, few of which have been
studied in well-designed trials.408 About 28% of children with
autism are using complementary and alternative medicine.409
It is important to respect the parents’ belief if the complemen-
tary medicine is not toxic, but if the treatment is potentially
harmful, negotiating a safer replacement practice should be
attempted. Examples of the more commonly used treatments
include nutritional supplements, melatonin, hormones,
gluten-free and casein-free diet, immunoglobulins, secretin,
and chelation therapy.410
A review411 of vitamin B6 and magnesium concluded that
the few studies available were inconclusive, and sample sizes
were too small for an adequate test of efficacy. Results of three
methodologically sound studies did not support that vitamin
B6 and magnesium benefit children with ASD.

Dimethylglycine, a nutritional supplement closely related
to the inhibitory transmitter glycine, has been proposed412 as
helpful for autistic children and adults, but it was ineffective
in two double-blind, placebo-controlled trials.413,414
Plasma fatty acid levels have been found to be decreased
in children with autism compared with typical controls,415,416
leading to interest in supplementation with omega-3 fatty
acids. Two small, randomized, double-blind, placebo-
controlled studies with 37 children did not show any benefi-
cial effect on autism symptoms.417
Children with autism often have sleep difficulties. Mela-
tonin therapy has been used to treat the sleep disturbances
in ASD, based on low plasma levels or urinary excretion of
melatonin.418,419 Melke and associates reported mutations
and polymorphisms in the acetylserotonin methyltransferase
(ASMT) gene,420 which encodes the last enzyme of melatonin
synthesis, which result in dramatic decreases in ASMT tran-
scripts in blood cell lines. Anecdotal and open label studies
of melatonin therapy have suggested significant improve-
ments in sleep architecture in children with ASD.408,421 Four
double-blind, placebo-controlled crossover studies were per-
formed in a total of 70 children with ASD using 3 to 10 mg
of regular or controlled-release melatonin.422–425 Up to 94% of
children derived significant benefits in sleep including sleep
duration and latency but not awakenings, without evidence
of significant side effects. An open label melatonin study in
24 ASD children that titrated the dose to a maximum of
9 mg showed sleep latency improved in most children at 1
or 3 mg doses.426 Larger long-term, double-blind, placebo-
controlled crossover studies will be needed to document
the efficacy of melatonin across the behavioral subtypes
of ASD.
Immunoglobulin has been administered intravenously in
open trials427,428 and not found to be useful. A double-blind,
placebo-controlled trial of oral human immunoglobulin was
conducted with 125 children and adolescents who had autism
and persistent gastrointestinal symptoms.429 There was no sig-
nificant benefit on gastrointestinal symptoms, measures of
autistic symptomatology, or behavior disturbances.
Reported dramatic improvement after the administration
of secretin as part of endoscopy in three autistic children430 led
to widespread use by parents. Subsequent blinded, random-
ized trials did not substantiate its efficacy.431 These trials
included single- and repeated-dose protocols.
Proponents of chelation therapy suggest that mercury
and other heavy metals may be poorly eliminated by children
with autism and that it interferes with neurodevelopment via
modulation of immune function and other biochemical
systems. Despite the lack of scientific evidence of a link
between exposure to mercury or other heavy metals and
autism, chelation is widely used. One trial432,433 administered
dimercaptosuccinic acid (DMSA) to 69 children with ASD.
Those who had a high urinary excretion of toxic metals (n =
49) were then randomized to either DMSA or placebo for an
additional six administrations. Some participants in both
groups demonstrated improvement of measures of autism
symptoms and disruptive behavior, but there were no signifi-
cant differences between the two groups, and the comparative
group that did not receive any treatment. There were no
serious adverse effects reported, although a significant increase
in excretion of potassium and chromium was noted. No
placebo-controlled studies have examined the safety or effi-
cacy of chelation for treating autism, and deaths resulting
from hypocalcemia have been reported from the inappropri-
ate use of a chelator, edetate disodium (EDTA),434 including
one boy with autism.
Hyperbaric oxygen therapy (HBOT) has been tried on the
theory that autism is associated with oxidative stress and
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Autistic Spectrum Disorders e1123
neuroinflammation.417 Although one randomized, controlled
trial showed a few differences in outcome between control and 57
HBOT treated groups, when replicated there were no differ-
ences, and HBOT carries a risk of barotrauma and exacerba-
tion of pulmonary disease.417,440
It is challenging to perform clinical trials enrolling children
with autism, but without well-designed, blinded studies, safe
and effective therapies cannot be determined. Problems
include standardization of diagnoses, heterogeneity of target
problem behaviors, and lack of cooperation of subjects. Many
outcome measures are available, including global measures
such as the Clinical Global Impression of Severity and others
targeted to specific symptoms. Whenever feasible, parents
should be encouraged to participate in clinical trials to make
progress in validating new pharmacologic and behavioral
therapies. Information about ongoing trials and their loca-
tions can be found at www.clinicaltrials.gov.
EDUCATIONAL AND BEHAVIORAL
INTERVENTIONS
The core deficits associated with autism affect all aspects of
the individual’s life, necessitating a comprehensive and mul-
tidisciplinary approach to intervention.437–439 A primary source
of intervention for most children with ASDs is through the
educational system. The Individual with Disabilities Educa-
tion Improvement Act (IDEA) of 2004 ensures a “free and
appropriate” public education, including early intervention
and special education services, to “children” between the ages
of 3 and 21 who have been diagnosed with learning disabili-
ties. IDEA Part B covers children from 3 to 21 years of age
through the public school systems, and IDEA Part C covers
children from birth to 36 months through early intervention
programs.
IDEA legislation specifies a team approach which includes
a role for parents as equal partners in education planning. This
act specifically covered autistic disorder, but whether the full
range of ASDs is covered may depend on the particular state’s
definition under the fifth edition of DSM. The quality and
extent of services that are provided vary from one community
to another, even within a particular school district. Parents
often need assistance in navigating and negotiating with edu-
cational systems, and resources such as Autism Speaks’ 100-Day
Kits (https://www.autismspeaks.org/family services/tool-kits)
can be extremely helpful.
The Treatment and Education of Autistic and Related Com-
munication Handicapped Children (TEACCH) program is a
structured teaching program founded at the University of
North Carolina, Chapel Hill, in the early 1970s. TEACCH as
a whole has not been rigorously tested, but its methods and
components are well supported in the literature.440 TEACCH
is a classroom-based program that structures teaching methods
to incorporate visual organization into the environment to
capitalize on relative strengths in ASD. It also incorporates
behavioral and naturalistic teaching methods and augmenta-
tive communication techniques to facilitate communication
skills. Originally developed for school-age children and adults,
TEACCH has subsequently been adapted for home-based
intervention for young children.441
Numerous comprehensive early intervention programs
for young children with ASDs have been developed and
described.439,442,443 Although there is evidence of efficacy
for several of these, there is unfortunately no comparative
efficacy data to inform decisions about which program is
better, nor are data available to determine which child will
respond best to which intervention.444,445 The National
Academy of Sciences442 report describes the common elements
e1124 PART VII  Neurodevelopmental Disorders
of successful early intervention programs and makes several
recommendations:
• Intervention should begin as soon as an ASD diagnosis is
suspected.
• Intervention should include active engagement in instruc-
tional programming for at least 25 hours per week, with
full-year programming.
• Intervention should include repeated, planned teaching
opportunities that are one-to-one designs or delivered in a
very small group, with individualized goals.
• Intervention should include family support and parent
training.
• Intervention programs should have low student to teacher
ratios, such as 2 to 1.
• Program evaluation and assessment of the child’s progress
should be ongoing.
• Priority of intervention should focus on six specific areas:
1. Functional spontaneous communication
2. Social instruction delivered throughout the day in
various settings
3. Play skills
4. Cognitive development
5. Proactive approaches to problem behaviors
6. Functional academics.
Comprehensive early intervention programs based on
basic learning principles for teaching skills and facilitating
more appropriate and adaptive behaviors have been exten-
sively tested for their effectiveness in children and adults with
autism and other developmental disabilities.446–450 Among the
most rigorously tested programs in this category are Applied
Behavioral Analysis (ABA) and Discrete Trial Training (DTT).
In the most rigorously designed studies of these programs,
improvements in cognitive functioning and language level
have been demonstrated at the group level. Improvements in
adaptive behavior and autism symptoms have been more vari-
able. At the group level, baseline IQ and language skills predict
better response to treatment. However, prediction at the indi-
vidual level is not yet established.443
ABA and DTT programs are established on principles of
learning and behavior modification. By carefully analyzing the
causes and consequences of a particular behavior, identifying
an opposite, competing behavior (i.e., desired behavior), and
consistently altering the consequences so that the desired
behavior is rewarded, the instructor can teach new skills or
transform inappropriate behaviors into more acceptable ones.
This relatively simple principle has been developed into tech-
niques that have been highly effective for teaching new skills,
increasing the frequency of appropriate or adaptive behaviors,
and decreasing the frequency of inappropriate or maladaptive
behaviors.
One way to increase generalization of learned skills is to
help parents reinforce and apply the behavioral techniques at
home and in the community. For this reason, good behavioral
programs always contain a parent-training component. When
parents are taught how to apply behavioral techniques, with
ongoing coaching, they can be effective in smoothing out
interactions between the individual with an ASD and other
family members.
Parents are most likely to learn behavior modification tech-
niques when enrolling their children in a comprehensive treat-
ment program. An alternative to enrollment in a comprehensive
school-based program is a home-based program. In this type
of program, parents hire an expert to train the parents and
paraprofessionals, who administer the treatment in shifts. As
these comprehensive treatment programs have evolved, there
have been trends toward teaching parents to implement the
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programs, and toward using the behavior-management tech-
niques in settings that are more naturalistic and that capitalize
on child-initiated or child-preferred activities.439 Learning
Experiences: Alternative Programs for Preschoolers and Parents
(LEAP) was developed for implementation in early education
classrooms. LEAP integrates behavioral techniques into natu-
ralistic teaching situations, with a focus on integrating chil-
dren with disabilities into the activities of typically developing
children, and has a strong parent education component. This
program, when delivered with adequate teacher training, has
been shown to improve language and social skills and reduce
problem behavior.451
Some comprehensive treatment programs derive strategies
from a developmental theoretical framework. Pivotal Response
Treatment (PRT)452-454 is a naturalistic behavioral program
that has been shown in single-subject design studies to be
effective for young children with ASD, but has not undergone
a randomized, controlled trial. PRT emphasizes the teaching
of early developing “pivotal” social skills that serve as the
foundation for more generalized social and academic skills
and emphasizes a more naturalistic and child-directed
approach.
The Denver Model455–457 and its adaptation for toddlers, the
Early Start Denver Model (ESDM),456 emphasize the need to
establish interpersonal relationships as a foundation to achiev-
ing other developmental milestones. ESDM was compared
with usual community care in a randomized, controlled
trial.457 The ESDM intervention is delivered by trained thera-
pists and by parents, with combined in-home and clinic-
delivered programming for 30 hours per week. Techniques
taught to parents incorporate the developmental techniques
from the Denver Model and applied behavior analysis. In a
randomized, controlled trial, children in the ESDM model
showed significantly greater improvements in IQ, language,
and adaptive skills than the community-treated children with
ASD. The gains were greater after 2 years than after 1 year,
suggesting benefits from ongoing intervention. An adaptation
of ESDM delivered by parents only in the home for fewer
hours did not find the same effects, suggesting that intensity
may be a critical component of this intervention.458
Core deficits in social understanding and social relation-
ships are concerns throughout the life span, and social skills
training (SST) is often a component of a treatment plan.
Group-based SST programs show promise, but with a few
exceptions, they have not been rigorously evaluated.459 The
inclusion of nonautistic peers to assist with SST may be impor-
tant, but again, rigorous studies are needed.460
Interventions targeting social skills in very young children
focus on preverbal or nonverbal communicative behaviors as
foundations for developing more complex social behaviors.
The Joint Attention, Symbolic Play, and Regulation (JASPER)
program is a parent-delivered, in-home, manualized treatment
program for preschool children with ASD. This treatment
model has been shown to improve both responsiveness to
joint attention and initiation of joint attention, as well as
symbolic play, with gains maintained over a 3-month follow-
up period.461,462
The Children’s Friendship Training (CFT) program for
school-aged children with ASD integrates parents into a group-
based social skills program focusing on behaviors critical to
initiating and maintaining friendships. A randomized, con-
trolled trial showed improvement on measures of social skills,
play date behavior, popularity, and self-reported loneliness.463
Improvements persisted for at least 3 months after the
intervention.
The Program for the Education and Enrichment of
Relational Skills (PEERS) is a group-based intervention for
adolescents with ASD that integrates parents into the program

to help with generalization of skills into the home and
community. Results of an initial positive randomized trial464
have been replicated,465 and both studies demonstrated
benefits in social skills and increased frequency of peer social-
ization, and these benefits were maintained over long-term
follow-up.466
The PEERS and CFT programs described previously were
originally developed for children with ADHD and adapted for
use with children and teens with ASD. Similarly, cognitive
behavior therapy (CBT) for children with anxiety disorder has
been adapted to treat anxiety in high-functioning ASD. A ran-
domized, controlled trial of CBT for anxiety in 7- to 11-year-
old children with ASD demonstrated reduction of anxiety
symptoms.467 These studies suggest that adapting evidence-
based interventions for specific symptom domains and comor-
bid symptoms in ASD is a reasonable strategy, but there
remains a great need for rigorously designed research to dem-
onstrate efficacy.
As the needs of individuals with ASDs change over time,
there is need for lifelong support. In particular, transitions
(e.g., to high school, to higher education or vocational train-
ing, or to independent or assisted living) are critical periods
during which supports already in place may be lost because
of changes in eligibility or funding sources.
RESOURCES FOR FAMILIES AND
PRACTITIONERS
• Autism Speaks (www.autismspeaks.org) offers numerous
services and resources for families on its website. Of particu-
lar interest are the 100-Day Kits for parents of newly diag-
nosed young (https://www.autismspeaks.org/docs/family
_services_docs/100day2/100_Day_Kit_Version_2_0.pdf)
and school-aged children 5 years and older (https://
www.autismspeaks.org/sites/default/files/docs/100_day
_kit_for_school_age_children_final_small.pdf) that are spe-
cifically developed to assist parents during the stressful
period after diagnosis. There are additional Autism Speaks
Tool Kits available addressing other topics, such as advo-
cacy, behavioral health treatments, psychopharmacology,
and deciding whether to begin medication, toilet training,
and sleep tools (https://www.autismspeaks.org/family
services/tool-kits).
• The American Academy of Pediatrics has a useful website
(www.healthychildren.org) on which one search on the
topic “autism.” The AAP has recently published a book
specifically addressing pertinent behavioral and medical
advice topics facing parents of children with ASD ranging
in age from very young toddlers through adolescence
(http://shop.aap.org/Autism-Spectrum-Disorders-What
-Every-Parent-Needs-to-Know-Paperback/).
• The Department of Education’s Center for Parent Informa-
tion and Resources (www.parentcenterhub.org) has autism-
specific information on special education laws and on
educational practices.
• The Arc maintains a website (http://www.thearc.org/page
.aspx?pid = 2530) for people with intellectual and develop-
mental disabilities and their families that provides a wealth
of information on the special education. The Arc’s Autism
Now Center provides information resources, including the
IEP process (http://autismnow.org/).
• The Organization for Autism Research has several useful
brochures and educational publications geared toward fam-
ilies, educators, and other professionals, many of which are
in Spanish and English (www.researchautism.org).
• The National Autism Association’s Big Red Safety Toolkit
(http://nationalautismassociation.org/docs/BigRedSafety
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Autistic Spectrum Disorders e1125
Toolkit.pdf) provides information and resources for fami-
lies on wandering and water safety. 57
• The National Research Council produced a monograph that
evaluated evidence-based interventions for children with
ASD aged 8 years and under (http://www.nap.edu/openbook
.php?isbn = 0309072697).
• For clinicians, the AAN/CNS Practice Parameter: Screening
and Diagnosis of Autism (http://www.childneurologysociety
.org/resources/resources-detail-view/practice-parameter-
screening-and-diagnosis-of-autism) and the detailed back-
ground paper (http://www.childrenslearninginstitute.org/
duncan-programs/autism-center/documents/AU2906
_241reprint.pdf) continue to be valuable resources.
• The First Signs program provides resources, including
a video glossary of signs of ASD and referral guidelines.
The First Signs website (http://www.firstsigns.org) includes
recommendations and information about obtaining
autism screening instruments. There are also summaries
of evidence-based interventions available to parents and
practitioners.
• The Agency for Healthcare Research and Quality provides
a summary of the evidence for effectiveness of interven­
tions for children, youth and adults with ASD (http://
effectivehealthcare.ahrq.gov).
• The National Autism Center (www.nationalautismcenter.org)
provides resources for parents and professionals including
a National Standards Report, which synthesizes research
related to the effectiveness of interventions for ASD based
on age, diagnostic groups, and intervention targets.
• The National Institutes of Health website (www.nih.gov)
can be searched for current research, as can those of specific
institutes, including the National Institute of Neurologic
Disorders and Stroke (www.ninds.nih.gov), the National
Institute of Child Health and Human Development
(www.nichd.nih.gov), and the National Institute of Mental
Health (www.nimh.nih.gov). The CDC’s National Center
for Birth Defects and Developmental Disabilities has a
website (www.cdc.gov/ncbddd/autism/index.html) devoted
to providing evidence-based information on ASD and its
treatment, including links to resources.
• The National Dissemination Center for Children with Dis-
abilities is now affiliated with the Center for Parent Infor-
mation and Resources (http://www.parentcenterhub.org)
and has information on special education laws and on edu-
cational practices, among other timely topics.
• The federal Interagency Autism Coordinating Committee
(IACC) website has compiled information about research
and Federal activities related to research and service provi-
sion for ASD (http://iacc.hhs.gov/index.shtml).
An enormous amount of information is available to families
on the Internet; they often need specific counseling regarding
evaluation of treatments that are espoused without adequate
scientific study. The American Academy of Pediatrics has a
useful website, (www.healthychildren.org), on which one can
search on the topic “autism.” The Department of Education’s
Center for Parent Information and Resources (www
.parentcenterhub.org) has autism-specific information on
special education laws and on educational practices. Autism
Speaks (www.autismspeaks.org) offers services and resources
for families on its website. Of particular interest is the 100-Day
Kit (https://www.autismspeaks.org/family services/tool-kits)
specifically developed to assist parents during the stressful
period after diagnosis. The Organization for Autism Research
has several useful brochures and educational publications
geared toward families, educators, and other professionals,
many of which are in Spanish and English (www
.researchautism.org).
e1126 PART VII  Neurodevelopmental Disorders
For practitioners, the AAN/CNS practice parameter for
evaluation of children with autism and the detailed back-
ground paper can be found on the For OC Kids website:
(http://www.childneurologysociety.org/resources/resources
-detail-view/practice-parameter-screening-and-diagnosis-of-
autism). Another effort, the First Signs program, is developing
methods to inform physicians about the importance of early
identification of autism, and it provides resources, including
screening tools and referral guidelines. The First Signs website
(http://www.firstsigns.org) includes recommendations and
information about obtaining autism screening instruments.
There are summaries of evidence-based interventions avail-
able to parents and practitioners. The Agency for Healthcare
Research and Quality provides a summary of the evidence for
effectiveness of interventions for children, youth and adults
with ASD (http://effectivehealthcare.ahrq.gov). The National
Autism Center (www,nationalautismcenter.org) provides
resources for parents and professionals including a National
Standards Report, which synthesizes research related to the
effectiveness of interventions for ASD based on age, diagnostic
groups, and intervention targets.
The National Institutes of Health website (www.nih.gov)
can be searched for current research, as can those of specific
institutes, including the National Institute of Neurologic Dis-
orders and Stroke (www.ninds.nih.gov), the National Institute
of Child Health and Human Development (www.nichd
.nih.gov), and the National Institute of Mental Health
(www.nimh.nih.gov). The CDC’s National Center for Birth
Defects and Developmental Disabilities has a website (www
.cdc.gov/ncbddd/autism/index.html) devoted to providing
evidence-based information on ASD and its treatment, includ-
ing links to resources. The federal Interagency Autism Coordi-
nating Committee (IACC) website has compiled information
about research and Federal activities related to research and
service provision for ASD.
DISCLAIMER
The views expressed in this chapter are those of the authors
and do not necessarily reflect the official position of the
National Institute of Mental Health, the National Institute of
Neurologic Diseases and Stroke, the National Institutes of
Health, or any other part of the U.S. Department of Health
and Human Services.
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